Use of F-BODIPYs as a protection strategy for dipyrrins: Optimization of BF2 removal

Article abstract of DOI:10.1021/jo3002003

We recently reported the first general method for the deprotection of 4,4-difluoro-4-bora-3a,4a-diaza-s-indacenes (F-BODIPYs) involving a microwave-assisted procedure for the removal of the BF₂ moiety, and liberation of the corresponding free-base dipyrrin. Further optimization of the reaction has resulted in a more convenient and accessible protocol. The availability of this new methodology enables BF₂-complexation to be used as a dipyrrin protection strategy. Herein lies a detailed examination of the deprotection reaction, with a view to optimization and gaining mechanistic insight, and its application in facilitating a multistep synthesis of pyrrolyldipyrrins.

Full text of DOI:10.1021/jo3002003

Article
pubs.acs.org/joc
Use of F-BODIPYs as a Protection Strategy for Dipyrrins:
Optimization of BF2 Removal
Deborah A. Smithen, Alexander E. G. Baker, Matthew Offman, Sarah M. Crawford, T. Stanley Cameron,
and Alison Thompson*
Department of Chemistry, Dalhousie University, P.O. Box 15000, Halifax, Nova Scotia, Canada, B3H 4R2
S
* Supporting Information
ABSTRACT: We recently reported the first general method
for the deprotection of 4,4-difluoro-4-bora-3a,4a-diaza-s-indacenes
(F-BODIPYs) involving a microwave-assisted procedure for the
removal of the BF2 moiety, and liberation of the corresponding
free-base dipyrrin. Further optimization of the reaction has resul-
ted in a more convenient and accessible protocol. The availability
of this new methodology enables BF2-complexation to be used as a dipyrrin protection strategy. Herein lies a detailed examination of
the deprotection reaction, with a view to optimization and gaining mechanistic insight, and its application in facilitating a multistep
synthesis of pyrrolyldipyrrins.
under most reaction conditions, and so removal of the BF2 moiety
has been previously unavailable.
INTRODUCTION
■
Dipyrrins (1, Figure 1), consisting of a pyrrole ring and an aza-
First reported in 1968,11 F-BODIPYs are widely used as
labeling dyes in biological systems,12,13 courtesy of intense absorp-
tion and fluorescence spectroscopic properties.9,10,14 Furthermore,
their high quantum yields and tunable structure-based fluorescence
properties facilitate their utility in areas as diverse as electro-
luminescent films,15−17 dye lasers,18−20 fluorescent switches,21 sen-
sitizers for solar cells,22 and electron-transfer reagents.23 Unlike
dipyrrins or their transition metal complexes, F-BODIPYs exhibit
low sensitivity to solvent polarity and pH,9,12 and possess other
desirable chemical properties, such as good solubility plus high
thermal and photochemical stability.24
fulvene moiety linked via an sp2 hybridized carbon center, are a
Figure 1. Skeletal structures of dipyrrins (1) and F-BODIPYs (2).
common motif, particularly for the synthesis of porphyrins and
related structures and, more recently, within coordination
chemistry.1−4 These compounds have a wide range of inter-
esting properties, not least their high molar absorptivities.3−5
While synthesis of dipyrrins is often facile, generally involving
either the acid-catalyzed condensation of a 2-formyl pyrrole
with an α-free (2-unsubstituted) pyrrole,6 or oxidation of a dipyr-
romethane with DDQ,7 the resulting free-bases are frequently
unstable, particularly when lacking substituents in the α-
positions (i.e., 1 and 9-positions, 1, Figure 1) or in the absence of
deactivating groups, and are usually isolated as their crystalline
HBr salts. Surprisingly, there are limited reported examples of the
chemical manipulation of dipyrrins themselves.3,4
To overcome this inherent instability, dipyrrins may be iso-
lated as neutral complexes of the respective dipyrrinato ligands
coordinated to a transition metal center8 or as the corresponding
4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (boron difluoride dipyrri-
nato complex, F-BODIPY,9,10 2, Figure 1). Although these strategies
enable purification and have certain synthetic advantages, lability and
stability, respectively, limit their utility: (i) lability of the dipyrrinato
ligands from transition metals under acidic conditions results in
untimely deprotection; and (ii) the high stability of F-BODIPYs
The conversion of dipyrrins to the corresponding F-BODIPYs is
thus an ideal protecting group strategy, particularly as F-BODIPYs
are typically facile to isolate owing to their distinct fluorescent
properties and stability. However, for the use of boron difluoride
complexes of dipyrrins to be considered as a viable protecting
group strategy, facile removal of the BF2 unit to reveal the parent
dipyrrin is essential. We recently communicated the first general
method for the decomplexation of F-BODIPYs using a microwave-
assisted procedure: deprotection employed 6 equiv of potassium
tert-butoxide in tert-butanol solvent, with heating at 92 °C in a
sealed vessel for 40 min.25 Good to excellent isolated yields were
obtained for a range of substituted dipyrrins, both meso-substituted
and unsubstituted, providing scope for BF2-complexation to be-
come a common protecting group strategy for the synthesis and
manipulation of dipyrrins. We herein report the full scope of this
deprotection, alongside simplified and further optimized reaction
conditions, as well as the first application in the synthesis of pyr-
rolyldipyrrins.
Received: February 1, 2012
Published: February 22, 2012
© 2012 American Chemical Society
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the starting F-BODIPY (3) to reveal the free dipyrrin. Instead,
nucleophilic substitution of the two fluorine atoms at boron
occurred to generate the diisopropoxide-BODIPY 5 in a 51%
yield (Table 2, entry 2). The use of methoxide, also as its
RESULTS AND DISCUSSION
■
Previous results25 were obtained using a CEM Mars-X
microwave digestion oven. We wished to evaluate the protocol
using a standard robot microwave reactor, and we chose
BODIPY 3 as our model substrate given its ease of synthesis
and its full substitution pattern about the pyrrolic periphery.
Furthermore, 3 features a meso-unsubstituted dipyrrin and we
wished to work with this class of BODIPY since useful
deprotection conditions must facilitate the isolation of free-base
meso-unsubstituted dipyrrins, compounds that are rather less
stable than meso-substituted dipyrrins. Using the robot
microwave reactor, deprotection of 3 was successful using the
original conditions and gave the corresponding dipyrrin (4) in
an 85% yield (Scheme 1), comparable to that previously
a
Table 2. Effect of Alkoxide
b
entry
R
product obtained
yield (%)
1
2
3
tBu
iPr
4
85
51
Scheme 1. Assessment of Deprotection Reaction using
Robot Microwave Reactor
5
Me
6 + 7
48 (6) and 52 (7)
a
Reactions carried out in a robot microwave reactor, with 6 equiv of
b
ROK and heating at 92 °C for 40 min. Isolated yield.
potassium salt, was then examined. Again, decomplexation of
the BF2 moiety was unsuccessful: this reaction resulted in two
fluorescent compounds, which were isolated and identified as
the previously reported mono- and dimethoxy substituted
BODIPYs 6 and 7 in yields of 48 and 52%, respectively (Table 2,
entry 3).25 This study revealed that the use of a strong and bulky
alkoxide base were key factors for successful removal of the BF2
moiety from F-BODIPYs. Furthermore B−O bond formation, with
concomitant B−F bond breakage, is preferred where sterically
feasible under the reaction conditions, resulting in the correspond-
reported (90%).25 Note that under these conditions, the
solvent is heated past its boiling point inside the appropriate
pressure-resistant microwave vial for the microwave reactor
being used.
To optimize, and hopefully simplify, the reaction conditions
for use in the robot microwave reactor, we investigated the role
of each component of the reaction mixture.
Variation of Associated Cation. We first examined the
influence of the cation associated with the tert-butoxide nucleo-
phile. This showed a trend, with smaller and more strongly asso-
ciated cations resulting in less effective deprotection and a decrease
in isolated yield of product 4 (Table 1, entries 1−3).
t
ing O-BODIPY. As such, BuOK is the reagent of choice.
Stoichiometry. We then examined the importance of the
t
stoichiometry of BuOK, with a view to gaining insight into the
deprotection mechanism. On the basis of original observa-
tions25 that the use of 3 equiv of BuOK resulted in quantitative
t
recovery of starting material, we suspected there to be a threshold
for the amount of reagent required for effective deprotection. In the
early screens, however, reactions were carried out for only 15 min.25
Results from reactions carried out over 40 min demonstrated
a
Table 1. Effect of Cation
t
a more linear trend between equivalents of BuOK used and the
effectiveness of the deprotection to give the dipyrrin 4 (Table 3).
a
t
Table 3. Variation of BuOK Stoichiometry
b
b
entry
M
product 4 (%)
recovered starting material 3 (%)
1
2
3
K
85
71
21
0
0
Na
Li
68
a
Reactions carried out in a robot microwave reactor, with 6 equiv of
recovered
starting
b
b
tBuOM and heating at 92 °C for 40 min. Isolated yield.
product 4
b
,
c
t
entry
equiv BuOK
(%)
material 3 (%)
We concluded from this series of results that the ability of the
alkoxide to dissociate from its counterion is a key factor for
successful deprotection reactions, and so potassium remained
our cation of choice.
1
2
3
8
6
5
4
3
2
1
74 (71)
85 (74)
55 (57)
26 (31)
21
0
0
d
0
e
4
0
e
Variation of Alkoxide. This study focused on the roles of
steric effects and the nucleophilic nature of the reagent. To this
end, isopropoxide and methoxide, alongside tert-butoxide, were
selected for study.
5
6
e
6
e
trace
33
70
7
0
a
Reactions carried out in a robot microwave reactor, with heating at
92 °C for 40 min. Isolated yield. Repeat reaction in parentheses.
Repeat reaction carried out at 105 °C. Intermediate 8 observed.
t
b
c
In contrast to the success observed when using BuOK, the
d
e
use of isopropoxide as the base resulted in no deprotection of
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We observed a gradual increase in isolated yield of the dipyrrin (4)
and a concurrent decrease in the amount of starting material (3)
t
recovered as the number of equivalents of BuOK was increased
t
(entries 2−7). Addition of 8 equiv of BuOK (entry 1) did not
serve to provide dipyrrin 4 in a greater yield than the use of
6 equiv of tBuOK, neither did increasing the temperature to 105 °C
(entry 2, repeat).
During the course of our studies regarding the stoichiometry
of reactants (Table 3), several milligrams of an unknown
fluorescent compound were isolated from reactions involving
1−4 equiv of BuOK (entries 4−7). Following analysis, this
compound was identified as the mono-tert-butoxide BODIPY
(8, Figure 2) in a yield of <4% in each case. Isolation of this
Figure 3. Isolated dihydroxy BODIPY 11, with X-ray crystal structure.
t
their propensity to decompose to yield boric acid under
aqueous/acidic conditions.27,29 However, we obtained a crystal
structure of this unexpected byproduct, which confirmed the
presence of two boron-hydroxyl substituents. Solving the
structure also revealed stabilizing solvent bonding interactions
(see Supporting Information). To the best of our knowledge,
this is the first X-ray-confirmed structure of a dihydroxy-
O-BODIPY.
Returning to the deprotection of 9, we decided to re-examine
the reaction conditions. In the original trials, the reactions were
carried out at 600 W.25 However, the power of the robot
microwave model only reached 300 W during the reaction. It
was suspected that while this lower power is sufficient for the
meso-H BODIPY 3, additional energy may be required for the
efficient deprotection of the meso-phenyl BODIPY 9. The
reaction was therefore repeated at 140 °C (Table 4, entry 2). As
hoped, this resulted in a more effective deprotection and a
higher yield of dipyrrin 10.
Effect of Water. We then investigated the water content of
the solvent. Results from this series of reactions, using a new
bottle of HPLC grade solvent so as to be sure of the analytical
constitution, showed a correlation between the amount of
water present and the amount of product isolated (Table 5): a
Figure 2. Isolated intermediate.
intermediate was significant as it indicated the role of tert-
butoxide as a bulky nucleophile able to form B−O bonds. This
finding provides key mechanistic insight into the deprotection
reaction, and supports a step-wise substitution process whereby
the accommodation of two tert-butoxy substituents is unviable
for maintaining N−B−N chelation (unlike for OMe and OiPr
derivatives), and so deprotection thus ensues.
In the original study, the BF2-deprotection reaction was
optimized for the meso-phenyl substituted BODIPY 9.25 A trial
deprotection of this complex using the robot microwave reactor
resulted in complete consumption of the starting material (9),
according to analysis using TLC, but only 9% isolated yield of
free dipyrrin 10 was obtained (Table 4, entry 1). This did not
Table 5. Investigation of the Effect of Water on the
Deprotection of 9
a
a
Table 4. Re-examination of Deprotection of 9
b
b
entry
solvent grade
equiv water added
10 (%)
entry
equiv base
temp. (°C)
10 (%)
c,d
1
2
3
HPLC
HPLC
HPLC
HPLC
0
20
62
71
71
59
1
2
6
6
92
9
e
140
82
a
50
Reactions carried out in a robot microwave reactor, with heating for
40 min. Isolated yield. 15 mL of solvent. Byproduct 11 isolated in
40% yield. 10 mL of solvent.
c
b
c
d
4
100
e
a
Reactions carried out in a robot microwave reactor, using 10 mL of
solvent, with heating at 140 °C for 40 min. Single isolated yields.
Byproduct observed.
b
match with the previous success (92% of 10 isolated)25 using
the same conditions (time, temperature, and equivalents of
tBuOK) using the Mars-X microwave oven. In addition, a
previously unobserved fluorescent compound was isolated,
analysis of which indicated the dihydroxy BODIPY 11 (Figure 3)
in a 40% isolated yield after aqueous workup between ethyl
acetate and saturated aqueous sodium bicarbonate solution, and
purification via column chromatography over basic alumina,
eluting with 0−5% methanol in ethyl acetate.
c
yield of 71% was obtained following the addition of both 20
and 50 equiv of water, with respect to the stoichiometry of F-
BODIPY 9 (Table 5, entries 2 and 3). Further increasing the
amount of water present resulted in a lower isolated yield
(Table 5, entry 4), along with the observed formation of the
corresponding dihydroxy-BODIPY (<5%), similar to that
previously encountered (11, Table 4, entry 1).
Examination of KOH. With such a large quantity of water
present in the reaction, we believed that potassium hydroxide
could be an equally effective reagent as it would undoubtedly
There are limited reports of the isolation of boron complexes
of this type,26−28 in which the boron atom bears two hydroxyl
substituents, most likely owing to their relative instability and
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be forming in situ in the tert-butanol. A trial reaction was thus
carried out in which 10 equiv of potassium hydroxide were used
instead of the usual potassium tert-butoxide, and without the
addition of water (Table 6, entry 1). This modification resulted
(Table 7, entries 1 and 2). Modification of the conditions to
include the presence of water, in a convenient 100:1 (v/v) ratio
of tBuOH/H2O, and maintaining the higher temperature of 140 °C
resulted in a significantly improved isolated yield (88%) of the
decomplexed product 4 (Table 7, entry 3). Excellent yields
were also attainable after reaction times of 15 and 5 min (Table 7,
entries 4 and 5), suggesting that microwave irradiation during the
first few minutes of the reaction is sufficient to disrupt B−N bond-
ing. Very short reaction times would also prove to be of use with
less stable substrates. Unsurprisingly, conducting the reaction in
water, in the absence of tert-butanol, again resulted in no observed
formation of dipyrrin 4 (Table 7, entry 6), with a 54% recovery of
starting material (3) resulting instead.
Table 6. Examination of KOH as a Base for the Deprotection
a
of 9
We then determined the influence of the cation used in
conjunction with hydroxide. Sodium and lithium hydroxide
were thus employed in separate reactions, the outcome of
which was very similar to that seen previously: slight reduction
in yield going from potassium to sodium counterion (Table 8,
b,c
entry
solvent
equiv. KOH
Temp (°C)
10 (%)
1
2
3
4
5
tBuOH
DMSO
tBuOH
tBuOH
tBuOH
10
10
6
140
140
140
140
92
80 (75)
d,e
0
83
78
43
d
d
3
a
6
Table 8. Effect of Hydroxide Counterion
a
Reactions carried out in a robot microwave reactor in 10 mL of
HPLC grade solvent, with heating for 40 min, unless otherwise stated.
b
c
d
Isolated yield. Repeat reaction in parentheses. Decomposition
e
products observed. Sixteen percent of 9 recovered.
in complete decomplexation, with an 80% isolated yield of the
product (10).
b
b
entry
M+
4 (%)
3 (%)
Recalling the isolation of intermediate 8 in earlier studies, we
believe that tert-butoxide is still the reactive species and is
formed in situ. To test this theory, the reaction was repeated using
DMSO as the solvent (Table 6, entry 2); no signs of deprotection
were observed. The optimum amount of KOH was assessed
and found to be 6 equiv (Table 6, entry 3), comparable to
earlier results stemming from the use of potassium tert-butoxide
(Table 3). The effect of temperature upon the reaction was
probed, whereby higher temperatures were still found to be
essential using the lab robot microwave, which operated at a
lower power rating compared to that obtainable in the original
Mars-X microwave oven.
1
2
3
K
95
83
33
0
0
Na
Li
44
a
Reactions carried out in a robot microwave reactor in 10 mL of
HPLC grade solvent. Isolated yield.
b
entries 1 and 2), then a significant decrease in yield, along with
a considerable amount of recovered starting material, when
using the lithium salt (entry 3). The similarity between these
results (Tables 1 and 8) suggest that the same mechanism is in
operation in both cases.
Now satisfied with our optimized set of reaction conditions,
we applied them to a series of substituted F-BODIPYs to
examine the scope of the reaction (Table 9).
The use of KOH was also assessed in the deprotection of 3,
whereby initial reactions carried out under the same conditions,
at temperatures of both 92 and 140 °C, were disappointing,
resulting in yields of 38 and 59% of dipyrrin 4, respectively
Table 9. Investigations Regarding the Scope of the Newly
Developed Reaction Conditions, As Applied to the
Deprotection of Various F-BODIPYs
a
a
Table 7. Modified BF2-Deprotection of 3 Using KOH
b
entry
starting material
R1
R2
yield (%)
b,c
c
entry
temp (°C)
time (min)
4 (%)
1
2
3
4
5
6
3
9
Et
Et
Et
H
H
88 (97) (4)
d
e
1
92
140
140
140
140
140
40
40
40
15
5
38
Ph
Me
H
94 (10)
d
c,d
2
59
12
13
14
15
89 (97) (16)
e
3
4
5
88 (88)
95
79 (17)
f
Ac
Ph
H
45 (18)
f
97
C(O)C6H13
0 (19)
f
e
,
g
a
6
15
0
Reactions carried out in a robot microwave reactor in 10 mL of
HPLC grade solvent. Isolated yield. Repeat reaction in parentheses was
carried out for 5 min. Product isolated as the vinylic dipyrrole tautomer
(see Experimental Section). Product isolated as the zinc-complex to
avoid handling the free-base dipyrrin, which is a powerful sternutator
(see Experimental Section). Decomposition products observed.
a
b
c
Reactions carried out in a robot microwave reactor in 10 mL of
HPLC grade solvent. Isolated yield. Repeat reaction in parentheses.
Without the addition of water. Decomposition products observed.
One hundred percent water solvent used. Fifty-four percent of 3
b
c
d
d
e
e
f
g
f
recovered.
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A variety of symmetric F-BODIPYs were examined, for
example, those bearing meso-H (3, 13, 15), alkyl (12), and aryl
(9, 14) substituents, and were generally found to undergo clean
deprotection under the optimized conditions using 6 equiv
KOH and the addition of water (100:1, tBuOH/H2O).
Furthermore, we looked at a β-unsubstituted BODIPY (13)
and those bearing ketone substituents (14, 15). Yields for these
reactions were excellent in general, with the exception of the
keto-substituted BODIPYs (14 and 15, Table 9, entries 5 and 6),
to the extent that no product was isolated from the less stable
substrate 15. In these cases, side reactions between the ketone
moiety and hydroxide reagent must be in operation. No starting
material was recovered in either case, and the reactions were
not improved upon reducing the duration of the reaction and/
or temperature.
We wanted to test our improved deprotection protocol on
more challenging substrates, to further address the question of
substrate scope (Table 10). A wide range of F-BODIPYs were
chosen, that were both symmetric (26, 28) and asymmetric
(20, 22, 24, 30, 32, 34), with functionality that included one or
multiple unsubstituted positions (20, 22, 30, 32, 34), long
chain alkyl (22), aromatic (26), or hydroxy (24) substituents
and increased steric crowding around the boron center (28). In
almost all cases, the corresponding dipyrrin was obtained in
excellent yield, demonstrating good functional group tolerance.
Increasing the steric congestion around the boron center (28,
Table 10, entry 5) resulted in a slight decrease in isolated yield
of the product (29) compared to the open chain substrate (3)
under the same reaction conditions (Table 8, entry 3). This was
expected based on previous observations.25
The presence of α-H or β-H substituents in general were well
tolerated, giving rise to acceptable product yields (Table 10,
entries 1, 2, and 7). However, replacing one of the α-methyl
groups of 3 with a proton resulted in a 16% decrease in yield
under the same reaction conditions (Table 10, entry 7), and
further reducing the substitution (30, Table 10, entry 6)
resulted in a mere 26% yield of 31. This trend in isolated yield
was anticipated based on the knowledge that the completely
unsubstituted dipyrrin is unstable above −40 °C,30 and these
lower yields are thus attributed to the relative instability of the
forming dipyrrin.
A more structurally complex substrate examined in this series
of deprotection reactions was F-BODIPY-protected pyrrolyldi-
pyrrin 34 (Table 10, entry 8). Pleasingly, the deprotection
proceeded smoothly, as hoped, giving the corresponding
pyrrolyldipyrrin (35) in a 94% yield, with minimal purification
required.
The deprotections of the mixed F-, O-BODIPY 6 and the O-
BODIPY 7 were explored (Table 10, entries 9 and 10),
whereby the former was found to be a viable substrate, giving
the product (4) in a good yield of 89%. Dimethoxy BODIPY 7,
on the other hand, did not undergo decomplexation, the
reaction instead resulting in only decomposition products.
These results are comparable to those obtained in earlier
studies,25 and demonstrate the mechanistic need for the F-
BODIPY boron center to accept an oxygen based nucleophile,
a
Table 10. Microwave-Assisted Deprotection of Further BODIPY Substrates
a
b
c
Reactions carried out in a robot microwave reactor in 10 mL of HPLC grade solvent for 15 min. Isolated yield. Reaction was carried out for 5
d
min. Decomposition products observed.
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forming a stronger B−O bond. This is not advantageous for O-
BODIPY 7 as it already has two such B−O bonds.
Proposed Deprotection Mechanism. Results to date
have enabled us to propose a mechanism for the deprotection
reaction (Scheme 2). On the basis of the observation that
complex (37a) by reaction with boron trifluoride diethyl
etherate, in the presence of triethylamine (Scheme 3). This
proceeded in a 54% isolated yield of 37a, after a slightly ex-
tended reaction time of 18 h, but without further optimiza-
Scheme 3. Application of BF2 Protection to the Synthesis of
Pyrrolyldipyrrins
a
Scheme 2. Proposed Mechanism for BF2 Removal
a
Reaction conditions: (a) BF3·OEt2, NEt3, CH2Cl2, N2, rt, 18 h; (b) N-
t
Boc pyrrole-2-boronic acid, LiCl, Pd(PPh3)4, 1,2-DME, 2 M aq
Na2CO3, 85 °C, 24 h; (c) KOH, BuOH·H2O (100:1 v/v), MW,
140 °C, 15 min; (d) H2SO4, MeOH, Δ, 3 h.
mixed F-, BuO-BODIPY 8 (Figure 2) was formed as an
t
intermediate during one study (Table 3), we believe that tert-
butoxide is the active reagent, formed in situ from potassium
hydroxide and tert-butanol.
tion of existing methods. This bromo-substituted F-BODIPY
(37a) was then subjected to Suzuki coupling reaction with N-
Boc-pyrrole-2-boronic acid, which completed the synthesis of
the pyrrolyldipyrrin core, but surprisingly left the N-Boc group
intact, as opposed to the in situ deprotection normally observed.33
The enhanced stability of the N-Boc group is attributed to the
electron withdrawing nature of the BF2 moiety. The isolated yield
for this reaction (38a, 36%) was slightly higher than that of the
non-BF2-protected bromo-dipyrrin (30% average yield). The final
step of deprotection worked exceptionally well: decomplexing the
BF2 moiety and removing the N-Boc group under our new
optimized conditions gave 39a in an excellent 97% isolated yield
following purification over neutral alumina.
The success of this synthesis (Scheme 3) demonstrated the
use of a BF2-protecting group strategy for the synthesis of pyr-
rolyldipyrrins as a viable alternative to the traditional synthesis. We
thus turned our attention to a more challenging target to test the
utility of this alternative approach. Bromo-dipyrrin 36b, possessing
an alkyl ester on the future C-ring and alkyl substituents on what
was to become the B-ring, was chosen as a second trial starting
material, which was protected with BF2 under the same reaction
conditions and in comparable yield (53%). F-BODIPY 37b then
underwent Suzuki coupling to give protected pyrrolyldipyrrin 38b,
again in comparable yield and still possessing the N-Boc group.
Deprotection at this stage was further complicated by the presence
of an additional ester group that would undoubtedly be hydrolyzed
to give free carboxylic acid 39b. The reaction mixture was thus con-
centrated and the crude product simply subjected to re-esterification
This reagent is thought to attack the boron center, forming a
strong B−O bond and temporarily disrupting one of the weaker
boron nitrogen bonds.31 This is followed by recomplexation of
boron to nitrogen, with loss of fluoride, giving the observed
BODIPY intermediate 8. Attack of a second equivalent of tert-
butoxide ensues, with the steric bulk of the two bulky pendant
alkoxide groups preventing recomplexation. Loss of fluoride forms
a charge-neutral species that undergoes further nucleophilic attack,
presumably by a smaller hydroxide species to explain the need for
water, resulting in complete dissociation of boron to give the free-
base dipyrrin, which is stabilized by the basic reaction conditions.
With bulky tert-butyl groups being key to the sterically inhibited
reformation of the B−N bond, the isolation of O-BODIPYs when
using the small alkoxides methoxide and isopropoxide as reagents
can be appreciated (Table 2, compounds 6 and 7).
F-BODIPYs as a Protecting Group Strategy. We were
satisfied with the efficacy of our improved deprotection pro-
tocol and wished to evaluate the potential for BF2 complexation
to be used as a protecting group strategy in a multistep synthesis.
The design and synthesis of C-ring modified pyrrolyldipyrrins
is an ongoing area of interest, and this seemed like the perfect
model for study. Our initial target was 39a, chosen for the
purpose of comparison to the traditional synthetic approach.
Starting from 2,4-dimethyl-3-pentyl-1H-pyrrole-5-carboxaldehyde,
the synthesis of 2-pentyl-9-bromodipyrrin 36a followed a pre-
viously reported synthetic pathway.32
At this point, the synthesis deviated from the traditional
route, with conversion of the dipyrrin 36a to the protected BF2
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conditions. This provided us with the corresponding methyl ester
pyrrolyldipyrrin (40b) in an overall 52% isolated yield (from 38b).
Previous attempts within the group to synthesize pyrrolyldi-
pyrrins lacking the B-ring methoxy group have proved
especially challenging, with the final Suzuki coupling reaction
often proceeding in yields of <5%.33 This is also true of certain
bromo- and triflate-dipyrrins that lack a deactivating group
(e.g., carbonyl) directly adjacent to the pyrrole ring. This
work thus represents an important alternative for the synthesis of
pyrrolyldipyrrins with diverse substitution patterns and represents
just one example of the broad scope of BF2 complexation for the
protection and chemical manipulation of dipyrrins.
etherate (9 mmol, 9 equiv) was then added dropwise over 5 min
and the resulting solution was stirred at room temperature, under
nitrogen, for 2 h, before concentrating in vacuo and separating the
residue between diethyl ether (80 mL) and 1 M aqueous HCl (80
mL). The aqueous phase was extracted with diethyl ether (3 × 50
mL) and the organic extracts were combined and washed with
brine, dried over anhydrous magnesium sulfate, filtered through a
short pad of silica, washed with diethyl ether, and concentrated in
vacuo. This gave the corresponding F-BODIPY without the need
for further purification, unless otherwise stated.
4,4-Difluoro-1,3,5,7-tetramethyl-2,6-diethyl-8-H-4-bora-
3a,4a-diaza-s-indacene (3).25
CONCLUSIONS
■
We have developed a microwave-assisted procedure for the
removal of BF2 from F-BODIPYs to reveal the free-base dipyrrin.
Optimization of the protocol resulted in a general procedure for
use in a standard lab robot microwave, with potassium hydroxide
as an improved reagent and a shorter reaction time of 5 min. This
method is effective for a wide range of F-BODIPYs, with studies
also providing insight into the deprotection mechanism. Further
work included the application of this methodology to the synthesis
of both known and novel pyrrolyldipyrrins, whereby it was found
that the use of a BF2 moiety as a protecting group enables the
synthesis of more challenging target compounds.
Compound 3 was synthesized from the corresponding dipyrrin·-
HBr salt34 using GP1 as a shiny reddish-brown solid (3.703 g, 82%
yield). Mp 178−181 °C; 1H NMR (CDCl3, 500 MHz) δ 6.95 (s,
1H), 2.49 (s, 6H), 2.38 (q, 4H, J = 7.7 Hz), 2.16 (s, 6H), 1.06
(t, 6H, J = 7.7 Hz). NMR data matches that previously reported
for this compound.25
4,4-Diisopropoxy-1,3,5,7-tetramethyl-2,6-diethyl-8-H-4-
bora-3a,4a-diaza-s-indacene (5).
EXPERIMENTAL SECTION
■
General Methods. All chemicals and reagents were
purchased from commercial sources and were used as received,
unless otherwise noted. Ethyl acetate, hexanes, dichloromethane,
and tert-butanol were obtained crude and purified via distillation,
under air and at 1 atm pressure, before use. HPLC grade
methanol, chloroform, and tert-butanol were employed in
reactions where stated. Anhydrous dichloromethane was
purchased from EMD Chemicals. Column chromatography was
performed using 230−400 mesh Silicycle Ultra Pure Silica Gel,
150 mesh Brockmann III activated neutral aluminum oxide, or 150
mesh Brockmann III activated basic aluminum oxide, as indicated.
TLC was performed on silica gel or neutral aluminum oxide plates
and visualized using UV light (254 and/or 365 nm) and/or
developed with Vanillin stain. NMR spectra were recorded using a
Potassium isopropoxide (5% solution in isopropyl alcohol,
1.97 mL, 0.99 mmol) was added to a stirred suspension of 3
(50 mg, 0.16 mmol) in freshly distilled isopropoxide (15 mL) in a
20 mL capacity microwave vial. The vial was then sealed and
placed in the microwave reactor, where it was heated at 92 °C for
40 min, at a maximum of 400 W power. After cooling, the reaction
mixture was partitioned between saturated aqueous sodium
bicarbonate solution (50 mL) and diethyl ether (50 mL). The
aqueous phase was extracted with diethyl ether (2 × 50 mL) and
the combined organic extracts were washed with brine (100 mL),
dried over anhydrous magnesium sulfate, and concentrated to give
the crude product, which was purified using column chromatog-
raphy on basic alumina (Brockmann type III), eluting with 15%
ethyl acetate in hexanes, to give the product 5 (32 mg, 51% yield)
as an orange solid. Mp 135−138 °C; 1H NMR (CDCl3, 500 MHz)
δ 6.90 (s, 1H), 3.21 (sep, 2H, J = 6.0 Hz), 2.54 (s, 6H), 2.38 (q,
4H, J = 7.5 Hz), 2.18 (s, 6H), 1.04 (t, 6H, J = 7.5 Hz), 0.80 (d,
12H, J = 6.0 Hz); 13C NMR (CDCl3, 125 MHz) δ 155.6, 134.7,
133.4, 131.6, 118.3, 62.9, 24.9, 17.6, 15.0, 13.7, 9.6; 11B {1H} NMR
(CDCl3, 160 MHz) δ 1.63 (s); LRMS-ESI (m/z): 407.3 [M +
Na]+; HRMS-ESI (m/z): [M + Na]+ calcd for C23H37N2BO2Na
407.2844; found, 407.2840; ε529 nm = 86 000.
1
500 or 250 MHz spectrometers. All H, 11B, and 13C NMR
chemical shifts are expressed in parts per million (ppm) using the
solvent signal [CDCl3 (1H 7.26 ppm; 13C 77.16 ppm); DMSO
(1H 2.50 ppm; 13C 39.52 ppm)] as the internal reference or
BF3·OEt2 (11B 0.00 ppm) as an external reference. Splitting
patterns are indicated as follows: br, broad; s, singlet; d, doublet; t,
triplet; at, apparent triplet; q, quartet; m, multiplet; sep, septet. All
coupling constants (J) are reported in Hertz (Hz). Mass spectra
were recorded using ion trap (ESI TOF) instruments. UV analysis
was carried out using HPLC grade dichloromethane solvent, with
the baseline manually corrected for the solvent, and the
wavelength measured in nanometers (nm). Microwave reactions
were carried out using a robot-type microwave reactor (in our case
a Biotage Initiator 8 Microwave) with 0−400 W power at
2.45 GHz with an integrated internal probe by which to monitor
the temperature of the reaction mixtures.
4-Fluoro-4-methoxy-1,3,5,7-tetramethyl-2,6-diethyl-8-H-
4-bora-3a,4a-diaza-s-indacene (6)25 and 4,4-Dimethoxy-
1,3,5,7-tetramethyl-2,6-diethyl-8-H-4-bora-3a,4a-diaza-s-in-
dacene (7).25
Synthesis of F-BODIPYs. General Procedure for the
Synthesis of F-BODIPYs (GP1). Triethylamine (6 mmol, 6 equiv)
was added dropwise to a solution of dipyrrin HBr salt (1 mmol, 1
equiv) in dry dichloromethane (65 mL) under nitrogen, with
stirring at room temperature for 10 min. Boron trifluoride diethyl
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Potassium methoxide (69 mg, 0.99 mmol) was added to a
stirred suspension of 3 (50 mg, 0.16 mmol) in methanol (15 mL)
in a 20 mL capacity microwave vial. The vial was then sealed and
placed in the microwave reactor, where it was heated at 92 °C for
40 min, at a maximum of 400 W power. After cooling, the reaction
mixture was partitioned between saturated aqueous sodium
bicarbonate solution (50 mL) and diethyl ether (50 mL). The
aqueous phase was extracted with diethyl ether (2 × 50 mL) and
the combined organic extracts were washed with brine (100 mL),
dried over anhydrous magnesium sulfate, and concentrated to give
the crude product, which was purified using column chromatog-
raphy on basic alumina (Brockmann type III), eluting with 10−
30% ethyl acetate in hexanes, to give 6 (25 mg, 48%) as a dark red
were washed with water (100 mL) and brine (100 mL), dried over
anhydrous magnesium sulfate, filtered, and concentrated in vacuo
to give the crude product, which was purified using column chro-
matography on silica, eluting with 15% ethyl acetate in hexanes to
give the desired dipyrromethane (1.39 g, 84%) as a light brown
solid. DDQ (0.87 g, 3.8 mmol) was then added to a solution of
the preceding dipyrromethane (1.28 g, 3.83 mmol) in anhydrous
dichloromethane (80 mL), with stirring under nitrogen for 1 h.
After this time, no starting material remained according to analysis
using TLC, and thus, triethylamine (3.20 mL, 23.0 mmol) and
then boron trifluoride diethyl etherate (4.25 mL, 34.5 mmol) were
added dropwise over 5 min, with continued stirring for 3 h. The
reaction mixture was then diluted with dichloromethane (50 mL)
and washed with 0.1 M NaOH (100 mL), 1 M HCl (100 mL),
and brine (100 mL); dried over anhydrous sodium sulfate; and
concentrated in vacuo to give the crude product, which was
purified using column chromatography on silica, eluting with 20%
ethyl acetate in hexanes, to give 9 (0.689 g, 47%) as a dark red/
1
solid; mp 140−143 °C; H NMR (CDCl3, 500 MHz) δ 6.93
(s, 1H), 2.89 (s, 3H), 2.49 (s, 6H), 2.39 (q, 4H, J = 7.5 Hz),
2.17 (s, 6H), 1.06 (t, 6H, J = 7.5 Hz); and compound 7 (28 mg,
1
52%) as a dark red solid. Mp 143−146 °C; H NMR (CDCl3,
500 MHz) δ 6.91 (s, 1H), 2.85 (s, 6H), 2.47 (s, 6H), 2.39 (q, 4H,
J = 7.5 Hz), 2.17 (s, 6H), 1.07 (t, 6H, J = 7.5 Hz). NMR data
matches that previously reported for these compounds.25
1
green solid. Mp 165−167 °C; H NMR (CDCl3, 500 MHz)
δ 7.49−7.46 (m, 3H), 7.29−7.27 (m, 2H), 2.53 (s, 6H), 2.30
(q, 4H, J = 7.5 Hz), 1.27 (s, 6H), 0.98 (t, 6H, J = 7.5 Hz). NMR
data matches that previously reported for this compound.25
4-Fluoro-4-tbutoxy-1,3,5,7-tetramethyl-2,6-diethyl-8-H-4-
bora-3a,4a-diaza-s-indacene (8).
4,4-Dihydroxy-1,3,5,7-tetramethyl-2,6-diethyl-8-phenyl-4-
bora-3a,4a-diaza-s-indacene (11).
Potassium tert-butoxide (55 mg, 0.49 mmol) was added to a
stirred suspension of 3 (75 mg, 0.25 mmol) in tert-butanol
(15 mL) in a 20 mL capacity microwave vial. The vial was then
sealed and placed in the microwave reactor, where it was heated
at 92 °C for 40 min, at a maximum of 400 W power. After
cooling, the reaction mixture was partitioned between saturated
aqueous sodium bicarbonate solution (50 mL) and diethyl
ether (50 mL). The aqueous phase was extracted with diethyl
ether (2 × 50 mL) and the combined organic extracts were
washed with brine (100 mL), dried over anhydrous magnesium
sulfate, and concentrated to give the crude product, which was
purified immediately using column chromatography on basic
alumina (Brockmann type III), eluting with 10% ethyl acetate
in hexanes, to give the product 8 (2 mg, 2% yield) as a deep
Potassium tert-butoxide (89 mg, 0.79 mmol) was added to a
stirred suspension of 9 (50 mg, 0.13 mmol) in tert-butanol (15 mL)
in a 20 mL capacity microwave vial. The vial was then sealed and
placed in the microwave reactor, where it was heated at 92 °C for
40 min, at a maximum of 400 W power. After cooling, the reaction
mixture was partitioned between saturated aqueous sodium bicar-
bonate solution (50 mL) and diethyl ether (50 mL). The aqueous
phase was then extracted with diethyl ether (50 mL) and ethyl
acetate (50 mL) and the combined organic extracts were washed
with brine (100 mL), dried over anhydrous magnesium sulfate, and
concentrated to give the crude product, which was purified im-
mediately using column chromatography on basic alumina (Brock-
mann type III), eluting with 10% ethyl acetate in hexanes, followed
by 5% methanol in ethyl acetate, to give 11 as a dark red solid
(20 mg, 40% yield). Mp 125−130 °C (mp/dp); 1H NMR (CDCl3,
500 MHz) δ 7.47−7.45 (m, 3H), 7.28−7.26 (m, 2H), 2.63 (s, 6H),
2.29 (q, 4H, J = 7.5 Hz), 1.25 (s, 6H), 0.97 (t, 6H, J = 7.5 Hz); 13C
NMR (CDCl3, 125 MHz) δ 153.8, 140.0, 136.8, 136.6, 132.7, 130.8,
129.0, 128.6, 128.5, 17.3, 14.9, 13.3, 11.7; 11B {1H} NMR (CDCl3,
160 MHz) δ 1.29 (s); LRMS-ESI (m/z) 333.2 [free base dipyrrin
4 + H]+. A crystal suitable for X-ray crystallography was obtained by
recrystallization of a solution of compound 11 in 10% ether in
hexanes by slow evaporation at room temperature. Data for 11:
1
pink film. H NMR (CDCl3, 500 MHz) δ 6.92 (s, 1H), 2.52
(s, 6H), 2.37 (q, 4H, J = 7.5 Hz), 2.16 (s, 6H), 1.03 (t, 6H, J =
7.5 Hz), 0.85 (s, 9H); 11B {1H} NMR (CDCl3, 160 MHz)
δ 0.45 (d, J = 23.8 Hz); 19F NMR (CDCl3, 282 MHz) δ 151.0;
LRMS-ESI (m/z): 381.2 [M + Na]+; HRMS-ESI (m/z): [M +
Na]+ calcd for C21H32N2BOFNa 381.2482; found, 381.2484.
Starting material 3 (25 mg, 33%) was also recovered.
4,4-Difluoro-1,3,5,7-tetramethyl-2,6-diethyl-8-phenyl-4-
bora-3a,4a-diaza-s-indacene (9).25
C
101H138B4N8O8, M = 1635.49, deep orange plate, 0.03 × 0.09 ×
0.14 mm3, triclinic, space group P1, a = 12.86150(10) Å, b =
̅
19.9997(4) Å, c = 20.5839(2) Å, V = 5113.57(12) Å3, Z = 2,
T = 296.1 K, ρ = 1.062 g cm−3, μ(Mo Kα) = 0.066 mm−1, 146
260 reflections (6659 unique, Rint = 0.121), R = 0.0667,
Rw = 0.0715, GOF = 1.065.
2,4-Dimethyl-3-ethylpyrrole (2.0 mL, 14.8 mmol) was added to
a stirred solution of benzaldehyde (0.50 mL, 4.9 mmol) in
0.18 M aqueous HCl (50 mL), with stirring at room temperature for
4 h.35 The precipitate formed during this time was then extracted
into ethyl acetate (3 × 50 mL) and the combined organic extracts
Compound 11 was also synthesized according to the following
procedure. BCl3 (1 M in hexanes, 0.37 mL, 0.37 mmol) was added
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to a solution of 9 (70 mg, 0.18 mmol) in anhydrous
dichloromethane (15 mL), with stirring at room temperature
under nitrogen for 30 min. The reaction mixture was then
partitioned between dichloromethane (50 mL) and saturated
aqueous NaHCO3 (50 mL) and the aqueous phase was extracted
with dichloromethane (2 × 30 mL). The combined organic extracts
were dried over anhydrous sodium sulfate, filtered, and concentrated
in vacuo to give the crude product, which was purified using column
chromatography on basic alumina, eluting with 0−30% acetonitrile in
dichloromethane, to give 11 (27 mg, 39%) as a shiny dark red solid.
4,4-Difluoro-1,3,5,7,8-tetramethyl-2,6-diethyl-4-bora-
3a,4a-diaza-s-indacene (12).25
(CDCl3, 500 MHz) δ 7.55 (at, 3H, J = 3.3 Hz), 7.29−7.26 (m, 2H),
2.79 (s, 6H), 2.42 (s, 6H), 1.57 (s, 6H); 13C NMR (CDCl3, 125
MHz) δ 196.5, 158.0, 146.2, 144.8, 134.4, 130.0, 129.91, 129.86,
127.8, 127.7, 32.1, 15.2, 14.1; 11B {1H} NMR (CDCl3, 160 MHz)
δ 0.67 (t, J = 32.2 Hz); LRMS-ESI (m/z): 431.2 [M + Na]+;
HRMS-ESI (m/z): [M + Na]+ calcd for C23H23N2O2BF2Na
431.1706; found, 431.1713; ε507 nm = 124 000.
4,4-Difluoro-1,3,5,7-tetramethyl-2,6-diheptanoyl-8-H-4-
bora-3a,4a-diaza-s-indacene (15).
Compound 15 was synthesized from the corresponding
dipyrrin using GP1, followed by purification on silica, eluting
with 20% ethyl acetate in hexanes to give the title compound as
a bright orange solid (235 mg, 61% yield). Mp 139−142 °C; 1H
NMR (CDCl3, 500 MHz) δ 7.40 (s, 1H), 2.80 (s, 6H), 2.75
(t, 4H, J = 7.3 Hz), 2.51 (s, 6H), 1.72−1.66 (m, 4H), 1.39−1.29
(m, 12H), 0.89 (t, 6H, J = 6.8 Hz); 13C NMR (CDCl3, 125 MHz)
δ 198.1, 160.5, 142.7, 133.3, 130.3, 123.4, 43.6, 31.9, 29.2, 24.2,
22.7, 15.8, 14.2, 12.7; 11B {1H} NMR (CDCl3, 160 MHz) δ
0.81 (t, J = 32.2 Hz); LRMS-ESI (m/z): 495.3 [M + Na]+;
HRMS-ESI (m/z): [M + Na]+ calcd for C27H39N2O2BF2Na
495.2988; found, 495.2965; ε511 nm = 155 000.
Compound 12 was synthesized from the corresponding
dipyrrin·HCl salt20 using GP1 as a dark red solid (285 mg, 92%
1
yield). Mp 203−205 °C; H NMR (CDCl3, 500 MHz) δ 2.60
(s, 3H), 2.50 (s, 6H), 2.40 (q, 4H, J = 7.5 Hz), 2.33 (s, 6H), 1.04
(t, 6H, J = 7.5 Hz). NMR data matches that previously reported
for this compound.25
4,4-Difluoro-1,3,5,7-tetramethyl-8-H-4-bora-3a,4a-diaza-s-inda-
cene (13).25
4,4-Difluoro-1,3,5,7-tetramethyl-6-ethyl-2,8-H-4-bora-
3a,4a-diaza-s-indacene (20).
Compound 13 was synthesized from the corresponding
dipyrrin·HBr salt36 using GP1 as a dark red solid (208 mg, 94%
yield). Mp 208−210 °C; 1H NMR (CDCl3, 500 MHz) δ 7.04 (s,
1H, meso-H), 6.04 (s, 2H), 2.53 (s, 6H), 2.24 (s, 6H). NMR data
matches that previously reported for this compound.25
4,4-Difluoro-1,3,5,7-tetramethyl-2,6-diacetyl-8-phenyl-4-
bora-3a,4a-diaza-s-indacene (14).
Compound 20 was prepared previously from the dipyrrin·HBr39
salt using GP1 and repurified using column chromatography on
silica, eluting with 5−10% ethyl acetate in hexanes. Mp 118−122 °C;
1H NMR (CDCl3, 500 MHz) δ 6.99 (s, 1H), 6.00 (s, 1H),
2.51 (s, 6H), 2.39 (q, 2H, J = 7.7 Hz), 2.23 (s, 3H), 2.17 (s, 3H),
1.07 (t, 3H, J = 7.7 Hz); 13C NMR (CDCl3, 125 MHz) δ 156.7,
155.4, 140.0, 137.7, 133.3, 133.0, 132.6, 119.4, 118.4, 17.5, 14.7,
14.6, 12.8, 11.3, 9.5; 11B {1H} NMR (CDCl3, 160 MHz) δ 0.81 (t,
J = 32.7 Hz); LRMS-ESI (m/z): 299.1 [M + Na]+; HRMS-ESI
(m/z): [M + Na]+ calcd for C15H19N2BF2Na 299.1502; found,
299.1502; ε519 nm = 95 000.
4,4-Difluoro-1,3,5,7-tetramethyl-6-heptyl-2,8-H-4-bora-
3a,4a-diaza-s-indacene (22).
TFA (5 drops) was added to a solution of 3-acetyl-2,4-dimeth-
ylpyrrole37 (1.50 g, 10.9 mmol) and benzaldehyde (0.56 mL, 5.5
mmol) in dichloromethane (200 mL), with stirring at room
temperature under nitrogen for 24 h.38 A solution of DDQ (1.24 g,
5.47 mmol) in dichloromethane (30 mL) was then added dropwise
over 10 min, with continued stirring for 1 h. After this time, the
reaction mixture was washed with saturated aqueous NaHCO3 (200
mL) and the aqueous phase was extracted with dichloromethane (2
× 150 mL). The combined organic extracts were washed with brine
(100 mL), dried over anhydrous sodium sulfate, and concentrated
to give the crude product, which was purified using column
chromatography on basic alumina (Brockmann type III), eluting
with 20−40% ethyl acetate in hexanes, to give the dipyrrin product
(18, 540 mg, 27% yield) as a bright orange solid. Compound 14
was synthesized from the preceding dipyrrin (18) using GP1,
followed by purification on neutral alumina, eluting with 10−30%
ethyl acetate in hexanes to give the title compound as a bright
Compound 22 was synthesized from the corresponding
dipyrrin·HBr salt using GP1, followed by purification on silica,
eluting with 5−10% ethyl acetate in hexanes to give the title
compound as a dark red solid (321 mg, 69% yield). Mp 68−72 °C;
1H NMR (CDCl3, 500 MHz) δ 6.99 (s, 1H), 6.00 (s, 1H), 2.52
(s, 3H), 2.50 (s, 3H), 2.35 (t, 2H, J = 7.8 Hz), 2.23 (s, 3H),
2.16 (s, 3H) 1.45−1.39 (m, 2H), 1.32−1.26 (m, 8H), 0.89
(t, 3H, J = 7.0 Hz); 13C NMR (CDCl3, 125 MHz) δ 156.9, 155.1,
139.9, 138.1, 133.2, 132.9, 131.3, 119.4, 118.3, 32.0, 30.2, 29.6,
29.3, 24.2, 22.8, 14.7, 14.3, 13.0, 11.4, 9.8; 11B {1H} NMR (CDCl3,
160 MHz) δ 0.81 (t, J = 33.1 Hz); LRMS-ESI (m/z): 369.2
1
orange solid (62 mg, 21% yield). Mp 190−195 °C; H NMR
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1
[M + Na]+; HRMS-ESI (m/z): [M + Na]+ calcd for
C20H29N2BF2Na 369.2272; found, 369.2284; ε520 nm = 81 000.
4,4-Difluoro-1,3,5,7-tetramethyl-2-(2,2,2-trifluoroetha-
nol)-6-ethyl-8-H-4-bora-3a,4a-diaza-s-indacene (24).40
yield). Mp 132−135 °C; H NMR (CDCl3, 500 MHz) δ 7.64
(s, 1H), 7.20 (s, 1H), 6.93 (d, 1H, J = 3.5 Hz), 6.43 (s, 1H), 6.16
(s, 1H), 2.59 (s, 3H), 2.28 (s, 3H). NMR data matches that
previously reported for this compound.41
4,4-Difluoro-1,3,7-trimethyl-2,6-diethyl-5,8-H-4-bora-
3a,4a-diaza-s-indacene (32).
Compound 24 was prepared previously from the dipyrrin·HBr
salt40 using GP1. Mp 177−180 °C; 1H NMR (CDCl3,
500 MHz) δ 7.04 (s, 1H), 5.08−5.03 (m, 1H), 2.55 (s, 3H),
2.53 (s, 3H), 2.47 (d, 1H, J = 3.5 Hz), 2.39 (q, 2H, J = 7.7 Hz),
2.28 (s, 3H), 2.18 (s, 3H), 1.07 (t, 3H, J = 7.7 Hz). NMR data
matches that previously reported for this compound.40
4,4-Difluoro-1,7-diethyl-2,6-diphenyl-3,5-dimethyl-8-H-4-
bora-3a,4a-diaza-s-indacene (26).
Compound 32 was synthesized from the corresponding dipyrrin·
HBr salt42 using GP1, followed by purification on silica, eluting
with 15% ethyl acetate in hexanes to give the title compound as a
1
dark red solid (142 mg, 79% yield). Mp 118−122 °C; H NMR
(CDCl3, 500 MHz) δ 7.42 (s, 1H), 7.06 (s, 1H), 2.52
(s, 3H), 2.44−2.37 (m, 4H), 2.19 (s, 3H), 2.18 (s, 3H), 1.18
(t, 3H, J = 7.5 Hz), 1.07 (t, 3H, J = 7.5 Hz); 13C NMR (CDCl3,
125 MHz) δ 159.4, 139.3, 138.5, 135.4, 134.5, 133.3, 132.5, 132.2,
120.6, 18.3, 17.4, 14.5, 14.3, 13.1, 9.62, 9.60; 11B {1H} NMR
(CDCl3, 160 MHz) δ 0.41 (t, J = 31.9 Hz); LRMS-ESI (m/z):
313.2 [M + Na]+; HRMS-ESI (m/z): [M + Na]+ calcd for
C16H21N2BF2Na 313.1652; found, 313.1658; ε526
61 000.
4,4-Difluoro-1-methoxy-3-pyrrolyl-5,7-dimethyl-6-(hexan-
1-ol)-2,8-H-4-bora-3a,4a-diaza-s-indacene (34).
=
nm
Compound 26 was synthesized from the corresponding
dipyrrin·HBr salt using GP1, followed by purification on silica,
eluting with 10% ethyl acetate in hexanes to give the title com-
pound as a bright orange solid (54 mg, 78% yield). Mp 190−
195 °C; 1H NMR (CDCl3, 500 MHz) δ 7.44 (t, 4H, J = 7.5 Hz),
7.36 (t, 2H, J = 7.5 Hz), 7.27−7.25 (m, 4H), 7.17 (s, 1H), 2.64 (q,
4H, J = 7.5 Hz), 2.51 (s, 6H), 1.12 (t, 6H, J = 7.5 Hz); 13C NMR
(CDCl3, 125 MHz) δ 155.5, 144.2, 133.9, 132.2, 131.8, 129.8,
128.6, 127.3, 120.4, 18.2, 17.1, 13.5; 11B {1H} NMR (CDCl3, 160
MHz) δ 1.0 (t, J = 34.1 Hz); LRMS-ESI (m/z): 451.2 [M + Na]+;
HRMS-ESI (m/z): [M + Na]+ calcd for C27H27N2BF2Na
451.2140; found, 451.2128; ε535 nm = 74 000.
Compound 34 was synthesized from the corresponding
prodigiosene·HCl salt using GP1, with stirring for 48 h. Purification
was carried out on neutral alumina, eluting with 20−50% ethyl
acetate in hexanes to give the title compound as a dark purple solid
(33 mg, 39% yield). Mp 71−76 °C; 1H NMR (CDCl3, 500 MHz)
δ 10.42 (brs, 1H), 7.08 (s, 1H), 7.05 (s, 1H), 6.85 (s, 1H), 6.33
(s, 1H), 6.10 (s, 1H), 3.95 (s, 3H), 3.65 (t, 2H, J = 6.0 Hz), 2.48
(s, 3H), 2.37 (t, 2H, J = 7.0 Hz), 2.15 (s, 3H), 1.65−1.50 (m, 2H),
1.50−1.40 (m, 2H), 1.40−1.29 (m, 4H); 13C NMR (CDCl3, 125
MHz) δ 162.7, 150.1, 148.0, 134.3, 130.7, 129.2, 126.4, 124.3, 124.2,
115.7, 114.8, 110.9, 96.5, 63.2, 58.4, 33.0, 30.5, 29.5, 25.8, 24.3, 12.6,
9.7; 11B {1H} NMR (CDCl3, 160 MHz) δ 1.31 (t, J = 36.7 Hz);
LRMS-ESI (m/z): 438.2 [M + Na]+; HRMS-ESI (m/z): [M +
Na]+ calcd for C22H28N3O2BF2Na 438.2138; found, 438.2135;
ε565 nm = 116 000.
6,6-Difluoro-12,14-dimethyl-2,3,4,6,8,9,10,11-octahydro-1H-
[1,3,2]diazaborinino[1,6-a:3,4-a′]diindol-5-ium-6-uide (28).
Compound 28 was synthesized from the corresponding dipyrrin·HBr
salt using GP1, followed by purification on silica, eluting with 10%
ethyl acetate in hexanes to give the title compound as a dark red solid
(59 mg, 59% yield). Mp 250−255 °C (d.p.); 1H NMR (CDCl3, 500
MHz) δ 6.99 (s, 1H), 2.98 (t, 4H, J = 6.0 Hz), 2.42 (t, 4H, J = 6.0
Hz), 2.13 (s, 6H), 1.84−1.79 (m, 4H), 1.77−1.72 (m, 4H); 13C NMR
(CDCl3, 125 MHz) δ 156.7, 136.1, 133.0, 126.9, 119.1, 24.7, 22.8,
22.5, 21.7, 9.5; 11B {1H} NMR (CDCl3, 160 MHz) δ 0.66 (t, J = 33.0
Hz); LRMS-ESI (m/z): 351.2 [M + Na]+; HRMS-ESI (m/z):
[M + Na]+ calcd for C19H23N2BF2Na 351.1801; found, 351.1815;
ε538 nm = 67 000.
4,4-Difluoro-1,3-dimethyl-2-pentyl-5-bromo-7-methoxy-
6,8-H-4-bora-3a,4a-diaza-s-indacene (37a).
4,4-Difluoro-5,7-dimethyl-1,2,3,6,8-H-4-bora-3a,4a-diaza-
s-indacene (30).41
Compound 37a was synthesized from the corresponding dipyrrin
using GP1 and a reaction time of 18 h, followed by purification on
basic alumina, eluting with 10−20% ethyl acetate in hexanes to
give the title compound as a dark orange solid (122 mg, 54%
yield). Mp 105−108 °C; H NMR (CDCl3, 500 MHz) δ 7.08
(s, 1H), 5.89 (s, 1H), 3.88 (s, 3H), 2.49 (s, 3H), 2.34 (t, 2H,
1
Compound 30 was synthesized from the corresponding dipyrrin·
HBr salt30 using GP1 as a metallic green solid (235 mg, 68%
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J = 7.5 Hz), 2.13 (s, 3H), 1.45−1.39, (m, 2H), 1.35−1.27, (m, 4H),
0.89 (t, 3H, J = 7.0 Hz); 13C NMR (CDCl3, 125 MHz) δ 160.8,
158.5, 138.9, 133.0, 132.1, 126.2, 123.5, 117.2, 101.4, 58.6, 31.8,
29.8, 24.2, 22.7, 14.2, 13.2, 9.7; 11B {1H} NMR (CDCl3, 160 MHz)
δ 0.56 (t, J = 32.0 Hz); LRMS-ESI (m/z): 421.1 [M + Na]+;
HRMS-ESI (m/z): [M + Na]+ calcd for C17H22N2OBrBF2Na
421.0858; found, 421.0869; ε514 nm = 95 000.
HRMS-ESI (m/z): [M + Na]+ calcd for C26H34N3O3BF2Na
508.2531; found, 508.2553; ε516 nm = 74 000.
4,4-Difluoro-1-ethyl-2,5,7-trimethyl-3-(N-Boc-pyrrolyl)-6-
(methylethanoate)-8-H-4-bora-3a,4a-diaza-s-indacene
(38b).
4,4-Difluoro-1,3,6-trimethyl-2-(methylethanoate)-5-
bromo-7-ethyl-8-H-4-bora-3a,4a-diaza-s-indacene (37b).
N-Boc-pyrrole-2-boronic acid (83 mg, 0.39 mmol), lithium
chloride (42 mg, 0.98 mmol) and tetrakis(triphenylphosphine)-
palladium (38 mg, 0.033 mmol) were added to a solution of 37b
(135 mg, 0.327 mmol) in 1,2-dimethoxyethane (14 mL) and the
resulting mixture was purged with nitrogen for 15 min. Sodium
carbonate solution (2.0 M, 0.65 mL, 1.3 mmol), previously bub-
bled with nitrogen, was then added dropwise and the reaction
mixture was heated to 85 °C, with stirring under nitrogen for 24 h.
After cooling to room temperature, the reaction mixture was dilut-
ed with water (30 mL) and thoroughly extracted with ethyl
acetate (3 × 30 mL). The organic extracts were combined and
washed with water (50 mL) and brine (50 mL), then dried over
anhydrous magnesium sulfate before filtering and concentrating to
give the crude product, which was purified using column
chromatography on neutral alumina, eluting with 5−20% ethyl
acetate in hexanes, to give the product 38b as a dark red solid (62
Compound 37b was synthesized from the corresponding dipyrrin·
HBr salt using GP1 and a reaction time of 18 h, followed by
purification on silica, eluting with 20−40% ethyl acetate in hexanes
to give the title compound as a dark brown solid (135 mg, 53%
1
yield). Mp 137−142 °C; H NMR (CDCl3, 500 MHz) δ 7.00
(s, 1H), 3.69 (s, 3H), 3.40 (s, 2H), 2.61 (q, 2H, J = 7.7 Hz), 2.53
(s, 3H), 2.22 (s, 3H), 2.01 (s, 3H), 1.17 (t, 3H, J = 7.7 Hz); 13
C
NMR (CDCl3, 125 MHz) δ 170.9, 159.1, 143.4, 140.9, 133.7,
132.3, 130.4, 126.0, 123.9, 119.7, 52.4, 30.1, 18.5, 16.1, 13.2, 10.02,
9.98; 11B {1H} NMR (CDCl3, 160 MHz) δ 0.56 (t, J = 29.6 Hz);
LRMS-ESI (m/z): 435.1 [M + Na]+; HRMS-ESI (m/z): [M +
Na]+ calcd for C17H20N2O2BrBF2Na 435.0650; found, 435.0661;
ε529 nm = 78 000.
1
mg, 38% yield). Mp 52−54 °C; H NMR (CDCl3, 500 MHz) δ
4,4-Difluoro-1-methoxy-3-(N-Boc-pyrrolyl)-5,7-dimethyl-
6-pentyl-2,8-H-4-bora-3a,4a-diaza-s-indacene (38a).
7.47 (dd, 1H, J = 2.0, 3.5 Hz), 7.10 (s, 1H), 6.46−6.45 (m, 1H),
6.32 (t, 1H, J = 3.5 Hz), 3.68 (s, 3H), 3.38 (s, 2H), 2.63 (q, 2H,
J = 7.7 Hz), 2.43 (s, 3H), 2.23 (s, 3H), 1.85 (s, 3H), 1.33 (s, 9H),
1.21 (t, 3H, J = 7.7 Hz); 13C NMR (CDCl3, 125 MHz) δ 171.2,
156.7, 148.9, 142.8, 139.3, 133.1, 132.2, 127.1, 123.2, 122.6, 121.5,
120.3, 117.5, 110.9, 83.5, 60.5, 52.2, 30.1, 27.7, 18.1, 16.1, 13.0,
10.0, 9.3; 11B {1H} NMR (CDCl3, 160 MHz) δ 0.52 (t, J = 30.6 Hz);
LRMS-ESI (m/z): 522.2 [M + Na]+; HRMS-ESI (m/z):
[M + Na]+ calcd for C26H32N3O4BF2Na 522.2341; found,
522.2346; ε533 nm = 60 000.
N-Boc-pyrrole-2-boronic acid (91 mg, 0.43 mmol), lithium
chloride (46 mg, 1.1 mmol), and tetrakis(triphenylphosphine)-
palladium (41 mg, 0.036 mmol) were added to a solution of 37a
(143 mg, 0.358 mmol) in 1,2-dimethoxyethane (15 mL) and the
resulting mixture was purged with nitrogen for 15 min. Sodium
carbonate solution (2.0 M, 0.72 mL, 1.4 mmol), previously
bubbled with nitrogen, was then added dropwise and the reaction
mixture was heated to 85 °C, with stirring under nitrogen for 24 h.
After cooling to room temperature, the reaction mixture was
diluted with water (30 mL) and thoroughly extracted with ethyl
acetate (3 × 30 mL). The organic extracts were combined and
washed with water (50 mL) and brine (50 mL), then dried over
anhydrous magnesium sulfate before filtering and concentrating to
give the crude product, which was purified using column chroma-
tography on silica, eluting with 10−30% diethyl ether in hexanes,
to give the product 38a as a dark red solid (62 mg, 36% yield).
Mp 152−154 °C; 1H NMR (CDCl3, 500 MHz) δ 7.42 (dd, 1H,
J = 3.5, 1.5 Hz), 7.18 (s, 1H), 6.58 (dd, 1H, J = 3.5, 1.5 Hz), 6.27
(t, 1H, J = 3.5 Hz), 5.82 (s, 1H), 3.90 (s, 3H), 2.40 (s, 3H), 2.33
(t, 2H, J = 7.5 Hz), 2.15 (s, 3H), 1.44−1.38 (m, 2H), 1.41 (s, 9H),
1.34−1.26 (m, 4H), 0.89 (t, 3H, J = 7.0 Hz); 13C NMR (CDCl3,
125 MHz) δ 160.9, 156.4, 149.0, 146.9, 137.5, 132.6, 131.1, 124.9,
123.7, 117.9, 117.6, 110.9, 100.2, 83.7, 58.4, 31.8, 29.9, 27.8, 24.2,
22.7, 22.6, 14.2, 13.0, 9.7; 11B {1H} NMR (CDCl3, 160 MHz)
δ 0.60 (t, J = 31.5 Hz); LRMS-ESI (m/z): 508.3 [M + Na]+;
Microwave-Assisted Deprotection of F-BODIPYs.
General Procedure for the Deprotection of F-BODIPYs (GP2).
Potassium hydroxide (6 equiv) was added to a stirred suspension
of BODIPY compound (50 mg, 1 equiv) in HPLC grade tert-
butanol (10 mL) and distilled water (0.1 mL), in a 20 mL capacity
microwave vial. The vial was then sealed and placed in the
microwave reactor, where it was heated at 140 °C for 15 min, at a
maximum of 400 W power. After cooling, the reaction mixture was
partitioned between saturated aqueous sodium bicarbonate
solution (30 mL) and diethyl ether (30 mL). The aqueous
phase was extracted with diethyl ether (2 × 30 mL) and the
combined organic extracts were washed with brine (50 mL), dried
over anhydrous magnesium sulfate, and concentrated to give the
crude product, which was purified immediately using column
chromatography on basic alumina (Brockmann type III), unless
otherwise stated.
(Z)-3-Ethyl-5-((4-ethyl-3,5-dimethyl-2H-pyrrol-2-ylidene)-
methyl)-2,4-dimethyl-1H-pyrrole (4).25
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Compound 4 was synthesized from the corresponding F-
BODIPY (3), using GP2 and a reaction time of 5 min, and
purified over basic alumina (Brockmann type III), eluting with
5% ethyl acetate in hexanes, to give the title compound as a
give the crude product, which was dissolved in pentane and
filtered through a short pad of basic alumina (Brockmann type
III), washing with 10% diethyl ether in pentane, to give the title
compound as a pale brown solid (37 mg, 79% yield). Mp 208−
1
1
brown solid (41 mg, 97% yield). Mp 111−114 °C; H NMR
212 °C; H NMR (CDCl3, 500 MHz) δ 7.02 (s, 2H), 5.99
(CDCl3, 500 MHz) δ 6.63 (s, 1H), 2.36 (q, 4H, J = 7.7 Hz),
2.29 (s, 6H), 2.12 (s, 6H), 1.05 (t, 6H, J = 7.7 Hz). NMR data
matches that previously reported for this compound.25
(s, 4H), 2.32 (s, 12H), 1.95 (s, 12H). NMR data matches that
previously reported for this compound.25
(Z)-1-(2-((4-Acetyl-3,5-dimethyl-1H-pyrrol-2-yl)(phenyl)-
(Z)-3-Ethyl-5-((4-ethyl-3,5-dimethyl-2H-pyrrol-2-ylidene)-
methylene)-3,5-dimethyl-2H-pyrrol-4-yl)ethanone (18).
(phenyl)methyl)-2,4-dimethyl-1H-pyrrole (10).25
Compound 18 was synthesized from the corresponding F-BODIPY
(14), using GP2, and purified over basic alumina (Brockmann type
III), eluting with 30% ethyl acetate in hexanes, to give the title
compound as a bright orange solid (20 mg, 45% yield). Mp 152−
Compound 10 was synthesized from the corresponding F-BODIPY
(9), using GP2, and purified over basic alumina (Brockmann type
III), eluting with 10% ethyl acetate in hexanes, to give the title
compound as a brown solid (41 mg, 94% yield). Mp 144−147 °C;
1H NMR (CDCl3, 500 MHz) δ 13.10 (brs, 1H), 7.42−7.40 (m,
3H), 7.32−7.30 (m, 2H), 2.32 (s, 6H), 2.27 (q, 4H, J = 7.6 Hz),
1.19 (s, 6H), 0.97 (t, 6H, J = 7.6 Hz). NMR data matches that
previously reported for this compound.25
1
154 °C; H NMR (CDCl3, 500 MHz) δ 13.93 (brs, 1H), 7.50−
7.46 (m, 3H), 7.30−7.28 (m, 2H), 2.58 (s, 6H), 2.39 (s, 6H), 1.53
(s, 6H); 13C NMR (CDCl3, 125 MHz) δ 196.7, 154.5, 143.7, 143.6,
137.2, 137.1, 131.0, 129.4, 129.3, 129.2, 31.8, 18.1, 14.5; LRMS-ESI
(m/z): 361.2 [M + H]+; HRMS-ESI (m/z): [M + H]+ calcd for
C23H25N2O2 361.1916; found, 361.1911.
5,5′-(Ethene-1,1-diyl)bis(3-ethyl-2,4-dimethyl-1H-pyrrole)
(Z)-2-((4-Ethyl-3,5-dimethyl-2H-pyrrol-2-ylidene)methyl)-
3,5-dimethyl-1H-pyrrole (21).44
(16).43
Compound 16 was synthesized from the corresponding
F-BODIPY (12), using GP2 and a reaction time of 5 min,
and purified over basic alumina (Brockmann type III), eluting
with 6% ethyl acetate in hexanes, to give the title compound
Compound 21 was synthesized from the corresponding F-
BODIPY (20), using GP2, and purified over basic alumina
(Brockmann type III), eluting with 10% ethyl acetate in
hexanes, to give the title compound as a yellow solid (41 mg,
1
1
as a dark yellow oil (33 mg, 97% yield). H NMR (CDCl3,
98% yield). Mp 64−65 °C; H NMR (CDCl3, 500 MHz)
500 MHz) δ 7.56 (brs, 2H), 5.04 (s, 2H), 2.41 (q, 4H, J = 7.5 Hz),
2.17 (s, 6H), 1.97 (s, 6H), 1.09 (t, 6H, J = 7.5 Hz); 13C NMR
(CDCl3, 125 MHz) δ 132.4, 125.6, 123.0, 122.4, 117.1, 108.3,
17.8, 15.8, 11.2, 10.3. NMR data matches that previously
reported for this compound.43
δ 9.09 (brs, 1H), 6.64 (s, 1H) 5.85 (s, 1H), 2.36 (q, 2H, J = 7.5
Hz), 2.33 (s, 3H), 2.31 (s, 3H), 2.21 (s, 3H), 2.12 (s, 3H), 1.05
(t, 3H, J = 7.5 Hz); 13C NMR (CDCl3, 125 MHz) δ 161.7,
143.6, 142.5, 136.9, 133.8, 133.4, 132.1, 115.7, 113.6, 18.1, 16.0,
14.9, 14.7, 11.4, 9.7; LRMS-ESI (m/z): 229.2 [M + H]+;
HRMS-ESI (m/z): [M + H]+ calcd for C15H21N2 229.1708;
found, 229.1699.
Zinc[κ2-(3,3′, 5,5′-tetramethyl-meso-H-dipyrrinato)]
(17).25
(Z)-2-((4-Heptyl-3,5-dimethyl-2H-pyrrol-2-ylidene)methyl)-
3,5-dimethyl-1H-pyrrole (23).
CAUTION! The free-base dipyrrin derived from 13 is a power-
ful sternutator and must be handled only under adequate
ventilation.25 Compound 17 was thus synthesized from the
corresponding F-BODIPY (13), using GP2, followed by
addition of Zn(OAc)2·2H2O (400 mg, 1.82 mmol, 9 equiv.)
to the microwave vial following deprotection with stirring at
room temperature for 30 min. The reaction mixture was then
partitioned between saturated aqueous sodium bicarbonate
solution (30 mL) and diethyl ether (30 mL). The aqueous
phase was extracted with diethyl ether (2 × 30 mL) and the
combined organic extracts were washed with brine (50 mL),
dried over anhydrous magnesium sulfate, and concentrated to
Compound 23 was synthesized from the corresponding F-
BODIPY (22), using GP2, and purified over basic alumina
(Brockmann type III), eluting with 10% ethyl acetate in
hexanes, to give the title compound as a dark yellow oil (41 mg,
95% yield). 1H NMR (CDCl3, 500 MHz) δ 9.13 (brs, 1H), 6.65
(s, 1H), 5.85 (s, 1H), 2.34−2.32 (m, 5H), 2.31 (s, 3H), 2.21
(s, 3H), 2.11 (s, 3H), 1.45−1.41 (m, 2H), 1.31−1.27 (m, 8H),
0.88 (t, 3H, J = 7.0 Hz); 13C NMR (CDCl3, 125 MHz) δ 162.0,
143.6, 142.5, 137.3, 133.3, 132.5, 132.1, 115.7, 113.6, 32.1, 30.3, 29.6,
29.4, 24.9, 22.8, 16.1, 15.0, 14.3, 11.4, 9.9; LRMS-ESI (m/z): 299.3
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[M + H]+; HRMS-ESI (m/z): [M + H]+ calcd for C20H31N2
299.2477; found, 299.2482.
(Z)-1-(5-((4-Ethyl-3,5-dimethyl-2H-pyrrol-2-ylidene)-
methyl)-2,4-dimethyl-1H-pyrrol-3-yl)-2,2,2-trifluoroethanol
(25).25
Compound 31 was synthesized from the corresponding F-
BODIPY (30), using GP2 and a reaction time of 5 min, and
purified over basic alumina (Brockmann type III), eluting with
0−5% ethyl acetate in hexanes, to give the title compound as a
yellow film (8 mg, 26% yield). 1H NMR (CDCl3, 500 MHz) δ
7.13 (s, 1H), 6.73 (s, 1H), 6.62 (dd, 1H, J = 3.5, 1.0 Hz), 6.26
(dd, 1H, J = 3.5, 2.5 Hz), 6.12 (d, 1H, J = 1.5 Hz), 2.33 (s, 3H),
2.20 (s, 3H); LRMS-ESI (m/z): 173.1 (M + H)+; HRMS-ESI
(m/z): [M + H]+ calcd for C11H13N2 173.1067; found, 173.1073.
This compound is very unstable and prone to decomposition;
color change occurred from yellow to brown to black, beginning
directly after the column.
Compound 25 was synthesized from the corresponding racemic
F-BODIPY (24), using GP2, and purified over basic alumina
(Brockmann type III), eluting with 30% ethyl acetate in hexanes,
to give the title compound as a yellow solid (42 mg, 96% yield).
Mp 160−163 °C; 1H NMR (CDCl3, 500 MHz) δ 6.65 (s, 1H),
5.03 (q, 1H, J = 7.3 Hz), 4.96 (brs, 1H), 2.39 (s, 3H), 2.36
(q, 2H, J = 7.6 Hz), 2.31 (s, 3H), 2.23 (s, 3H), 2.11 (s, 3H),
1.06 (t, 3H, J = 7.6 Hz). NMR data matches that previously
reported for this compound.25
(Z)-3-Ethyl-5-((4-ethyl-3-methyl-2H-pyrrol-2-ylidene)-
methyl)-2,4-dimethyl-1H-pyrrole (33).
(Z)-3-Ethyl-2-((3-ethyl-5-methyl-4-phenyl-2H-pyrrol-2-
ylidene)methyl)-5-methyl-4-phenyl-1H-pyrrole (27).
Compound 33 was synthesized from the corresponding F-
BODIPY (32), using GP2 and a reaction time of 5 min, and
purified over basic alumina (Brockmann type III), eluting with 5%
ethyl acetate in hexanes, to give the title compound as a yellow
1
solid (34 mg, 81% yield). Mp 50−51 °C; H NMR (CDCl3,
500 MHz) δ 6.90 (s, 1H), 6.63 (s, 1H), 2.43 (q, 2H, J = 7.5 Hz),
2.35 (q, 2H, J = 7.7 Hz), 2.30 (s, 3H), 2.16 (s, 3H), 2.11 (s, 3H),
1.17 (t, 3H, J = 7.5 Hz), 1.05 (t, 3H, J = 7.7 Hz); 13C NMR
(CDCl3, 125 MHz) δ 167.1, 146.3, 138.5, 135.8, 130.6, 127.9,
127.2, 126.0, 115.9, 18.5, 18.2, 16.7, 14.7, 14.6, 9.7, 9.4; LRMS-ESI
(m/z): 243.2 [M + H]+; HRMS-ESI (m/z): [M + H]+ calcd for
C16H23N2 243.1860; found, 243.1856.
Compound 27 was synthesized from the corresponding F-
BODIPY (26), using GP2, and purified over basic alumina
(Brockmann type III), eluting with 10% ethyl acetate in hexanes,
to give the title compound as a brown solid (34 mg, 83% yield).
Mp 129−131 °C; 1H NMR (CDCl3, 500 MHz) δ 9.34 (brs, 1H),
7.42 (t, 4H, J = 7.5 Hz), 7.31 (t, 2H, J = 7.5 Hz), 7.29−7.27 (m,
4H), 6.86 (s, 1H), 2.63 (q, 4H, J = 7.5 Hz), 2.34 (s, 6H), 1.14 (t,
6H, J = 7.5 Hz); 13C NMR (CDCl3, 125 MHz) δ 151.8, 141.3,
136.5, 135.6, 130.0, 129.7, 128.4, 126.5, 117.3, 18.2, 17.4, 15.4;
LRMS-ESI (m/z): 381.2 [M + H]+; HRMS-ESI (m/z): [M + H]+
calcd for C27H29N2 381.2314; found, 381.2325.
(Z)-6-(2-((4-Methoxy-1H,1′H-[2,2′-bipyrrol]-5-yl)-
methylene)-3,5-dimethyl-2H-pyrrol-4-yl)hexan-1-ol (35).
(Z)-3-Methyl-2-((3-methyl-4,5,6,7-tetrahydro-1H-indol-2-
yl)methylene)-4,5,6,7-tetrahydro-2H-indole (29).45
Compound 35 was synthesized from the corresponding F-
BODIPY (34), using GP2, and purified over neutral alumina
(Brockmann type III), eluting with 60−80% ethyl acetate in
hexanes, to give the title compound as a dark red solid (12.5 mg,
94% yield). Mp 56−60 °C; 1H NMR (CDCl3, 500 MHz) δ 6.89
(s, 1H), 6.642 (s, 1H), 6.635 (s, 1H), 6.13 (t, 1H, J = 3.0 Hz),
6.06 (s, 1H), 3.96 (s, 3H), 3.58 (t, 2H, J = 6.8 Hz), 2.22 (t, 2H, J =
7.5 Hz), 2.11 (s, 3H), 1.77 (s, 3H), 1.54−1.49 (m, 2H), 1.37−1.30
(m, 4H), 1.28−1.25 (m, 2H); 13C NMR (CDCl3, 125 MHz) δ
168.5, 132.3, 132.2, 132.1, 128.7, 128.6, 125.6, 123.0, 122.6, 113.5,
112.0, 109.8, 95.2, 63.1, 58.5, 32.8, 30.7, 29.4, 25.7, 24.2, 10.6, 9.8;
LRMS-ESI (m/z): 368.2 [M + H]+; HRMS-ESI (m/z): [M + H]+
calcd for C22H30N3O2 368.2327; found, 368.2333.
Compound 29 was synthesized from the corresponding F-
BODIPY (28), using GP2, and purified over basic alumina
(Brockmann type III), eluting with 10−30% ethyl acetate in
hexanes, to give the title compound as a brown solid (30 mg,
1
72% yield). Mp 141−144 °C; H NMR (CDCl3, 500 MHz) δ
6.69 (s, 1H), 2.71 (t, 4H, J = 6.0 Hz), 2.43 (t, 4H, J = 6.0 Hz),
2.10 (s, 6H), 1.81−1.77 (m, 4H), 1.76−1.72 (m, 4H); 13C
NMR (CDCl3, 125 MHz) δ 153.8, 137.2, 132.8, 125.4, 116.0,
26.3, 23.5, 23.4, 22.1, 9.5; LRMS-ESI (m/z): 281.2 [M + H]+;
HRMS-ESI (m/z): [M + H]+ calcd for C19H25N2 281.2010;
found, 281.2012.
(Z)-5-((3,5-Dimethyl-4-pentyl-2H-pyrrol-2-ylidene)methyl)-
4-methoxy-1H,1′H-2,2′-bipyrrole (39a).
(Z)-2-((3,5-Dimethyl-2H-pyrrol-2-ylidene)methyl)-1H-pyr-
role (31).
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Compound 39a was synthesized from the corresponding F-
BODIPY (38a), using GP2, and purified over neutral alumina
(Brockmann type III), eluting with 20% ethyl acetate in hexanes,
to give the title compound as a dark red solid (10.4 mg, 97%
yield). Mp 66−70 °C; H NMR (CDCl3, 500 MHz) δ 6.88
(s, 1H), 6.67 (s, 1H), 6.63 (s, 1H), 6.15 (s, 1H), 6.04 (s, 1H), 3.95
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1
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* Supporting Information
NMR spectra for all previously unpublished compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
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*E-mail: Alison.Thompson@Dal.Ca
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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This work was supported by the Natural Sciences and
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