Chemistry at boron: Synthesis and properties of red to near-IR fluorescent dyes based on boron-substituted diisoindolomethene frameworks

ARTICLE

pubs.acs.org/joc

Chemistry at Boron: Synthesis and Properties of Red to

Near-IR Fluorescent Dyes Based on Boron-Substituted

Diisoindolomethene Frameworks

Gilles Ulrich,*^,†Sꢀebastien Goeb,^†,§Antoinette De Nicola,^†Pascal Retailleau,^‡and Raymond Ziessel*^,†

^†Laboratoire de Chimie Molꢀeculaire et Spectroscopies Avancꢀees (LCOSA), ECPM, CNRS, 25 rue Becquerel, 67087 Strasbourg Cedex

02, France

^‡Laboratoire de Crystallochimie, ICSN - CNRS, B^at 27 - 1 avenue de la Terrasse, 91198 Gif-sur-Yvette Cedex, France

^§Laboratoire MOLTECH-Anjou, Groupe SOMaF, Universitꢀe d⁰Angers, 2 bd Lavoisier, 49045 Angers Cedex, France

S Supporting Information

b

ABSTRACT: A general method for the synthesis of diﬂuor-

obora-diisoindolomethene dyes with phenyl, p-anisole, or ethyl-

thiophene substituents has been developed. The nature of the

substituents allows modulation of the ﬂuorescence from 650 to

780 nm. Replacement of the ﬂuoro ligands by ethynyl-aryl or

ethyl residues is facile using Grignard reagents. Several X-ray

molecular structures have been determined, allowing establish-

ment of structureꢀﬂuorescence relationships. When the steric crowding around the boron center is severe, the aromatic

substituents R to the diisoindolomethene nitrogens are twisted out of coplanarity, and hypsochromic shifts are observed in the

absorption and emission spectra. This shift reached 91 nm with ethyl substituents compared to ﬂuoro groups. When ethynyl linkers

are used, the core remains ﬂat, and a bathochromic shift is observed. All the ﬂuorophores exhibit relatively high quantum yields for

emitters in the 650ꢀ800 nm region. When perylene or pyrene residues are connected to the dyes, almost quantitative energy

transfer from them to the dye core occurs, providing large virtual Stokes shifts spanning from 8000 to 13 000 cm^ꢀ1depending on the

nature of the dye. All the dyes are redox active, providing the Bodipy radical cation and anion in a reversible manner. Stepwise

reduction or oxidation to the dication and dianion is feasible at higher potentials. We contend that the present work paves the way for

the development of a new generation of stable, functionalized luminophores for bioanalytical applications.

’ INTRODUCTION

most common solvents including polar ones. Due to their special

photophysical properties (high ﬂuorescence quantum yields,

large molar extinction coeﬃcients, sharp ﬂuorescence peaks) cou-

pled to a chemical versatility and color tunability, the diﬂuoro-

bora-diaza-s-indacene family of Bodipy dyes represents a unique

category of ﬂuorophore.⁵Several strategies have been used to

bathochromically shift the emission of such dyes: (i) extension of

the π conjugation of the cyanine core at the 3,5-^6ꢀ9or 2,6-

positions,¹⁰(ii) fusion of aromatic moieties onto the indacene

skeleton,¹¹(iii) replacement of the C8-carbon by a nitrogen, pro-

viding azaBodipy dyes,¹²(iv) decoration with electron-donating

groups,¹³and (v) fusion with a cyanine skeleton.¹⁴However, most

of these compounds suﬀer from the inherently low Stokes shifts

characteristic of organic ﬂuorophores, which is a major drawback

in biological experiments, and there is a need to overcome this

problem to enhance the sensitivity of the probes. Two strategies

have been applied to excite the sample well away from the emission

wavelength: (i) the use of two-photon excitation with suitable

ﬂuorophores¹⁵or (ii) building a so-called cassette system by

The existence of an absorption window of blood between 650

and 900 nm (due to concomitant low absorption and minimal

autoﬂuorescence of hemoglobin and water)¹has stimulated re-

search into the development of eﬃcient ﬂuorophores emitting in

this particular spectral region. Such dyes should ﬁnd numerous

applications in noninvasive and in vivo ﬂuorescence imaging²

and mapping deeper tissues or DNA sequences.³Before being

used under biological conditions of analysis, they must, however,

meet many criteria such as: (i) high absorption and high ﬂuores-

cence quantum yields, (ii) solubility in various solvents without

forming nonemissive aggregates, (iii) resistance to photodecom-

position under intense light sources, (iv) pronounced Stokes shifts

to facilitate signal detection, (v) low toxicity if in vivo analysis is

intended. Existing red ﬂuorophores from the cyanine family (e.g.,

CyDye, namely, Cy 5.0 and Cy 5) despite their high extinction

coeﬃcients suﬀer from low ﬂuorescence quantum yields and limited

photochemical stability. Nowadays most common red emitters

are from the rhodamine family (Texas Red, Alexa...). They have

good brightness, but they are essentially limited to the 650ꢀ700 nm

region.⁴There is an ongoing synthetic challenge for the devel-

opment of brilliant red-NIR organic emitters which are soluble in

Received: February 14, 2011

Published: April 18, 2011

r

2011 American Chemical Society

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Scheme 1. Synthesis of Diisoindolemethene Borates

Scheme 2. Synthesis of Homodisubstituted E-Bodipys

connection of an appropriate high-energy absorber to the emit-

ting molecule.^16,17The latter was successfully applied to various

Bodipys emitting in the greenꢀorange region by attaching poly-

aromatic substituents to the Bodipy core¹⁸or at the boron

center.¹⁹The cassette strategy was also recently successfully applied

to a water-soluble Bodipy system used for monitoring interac-

tions in living cells²⁰and by attachment to Nile Red as an acceptor

red-emitting dye.²¹

We present here our comprehensive investigations of cassette-

like systems derived by the linking of diisoindolomethene-based

Bodipys to polyaromatic chromophores.²²The chromophores have

been connected to the boron atom via an ethynyl tether to pre-

vent steric congestion inducing strong perturbation of the optical

properties.²³

4aꢀc with an ammonium salt. In this reaction, the bis-isoindo-

lylmethane intermediate underwent formaldehyde elimination

by a retro-aldol reaction before being oxidized by air.²⁶Finally,

the formation of 6aꢀc was accomplished by reaction of 5aꢀc

with boron triﬂuoride in the presence of H€unig’s base.

Developing upon our previous work performed on “cascatelle”

dyes obtained by linking high-energy chromophores to the boron

center of yellow Bodipy ﬂuorophores via acetylenic bridges,^18,27

we ﬁrst attempted to connect similar polyaromatic fragments to a

diisoindolomethene acceptor via the same procedure. The use of

lithium acetylide was unsuccessful, leading to decomposition of the

dye. We then decided to use a Grignard acetylide, known to be

useful for substitution of halides on a trigonal boron center.²⁸

This choice was also based on the fact that reaction of a lithium

alkyl with β-diketiminate boron(III) chelates results in attack at a

ring carbon atom, whereas reaction with a Grignard results in

substitution at boron.²⁹A general procedure was optimized to

synthesize the diisoindolomethene diacetylide (E-Bodipy)³⁰de-

rivatives (Scheme 2) by using a large excess (2.4ꢀ3 equiv) of the

appropriate magnesium acetylide bromide, generated by addition of

ethylmagnesium bromide to an anhydrous THF solution of the

arylacetylene. This solution was heated at 60 °C prior to use, to

ensure complete formation of the Grignard. The acetylide was then

added to diisoindolomethene diﬂuoride derivatives 6aꢀc at room

temperature, and the mixture was heated overnight at 60 °C.

Standard workup and chromatography on silica aﬀorded the desired

compounds, and the average yields are given in Table 1. Several

compounds obtained by varying the high-energy donor as well as

the low-energy emitters were prepared with satisfactory yields,

which were not dependent on the nature and size of the polyaro-

matic substituents R₃. No monoacetylide derivatives were detected,

’ RESULTS AND DISCUSSION

A convenient sequence leading to the symmetrically substi-

tuted diisoindolometheneboron diﬂuoride compounds 6aꢀc is

depicted in Scheme 1.²⁴It allows the nature of the substituents R₁

and R₂on both sides to be changed through preparation of the

precursor 2-acylacetophenones 4aꢀc. These substituents have a

direct inﬂuence on the resulting diazaboraindacene absorption

and emission wavelengths.

Commercially available 2-acetylphenols bearing R₂were re-

acted with benzo or thieno (R₁group) carbohydrazides 2aꢀc,

obtained from their corresponding ethyl esters, to give acylhy-

drazones 3aꢀc. The treatment of 3aꢀc with lead tetraacetate led

to intramolecular migration²⁵and the replacement of the phenolic

hydroxyl by the acyl substituent as in 4aꢀc. The diisoindolo-

methenes 5aꢀc were obtained by condensation of diketones

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Table 1. Summary of the Diﬀerent Substituents of the Homodisubstituted Diisoindolomethene Borates

^aCalibrated referring to residual glass B₂O₃.

but small amounts (<5%) of starting material did remain. It seems

that the formation of the ﬁrst BꢀCsp bond favors the attack of a

second molecule of magnesium bromide acetylide on the boron.

The ﬂuoride substitution is easily monitored by ¹¹B NMR, where

disappearance of the characteristic triplet of B bound to two

ﬂuorines is observed and a highly shielded singlet appears (Table 1).

Fortuitously, the conditions under which the alkyl-substituted

compound 14 was obtained provided the key for the synthesis of

the boron heterodisubstituted derivatives 15 and 16 (Scheme 3).

The reaction of ethylmagnesium bromide with 6a at RT appeared to

be almost instantaneous, and the diethylboron compound 14 was

obtained in 68% yield after puriﬁcation. Taking this to mean that

the intermediate monoethyl compound must be highly activated

toward all nucleophiles, the reaction was conducted using an equi-

molar mixture of ethyl- and ethynyl-magnesium bromides and,

gratifyingly, was found to lead to a mixture of diethyl-, dialkynyl-,

and alkynylethylboron derivatives which could be easily sepa-

rated by ﬂash chromatography (Scheme 3).

This procedure provided a means to introduce two diﬀerent

molecular subunits on the boron center, one carrying a polyaromatic

residue and the second a masked function. One of our objectives

here was to introduce an pyrenylethynyl unit as well as a sub-

stituent which could function as a potential anchoring arm

(an activated succinic-ester for instance see Scheme 5). The

succinimidyl ester (NHS ester) group is an exceptionally

useful grafting entity that, for example, preferentially acylates

amino groups under mild reaction conditions. Thus, the coupl-

ing of biopolymers such as proteins can be envisaged. The ﬁrst

step in its synthesis was the preparation of the oxazoline 19.

4-Iodobenzoylchloride was reacted with 2-amino-2-methylpro-

panol to give oxazoline 17, which was subjected to Sonagashira

coupling with trimethylsilylacetylene to give 18 in 98% yield.

Deprotection of the acetylene unit using K₂CO₃then provided

19 in essentially quantitative yield (Scheme 4).³¹Dyes 20aꢀc

were obtained by the sequence of reactions listed in Scheme 5

where the reaction of derivatives 6aꢀc with a mixture of the

Grignards from compound 19 and from ethynylpyrene gave 20a

43%, 20b 56%, and 20c 9%. Various reaction conditions were

explored to transform the oxazoline function into carboxylic ester

without degradation of the dibenzopyrromethene backbone and

substitution on the boron center. Hydrolysis in a mixture of aqueous

3 M H₂SO₄and THF proved eﬀective for compounds 20aꢀc.

The resulting polar amino-esters were transesteriﬁed to facilitate

puriﬁcation. Thus, reaction with sodium methoxide gave the methyl

esters in good yields (21a 80%, 21b 67%, 21c 86%). To assess its

suitability for biolabeling, compound 21a was hydrolyzed with

NaOH at room temperature overnight. The crude acid ob-

tained by neutralizing the product solution with NH₄Cl was

treated at room temperature with N-hydroxysuccinimide in the

presence of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide

(EDCI) and 4-dimethylaminopyridine (DMAP) to give the

activated ester in good yield (67%), and as expected, reaction of

n-propylamine with this NHS ester led instantaneously to the

amide 22a (81%).

X-ray Structure Determinations. Single-crystal X-ray diffrac-

tion measurements provided the molecular structures of com-

pounds 6c, 8, 11, 13, 14, 15, and 16, confirming the identity ex-

pected on the basis of their synthesis and defining, in particular,

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Scheme 3. Approaches to Heterodisubstituted Diisoindolemethene Borates

Scheme 4. Synthesis of 4-Ethynyl-1-(dimethyloxazolidinyl)-benzene

the influence of the boron substituents on the planarity of the

edifice (Figures 1ꢀ7). Characteristic bond lengths and angles are

reported in Table 2. In all structures, the boron atom has a distorted

tetrahedral environment. NꢀBꢀN angles fall within the range

for known species [mean 106.34(12)° from 200 hits found in the

Cambridge Structural Database (CSD version 5.31, with August

2010 updates)],³²but the CꢀBꢀC angle is slightly larger than

that observed in C- or E-borondipyrromethenes³⁰[115.2(5)° from

16 hits]. The average BꢀN bond length is slightly longer than

that for the corresponding F-Bodipy.³³The average N1ꢀC4/

N2ꢀC5 length is 1.36 Å, typical of this family of dyes, as is the

longer bond length of 1.42 Å for N1ꢀC1/N2ꢀC8.³³The elon-

gated BꢀC bonds in 8 and 13ꢀ16 of ca. 1.59 Å are similar to

those found in other C- or E-Bodipy. The triple bond character

of the ethyne link is maintained, with an average bond length

of 1.20 Å in 8, 13, 15, and 16. A slight distortion from planarity

of the cyanine core is observed as previously described for

Bodipys bearing bulky groups in the 3,5-positions.³³It may be

described as a “butterfly” conformation, with the wings being

the BN1C1C2C3C4C9 and BN2C5C6C7C8C9 planes. The

dihedral angles are larger with phenyl substituents on the C4,

C5 ortho positions than with thiophene residues (ca. 9ꢀ12°

versus 2ꢀ6°).

A tilt between the R₁aromatic groups located in the 3,5-po-

sitions and the indacene core is observed and may be indicative of

the steric congestion induced by the boron substituent. The ethynyl

substituents seem to minimize congestion around the boron center,

and thus the tilt is very similar to that induced by ﬂuorine (com-

pare 6c and 13) (Figures 1 and 2). When the substituent is a

ﬂexible, saturated group such as ethyl, the tilt angle is much greater

(15 and 16) (Figures 3 and 4), with the two bulky substituents

(14) becoming almost orthogonal (Figure 5). Comparison of the

thienyl-substituted compound structures shows that the sulfur

atoms point in opposite directions in the homodisubstituted dyes 8

(Figure6) and14 but predominantly (in about 70% of molecules) in

the ethynyl bond direction in the case of 15 (Figure 3). The crystal

structure features of 11 (Figure 7) with two ethynylpyrene residues

is similar to 13 bearing two ethynyltolyl fragments (Figure 2).

With respect to the molecular packing, each of the seven crystal

structures displays inversion-related pairs of diisoindolomethene

fragments with mean plane-to-plane distances ranging from

3.37 Å (13, Figure S1, Supporting Information) to 3.69 Å (14,

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Scheme 5. Synthesis of Diisoindolemethene Borates Bearing Ethynylpyrene and Benzoic Acid Precursor Substituents on the

Boron Center

Figure 1. Orthogonal ORTEP views of the molecular structure of 6c.

(Here and in all other ﬁgures, probability displacement ellipsoids are

shown at the 30% level.)

Figure 2. Orthogonal ORTEP views of the molecular structure of 13.

Supporting Information) with 3.428 and 3.483 Å pyrene-to-

pyrene distances and with methoxy groups or thiophene groups,

respectively, on both sides of the pairs of pyrenes.

Figure S2, Supporting Information). The absence of cumber-

some substituents at the boron atom for 6c results in the

formation of inﬁnite stacks of 6c molecules along the a

direction. In the case of 14, the greatest overlap is found

between the outer phenyl groups with a centroidꢀcentroid

distance of 3.655(2) Å (Figure S2, Supporting Information).

Pyrene interactions with an interplanar distance of 3.431 Å,

parallel to (100), and sandwiched here by edge-to-face inter-

actions with the outer phenyl groups of pairs of diisoindole-

methene groups are observed for compound 16 (Figure 8). Similar

packing is seen in compounds 11 (Figure 9) and 15 (Figure S3,

Electrochemical Properties. Cyclic voltammetry in dichlor-

omethane solution was used to probe the electronic effects of the

various substituents on the Bodipy electrophore. Table 3 lists the

potentials (relative to the SCE reference electrode) for the waves

observed in the þ1.6 to ꢀ2.2 V windows.

For the starting materials 6a, 6b, and 6c, a single anodic wave,

safely assigned to the (Bodipy/Bodipy^þ) couple, was observed in

the region between þ0.73 and þ0.43 V (Figure 10). All were re-

versible (i_pa/i_pc≈ 1), with a shape characteristic of a Nernstian

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Table 2. Selected Geometric Parameters Deduced from the X-ray Structural Data

average

average C4/

average C4/ N1ꢀBꢀN2 X1ꢀBꢀX2

dihedral angles

dihedral angles BN1C1C2C3C4C9/

BN2C5C6C7C8C9

compds BꢀN (Å) BꢀX (Å)

5dN (Å)

5ꢀC3/6 (Å)

(deg)

diisoindolomethene/R1

6c

1.57

1.38

1.35

1.42

107.9 (1) 110.9(1)

59.2/54.4

58.8/54.1

54.4/32.3

68.1/38.1

84.5/65.4ꢀ45.2

68.2/53.4

67.5/53.2

81.1/78.8

61.1/

8.6

8.7

8

1.60

1.59

1.58

1.36

1.43

107.4 (3) 118.1(3)

1.7

11

107.2 ( 0.3 116.9 ( 0.7

9.2 ( 2.2

13

1.59

1.58

1.35

1.42

106.6 (1) 118.4(1)

12.3

14

15

1.61

1.60

1.61

1.59

1.35

1.36

1.42

1.43

105.0(2)

115.1(2)

6.0

4.9

106.4 (3) 112.7(3)

83.9ꢀ65.0

69.9/65.3

68.6/65.6

16

1.59

1.58

1.35

1.39

106.6(3)

117.8(3)

9.0

Figure 5. Orthogonal ORTEP views of the molecular structure of 14.

Figure 3. Orthogonal ORTEP views of the molecular structure of 15.

Figure 6. Orthogonal ORTEP views of the molecular structure of 8.

Figure 4. Orthogonal ORTEP views of the molecular structure of 16.

one-electron process (ΔE_p= 60ꢀ70 mV). Note that this wave is

less anodic for the dye substituted with ethylthiophene fragments

(derived from 6a) than for the anisole- and phenyl-substituted

dyes (derived from 6b and 6c, respectively), the last being the

most diﬃcult to oxidize. This reﬂects the fact that the thiophene

and anisole residues are better electron-donating groups than

phenyl. Interestingly, oxidation of these blue and green dyes is

easier by 370ꢀ670 mV relative to that of the yellow dyes of type

A in Chart 1.³⁴

The second oxidation found at higher potential in the þ1.3 to

1.59 V range for the same dyes is assigned to formation of the

(Bodipy^2þ) dication and appears to be reversible for dyes 6a and

6b but irreversible for 6c. The formation of Bodipy^2þdications

has previously been observed in particular solvent conditions and

when pyridine moieties are grafted onto the central position of

the basic yellow molecules.³⁴

Figure 7. Orthogonal ORTEP views of the molecular structure of 11.

Dyes 6a, 6b, and 6c are also reducible, displaying a reversible

reduction to the radical anion (Bodipy^ꢀ) in the range ꢀ0.92 to

ꢀ1.08 V and an irreversible reduction to the dianion (Bodipy^2ꢀ

)

at more cathodic potentials (Table 3). It is interesting to note

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that the HOMOꢀLUMO gaps of 1.35 eV for 6a, 1.58 eV for 6b,

and 1.79 eV for 6c are in keeping with the bathochromic shift of

the emission wavelength for the corresponding dyes in dilute so-

lution (vide infra).

The electron-rich polyaromatic units seem to facilitate this

second oxidation, in contrast with the alkyl substituent which

does not signiﬁcantly perturb the process. However, the substitu-

tion of the ﬂuoro groups renders the ﬁrst reduction more diﬃcult

by about 200 mV for an alkyne substitution and by 470 mV for an

alkyl substitution (dye 14). An intermediate situation is found for

dye 15 bearing an ethynylpyreneandanethylfragment. Inallcases,

the ﬁrst electrochemical reduction remains reversible and mono-

electronic just like the ﬁrst oxidation wave.

As would be expected based on the increase of electron density,

substitution of the ﬂuoro groups by arylethynyl fragments perturbs

the second reduction of the Bodipy core, which is more cathodic

by at least 140 mV. This reduction potential is located around

ꢀ1.91 V and does not depend on the nature of the polyaromatic

rings, excluding the direct reduction of the aryl to the radical anion

[compare dye 7 (pyrenylethynyl) with dye 8 (phenylethynyl)].

Furthermore, this redox potential is shifted to ꢀ1.96 V for dye 15

(bearing pyrenylethynyl and ethyl groups) and to ꢀ2.20 V in the

case of dye 14 (with two ethyl groups). The same trends are seen

in the series constructed from dye 6b with an anisole fragment

and dye 6c with an unsubstituted phenyl group (for details see

Table 3).

Surprisingly, along a series of dyes constructed from the same

skeleton, for instance, the ethylthienyl derivative of 6a, the sub-

stitution of both ﬂuoro groups with an arylethynyl or alkyl fragment

has little eﬀect on the ﬁrst oxidation potential, which remains around

þ0.41 V. This is in strong contrast with the previous observation

made for the yellow dyes A and B, where ﬂuoride substitution

leading to dyes C resulted in a shift of ∼100 mV toward the anodic

region for both the radical cation and radical anion, although the

HOMO/LUMO gap remained similar to that of molecules A and

B.^18b,22However, note that the second oxidation process leading

to the dication (Bodipy^2þ), with the exception of dye 14 where

ethyl groups replace the ﬂuoro residues, is diﬃcult to compare

due to the irreversibility of most of the processes. However,

it seems that this second oxidation is facilitated and sensitive

to the presence of the alkyne fragments on the boron center.

These observations reﬂect the diﬀerent electronic environments

of Bodipy dyes and indicate that signiﬁcant electronic interac-

tions may result from substitution of the isoindole core. They clearly

reﬂect the combined eﬀects of electron donation of the thiophene

and anisole fragments and the polyaromatic moieties grafted onto

the boron center.

Optical Properties. Spectroscopic data relevant to the present

discussion are collected in Table 4. In solution, all the compounds

show a strong S₀fS₁(πꢀπ*) transition between λ≈630ꢀ720 nm

with an absorption coefficient of 80 000ꢀ120 000 M^ꢀ1cm^ꢀ1

,

unambiguously assigned to the boradiisoindolomethene chro-

mophores (Figure 11). The spectral profile is slightly dependent

on the solvent polarity, and in using dioxane, dichloromethane or

ethanol shifts of only a few nanometers were observed. The

absorption wavelength of this band is directly affected by the level

of delocalization of the boradiazaindacene πꢀπ* system and also

dependent on the free rotation ability of the aromatic substituent

in the ortho position to the nitrogen atoms. For instance, in the

compounds where bulky substituents are present on the boron,

Figure 8. View of packing of compound 16 down the bꢀc direction.

Cyan dashed lines indicate pyreneꢀpyrene stacking parallel to (100)

between molecules at x, y, z and ꢀx, 3 ꢀ y, 1 ꢀ z.

Figure 9. Packing of compound 11. Cyan dashed lines indicate πꢀπ stacking interactions between diisoindolemethene platforms related by inversion.

Ethynylpyrene rings are colored in light and dark gray to underline the alternate positions with occupancy factors of 0.5 taken along the a axis. Therefore,

pyrene stacking is observed every two a unit cell dimensions.

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Table 3. Solution Electrochemical Properties of the Dyes^a

E_ox, V (ΔE, mV)

E_red, V (ΔE, mV)

compds

Bodipy^þ/Bodipy

Bodipy^2þ/Bodipy^þ

Bodipy/Bodipy^ꢀ

Bodipy/Bodipy^2ꢀ

6a

7

0.43(70)

0.40 (80)

0.41 (70)

0.40 (80)

0.41 (70)

0.42 (80)

0.40 (80)

0.50 (70)

0.44 (70)

0.42 (60)

0.73 (70)

0.65 (80)

0.66 (60)

0.64 (80)

1.03 (70)

0.97 (irr.)

0.98 (irr.)

1.05 (90)

0.96 (irr.)

0.98 (irr.)

1.17 (80)

1.16 (irr.)

1.15 (irr.)

1.18 (irr.)

1.59 (irr.)

1.44 (irr.)

1.34 (irr.)

1.37 (irr.)

ꢀ0.92 (70)

ꢀ1.10 (80)

ꢀ1.12 (80)

ꢀ1.11 (80)

ꢀ1.39 (90)

ꢀ1.25 (70)

ꢀ1.12 (80)

ꢀ1.08 (70)

ꢀ1.20 (70)

ꢀ1.25 (70)

ꢀ1.27 (100)

ꢀ1.06 (80)

ꢀ1.27 (80)

ꢀ1.29 (80)

ꢀ1.27 (80)

ꢀ1.77 (irr.)

ꢀ1.91 (irr.)

ꢀ1.92 (irr.)

ꢀ2.20 (irr.)

ꢀ1.96 (irr.)

ꢀ1.92 (irr.)

ꢀ1.99 (irr.)

ꢀ1.96 (irr.)

ꢀ1.98 (irr.)

ꢀ2.00 (irr.)

ꢀ1.90 (irr.)

ꢀ1.98 (irr.)

ꢀ1.97 (irr.)

ꢀ1.90 (irr.)

8

9

10

14

15

20a

6b

11

12

20b

6c

13

16

20c

^aPotentials determined by cyclic voltammetry in deoxygenated CH₂Cl₂solution, containing 0.1 M TBAPF₆, at a solute concentration of ca. 1 mM and at

rt. Potentials are given versus the saturated calomel electrode (SCE) and in the case of the series 6c standardized vs ferrocene (Fc) as internal reference

assuming that E_1/2(Fc/Fc^þ) = þ0.38 V (ΔE_p= 70 mV) vs SCE. The error in half-wave potentials is (15 mV. Where the redox processes are irreversible,

the peak potentials (E_apor E_cp) are quoted. All reversible redox steps result from one-electron processes unless otherwise speciﬁed.

Chart 1. Nonconjugated Bodipy Dyes with Various Substit-

uents on the Core and the Boron Atom

the dihedral angle is smaller (ca. 64°), and the delocalization path-

way in the dye is enhanced, leading to an absorption at 680 nm in

Figure 10. Cyclic voltammograms: of 6a (green line), 6b (blue line),

and 6c (red line) in dichloromethane at rt, using tetrabutylammonium

hexaﬂuorophosphate as the supporting electrolyte. Potentials are plotted

against the saturated calomel electrode (SCE).

dye 15. With two tolylethynyl substituents (dye 8), the steric con-

gestion around the boron is weaker (dihedral angle dye/thienyl

about 54°), and a bathochromic shift is observed with an absorption

located at 707 nm. With two fluorine atoms (dye 6a), the red shift

is even stronger (λ_abs= 732 nm). Similar conclusions apply for

compounds 6c and 16, where the dihedral angle between the

phenyl group and the cyanine is around 55° in the solid state struc-

ture of 6c but becomes larger (ca. 65° in the solid structure of 16)

where a single ethyl group is present on the boron center. In this

case, a hypsochromic shift from 634 to 612 nm is observed for the

S₀ꢀS₁transition. Interestingly, the use of an ethynyl tether to

connect an even bulkier polyaromatic group such as pyrene or

perylene to the boron atom does not dramatically affect the color

of the dye with respect to the reference difluoro compounds. There

is an apparent correlation between the dihedral angles observed

crystallographically in the molecular structures and the spectro-

scopic data; however, we have to keep in mind that these dihedral

angles are not fixed in solution, and the electronic as well as steric

effects of the substituents may be significantly different in both

coplanarity of the 3,5-aryl substituents with the cyanine core is

disfavored, and as a consequence the absorption is hypsochro-

mically shifted by 91 and 52 nm (cases 14 and 15) with respect to

6a (Figure 11a). Conversely, the use of ethyne tethers or fluoro

groups reduces the steric congestion, and the absorption profile

is bathochromically shifted by 66 nm in the case of 8 with respect

to dye 14. Interestingly, a correlation can be made between the

dihedral angle between the boradiisoindole plane and that of the

aromatic substituents R to the nitrogen atom (see Table 2) with

the observed color of the dyes. For a given diisoindolomethene

skeleton bearing the bulkier substituents on the boron (two ethyl

groups in 14), the absorption lies at 641 nm, and the dihedral

angle between the cyanine core and the thienyl group is ca. 80°.

When an ethyl group is replaced by an arylethynyl substituent,

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Table 4. Spectroscopic Data for the Compounds at 298 K^a

c

compds

λ_abs(nm)

ε (M^ꢀ1cm^ꢀ1

)

λ_F(nm)

Φ_F^b(%)

P_ET

τ_F(ns)

k_r^d(10⁷s^ꢀ1

)

k_nr^d(10⁷s^ꢀ1

)

Stokes shift (cm^ꢀ1

)

6a

7

732

720

370

707

720

464

77800

78100

780

756

16

21

29

24

15

4

2.6

5.3

6.35

3.96

32.1

14.9

840

660

1117000

85000

100

63

13800

740

8

9

746

755

496

750

7.5

4.6

3.9

5.2

3.2

9.5

16.5

18.5

82000

644

117000

8307

1390

771

10

709

324

641

680

371

717

371

716

371

713

371

679

669

370

668

671

368

669

368

641

632

612

370

634

368

634

368

82000

110000

91200

78000

70000

79000

76000

83000

79000

84000

101500

89800

84500

102000

76100

89800

73200

75800

54000

103700

82500

94100

46700

82900

52600

92300

55100

22

16

43

26

20

24

19

17

24

21

49

52

49

57

50

49

65

60

71

70

62

61

65

64

5.2

4.2

3.1

7.9

4.9

3.8

5.1

3.5

3.1

4.6

4.1

7.2

7.5

6.5

7.7

7.8

7.6

9.8

6.2

11.5

11.3

7.6

7.4

10.2

10.0

15.0

16.2

10.6

14.0

15.1

16.2

15.0

15.4

14.6

15.2

7.5

72

17530

1250

1137

13386

631

14

15

697

737

5.4

5.3

77

20a

21a

22a

753

751

750

4.7

5.4

5.2

13700

650

89

88

13700

692

13600

603

6b

11

708

695

6.8

6.9

560

100

6.9

12638

684

12

700

701

7.5

7.4

6.8

20b

5.8

638

100

98

5.8

12910

682

21b

701

6.4

7.8

7.9

12910

518

6c

13

16

663

656

643

6.6

9.6

6.2

5.3

4.2

479

4.7

788

99

98

4.8

11475

575

20c

21c

658

660

8.2

6.4

4.6

4.8

11976

621

5.5

5.6

12000

^aMeasured in CH₂Cl₂at 25 °C. ^bDetermined in dichloromethane solution, ca. 5 ꢁ 10^ꢀ7M. Using Cresyl Violet, as reference (φ_F= 0.50 in ethanol)⁴²

and compounds (φ_F= 0.51 in methanol) 6b.^22aAll Φ_Fare corrected for changes in refractive index. ^cEnergy transfer eﬃciency calculated by dividing the

photoluminescence quantum yield obtained by irradiation in the aryl fragment by the yield obtained by direct excitation in the S₁transition. ^dCalculated

using the following equations: k_r= Φ_F/τ_F, k_nr= (1 ꢀ Φ_F)/τ_F, assuming that the emitting state is produced with unit quantum eﬃciency.

situations. Similar observations were recently reported for F-Bodi-

pys bearing various aromatic substituents on the 3,5-positions.³⁵

Other spectroscopic characteristics are the broad bands observed

in the 350ꢀ420 nm window corresponding to the S₀fS₂(πꢀπ*)

transition³⁶of the boradiazaindacene. We have previously noted

that the S₀fS₂transition of extended Bodipys is not shifted sig-

nificantly by increasing the delocalization pathway.³⁷The poly-

aromatic fragments introduce strong πꢀπ* transitions with marked

vibronic structure at 320ꢀ370 and 230ꢀ310 nm for pyrene,³⁸

250ꢀ340 nm for fluorene,³⁹and 400ꢀ480 nm for perylene.⁴⁰

The absorption envelope in the 350ꢀ420 nm window of com-

pounds 7ꢀ11 and 15ꢀ22a can be analyzed as a superposition of

the separate absorptions of the boradiazaindacene and the polyaro-

matic fragments. This observation confirms that each module re-

mains isolated and that delocalization over the Bodipy core and

the polyaromatic fragments is not effective. This result is in keeping

with the absence of available orbitals on the boron(III) center.

Excitation of all the compounds in the S₀fS₁transition pre-

sent in the 632ꢀ727 nm range leads to emission in the region

640ꢀ780 nm, and the small Stokes shifts observed indicate that

the ﬂuorescence originates from a weakly polarized state in which

little reorganization is occurring (Figure 11b). The relatively high

quantum yield values observed for the red emitters decrease as

the emitting wavelength energy decreases, in keeping with the

energy gap law, from 65% for 6c to 16.5% for 6a (Table 4).⁴¹The

ﬂuorescence decay proﬁles can be described by a single expo-

nential ﬁt, with ﬂuorescence lifetimes in the range of 3ꢀ9 ns, a

result in accordance with a singlet excited state. In fact, the radiative

rate constants are much faster than the nonradiative rate constants

for compounds emitting below 680 nm, indicating minimal in-

teraction of the emitting state with an energetically low-lying

localized state (triplet, charge transfer states, or vibronic energy

loss) reﬂected in the high quantum yields. For compounds emitting

in the NIR region, the nonradiative rate constant is higher than the

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Figure 11. (a) Absorption spectra of 6a (black line), 8 (blue line), 15

(green line), and 14 (red line) in dichloromethane at rt. (b) Emission

spectra of 6a (black line), 8 (blue line), 15 (green line), and 14 (red line)

in dichloromethane at rt (excitation in the respective S₀ꢀS₁absorption

band, respectively, at 700, 660, 630, and 595 nm).

Figure 12. (a) Absorption (full lines) and emission spectra (dotted

lines, excitation in the high-energy polyaromatic band, λ = 360 nm) of 7

(black), 11 (blue), and 16 (green) in dichloromethane, at rt. (b) Absorp-

tion (dark lines) and emission spectra (light lines, excitation in the high-

energy polyaromatic band) of 9 (black), 7 (blue), and 10 (green) in

dichloromethane, at rt.

radiative one. No signiﬁcant solvatochromic eﬀect was observed

in the absorption and ﬂuorescence spectra, conﬁrming weak po-

larization of the ground and excited states which is also in keeping

with a singlet excited state.

For compounds 7ꢀ11, 15, 16, and 20ꢀ22, excitation in the

most intense absorption band of the polyaromatic fragments

(250ꢀ470 nm range) did show weak residual emission of the

polycyclic fragments and the characteristic emission of the boradia-

zaindacene core (Figure 12 and Figures S67, S69, S74, and S76ꢀ82,

Supporting Information). In all cases, the ﬂuorescence excitation

spectra match the absorption spectra, conﬁrming a very eﬃcient

energy transfer from the polyaromatic parts to the indacene emitter

(Figure 13 and Figure S64ꢀS83, Supporting Information). The

quantum yield measurements are in agreement with an intramo-

lecular energy transfer eﬃciency of 70ꢀ100% (calculated by di-

viding the photoluminescence quantum yield obtained by irra-

diation in the aryl fragment by the yield obtained by direct excitation

in the S₁transition). The eﬃciency of the energy transfer is likely

due to a good overlap of the S₀fS₂band of the boradiazainda-

cene emitter with the emission band of the pyrene and ﬂuorene

unit leading to a very eﬃcient F€orster-type energy transfer, as we

have previously observed with the pyrene-substituted Bodipy

dyad^19dand polychromophoric systems based on the compound

6a skeleton bearing multiple phenyl-ethynyl-polyaromatic on the

boron center.³⁶In the case of compound 9, a weak overlap between

perylene emission and S₀fS₁transition takes place; the energy

transfer is less eﬃcient and a residual emission of 4% of the

perylene could be observed (Figure 12b).

band (Figure 12a). This interesting feature is maintained even

within the series of compounds possessing a benzoate group

(21) and for the product 22a of coupling to a primary amine.

’ CONCLUSION

By using diisoindolomethene-based Bodipy dyes bearing various

substituents on the core (ethylthiophene, anisole, or phenyl rings),

we have been able to build eﬃcient cassette systems after intro-

duction of 1-ethynylpyrene or 3-ethynylperylene units on the

boron center by means of Grignard reagents. The simultaneous

addition of two diﬀerent carbanions during the substitution reaction

gave us the opportunity to construct several boron-centered hetero-

disubstituted systems. This has provided dyes with pyrene as a

high-energy input unit and an activated acid function allowing

grafting on various supports. Steric hindrance around the boron

center is a means of tuning the absorption and emissive proper-

ties. In particular, bulky groups tethered on the boron induce a

pronounced rotation of the substituents ortho to the nitrogen

atoms, reducing the delocalization pathway and resulting in a pro-

nounced hypsochromic shift of about 91 nm compared to the

diﬂuoro starting material. The pyrene residue can be used as an

input energy module promoting very eﬃcient intramolecular energy

transfer to the Bodipy subunit, which then emits the light ab-

sorbed by the pyrene. This is also true for perylene substituents.

Compounds bearing the same antenna (e.g., pyrene in 7, 11,

and 16) on the boron form a model family of Red-NIR dyes

having a common excitation wavelength and diﬀerent emission

In these two cases, Stokes shifts of around 13 000 and 8000 cm^ꢀ1

,

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1.1 Hz), 1.31 (t, 3H, ³J = 7.3 Hz). ¹³C NMR (50 MHz, CDCl₃): δ 163.5,

153.2, 133.1, 128.8, 124.3, 23.6, 15.6. ES-MS m/z(nature of the peak, relative

intensity) 171.2 ([M þ H]^þ, 100), 139.2 ([M ꢀ NHNH₂]^þ, 20). Anal.

Calcd for C₇H₁₀N₂OS.2H₂O: C, 40.76; H, 6.84; N, 13.58. Found: C, 40.55;

H, 6.77; N, 13.37%.

(E)-5-Ethyl-N⁰-(1-(2-hydroxy-4-methoxyphenyl)ethylidene)-

thiophene-2-carbohydrazide (3a): a mixture of 2a (2.90 g,

17.04 mmol) and 2-hydroxy-4-methoxyacetophenone (2.83 g, 17.04 mmol)

was stirred without solvent at 75 °C for 1 h. The resulting yellowish

solid was purified by recrystallization from a mixture of dichloromethane

and methyl alcohol to give 4.52 g (87%) of 3a as a white solid: mp

1

110ꢀ111 °C. H NMR (200 MHz, CDCl₃): δ 9.18 (s, 1H), 7.52

(s, 1H), 7.29 (d, 1H, ³J = 8.2 Hz), 6.72 (d, 1H, ³J = 3.6 Hz),

6.43ꢀ4.34 (m, 2H), 3.75 (s, 3H), 2.80 (q, 2H, ³J = 7.5 Hz), 2.31 (s,

3H), 1.27 (t, 3H, ³J = 7.5 Hz). ¹³C NMR (50 MHz, CDCl₃): δ 162.3,

161.1, 156.4, 154.4, 132.9, 132.2, 129.9, 129.0, 124.6, 112.5, 106.3,

101.8, 55.3, 23.7, 15.6, 12.8. ES-MS m/z (nature of the peak, relative

intensity) 319.2 ([M þ H]^þ, 100). Anal. Calcd for C₁₆H₁₈N₂O₃S.H₂O:

C, 57.12; H, 5.99; N, 8.33. Found: C, 56.81; H, 5.73; N, 8.19%.

(5-ethyl-2-thienyl)(2-acetyl-5-methoxy-1-phenyl) ketone

(4a): to a solution of 3a (4.30 g, 14.15 mmol) in THF (150 mL) was

added slowly at 25 °C Pb(OAc)₂(7.52 g, 16.96 mmol). After 1 h the

solution was filtered, and the solvent was removed by rotary evaporation.

The residue was treated with water and extracted with dichloromethane.

The organic extracts were washed with water and brine and dried over

magnesium sulfate. The solvent was removed by rotary evaporation. The

residue was purified by chromatography on alumina, eluting with dichlor-

omethaneꢀcyclohexane (v/v 40/60) to give 4.01 g (98%) of 4a as a

white solid: mp 69ꢀ70 °C. ¹H NMR (200 MHz, CDCl₃): δ 7.83 (d, 1H,

³J = 8.6 Hz), 7.06 (d, 1H, ³J = 3.7 Hz), 6.98 (dd, 1H, ³J = 8.6 Hz, ⁴J = 2.5

Hz), 6.88 (d, 1H, ⁴J = 2.5 Hz), 6.72 (dd, 1H, ³J = 3.7 Hz, ⁴J = 0.8 Hz),

3.84 (s, 3H), 2.84 (q, 2H, ³J = 7.3 Hz), 2.46 (s, 3H), 1.29 (t, 3H, ³J = 7.8

Hz). ¹³C NMR (50 MHz, CDCl₃): δ 196.3, 189.3, 162.4, 157.6, 142.8,

141.4, 134.2, 131.8, 129.2, 124.7, 114.2, 113.6, 55.6, 27.0, 23.9, 15.3.

ES-MS m/z (nature of the peak, relative intensity) 289.1 ([M þ H]^þ,

100). Anal. Calcd for C₁₆H₁₆O₃S: C, 66.64; H, 5.59. Found: C, 66.41;

H, 5.35%.

Figure 13. Absorption (blue line), emission (green line, λ_exc380 nm),

and excitation (red line, λ_em780 nm) spectra of 20a.

respectively, were obtained. In the extreme case of a functiona-

lized ﬂuorene, the value reached 17 500 cm^ꢀ1

.

Finally, these dyes are redox active, exhibiting reversible reduction

and oxidation to the radical cation and radical anion. In some

cases, further reduction to the dication and dianion is also readily

observed. To obtain red-NIR emitters suitable for biological label-

ing, the next step is to balance the hydrophobic character of these

new dyes by decoration with hydrophilic groups, such as the charged

groups recently used to obtain water-soluble Bodipys emitting in

the 500ꢀ600 nm window.⁴³We are currently investigating dif-

ferent approaches to gain water solubility and thus emissive dyes

suitable for use in biological conditions and for bioconjugation to

vitamins, polypeptides, sugars, native or modiﬁed proteins, and

antibodies.

’ EXPERIMENTAL SECTION

Ethyl 5-Ethylthiophene-2-carboxylate (1a): to a solution of

2-ethylthiophene (10.00 g, 89.13 mmol) in THF (70 mL) at ꢀ78 °C was

added dropwise n-butyllithium (65 mL, 97.50 mmol, 1.50 M in hexanes).

The solution was stirred for 1 h and added via a cannula to a solution of

ethyl chloroformate (9.7 mL, 106.96 mmol) in THF (50 mL). The mix-

ture was stirred at ꢀ78 °C for 1 h and quenched with a saturated solution

of NH₄Cl (100 mL). The aqueous layer was extracted with dichlor-

omethane. The organic extracts were washed with water and brine and

dried over magnesium sulfate. The solvent was removed by rotary evap-

oration. The residue was purified by chromatography on silica gel, eluting

with dichloromethaneꢀcyclohexane (v/v 60/40) to give 14.71 g (89%)

of 1a as a colorless viscous liquid. ¹H NMR (200 MHz, CDCl₃): δ 7.61

(d, 1H, ³J = 3.6 Hz), 6.78 (dt, 1H, ³J = 3.6 Hz, ⁴J = 1.1 Hz), 4.31 (q, 2H, ³

J = 7.3 Hz), 2.85 (q, 2H, ³J = 7.3 Hz), 1.35 (t, 3H, ³J = 7.3 Hz), 1.31

(t, 3H, ³J = 7.3 Hz). ¹³C NMR (50 MHz, CDCl₃): δ 162.3, 155.3, 133.5,

130.9, 124.4, 60.8, 23.8, 15.6, 14.3. ES-MS m/z (nature of the peak,

relative intensity) 185.2 ([M þ H]^þ, 100), 140.2 ([M ꢀ OEt]^þ, 20). Anal.

Calcd for C₉H₁₂O₂S: C, 58.67; H, 6.56. Found: C, 58.41; H, 6.40%.

5-Ethylthiophene-2-carbohydrazide (2a): to a solution of 1a

(14.00 g, 75.98 mmol) in EtOH (30 mL) was added dropwise hydrazine

monohydrate (11 mL, 227.94 mmol). The mixture was refluxed for 12 h, and

then the solvent was removed by rotary evaporation. The residue was treated

with water and extracted with dichloromethane. The organic extracts were

washed with water and brine and dried over magnesium sulfate. The solvent

was removed by rotary evaporation. The residue was purified by recrystalli-

zation from warm cyclohexane to give 8.90 g (69%) of 2a as a white solid: mp

87ꢀ88 °C. ¹H NMR (200 MHz, CDCl₃): δ 7.38 (d, 1H, ³J = 3.6 Hz), 6.77

(dt, 1H, ³J = 3.6 Hz, ⁴J = 1.1 Hz), 3.99 (s, 2H), 2.85 (qd, 2H, ³J = 7.3 Hz, ⁴J =

Compound 5a: to a solution of 4a (330 mg, 1.14 mmol) in acetic

acid (2.4 mL) and ethyl alcohol (12 mL) at 65 °C was added ammonium

acetate (536 mg, 6.87 mmol) and ammonium chloride (61 mg, 1.14 mmol).

The solution was then refluxed at 90 °C for 30 min. The solvent was re-

moved by rotary evaporation. The residue was treated with water and

extracted with dichloromethane. The organic extracts were washed with

water and dried over absorbent cotton. The solvent was removed by rotary

evaporation. The residue was purified by chromatography on silica gel,

eluting with dichloromethane to give 149 mg (50%) of 5a as a deep blue

solid: 166 °C (dec). ¹H NMR (400 MHz, CDCl₃ꢀCCl₄(v/v 50/50)):

δ 7.61 (d, 2H, ³J = 8.5 Hz), 7.46 (s, 2H), 7.21 (s, 2H), 7.06 (s, 1H), 6.86

(m, 4H), 3.91 (s, 6H), 2.98 (q, 4H, ³J = 7.3 Hz), 1.46 (t, 6H, ³J = 7.4 Hz).

¹³C NMR (100 MHz, CDCl₃): δ 158.1, 148.3, 140.1, 135.5, 133.8,

130.8, 129.7, 124.8, 124.7, 120.2, 117.2, 109.2, 102.4, 55.3, 24.0, 16.2.

UVꢀvis (CH₂Cl₂): λ nm (ε, M^ꢀ1cm^ꢀ1) 359 (33000), 659 (48000).

ES-MS m/z (nature of the peak, relative intensity) 525.2 ([M þ H]^þ,

100). Anal. Calcd for C₃₁H₂₈N₂O₂S₂H₂O: C, 68.61; H, 5.57; N, 5.16.

3

Found: C, 68.33; H, 5.27; N, 5.03%.

Compound 3b: 4-Methoxyphenyl-1-carbohydrazide (2b) (4.00 g,

24.01 mmol) and 2-hydroxy-4-methoxyacetophenone (4.00 g, 24.01

mmol) were stirred in refluxing n-propanol overnight. After cooling,

the solid is filtered and recrystallized from boiling n-propanol, giving

5.10 g (67%) of pure 3b as a white solid. ¹H NMR (200 MHz, DMSO-

d₆): δ 13.71 (s, 1H), 11.07 (s, 1H), 7.49 (ABsys, 4H, J_AB= 9.0 Hz, νδ_AB

=

170.3 Hz), 7.54 (d, 1H, ³J = 9.3 Hz), 6.45ꢀ6.50 (m, 2H), 3.84 (s, 3H),

3.77 (s, 3H) 2.43 (s, 3H). ¹³C NMR (50 MHz, d₆-DMSO): δ 163.5,

162.1, 161.6, 160.7, 158.0, 129.9, 129.6, 124.9, 113.6, 112.7, 105.5, 101.5,

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55.4, 55.1, 13.9. IR (KBr): 3429, 3253, 2835, 1634, 1615, 1597, 1493,

1254, 1181, 1022, 830 cm^ꢀ1. ES-MS m/z (nature of the peak, relative

intensity) 315.1 ([M þ H]^þ, 100). Anal. Calcd for C₁₇H₁₈N₂O₄: C,

64.96; H, 5.77; N, 8.91. Found: C, 64.78; H, 5.55; N, 8.76%.

CDCl₃ꢀCCl₄(v/v 50/50)): δ 158.3, 151.6, 132.0, 131.4, 129.8, 128.9,

125.1, 120.8, 120.2, 103.1, 55.5, 23.7, 15.6. ¹¹B NMR (128 MHz, CDCl₃ꢀ

CCl₄(v/v 50/50)): 5.15 (s). UVꢀvis (CH₂Cl₂):λ nm (ε, M^ꢀ1cm^ꢀ1) 353

(29000), 380 (25000), 650 (sh, 21000), 727 (90000). ES-MS m/z (nature

of the peak, relative intensity) 573.2 ([M þ H]^þ, 100), 534.2 ([M ꢀ 2F]^þ,

35). Anal. Calcd for C₃₁H₂₇BF₂N₂O₂S₂: C, 65.04; H, 4.75; N, 4.89. Found:

C, 64.92; H, 4.62; N, 4.74%.

Compound 4b: to a solution of compound 3b (7.00 g, 22.27 mmol)

in THF (170 mL) was added slowly at 25 °C Pb(OAc)₄(11.84 g, 26.72

mmol). After 1 h the solution was filtered, the solid extracted with

dichloromethane, and the final organic layer evaporated to dryness. The

residue was extracted with dichloromethane and washed with water and

brine and dried over magnesium sulfate. The residue was purified by chro-

matography (alumina Act IV, dichloromethane/cyclohexane 40:60) to

give 4.13 g (65%) of 4b as a white solid. ¹H NMR (300 MHz, CDCl₃):

δ 7.88 (d, 1H, ³J = 8.7 Hz), 7.31 (ABsys, 4H, J_AB= 8.8 Hz, νδ_AB= 248.0

Hz), 7.02 (dd, 1H, ³J = 8.7 Hz, ⁴J = 2.4 Hz), 6.85 (d, 1H, ⁴J = 2.4 Hz),

3.88 (s, 3H), 3.85 (s, 3H), 2.47 (s, 3H). ¹³C NMR (75 MHz, CDCl₃): δ

196.2, 196.1, 163.3, 162.7, 143.9, 131.8, 131.3, 130.0, 129.2, 114.1, 113.6,

113.3, 55.6, 55.4, 26.7. IR (KBr): 2942, 2844, 1670, 1654, 1600, 1567,

1422, 1261, 1174, 1023, 823 cm^ꢀ1. ES-MS m/z (nature of the peak,

relative intensity) 285.1 ([M þ H]^þ, 100). Anal. Calcd for C₁₇H₁₆O₄:

C, 71.82; H, 5.67. Found: C, 71.67; H, 5.40%.

Compound 6b. Compound 5b (0.705 g, 1.37 mmol), anhydrous di-

chloromethane (150 mL), N,N-diisopropylethylamine (0.7 mL, 4.11 mmol),

and boron trifluoride-diethyl etherate (1 mL, 11.62 mmol). 700 mg

1

(88%) of compound 6b was obtained as deep blue needles. H NMR

(300 MHz, CDCl₃ꢀCCl₄(v/v 50/50)): δ 7.90 (br d, 4H, ³J = 7.9 Hz),

7.72 (br d, 2H, ³J = 8.9 Hz), 7.28 (br s, 3H), 7.06 (d, 4H, ³J = 8.9 Hz),

6.96 (dd, 2H, ³J = 8.7 Hz, ⁴J = 2.2 Hz), 3.93 (s, 6H), 3.91 (s, 6H). ¹¹

B

NMR (128 MHz, CDCl₃ꢀCCl₄(v/v 50/50)): 5.00 (t, J = 31.9 Hz).

UVꢀvis (CH₂Cl₂): λ nm (ε, M^ꢀ1cm^ꢀ1), 367 (19200), 679 (89800).

ES-MS m/z (nature of the peak, relative intensity) 565.2 ([M þ H]^þ,

100), 545.2 ([M ꢀ F]^þ, 25), 526.2 ([M ꢀ2F]^þ, 5). Anal. Calcd for

C₃₃H₂₇BF₂N₂O₄: C, 70.23; H, 4.82; N, 4.96. Found: C, 70.07; H, 4.72;

N, 4.80%.

Compound 6c. Compound 5c (2.00 g, 5.04 mmol), anhydrous dichlor-

omethane (50 mL), N,N-diisopropylethylamine (2.6 mL, 14.92 mmol), and

boron trifluoride-diethyl etherate (1.9 mL, 14.92 mmol). 1.40 g (63%) of

Compound 5b: to a solution of compound 4b (2.70 g, 9.5 mmol) in

acetic acid (60 mL) and methanol (120 mL) was added dropwise NH₄OH

(35 mL). After addition completion, the solution was stirred at RT for

one day. The blue precipitate was filtered and then dissolved in chloro-

form. The blue organic solution was then washed with water (3 ꢁ 30 mL)

and dried over MgSO₄. Chromatography (SiO₂, dichloromethane) gave

5b as a deep blue solid (1.30 g, 53%). ¹H NMR (300 MHz, CDCl₃ꢀCCl₄

(v/v 50/50)): δ 7.90 (br d, 4H, ³J = 7.9 Hz), 7.72 (br d, 2H, ³J = 8.8 Hz),

7.22ꢀ7.29 (br s, 3H), 7.07 (d, 4H, ³J = 8.8 Hz), 6.96 (dd, 2H, ³J = 8.7 Hz,

⁴J = 2.2 Hz), 3.93 (s, 6H), 3.90 (s, 6H). ¹³C NMR (75 MHz, CDCl₃ꢀ

CCl₄(v/v 50/50)): δ 157.7, 128.7, 128.6, 120.2, 116.9, 114.6, 102.5,

55.5, 55.4. ES-MS m/z (nature of the peak, relative intensity) 517.2 ([M þ

H]^þ, 100). Anal. Calcd for C₃₃H₂₈N₂O₄: C, 76.73; H, 5.46; N, 5.42.

Found: C, 76.53; H, 5.20; N, 5.37%.

1

compound 6c was isolated as a deep blue solid. H NMR (200 MHz,

CDCl₃): δ 7.92 (d, 2H, ³J = 8.0 Hz), 7.80ꢀ7.85 (m, 4H), 7.63 (d, 2H, ³

J = 8.4 Hz), 7.43ꢀ7.50 (m, 9H), 7.21ꢀ7.28 (m, 2H). ¹³C NMR (75

MHz, CDCl₃): δ 151.7, 134.2, 131.0, 130.6, 130.2, 129.5, 129.0, 128.2,

125.3, 123.7, 118.9, 114.8. ¹¹B NMR (128 MHz, CDCl₃): 5.10 (t, J =

31.6 Hz). UVꢀvis (CH₂Cl₂): λ nm (ε, M^ꢀ1cm^ꢀ1) 299 (30000),

340 (21700), 641 (103700). ES-MS m/z (nature of the peak, relative

intensity) 445.2 ([M þ H]^þ, 100), 425.2 ([M ꢀ F]^þ, 25). Anal. Calcd

for C₂₉H₁₉BF₂N₂: C, 78.40; H, 4.31; N, 6.31. Found: C, 78.19; H, 4.15;

N, 6.20%.

General Procedure Following Experimental Conditions 2

for the Fluoro Substitution Leading to Compounds 7ꢀ16. A

Schlenk flask was charged with the ethynyl derivative (2.4 equiv) and

anhydrous THF. A solution of ethylmagnesium bromide (2.2 equiv, 1 M

in THF) was then added dropwise, and the mixture was stirred at 50 °C

for 2 h. The mixture was then added at 25 °C via a cannula to a solution

of difluoroborate complex (1equiv) in anhydrous THF. The mixture was

stirred at 70 °C for 16 h, and the solvent was removed by rotary evaporation.

The residue was treated with water and extracted with dichloromethane.

The organic extracts were washed with water and dried over MgSO₄. The

solvent was removed by rotary evaporation. The residue was purified by

chromatography.

Compound 5c: to a solution of 4c²⁵(10.00 g, 44 mmol) in acetic

acid (200 mL) and methanol (400 mL) was added dropwise concentrated

aqueous ammonia (100 mL). After addition was complete, the solution

was stirred at RT for one day, while the solution turned progressively deep

blue. The blue precipitate was filtered and then dissolved in chloroform.

The blue organic solution was then washed with water (3 ꢁ 30 mL) and

dried over MgSO₄. Chromatography (SiO₂, chloroform) gave 5c as a

deep blue solid (6.50 g, 74%). ¹H NMR (300 MHz, CDCl₃): δ 8.01ꢀ8.06

3

(m, 6H), 7.92 (d, 2H, J = 8.1 Hz), 7.59ꢀ7.54 (m, 5H), 7.47ꢀ7.43

(m, 2H), 7.38ꢀ7.35 (m, 2H), 7.32ꢀ7.29 (m, 2H). ¹³C NMR (75 MHz,

CDCl₃): δ 146.8, 136.2, 133.8, 133.3, 129.2, 129.1, 128.6, 127.5, 126.2,

124.8, 119.2, 111.2, 111.8. ES-MS m/z (nature of the peak, relative in-

tensity) 397.2 ([M þ H]^þ, 100). Anal. Calcd for C₂₉H₂₀N₂: C, 87.85; H,

5.08; N, 7.07. Found: C, 87.77; H, 4.99; N, 6.98%.

Compound 7. Prepared following experimental conditions 2; from 6a

(50 mg, 0.09 mmol), 4-ethynylpyrene (69 mg, 0.31 mmol), EtMgBr

(0.26 mL, 0.26 mmol, 1 M in THF), THF (8 mL); chromatography on

silica gel, eluting with dichloromethaneꢀcyclohexane (v/v 40/60) to give

41 mg (46%) of 7 as a green solid: 162 °C (dec). ¹H NMR (400 MHz,

CDCl₃ꢀCCl₄(v/v 50/50)): 8.55 (d, 2H, ⁴J = 3.6 Hz), 8.35 (d, 2H, ³J =

9.2 Hz), 8.10 (m, 4H), 7.99ꢀ7.93 (m, 10H), 7.82 ꢀ7.76 (m, 5H), 7.41

(s, 2H), 7.06 (dd, 2H, ³J = 8.0 Hz, ⁴J = 2.4 Hz), 6.91 (d, 2H, ⁴J = 3.6 Hz),

General Procedure Following Experimental Conditions 1

to Produce the BODIPY 6aꢀc. To a solution of compounds 5aꢀc

in anhydrous dichloromethane were added dropwise successively N,N-

diisopropylethylamine and boron trifluoride-diethyl etherate. The mix-

ture was stirred at room temperature until the complete consumption of

the starting material (determined by TLC), and then water was added.

The organic extracts were washed with water and dried over hydrophilic

cotton. The solvent was removed by rotary evaporation. The residue was

purified by chromatography on silica gel, eluting with dichloromethane

Compound 6a. Compound 5a (880 mg, 1.68 mmol), anhydrous di-

chloromethane (110 mL), N,N-diisopropylethylamine (650 mg, 5.03 mmol),

and boron trifluoride-diethyl etherate (1.43 g, 10.06 mmol). 773 mg (81%)

of compound 6a was obtained as a deep green solid: mp 277ꢀ278 °C.

¹H NMR (400 MHz, CDCl₃ꢀCCl₄(v/v 50/50)): δ 7.85 (s, 2H), 7.64

(d, 2H, ³J = 9.0 Hz), 7.39 (s, 1H), 7.29 (s, 2H), 6.98 (m, 4H), 3.86 (s,

6H), 2.98 (q, 4H, ³J= 7.5 Hz), 1.43 (t, 6H, ³J=7.5Hz).¹³CNMR(100MHz,

3.92 (s, 6H), 2.75 (q, 4H, ³J = 7.4 Hz), 1.08 (t, 6H, ³J = 7.4 Hz). ¹³

C

NMR (100 MHz, CDCl₃ꢀCCl₄(v/v 50/50)): 158.2, 151.2, 143.1,

133.6, 132.4, 132.0, 131.4, 130.5, 130.4, 129.9, 128.7, 127.6, 127.5, 127.4,

127.3, 126.8, 125.9, 125.0, 124.9, 124.62, 124.57, 124.5, 124.2, 120.4,

120.2, 119.9, 112.8, 102.9, 98.1, 55.5, 23.6, 15.5. ¹¹B NMR (128 MHz,

CDCl₃ꢀCCl₄(v/v 50/50)): ꢀ6.25 (s). UVꢀvis (CH₂Cl₂): λ nm

(ε, M^ꢀ1cm^ꢀ1) 248 (127000), 275 (94000), 286 (135000), 351

(108000), 370 (141000), 661 (33000), 719 (91500). ES-MS m/z (nature

of the peak, relative intensity) 985.1 ([M þ H]^þ, 100), 759.2 ([M ꢀ

ethynylpyrene]^þ, 15). Anal. Calcd for C₆₇H₄₅BN₂O₂S₂: C, 81.49; H, 4.60;

N, 2.84. Found: C, 81.46; H, 4.28; N, 2.68%.

4500

dx.doi.org/10.1021/jo200246q |J. Org. Chem. 2011, 76, 4489–4505

The Journal of Organic Chemistry

ARTICLE

Compound 8. Prepared following experimental conditions 2; from 6a

(60 mg, 0.10 mmol), 4-ethynyltoluene (43 mg, 0.37 mmol), EtMgBr

(0.31 mL, 0.31 mmol, 1 M in THF), THF (8 mL); chromatography on

silica gel, eluting with dichloromethaneꢀcyclohexane (v/v 40/60) to

give 50 mg (62%) of 8 as a green solid: 234 °C (dec). ¹H NMR

(400 MHz, CDCl₃ꢀCCl₄(v/v 50/50)): 8.32 (d, 2H, ⁴J = 3.6 Hz), 7.61

(m, 3H), 7.20 (m, 2H), 7.02ꢀ6.84 (m, 12H), 3.84 (s, 6H), 2.99 (q, 4H,

³J = 7.4 Hz), 2.28 (s, 6H), 1.42 (t, 6H, ³J = 7.4 Hz). ¹³C NMR (100 MHz,

CDCl₃ꢀCCl₄(v/v 50/50)): 157.8, 150.3, 142.7, 136.6, 133.3, 132.1,

131.5, 130.5, 128.5, 127.4, 124.7, 122.4, 119.9, 119.8, 113.1, 102.4,

98.5, 55.3, 23.7, 21.5, 15.9. ¹¹B NMR (128 MHz, CDCl₃ꢀCCl₄(v/v 50/

50)): ꢀ7.29 (s). UVꢀvis (CH₂Cl₂): λ nm (ε, M^ꢀ1cm^ꢀ1) 257 (101000),

267 (102000), 350 (24000), 380 (23000), 645 (26000), 709 (90500).

ES-MS m/z (nature of the peak, relative intensity) 765.2 ([M þ H]^þ, 100),

649.2 ([M ꢀ ethynyltoluene]^þ, 25). Anal. Calcd for C₄₉H₄₁BN₂O₂S₂: C,

76.95; H, 5.40; N, 3.66. Found: C, 76.70; H, 5.12; N, 3.46%.

119.8, 102.1, 97.7, 55.35, 54.6. ¹¹B NMR (CDCl₃/CCl₄50/50, 128

MHz): ꢀ6.65 (s). UVꢀvis (CH₂Cl₂) λ nm (ε, M^ꢀ1cm^ꢀ1) = 667

(88500), 618 (27000 sh), 371 (111000), 350 (88500), 286 (175000),

275 (152000), 248 (135000). ES-MS m/z (nature of the peak, relative

intensity) 977.3 ([M þ H]^þ, 100), 712.3 ([M ꢀ ethynylpyrene]^þ, 45).

Anal. Calcd for C₆₉H₄₅BN₂O₄: C, 84.83; H, 4.64; N, 2.87. Found: C,

84.67; H, 4.42; N, 2.57%.

Compound 12. Prepared following general procedure 2; from 6b

(46 mg, 0.08 mmol), 4-ethynyltoluene (41 mg, 0,35 mmol), EtMgBr

(0.30 mL 1 M dans THF, 0,30 mmol), THF (5 mL); chromatography

(silica gel, dichloromethane/cyclohexane, 30:70) gave 50 mg (62%) of

8 as a blue solid: 234 °C (dec). ¹H NMR (DMSO-d₆, 200 MHz): 8.54 (s,

1H), 8.13ꢀ8.05 (m, 6H), 7.24ꢀ7.12 (m, 6H), 6.88 (m, 2H), 6.86 (AB_sys

,

8H, J_AB= 7.9 Hz, νδ_AB= 52.9 HZ), 3.81 (s, 6H), 3.77 (s, 6H), 2.23 (s,

6H), ¹³C NMR (C₆D₆, 75 MHz): 160.7, 158.5, 150.5, 136.9, 133.2,

132.7, 132.1, 129.3, 128.8, 128.3, 127.6, 127.4, 126.9, 125.9, 123.1, 120.7,

120.2, 114.9, 114.0, 107.1, 102.4, 99.3, 55.0, 54.9, 21.0. ¹¹B NMR (CDCl₃

128 MHz): ꢀ6.87 (s). UVꢀvis (CH₂Cl₂) λ nm (ε, M^ꢀ1cm^ꢀ1) = 666

(85000), 363 (19000), 268 (99000). ES-MS m/z (nature of the peak,

relative intensity) 757.2 ([M þ H]^þ, 100). Anal. Calcd for C₅₁H₄₁BN₂O₄:

C, 80.95; H, 5.46; N, 3.70. Found: C, 80.72; H, 5.21; N, 3.42%.

Compound 13. Prepared following general procedure 2; from 6c

(100 mg, 0.22 mmol), 1-ethynyltoluene (104 mg, 0.90 mmol), EtMgBr

(0.41 mL, 0.41 mmol, 1 M in THF), THF (8 mL); chromatography (silica

gel, dichloromethane/cyclohexane, 30:70 to 50:50) gave 8 as a blue,

crystalline powder (60 mg, 42%). ¹H NMR (CDCl₃, 300 MHz): 8.2, (d,

4H, J = 6.6 Hz), 7.96 (d, 2H, J = 6.0 Hz), 7.92 (s, 1H), 7.61ꢀ7.39 (m,

11H), 7.22ꢀ7.18 (m, 1H), 6.88 (ABsys, 8H, J_AB= 8.0, νδ_AB= 24.3 Hz),

2.27 (s, 6H). ¹³C NMR (CDCl₃, 75 MHz): 151.2, 136.8, 133.7, 132.4,

131.3, 130.9, 130.3, 128.3, 128.1, 127.7, 127.6, 124.6, 123.0, 122.4, 121.7,

118.4, 115.8, 98.6, 21.3. ¹¹B NMR (CDCl₃, 128 MHz): ꢀ7.14(s).

UVꢀvis (CH₂Cl₂) λ nm (ε, M^ꢀ1cm^ꢀ1) = 632 (82500), 588 (27000

sh), 269 (12000). ES-MS m/z (nature of the peak, relative intensity)

637.1 ([M þ H]^þ, 100). Anal. Calcd for C₄₇H₃₃BN₂: C, 88.68; H, 5.23;

N, 4.40. Found: C, 88.40; H, 4.95; N, 4.18%.

Compound 9. Prepared following experimental conditions 2; from 6a

(50 mg, 0.09 mmol), 3-ethynylperylene (72 mg, 0.26 mmol), EtMgBr

(0.22 mL, 0.22 mmol, 1 M in THF), THF (8 mL); chromatography on

silica gel, eluting with ethylacetateꢀcyclohexane (v/v 15/85) to give 28 mg

1

(29%) of 9 as a dark green solid: mp >350 °C. H NMR (400 MHz,

CDCl₃ꢀCCl₄(v/v 50/50)): 8.37 (d, 2H, ⁴J = 3.6 Hz), 8.10 (d, 4H, ³J =

7.2 Hz), 8.05 (d, 2H, ³J = 7.2 Hz), 7.95 (m, 4H), 7.75 (d, 2H, ³J = 8.4 Hz),

7.67 (s, 1H), 7.59 (m, 4H), 7.42ꢀ7.33 (m, 8H), 7.30 (d, 2H, ³J = 8.0 Hz),

7.00 (dd, 2H, ³J = 8.0 Hz, ⁴J = 2.0 Hz), 6.87 (d, 2H, ⁴J = 3.6 Hz), 3.87

(s, 6H), 2.77 (q, 4H, ³J = 7.4 Hz), 1.14 (t, 6H, ³J = 7.4 Hz). ¹³C NMR

(100 MHz, CDCl₃ꢀCCl₄(v/v 50/50)): 158.2, 151.1, 143.2, 135.0,

134.8, 133.4, 132.4, 131.6, 131.3, 131.2, 130.8, 130.5, 130.4, 128.8, 128.7,

128.6, 127.8, 127.7, 127.5, 126.6, 124.5, 122.8, 120.4, 120.22, 120.17, 119.8,

119.6, 112.6, 102.8, 97.6, 55.5, 23.7, 15.6. ¹¹B NMR (128 MHz, CDCl₃ꢀ

CCl₄(v/v 50/50)): ꢀ6.40 (s). UVꢀvis (CH₂Cl₂): λ nm (ε, M^ꢀ1cm^ꢀ1

)

259 (192000), 436 (97000), 465 (120000), 660 (26000), 721 (82500).

ES-MS m/z (nature of the peak, relative intensity) 1085.2 ([M þ H]^þ,

100). Anal. Calcd for C₇₅H₄₉BN₂O₂S₂: C, 83.01; H, 4.55; N, 2.58. Found:

C, 82.90; H, 4.28; N, 2.43%.

Compound 14. To a solution of 6a (50 mg, 0.09 mmol) in THF

(6 mL) was added at 25 °C a solution of ethylmagnesium bromide 1 M

in THF (0.22 mL, 0.22 mmol). The mixture was stirred for 5 min. The

solvent was removed by rotary evaporation. The residue was treated with

water and extracted with dichloromethane. The organic extracts were

washed with water and then brine and dried over absorbent cotton. The

solvent was removed by rotary evaporation. The residue was purified by

chromatography on silica gel, eluting with dichloromethaneꢀcyclohexane

(v/v 60/40) to give 35 mg (68%) of 14 as a deep blue solid:

257ꢀ258 °C. ¹H NMR (200 MHz, CDCl₃ꢀCCl₄(v/v 50/50)):

7.84ꢀ7.78 (m, 3H), 7.10ꢀ7.03 (m, 4H), 6.81 (s, 4H), 3.87 (s, 6H),

2.91 (q, 4H, ³J = 7.5 Hz), 1.37 (t, 6H, ³J = 7.5 Hz), 0.70 (q, 4H, ³J = 7.5 Hz),

0.35 (t, 6H, ³J = 7.5 Hz). ¹³C NMR (100 MHz, CDCl₃ꢀCCl₄(v/v 50/

50)): 157.8, 150.0, 141.4, 133.9, 130.2, 130.0, 128.5, 127.2, 123.0, 119.2,

119.1, 115.9, 101.5, 96.2, 55.6, 23.5, 15.7, 9.3. ¹¹B NMR (128 MHz,

CDCl₃ꢀCCl₄(v/v 50/50)): 8.63 (br s). UVꢀvis (CH₂Cl₂): λ nm

(ε, M^ꢀ1cm^ꢀ1) 240 (48000), 300 (19000), 360 (13000), 595 (24000),

640 (90000). ES-MS m/z (nature of the peak, relative intensity) 593.2

([Mþ H]^þ, 100), 563.1 ([M ꢀ Et]^þ,20).Anal.CalcdforC₃₅H₃₇BN₂O₂S₂:

C, 70.93; H, 6.29; N, 4.73. Found: C, 70.65; H, 6.02; N, 4.55%.

Compound 15. Prepared following experimental conditions 2; from

6a (50 mg, 0.09 mmol), 4-ethynylpyrene (24 mg, 0.10 mmol), EtMgBr

(0.21 mL, 0.21 mmol, 1 M in THF), THF (8 mL); chromatography on

silica gel, eluting with dichloromethaneꢀcyclohexane (v/v 30/70) to

Compound 10. Prepared following experimental conditions 2; from

6a (50 mg, 0.09 mmol), 9,9-dibutyl-3-ethynyl-9H-fluorene (80 mg,

0.26 mmol), EtMgBr (0.22 mL, 0.22 mmol, 1 M in THF), THF (8 mL);

chromatography on silica gel, eluting with ethylacetateꢀcyclohexane

(v/v 4/96) to give 75 mg (76%) of 10 as a green solid: 147 °C (dec). ¹H

NMR (400 MHz, CDCl₃ꢀCCl4 (v/v 50/50)): 8.34 (d, 2H, ⁴J =

4.0 Hz), 7.69ꢀ7.60 (m, 5H), 7.48 (d, 2H, ³J = 8.0 Hz), 7.26 (m, 8H),

7.11 (m, 6H), 6.92 (dd, 2H, ³J = 8.0 Hz, ⁴J = 2.0 Hz), 3.90 (s, 6H), 3.07

3

(q, 4H, J = 7.4 Hz), 1.97ꢀ1.84 (m, 8H), 1.49 (t, 6H, J = 7.4 Hz),

1.10ꢀ1.01 (m, 8H), 0.67 (t, 12H, ³J = 7.4 Hz), 0.62ꢀ0.48 (m, 8H). ¹³

C

NMR (100 MHz, CDCl₃ꢀCCl₄(v/v 50/50)): 158.0, 150.8, 150.4, 150.1,

142.9, 141.0, 140.1, 133.1, 132.3, 130.9, 130.8, 128.6, 127.5, 127.1, 126.9,

125.5, 124.5, 124.0, 122.7, 120.0, 119.9, 119.1, 113.2, 102.5, 99.3, 55.3, 54.9,

40.5, 26.0, 23.9, 23.3, 16.0, 14.1. ¹¹B NMR (128 MHz, CDCl₃/CCl₄(v/v50/

50)): ꢀ7.43 (s). UVꢀvis (CH₂Cl₂): λ nm (ε, M^ꢀ1cm^ꢀ1) 298 (110000),

323 (136000), 380 (24000), 650 (30000), 710 (95000). ES-MS m/z(nature

of the peak, relative intensity) 1137.2 ([M þ H]^þ, 100), 835.2 ([M ꢀ 9,9-

dibutyl-3-ethynyl-9H-fluorene]^þ, 25). Anal. Calcd for C₇₇H₇₇BN₂O₂S₂: C,

81.31; H, 6.82; N, 2.46. Found: C, 81.11; H, 6.61; N, 2.16%.

Compound 11. Prepared following general conditions 2; from 6b

(50 mg, 0,09 mmol), 1-ethynylpyrene (60 mg, 0.26 mmol), EtMgBr

(0,24 mL 1 M dans THF, 0,24 mmol), THF (8 mL); chromatography

(silica gel, cyclohexane/dichloromethane, 60:40) 11 (35 mg, 41%) as a

blue solid. ¹H NMR (CDCl₃ꢀCCl₄50/50, 200 MHz): 8.36 (d, 2H, ³J =

9.2 Hz,), 8.13 (m, 8H), 8.05ꢀ7.94 (m, 10H), 7.86ꢀ7.78 (m, 5H), 7.03

(dd, 2H, ³J = 8 Hz, ⁴J = 2 Hz), 6.86 (m, 2H), 6.69 (m,4H), 3.76 (s, 6H),

3.19 (s, 6H). ¹³C NMR (CDCl₃/CCl₄50/50, 75 MHz): 160.1, 157.9,

150.7, 132.5, 132.2, 132.1, 131.51, 131.49, 130.5, 129.6, 128.9, 127.6,

127.5, 127.4, 127.0, 126.6, 126.0, 125.1, 125.0, 124.7, 124.6, 124.2, 120.5,

1

give 19 mg (28%) of 15 as a green solid: 227 °C (dec). H NMR

(400 MHz, CDCl₃ꢀCCl₄(v/v 50/50)): 8.47 (1H, ³J = 8.6 Hz,), 8.12

(m, 2H), 8.02ꢀ7.90 (m, 6H), 7.82 (d, 2H, ⁴J = 9.6 Hz), 7.78 (s, 1H),

7.70 (d, 2H, ⁴J = 3.2 Hz), 7.06 (m, 4H), 6.72 (d, 2H, ³J = 3.2 Hz), 3.84

(s, 6H), 2.73 (q, 4H, ³J = 7.4 Hz), 1.14 (t, 6H, ³J = 7.4 Hz), 1.04 (q, 2H, ³J

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= 7.8 Hz), 0.34 (t, 3H, ³J = 7.8 Hz). ¹³C NMR (100 MHz, CDCl₃ꢀCCl₄

(v/v 50/50)): 158.0, 150.6, 142.7, 133.0, 131.9, 131.7, 131.5, 131.4,

130.2, 130.1, 129.6, 128.0, 127.4, 127.3, 126.9, 125.9, 124.9, 124.8, 124.7,

124.6, 124.3, 123.6, 121.1, 119.8, 119.5, 114.4, 102.3, 98.4, 55.5, 23.4,

14.4, 8.9. ¹¹B NMR (128 MHz, CDCl₃ꢀCCl₄(v/v 50/50)): 1.07 (s).

UVꢀvis (CH₂Cl₂): λ nm (ε, M^ꢀ1cm^ꢀ1) 276 (144000), 286 (148000),

351 (54500), 370 (64000), 681 (71500). ES-MS m/z (nature of the peak,

relative intensity) 789.2 ([M þ H]^þ, 100). Anal. Calcd for C₅₁H₄₁BN₂O₂S₂:

C, 77.65; H, 5.24; N, 3.55. Found: C, 77.40; H, 5.05; N, 3.38%.

residue was treated with water and extracted with dichloromethane. The

organic extracts were washed with water and then brine and dried over

magnesium sulfate. The solvent was removed by rotary evaporation. The

residue was purified by chromatography on alumina, eluting with dichl-

oromethaneꢀcyclohexane (v/v 10/90) to give 0.91 g (99%) of 19 as a

white solid: mp 77ꢀ78 °C. ¹H NMR (200 MHz, CDCl₃): δ 7.70 (AB_sys

,

4H, ^ABJ = 8.6 Hz, νδ_AB= 74.7 Hz), 4.10 (s, 2H), 3.17 (s, 1H), 1.38

(s, 6H). ¹³C NMR (50 MHz, CDCl₃): δ 161.4, 132.0, 128.2, 128.1,

124.8, 83.1, 79.2, 79.1, 67.7, 28.4. ES-MS m/z (nature of the peak,

relative intensity) 200.1 ([M þ H]^þ, 100). Anal. Calcd for C₁₃H₁₃NO:

C, 78.36; H, 6.58; N, 7.03. Found: C, 78.24; H, 6.42; N, 6.92%.

General Procedure Following Experimental Conditions 3

for the Fluoro Substitution by Two Diffrenet Alkyne Moi-

eties Leading to Compounds 20aꢀc. Two Schlenk flasks were,

respectively, charged with 19, THF (6 mL), and 4-ethynylpyrene, THF

(6 mL). A solution of ethylmagnesium bromide in THF was then added

dropwise in each Schlenk flask, and the mixtures were stirred at 50 °C for

2 h. These mixtures were then added successively at 25 °C via a cannula

to a solution of dibenzopyrrometheneboron difluoride in anhydrous THF.

The mixture was stirred at 70 °C for 16 h, and the solvent was removed

by rotary evaporation. The residue was treated with water and extracted

with dichloromethane. The organic extracts were washed with water and

dried over absorbent cotton. The solvent was removed by rotary evapora-

tion. The residue was purified by chromatography on silica gel.

Compound 16. Prepared following experimental conditions 2; from

6c (100 mg, 0.225 mmol), 1-ethynylpyrene (51 mg, 0.225 mmol),

EtMgBr (0.20 mL, 2.2 M in THF, 0.45 mmol), THF (2 mL); chroma-

tography (silica gel, dichloromethane/petroleum ether 30:70), followed

by a recrystallization in a dichloromethane/cyclohexane mixture, gave 8 as

deep blue crystalline needles (60 mg, 40%). ¹H NMR (CDCl₃, 400 MHz):

8.36 (d, 1H, ³J = 9.1 Hz), 8.19ꢀ8.14 (m, 2H), 8.09 (s, 1H), 8.06ꢀ7.82

(m, 12H), 7.52ꢀ7.37 (m, 2H), 7.29ꢀ7.17 (m, 10H), 0.57 (q, 2H, ³J =

7.2 Hz), 0.29 (t, 3H, ³J = 7.3 Hz). ¹³CNMR (C₆D₆, 75 MHz): 151.6, 133.8,

133.1, 132.5, 131.9, 131.9, 130.9, 130.1, 129.1, 128.7, 127.6, 127.1, 127.0,

126.2, 125.5, 125.4, 125.3, 125.2, 124.8, 123.1, 121.2, 118.7, 117.3, 98.0,

27.3, 8.7. ¹¹B NMR (CDCL₃128 MHz): 1.09 (s) . FAB^þm/z: 660.6 ([M

þ H]^þ, 40), 631.5 ([M ꢀ Et, 100]^þ), 435.4 ([Mꢀpyr-ꢂ-, 25]^þ. UVꢀvis

(CH₂Cl₂) λ nm (ε, M^ꢀ1cm^ꢀ1) = 614 (78300), 574 (24000 sh), 370

(42000), 351 (37400). ES-MS m/z (nature of the peak, relative intensity)

661.2 ([M þ H]^þ, 100), 631.2 ([M ꢀ ethyl]^þ, 10). Anal. Calcd for

C₄₉H₃₃BN₂: C, 89.09; H, 5.04; N, 4.24. Found: C, 88.72; H, 4.75; N, 4.07%.

Preparation of Compound 17. To a solution of 4-iodobenzoyl-

chloride (3.50 g, 13.13 mmol) in anhydrous dichloromethane (100 mL)

was added dropwise 2-amino-2-methylpropanol (2.22 g, 24.96 mmol).

The solvent was removed by rotary evaporation to afford an amide.

Thionyl chloride (15 mL, 0.20 mol) was then slowly added, and the

resulting solution was stirred for 30 min at 25 °C. The thionyl chloride

was removed in vacuo, and water (250 mL) was added. The solution was

made basic with 25% NaOH and extracted with ether. The organic extracts

were washed with water and then brine and dried over magnesium sulfate.

The solvent was removed by rotary evaporation. The residue was purified by

chromatography on alumina, eluting with dichloromethaneꢀcyclohexane

(v/v 10/90) to give 3.51 g (88%) of 17 as a white solid: mp 59ꢀ60 °C.

¹H NMR (200 MHz, CDCl₃): δ 7.60 (AB, 4H, ^ABJ = 8.3 Hz, νδ_AB= 16.9

Hz), 4.00 (s, 2H), 1.28 (s, 6H). ¹³C NMR (50 MHz, CDCl₃): δ 161.1,

137.2, 129.6, 127.3, 97.9, 79.0, 67.5, 28.2. ES-MS m/z (nature of the

peak, relative intensity) 302.1 ([M þ H]^þ, 100). Anal. Calcd for C₁₁H₁₂INO:

C, 43.87; H, 4.02; N, 4.65. Found: C, 43.60; H, 3.74; N, 4.43%.

Preparation of Compound 18. To a solution of 17 (1.50 g,

4.95 mmol) in THF (10 mL) and diisopropylamine (4 mL) were added

CuI (59 mg, 0.30 mmol) and PdCl₂(PPh₃)₂(208 mg, 0.30 mmol). The

solution was argon-degassed for 30 min, and then ethynyltrimethylsilane

(736 mg, 7.42 mmol) was added. The solution was stirred for 6 h. The

solvent was removed by rotary evaporation. The residue was treated with

water and extracted with dichloromethane. The organic extracts were

washed with water and then brine and dried over magnesium sulfate. The

solvent was removed by rotary evaporation. The residue was purified by

chromatography on alumina, eluting with dichloromethaneꢀcyclohexane

(v/v 10/90) to give 1.33 g (98%) of 18 as a white solid: mp 92ꢀ93 °C.

¹H NMR (200 MHz, CDCl₃): δ 7.63 (AB, 4H, ^ABJ = 8.5 Hz, νδ_AB= 75.2

Hz), 4.03 (s, 2H), 1.32 (s, 6H), 0.21 (s, 9H). ¹³C NMR (50 MHz,

CDCl₃): δ 161.4, 131.7, 127.9, 127.8, 125.8, 104.4, 96.5, 79.0, 67.6, 28

.3, ꢀ0.2. ES-MS m/z (nature of the peak, relative intensity) 272.2 ([M þ

H]^þ, 100). Anal. Calcd for C₁₆H₂₁NOSi: C, 70.80; H, 7.80; N, 5.16.

Found: C, 70.69; H, 7.70; N, 5.04%.

Compound 20a. Prepared following experimental conditions 3;

from 19 (90 mg, 0.45 mmol), THF (6 mL), 4-ethynylpyrene (102 mg,

0.45 mmol), THF (6 mL), ethylmagnesium bromide (0.42 mL, 0.42 mmol,

1 M in THF), and 6a (200 mg, 0.35 mmol) in anhydrous THF (15 mL);

chromatography on silica gel, eluting with dichloromethaneꢀcyclohexane

(v/v 85/15) to dichloromethaneꢀcyclohexane (v/v 80/20) to give 146 mg

1

(43%) of 20a as a green solid: 162 °C (dec). H NMR (400 MHz,

CDCl₃ꢀCCl₄(v/v 50/50)): 8.36 (d, 2H, ⁴J = 3.8 Hz), 8.23 (d, 1H, ³J =

9.0 Hz), 8.08 (d, 2H, ³J = 7.5 Hz), 7.98ꢀ7.90 (m, 5H), 7.77 (t, 3H, ³J =

7.5 Hz), 7.71 (d, 2H, ³J = 8.0 Hz), 7.66 (s, 1H), 7.36 (s, 2H), 7.10ꢀ7.04

(m, 4H), 6.94 (d, 2H, ³J = 3.5 Hz), 4.05 (s, 2H), 3.89 (s, 6H), 2.87 (q,

4H, ³J=7.4Hz),1.36(s, 6H),1.27(t,6H,³J=7.4Hz).¹³CNMR(100MHz,

CDCl₃ꢀCCl₄(v/v 50/50)): 161.8, 158.2, 151.0, 143.1, 133.4, 132.4,

131.9, 131.5, 131.4, 131.3, 130.5, 129.9, 128.7, 128.4, 127.7, 127.5, 127.4,

127.3, 126.7, 126.3, 125.9, 125.02, 127.97, 124.6, 124.5, 124.1, 120.3,

120.2, 119.8, 112.7, 102.9, 98.7, 97.8, 79.1, 67.7, 55.5, 28.6, 23.7, 15.8.

¹¹B NMR (128 MHz, CDCl₃ꢀCCl₄(v/v 50/50)): ꢀ7.64 (s). UVꢀvis

(CH₂Cl₂): λ nm (ε, M^ꢀ1cm^ꢀ1) 351 (65000), 371 (79000), 650 (20000),

710 (79000). ES-MS m/z (nature of the peak, relative intensity) 958.1

([Mþ H]^þ, 100), 732.2 ([M ꢀ 19]^þ, 20). Anal. Calcd for C₆₂H₄₈BN₃O₃S₂:

C, 77.73; H, 5.05; N, 4.39. Found: C, 77.54; H, 4.73; N, 4.18%.

Compound 20b. Prepared following experimental conditions 3; from

19 (92 mg, 0.46 mmol), THF (3 mL), 1-ethynylpyrene (104 mg, 0.46

mmol), THF (3 mL), ethylmagnesium bromide (0.42 mL, 0.42 mmol, 1

M in THF), and 6b (200 mg, 0.35 mmol) in anhydrous THF (10 mL);

chromatography on silica gel, eluting with petroleum etherꢀdichloro-

methane (v/v 50/50) to give 185 mg (56%) of 20b as blue crystals. ¹H

3

NMR (CDCl₃/CCl₄50/50, 300 MHz): 8.34 (d, 1H, J = 9.0 Hz),

8.20ꢀ8.00 (m, 6H), 7.99ꢀ7.94 (m, 5H), 7.85ꢀ7.74 (m, 6H), 7.06

(dd, 2H, ³J = 8.8 Hz, ⁴J = 2.2 Hz), 6.97ꢀ6.1 (d, 8H), 4.09 (s, 2H), 3.79

(s, 6H), 3.62 (s, 6H), 1.39 (s, 6H). ¹³C NMRþ DEPT (CDCl₃/

CCl₄50/50, 75 MHz): 161.9, 160.1, 157.7, 150.1, 132.5, 131.95, 131.9,

131.3, 131.2, 131.1, 130.4, 129.4, 128.8, 128.1, 127.6, 127.5, 127.45,

127.2, 126.5, 126.4, 126.2, 126.0, 125.1, 125.05, 125.0, 124.4, 124.2, 120.3

(CH), 119.9, 119.8, 114.4, 113.5, 102.0, 98.9, 97.1, 79.1, 55.5, 55.2, 28.4.

UVꢀvis (CH₂Cl₂) λ nm (ε, M^ꢀ1cm^ꢀ1) = 667 (93000), 368 (73200),

350 (60500), 286 (99000). ES-MS m/z (nature of the peak, relative

intensity) 950.2 ([M þ H]^þ, 100), 751.2 ([M ꢀ 19]^þ, 15). Anal. Calcd

for C₆₄H₄₈BN₃O₅: C, 80.92; H, 5.09; N, 4.42. Found: C, 80.77; H, 4.81;

N, 4.19%.

Preparation of Compound 19. To a solution of 18 (1.25 g,

4.61 mmol) in THF (20 mL) was added a solution of K₂CO₃(3.19 g,

23.03 mmol) in water (10 mL) and methyl alcohol (3 mL). The mixture

was stirred for 1 h. The solvent was removed by rotary evaporation. The

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Compound 20c. Prepared following experimental conditions 3; from

19 (175 mg, 0.88 mmol), THF (6 mL), 4-ethynylpyrene (199 mg, 0.88

mmol), THF (6 mL), ethylmagnesium bromide, (0.81 mL, 0.81 mmol, 1

M in THF), and 6c (300 mg, 0.675 mmol) in anhydrous THF (15 mL);

chromatography on silica gel, eluting with dichloromethaneꢀcyclohexane

(gradient v/v 85/15 to 100/00) to give 50 mg (9%) of 20c as a blue

powder. H NMR (400 MHz, CDCl₃): 8.28 (d, 4H, J = 9.0 Hz),

8.22ꢀ8.12 (m, 4H), 8.07 (s, 1H), 8.02ꢀ7.92 (m, 7H), 7.81 (d, 2H, ³J =

7.9 Hz), 7.69ꢀ7.60 (m, 4H), 7.52ꢀ7.47 (m, 2H), 7.42ꢀ7.37 (m, 4H),

7.32ꢀ7.23 (m, 5H), 6.75 (d, 2H, ³J = 8.7 Hz), 4.07 (s, 2H), 1.36 (s, 6H).

¹³C NMR (100 MHz, CDCl₃): 151.9, 134.3, 132.7, 132.4, 131.8, 131.6,

131.5, 131.4, 130.9, 129.9, 129.4, 129.2, 128.8, 128.2, 128.0, 127.9, 127.7,

127.6, 126.7, 126.6, 126.3, 125.5, 125.4, 125.2, 124.8, 124.7, 124.5, 123.6,

120.0, 118.8, 116.2, 104.0, 91.6, 79.5, 28.8. ¹¹B NMR (128 MHz,

CDCl₃): ꢀ7.16 (s). UVꢀvis (CH₂Cl₂): λ nm (ε, M^ꢀ1cm^ꢀ1) 287

(79900), 350 (48300), 368 (52600), 634 (82900). ES-MS m/z (nature

of the peak, relative intensity) 830.2 ([M þ H]^þ, 100), 631.2 ([M ꢀ

18]^þ, 35). Anal. Calcd for C₆₀H₄₀BN₃O: C, 86.85; H, 4.86; N, 5.06.

Found: C, 86.58; H, 4.72; N, 4.80%.

General Procedure Following Experimental Conditions 4

for the Hydrolysis of the Oxazoline Leading to Compounds

21aꢀc. To a solution of the dissymmetric bodipy (20aꢀc) in THF was

added H₂SO_4.The mixture was stirred at 75 °C for 1 h and neutralized at

25 °C with a satured solution of NaHCO₃. The solvent was removed by

rotary evaporation. The residue was treated with water and extracted with

dichloromethane. The organic extracts were washed with water and dried

over absorbent cotton. The solvent was removed by rotary evaporation to

give the corresponding amino ester. THF (40 mL) and a satured solution of

sodium methoxide in methyl alcohol (6 mL) were then added, and the

solution was stirred at 25 °C for 10 min. The mixture was neutralized with a

solution of H₂SO₄3 M, and the solvent was removed by rotary evaporation.

The residue was treated with water and extracted with dichloromethane.

The organic extracts were washed with water and dried over absorbent

cotton. The residue was purified by chromatography on silica gel.

52.4. UVꢀvis (CH₂Cl₂) λ nm (ε, M^ꢀ1cm^ꢀ1) = 669 (70000), 616 (sh,

21000), 368 (55000), 350 (45000). ES-MS m/z (nature of the peak, re-

lative intensity) 911.2 ([M þ H]^þ, 100), 751.2 ([M ꢀ ethynylpyrene]^þ,

25). Anal. Calcd for C₆₁H₄₃BN₂O₆: C, 80.44; H, 4.76; N, 3.08. Found:

C, 80.22; H, 4.49; N, 2.68%.

Compound 21c. Prepared following experimental conditions 4; from

20c (50 mg, 0.06 mmol), THF (20 mL), H₂SO₄(2.5 mL, 3 M in water);

chromatography on silica gel, eluting with dichloromethaneꢀcyclohexane

(v/v 50/50) to dichloromethane to give 41 mg (86%) of 21c as a blue

solid. ¹H NMR (400 MHz, CDCl₃ꢀCCl₄(v/v 50/50)): 8.27 (d, 1H, ³

J = 9 Hz), 8.21(d, 4H, ³J = 7.5 Hz), 8.15ꢀ8.13 (m, 2H), 8.07 (s, 1H),

1

4

3

8.03ꢀ7.93 (m, 6H), 7.82ꢀ7.76 (m, 3H), 8.52 (d, 2H, J = 7.6 Hz),

7.52ꢀ7.48 (m, 2H), 7.39ꢀ7.43 (m, 4H), 7.33ꢀ7.25 (m, 5H), 6.78 (d,

2H, ³J = 8.5 Hz), 3.88 (s, 3H). ¹³C NMR (100 MHz, CDCl₃ꢀCCl₄(v/v

50/50)): 167.2, 151.9, 134.3, 132.7, 132.3, 131.8, 131.6, 131.5, 131.3,

130.9, 130.0, 129.9, 129.4, 129.1, 128.8, 128.6, 128.2, 128.0, 127.9, 127.6,

126.6, 126.3, 125.5, 125.4, 125.2, 124.8, 124.7, 124.5, 123.6, 119.9, 118.8,

116.2, 99.4, 97.6, 91.3, 86.6, 52.4. ¹¹B NMR (128 MHz, CDCl₃ꢀCCl₄

(v/v 50/50)): ꢀ7.01 (s). UVꢀvis (CH₂Cl₂): λ nm (ε, M^ꢀ1cm^ꢀ1) 286

(79900), 350 (50000), 368 (55100), 634 (92300). ES-MS m/z (nature

of the peak, relative intensity) 791.2 ([M þ H]^þ, 100), 631.2 ([M ꢀ

ethynylpyrene]^þ, 25). Anal. Calcd for C₅₇H₃₅BN₂O₂: C, 86.58; H, 4.46;

N, 3.54. Found: C, 86.39; H, 4.18; N, 3.11%.

Preparation of Compound 22a. Step 1: to a solution of 21a

(39 mg, 0.04 mmol) in THF (15 mL) was added a solution of sodium

hydroxide (4 mg, 0.08 mmol) in H₂O (3 mL) and MeOH (10 mL). The

mixture was stirred at 25 °C for one night and neutralized with a satured

solution of NH₄Cl. The solvent was removed by rotary evaporation. The

residue was treated with water and extracted with dichloromethane. The

organic extracts were washed with water and dried over absorbent cotton.

The solvent was removed by rotary evaporation to give the correspond-

ing carboxylic acid. Anhydrous CH₂Cl₂(10 mL), DMAP (10 mg, 0.08

mmol), EDCI (15 mg, 0.08 mmol), and N-hydroxysuccinimide (9 mg,

0.08 mmol) were then added, and the solution was stirred for 1 h. The

solvent was removed by rotary evaporation. The residue was treated with

water and extracted with dichloromethane. The organic extracts were

washed with water and dried over absorbent cotton. The residue was

purified by chromatography on silica gel, eluting with dichloromethaneꢀ

cyclohexane (v/v 80/20) to dichloromethane to give 29 mg (67%) of the

Compound 21a. Prepared following experimental conditions 4; from

20a (145 mg, 0.15 mmol), THF (40 mL), H₂SO₄(5 mL, 3 M in water);

chromatography on silica gel, eluting with dichloromethaneꢀcyclohexane

(v/v 50/50) to dichloromethane to give 112 mg (80%) of 21a as a green

solid: 132 °C (dec). ¹H NMR (400 MHz, CDCl₃ꢀCCl₄(v/v 50/50)):

NHS derivative as a green solid. UVꢀvis (CH₂Cl₂): λ nm (ε, M^ꢀ1cm^ꢀ1

)

4

3

8.39 (d, 2H, J = 3.8 Hz), 8.30 (d, 1H, J = 9.1 Hz), 8.06 (m, 2H),

7.96ꢀ7.88 (m, 5H), 7.81 (d, 1H, ⁴J = 3.9 Hz), 7.66 (d, 2H, ³J = 8.7 Hz),

7.62 (s, 1H), 7.50 (AB_sys, 4H, ^ABJ = 8.5 Hz, νδ_AB= 269.7 Hz), 7.28 (d,

2H, ⁴J = 2.5 Hz), 6.97 (d, 2H, ³J = 3.8 Hz), 6.93 (dd, 2H, ³J = 4.3 Hz, ⁴J =

1.0 Hz), 3.88 (s, 3H), 3.87 (s, 6H), 2.90 (q, 4H, ³J = 7.4 Hz), 1.29 (t, 6H,

³J = 7.4 Hz). ¹³C NMR (100 MHz, CDCl₃ꢀCCl₄(v/v 50/50)): 166.3,

158.2, 150.9, 142.9, 133.3, 132.3, 132.0, 131.5, 131.4, 131.3, 130.6, 130.5,

130.3, 129.8, 129.1, 128.6, 128.4, 127.59, 127.55, 127.51, 127.3, 126.6,

125.9, 125.0, 124.7, 124.6, 124.2, 120.3, 120.2, 119.8, 112.9, 102.6,

98.5, 98.0, 55.3, 51.9, 23.7, 15.8. ¹¹B NMR (128 MHz, CDCl₃ꢀCCl₄

(v/v 50/50)): ꢀ7.00 (s). UVꢀvis (CH₂Cl₂): λ nm (ε, M^ꢀ1cm^ꢀ1) 351

(655000), 371 (79000), 650 (sh, 21000), 717 (83000). ES-MS m/z

(nature of the peak, relative intensity) 919.2 ([M þ H]^þ, 100), 694.2

([M ꢀ ethynylpyrene]^þ, 25). Anal. Calcd for C₅₉H₄₃BN₂O₄S₂: C,

77.12; H, 4.72; N, 3.05. Found: C, 77.02; H, 4.69; N, 2.84%.

351 (64000), 371 (79000), 650 (sh, 21000), 718 (82000).

Step 2: a solution of the NHS derivative (20 mg, 0.02 mmol) in

n-propylamine (4 mL) was stirred at 25 °C for 5 min. The solvent was

removed by rotary evaporation. The residue was treated with water and

extracted with dichloromethane. The organic extracts were washed with

water and dried over absorbent cotton. The residue was puriﬁed by chro-

matography on silica gel, eluting with dichloromethane to give 15 mg

1

(81%) of 22a as a green solid: 148 °C (dec). H NMR (400 MHz,

CDCl₃ꢀCCl₄(v/v 50/50)): 8.35 (d, 2H, ⁴J = 3.96 Hz), 8.19 (d, 1H, ³J =

8.8 Hz), 8.08 (d, 2H, ³J = 7.9 Hz), 7.99ꢀ7.89 (m, 6H), 7.81 (d, 2H, ³J =

8.8 Hz), 7.75 (d, 1H, ³J = 8.0 Hz), 7.68 (s, 1H), 7.53 (d, 2H, 8.9), 7.39

(d, 2H, ⁴J = 2.2 Hz), 7.13ꢀ7.09 (m, 4H), 6.93 (d, 2H, ³J = 3.56 Hz), 3.91

(s, 6H), 3.38 (q, 2H, ³J = 7.5 Hz), 2.85 (q, 4H, ³J = 7.4 Hz), 1.62 (m, 2H,

³J = 7.5 Hz), 1.24 (t, 6H, ³J = 7.4 Hz), 0.99 (t, 3H, ³J = 7.5 Hz). ¹¹B NMR

(128 MHz, CDCl₃ꢀCCl₄(v/v 50/50)): ꢀ7.38 (s). ES-MS m/z (nature

of the peak, relative intensity) 946.2 ([M þ H]^þ, 100), 720.2 ([M ꢀ

ethynylpyrene]^þ, 25). Anal. Calcd for C₆₁H₄₈BN₃O₃S₂: C, 77.45; H,

5.11; N, 4.44. Found: C, 77.23; H, 4.92; N, 4.21%.

Compound 21b. Prepared following experimental conditions 4; from

20b (105 mg, 0.11 mmol), THF (40 mL), H₂SO₄(5 mL, 3 M in water);

chromatography on silica gel eluting with dichloromethane/cyclohexane

1

(v/v 50/50) to give 67 mg (67%) of 21b as a blue solid. H NMR

(CDCl₃/CCl₄50/50, 400 MHz): 8.28 (d, 1H, ³J = 9.0 Hz), 8.14ꢀ8.00

(m, 6H), 7.99ꢀ7.95 (m, 5H), 7.82ꢀ7.79 (m, 6H), 7.14 (d, 2H, ³J = 9.0

’ ASSOCIATED CONTENT

Hz), 6.93ꢀ6.90 (m, 8H), 3.89 (s, 3H), 3.81 (s, 6H), 3.59 (s, 6H). ¹³

C

S

Supporting Information. General methods, details of the

NMR (100 MHz, CDCl₃ꢀCCl₄(v/v 50:50)): 167.2, 164.1, 153.4,

145.4, 132.3, 131.7, 131.6, 131.5, 130.8, 130.3, 129.8, 129.2, 128.5, 127.9,

127.6, 126.4, 125.5, 125.4, 124.8, 124.7, 124.5, 120.3, 102.6, 97.4, 55.5,

b

X-ray crystal structure determination for compounds 6c, 8, 11,

and 13ꢀ16, as well as crystal packing, absorption, emission and

4503

dx.doi.org/10.1021/jo200246q |J. Org. Chem. 2011, 76, 4489–4505

The Journal of Organic Chemistry

ARTICLE

excitation spectra for all compounds, analytical data, and NMR

plots for all compounds are provided in this section. This material

is available free of charge via the Internet at http://pubs.acs.org.

(12) (a) Gorma, A.; Killoran, J.; O’Shea, C.; Kenna, T.; Gallagher,

W. M.; O’Shea, D. F. J. Am. Chem. Soc. 2004, 126, 10619–10631. (b) Hall,

M. J.; McDonnell, S. O.; Killoran, J.; O’Shea, D. F. J. Org. Chem. 2005,

70, 5571–5578. Zhao, W.; Carreira, E. M. Chem.—Eur. J. 2006, 12,

7254–7263.

(13) (a) Burghart, A.; Kim, H.; Welch, M. B.; Thorensen, L. H.;

Reibenspies, J.; Burgess, K. J. Org. Chem. 1999, 64, 7813–7819. (b) Yamad,

K.; Toyota, T.; Takakura, K.; Ishimura, M.; Sugawara, T. New. J. Chem.

2001, 25, 667–669.

’ AUTHOR INFORMATION

Corresponding Author

*E-mail: gulrich@unistra.fr; ziessel@unistra.fr.

(14) Yakubovskyi, V. P.; Shandura, M. P; Kovtun, Y. P. Eur. J. Org.

Chem. 2009, 3237–3243.

(15) (a) Zheng, Q.; Xu, G.; Prasad, P. N. Chem.—Eur. J. 2008, 14,

5812–5819. (b) Didier, P.; Ulrich, G.; Mꢀely, Y.; Ziessel, R. Org. Biomol.

Chem. 2009, 7, 3639–3642.

(16) (a) Ju, J.; Ruan, C.; Fuller, C. W.; Glazer, A. N.; Mathies, R. A.

Proc. Natl. Acad. Sci. U.S.A. 1995, 92, 4347–4351. (b) Glazer, A. N.;

Mathies, R. A. Curr. Opin. Biotechnol. 1997, 8, 94–102. (c) Burghart, A.;

Thoresen, L. H.; Chen, J.; Burgess, K.; Bergstr€om, F.; Johansson, L. B.-A.

Chem. Commun. 2000, 2203–2204.

(17) Ziessel, R.; Harriman, A. Chem. Commun. 2011, 47, 611–631.

(18) Wan, C.-W.; Burghart, A.; Chen, J.; Bergstr€om, F.; Johansson,

L. B.-A.; Wolford, M. F.; Kim, T. G.; Topp, M. R.; Hochstrasser, R. M;

Burgess, K. Chem.—Eur. J. 2003, 9, 4430–4431. Ziessel, R.; Goze, C.;

Ulrich, G.; Cꢀesario, M.; Retailleau, P.; Harriman, A.; Rostron, J. P. Chem.

—Eur. J. 2005, 11, 7366–7378.

(19) (a) Ulrich, G.; Goze, C.; Guardigli, M.; Roda, A.; Ziessel, R. Angew.

Chem., Int. Ed. 2005, 44, 3694–398. Angew. Chem. 2005, 117, 3760–3764.

(b) Goze, C.; Ulrich, G.; Ziessel, R. J. Org. Chem. 2007, 72, 313–322.

(c) Goze, C.; Ulrich, G.; Ziessel, R. Org. Lett. 2006, 8, 4445–4448. (d)

Harriman, A.; Izzet, G.; Ziessel, R. J. Am. Chem. Soc. 2006, 128, 10868–10875.

(20) Wu, L.; Loudet, A.; Barhoumi, R.; Burghardt, R. C.; Burgess, K.

J. Am. Chem. Soc. 2009, 131, 9156–9157.

’ ACKNOWLEDGMENT

The authors thank the CNRS and UdS for partial funding.

ANR is thankful for ﬁnancial support. We also acknowledge the

CNRS providing research facilities and ﬁnancial support and Pro-

fessor Jack Harrowﬁeld (ISIS, Strasbourg) for commenting on

the manuscript before publication.

’ REFERENCES

(1) (a)Weissleder, R. Nat. Biotechnol. 2001, 19, 316–317. (b) Weissleder,

R.; Ntziachristos, V. Nature Med. 2003, 9, 123–128.

(2) (a) Weissleder, R.; Tung, C.-H.; Mahmood, U.; Bogdanov, A., Jr.

Nat. Biotechnol. 1999, 17, 375–378. (b) Frangioni, J. V. Curr. Opin.

Chem. Biol. 2003, 74, 626–634. (c) Lavis, L. D.; Raines, R. T. ACS Chem.

Biol. 2008, 3, 142–155.

(3) Gomez-Hens, A.; Aguilar-Caballos, M. P. Trends Anal. Chem.

2004, 23, 127–136.

(4) Haugland, R. P. In Handbook of Molecular Probes and Research

Products; 9th ed.; Molecular Probes, Inc.: Eugene, OR, 2002.

(5) (a) Loudet, A.; Burgess, K. Chem. Rev. 2007, 107, 4891–4932.

(b) Ulrich, G.; Harriman, A.; Ziessel, R. Angew. Chem., Int. Ed. 2008, 47,

1202–1219.

(6) (a) Dost, Z.; Atilgan, S.; Akkaya, E. U. Tetrahedron 2006,

62, 8484–8488. (b) Yu, Y.-H.; Descalzo, A. B.; Shen, Z.; R€ohr, H.;

Liu, Q.; Wang, Y.-W.; Spieles, M.; Li, Y.-Z.; Rurack, K.; You, X.-Z. Chem.

Asian J. 2006, 1ꢀ2, 176–187. (c) Atilgan, S.; Ekmekci, Z.; Lale, A.;

Dogan,Guc,D.;Akkaya,E.U.Chem. Commun. 2006, 4398–4400. (d) Ziessel,

R.; Ulrich, G.; Harriman, A.; Alamiry, M. A. H.; Stewart, B.; Retailleau, P.

Chem.—Eur. J. 2009, 15, 1359–1369.

(21) Jose, J.; Ueno, Y.; Castro, J. C.; Li, L.; Burgess, K. Tetrahedron

Lett. 2009, 50, 6442–6445.

(22) (a) Ulrich, G.; Goeb, S.; De Nicola, A.; Retailleau, P.; Ziessel, R.

Synlett 2007, 1517–1520. (b) Goeb, S; Ziessel, R. Org. Lett. 2007, 9, 737–740.

(23) Goze, C.; Ulrich, G.; Mallon, L. J.; Allen, B. D.; Harriman, A.;

Ziessel, R. J. Am. Chem. Soc. 2006, 128, 10231–10239.

(24) Kang, H. C.; Haugland, R. P. U.S. Patent 5,433,896, Jul.18,

1995. Wu, Y.; Klaubert, D. H.; Kang, H. C.; Zhang, Y.-Z. U.S. Patent

6,005,113, Dec. 21, 1999.

(7) (a) Ziessel, R.; Bura, T.; Olivier, J.-H. Synlett 2010, 2304–2310.

(b) Bura, T.; Retailleau, P.; Ziessel, R. Angew. Chem., Int. Ed. 2010, 49,

6659–6663.

(25) Katritzky, A. R.; Harris, P. A.; Kotali, A. J. Org. Chem. 1991, 56,

5049–5051.

(8) (a) Rohand, T.; Qin, W.; Boens, N.; Dehaen, W. Eur. J. Org.

Chem. 2006, 4658–4663. (b) Li, L.; Han, J.; Nguyen, B.; Burgess, K.

J. Org. Chem. 2008, 73, 1963–1970. (c) Li, L.; Nguyen, B.; Burgess, K.

Biorg. Med. Chem. Lett. 2008, 18, 3112.

(26) Maekawa, E.; Suzuki, Y.; Sugiyama, S. Chem. Ber. 1968, 101,

847–854.

(27) Ulrich, G.; Goze, C.; Goeb, S.; Retailleau, P. New J. Chem. 2006,

30, 982–986.

(9) (a) Rihn, S.; Retailleau, P.; Bugsaliewicz, N.; De Nicola, A.;

Ziessel, R. Tetrahedron Lett. 2009, 50, 7008–7013. (b) Galangau, O.;

Dumas-Verdes, C.; Mꢀeallet-Renault, R.; Clavier, G. Org. Biomol. Chem.

2010, 8, 4546–4553.

(10) (a) Wan, C.-W.; Burghart, A.; Chen, J.; Bergstr€om, F.; Johansson,

L. B.-A.; Wolford, M. F.; Kim, T. G.; Topp, M. R.; Hochstrasser, R. M.;

Burgess, K. Chem.—Eur. J. 2003, 9, 4430–4431. (b) Cakmak, Y.; Akkaya,

E. U. Org. Lett. 2009, 11, 85–88. (c) Bonardi, L.; Ulrich, G.; Ziesssel, R.

Org. Lett. 2008, 10, 2183–2186. (d) Donur, V. R.; Zhu, S.; Green, S.; Liu,

H. Polymer 2010, 51, 5359–5368.

(11) (a) Wada, M.; Ito, S.; Uno, H.; Murashima, T.; Ono, N.; Urano,

T.; Urano, Y. Tetrahedron Lett. 2001, 42, 6711–6713. (b) Shen, Z.; Rohr,

H.; Rurack, K.; Uno, H.; Spieles, M.; Schulz, B.; Reck, G.; Ono, N. Chem.

—Eur. J. 2004, 10, 4853–4871.(c) Kang, H. C.; Haughland, R. P. US

Patent 5433896, 1995. (d) Wu, Y.; Klaubert, D. H.; Kang, H. C.; Zhang,

Y.-Z. US Patent 6005113, 1999. (e) Umezawa, K.; Matsui, A.; Nakamura, Y.;

Citterio, D.; Suzuki, K. Chem.—Eur. J. 2009, 15, 1096–1106. (f) Descalzo,

A. B.; Xu, H.-J.; Xue, Z.-L.; Hoﬀmann, K.; Shen, Z.; Weller, M. G.; You,

X.-Z.; Rurack, K. Org. Lett. 2008, 10, 1581–1584. (g) Umezawa, K.;

Nakamura, Y.; Makino, H.; Citterio, D.; Suzuki, K. J. Am. Chem. Soc.

2008, 130, 1550–1551.

(28) Souliꢀe, J.; Cadiot, P. Bull. Chem. Soc. Fr. 1966, 3846–3849.

(29) Qian, B.; Baek, S. W.; Smith, M. R., III. Polyhedron 1999,

18, 2405–2414.

(30) C- or E-borondipyrromethenes are, respectively, deﬁned as

aryl- or alkyl-substituted at the boron center (C-Bodipy) and ethynyl-

substituted at the boron center (E-Bodipy). Classical BF₂derivatives are

F-Bodipys⁰.

(31) Hiraoka, S.; Goda, M.; Shionoya, M. J. Am. Chem. Soc. 2009,

131, 4592–4593.

(32) Allen, F. H. Acta Crystallogr. 2002, B58, 380–388.

(33) Shen, Z.; Rohr, H.; Rurack, K.; Uno, H.; Spieles, M.; Schulz, B.;

Reck, G.; Ono, N. Chem.—Eur. J. 2004, 10, 4853–4871.

(34) Ulrich, G; Ziessel, R. J. Org. Chem. 2004, 69, 2070–2083.

(35) Poronik, Y. M.; Ykubovskyi, V. P.; Shandura, M. P.; Vlasenko,

Y. G.; Chernega, A. N.; Kovtun, Y. P. Eur. J. Org. Chem. 2010, 2746–2752.

(36) Karolin, J.; Johansson, L. B.-A.; Strandberg, L.; Ny, T. J. Am.

Chem. Soc. 1994, 116, 7801–7806.

(37) Harriman, A. H.; Mallon, L. J.; Goeb, S.; Ulrich, G.; Ziessel, R.

Chem.—Eur. J. 2009, 15, 4553–4564.

(38) Hissler, M.; Harriman, A.; Khatyr, A.; Ziessel, R. Chem.—Eur.

J. 1999, 5, 3366–3378.

4504

dx.doi.org/10.1021/jo200246q |J. Org. Chem. 2011, 76, 4489–4505

The Journal of Organic Chemistry

ARTICLE

(39) (a) Seneclauze, J. B.; Retailleau, P.; Ziessel, R. New J. Chem.

2007, 31, 1412–1421. (b) Bura, T.; Ziessel, R. Tetrahedron Lett. 2010,

51, 2875–2879.

(40) Harriman, A. H.; Izzet, G.; Ziessel, R. J. Am. Chem. Soc. 2006,

128, 10868–10875.

(41) Englman, R.; Jortner, J. Mol. Phys. 1970, 18, 145–164.

(42) Olmsted, J., III. J. Phys. Chem. 1979, 83, 2581–2584.

(43) (a) Niu, S. L.; Ulrich, G.; Ziessel, R.; Kiss, A.; Renard, P.-Y.;

Romieu, A. Org. Lett. 2009, 11, 2049–2052. (b) Niu, S.-L.; Ulrich, G.;

Retailleau, P.; Harrowﬁeld, J.; Ziessel, R. Tetrahedron Lett. 2009,

50, 3840–3844.

4505

dx.doi.org/10.1021/jo200246q |J. Org. Chem. 2011, 76, 4489–4505

Article Doi

Chemistry at boron: Synthesis and properties of red to near-IR fluorescent dyes based on boron-substituted diisoindolomethene frameworks

DOI: 10.1021/jo200246q

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