Diversity-oriented synthesis of intensively blue emissive 3-hydroxyisoquinolines by sequential Ugi four-component reaction/reductive heck cyclization

Article abstract of DOI:10.1002/chem.201404209

A convergent approach to highly functionalized 3-hydroxyisoquinolines is reported. The key steps are an Ugi multicomponent reaction and a subsequent intramolecular reductive Heck reaction; these can also be performed as a one-pot procedure. The structures

Full text of DOI:10.1002/chem.201404209

DOI: 10.1002/chem.201404209
Full Paper
&
Fluorescent Compounds
Diversity-Oriented Synthesis of Intensively Blue Emissive
3-Hydroxyisoquinolines by Sequential Ugi Four-Component
Reaction/Reductive Heck Cyclization
Lisa Moni,[a] Melanie Denißen,[b] Gianluca Valentini,[a] Thomas J. J. Mꢀller,*[b] and
Renata Riva*[a]
Abstract: A convergent approach to highly functionalized 3-
hydroxyisoquinolines is reported. The key steps are an Ugi
multicomponent reaction and a subsequent intramolecular
reductive Heck reaction; these can also be performed as
a one-pot procedure. The structures display very interesting
properties as blue-fluorescence emitters. Photophysical stud-
ies on the absorption and static fluorescence indicate that
the substitution pattern on the pyridyl part influences the
optical properties only to a minor extent, unless the amide
substituent becomes sterically demanding and leads to sig-
nificant nonradiative deactivation. The donor substitution on
the benzo core considerably enhances the fluorescence
quantum yields and trimethoxy substitution causes a pro-
nounced redshift of the emission bands. Protonation of the
isoquinolyl nitrogen atom causes efficient static quenching
of the fluorescence.
Introduction
nones allowed a plethora of multicomponent syntheses of
many classes of heterocycles[10] and fluorophores.[11] The
domino insertion/coupling sequence of alkynoyl ortho-iodo
anilides and alkynes furnished indolone-based frameworks
with conformationally rigidified, highly fluorescent butadiene
units in a spirocyclic corset,[12] solid-state luminescent push–
pull chromophores with indolone as the acceptor moiety,[13]
and pyranoindoles.[14] Conceptionally inspired by the insertion/
coupling/cycloisomerization scenario furnishing the latter pro-
tochromic pyranoindole luminophores, we became intrigued
in expanding this domino process to use Ugi four-component-
reaction (4CR) products as substrates for the synthesis of the
corresponding isoquinoline systems. Herein, we report the un-
expected formation of multiply substituted 3-hydroxyisoquino-
lines, the elaboration of the synthetic methodology, and pho-
tophysical studies of the self-evident intense blue lumines-
cence upon UV excitation.
The quest for novel functional p-electron systems,[1] that is,
chromophores, fluorophores, and electrophores as functional
molecular entities in molecule-based electronics,[2] molecular
photonics,[3] and biophysical analytics,[4] is an ongoing task for
synthetic chemistry. In particular, the efficient preparation of
these p systems in a diversity-oriented fashion[5] by multicom-
ponent processes[6] and domino reactions,[7] concepts with
considerable stimulation in pharmaceutical lead discovery, re-
mains a peculiar challenge and the concept of diversity-orient-
ed synthesis (DOS) is still quite novel with respect to functional
chromophores.[8]
Transition-metal-catalyzed processes have enabled rapid ac-
cesses to p-electron frameworks with extended conjugation.
Therefore, novel consecutive multicomponent syntheses of
heterocycles based upon transition-metal catalysis with excel-
lent compatibility of numerous polar functionalities and mild
reaction conditions turned out to be a conceptual break-
through in the DOS of fluorophores.[9] Based upon Sonogashira
alkynylation, the catalytic generation of alkynones and alke- Results and Discussion
Synthesis
[a] Dr. L. Moni, G. Valentini, Prof. Dr. R. Riva
Dipartimento di Chimica e Chimica Industriale
University of Genova
The initial scaffold we intended to synthesize was inspired by
structure 2 (Scheme 1), recently assembled through a domino
insertion/coupling/cycloisomerization sequence from acyclic
derivative 1, by taking advantage of a double Pd–Cu catalytic
system.[14] Indeed, we planned to prepare the homologous tri-
cyclic scaffold 3 from precursor 4, the product of an isocya-
nide-based Ugi multicomponent reaction (MCR), as illustrated
in the retrosynthetic plan. A similar approach (Ugi reaction, or
Ugi type reaction, followed by a domino organometallic proce-
Via Dodecaneso 31, 16146 Genova (Italy)
E-mail: riva@chimica.unige.it
[b] M. Denißen, Prof. Dr. T. J. J. Mꢀller
Institut fꢀr Organische Chemie und Makromoleculare Chemie
Heinrich-Heine-Universitꢁt Dꢀsseldorf
Universitꢁtsstraße 1, 40225 Dꢀsseldorf (Germany)
E-mail: thomasjjmueller@uni-duesseldorf.de
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201404209.
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Scheme 1. State of the art and retrosynthetic plan. Ar=aryl.
Scheme 2. Synthesis of the Ugi products.
dure) has been occasionally described for the synthesis of dif-
ferent scaffolds.[15]
cleophilic solvent, such as trifluoroethanol,[22] was required, to-
gether with the presence of NH4Cl. The reaction had to be
done in a sealed tube at 508C in the presence of a slight
excess of ammonia (not more than three equivalents), which is
necessary to suppress the formation of the Passerini product 9
and to avoid also the formation of 10, both of which were ob-
served when unoptimized conditions were used. This latter by-
product is often the result of the Brønsted acid catalyzed com-
petitive pathway that may occur when stronger carboxylic
acids (propynoic acids have pKa ꢀ2.2) are used.[23] On the other
hand, if an excessive amount of ammonia was used instead,
many other by-products were obtained, as during preforma-
tion of the imine.[22a,b]
An isoquinolinone scaffold was, however, built through
a Pd-mediated carbopalladation/Suzuki–Miyaura coupling se-
quence by starting from an acyclic derivative not obtained
through an MCR.[16]
To allow the final cyclization, substituent R4 in compounds 4
needs to be equal to hydrogen: these intermediates might be
synthesized by a classical Ugi 4CR reaction by using a primary
amine with a cleavable R4 group or directly by using ammonia
in the MCR. Even though it was less atom and step economi-
cal, we initially preferred to explore the first possibility, because
it is known that ammonia often behaves poorly as an “amine
surrogate” in the Ugi reaction.[17]
Initial aldehyde 5 was obtained in nearly quantitative yield
by oxidation of the corresponding alcohol, by using either cat-
alytic tetrapropylammonium perruthenate (2%) or 2,2,6,6-tetra-
methylpiperidine 1-oxyl (TEMPO) in the presence of N-methyl-
morpholine-N-oxide and [bis(acetoxy)iodo]benzene (BAIB) as
stoichiometric oxidants,[18] which thus avoided the use of
highly toxic pyridinium chlorochromate.[19] We were pleased to
find that both 2,4-dimethoxy- and 2-methoxybenzylamine
gave the desired Ugi adducts 6 and 7 in excellent yield, not-
withstanding the somewhat unpredictable reactivity of propy-
noic acids in such reactions (Scheme 2). For example, it is well
known that triple bonds may add to isocyanides to give zwit-
terions, which can react in a different way and lead to side
products.[20]
Another crucial aspect is represented by the concentration
of the ammonia solution: the commercially available 7m solu-
tion in methanol was most efficient, but only if a freshly
opened bottle was used were the yields satisfactory and repro-
ducible. By taking all these precautions, the overall yield was
good, with the consideration also that 8a is obtained in just
one step.
We then turned our attention to the domino cyclization, by
using the conditions of our previously described protocol.[14]
We were quite surprised not to identify expected product 11,
the result of a Heck carbocyclization, followed by a Sonogashira
coupling and the final cycloisomerization of 14 (Scheme 3).
The only new isolated compound was 3-hydroxyisoquinoline
16a instead, although in very low yield. Seemingly, on this
scaffold, the Sonogashira coupling did not take place and the
vinyl palladium species 13 underwent a protonolysis to afford
15a, whereas the released PdII species is reduced by an un-
identified agent to regenerate the active catalyst. Finally, 15a
isomerizes to the final aromatic product 16a.
Compound 16a is, therefore, the result of an Ugi reaction
followed by a reductive intramolecular Heck reaction. Some ex-
amples of Ugi MCRs followed by simple Heck cyclizations to
afford six- or seven-membered heterocycles[24] and other iso-
quinoline[25] or indole scaffolds,[26] or, with more complex se-
quences, such as ring-closing metathesis/Heck,[27] Pd-mediated
SN2’/Heck,[28] or Staudinger/aza Wittig/Heck,[29] have been re-
ported so far, but none of them involved a reductive Heck car-
By contrast, removal of the substituted benzyl group was
rather troublesome with either acidic (trifluoroacetic acid, TFA)
or oxidative conditions (cerium(IV) ammonium nitrate, CAN).
Compound 6 was too reactive and underwent extended de-
composition, whereas 7 gave 8a but under unpractical experi-
mental conditions (high excess of CAN, long reaction time,
etc.) with moderate and not reproducible yield. We demon-
strated that the cause of this unexpected behavior is the pres-
ence of the triple bond,[21] even though we are unable to ex-
plain the reason.
Therefore, we turned our attention to the Ugi 4CR with am-
monia (Scheme 2). As expected, the reaction was problematic
and required considerable optimization. In particular, a non-nu-
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Table 1. Reductive Heck reaction.[a,b,c]
Entry Base
([amount])
Reducing
agents
T
t
Yield
of 16a of 17
Yield
[8C] [h]
([amount])
[%]
[%]
1[d]
2
Et3N (3 equiv) PPh3 (5%)
120[e]
1
–
15
–
–
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
HCO2H
(2 equiv)
HCO2H
(2 equiv)
HCO2H
(3 equiv)
HCO2H
(1.2 equiv)
HCO2H
(1 equiv)
HCO2H
50 17
85 72
85 17
85 24
3
58
53
62
32[f]
30
–
–
11
7
4
5
6
85
8
2
8
7
90[e]
–
(1 equiv)
HCO2H
8
CsCO3
85 63
85 24
–
(4 equiv)
(2 equiv)
9
DBU (3 equiv) HCO2H
(1 equiv)
2
–
10
11
Et3N, then
DBU (3 equiv) (1.2 equiv)
Et3N, then HCO2H
DBU (2 equiv) (1 equiv)
HCO2H
85
7,[g] then 16 64
8
90[e] 2,[g] then 1 62
1
[a] All reactions were performed in the presence of 5% [PdCl2(PPh3)2].
[b] Unless stated otherwise, acetonitrile (0.2m) was used as the solvent.
[c] Unless stated otherwise, all reactions with Et3N had a 0.2m concentra-
tion of base. [d] The solvent was DMF. [e] Under microwave heating. [f] In
addition, 50% of 15a, as a diastereomeric mixture, was isolated. [g] Only
Et3N was added at the beginning. After heating for the first reported
time, DBU was added and the heating was continued as indicated.
Scheme 3. Attempted domino insertion/coupling/cycloisomerization reac-
tion. L=ligand.
Therefore, we decided to investigate the effect of an added
reducing agent. Triphenylphosphine was not effective at all
(Table 1, entry 1), whereas formic acid, which has been used
either as the free acid or as the sodium salt in the reductive
Heck cyclization,[30] gave encouraging results with a noticeable
increase of both the yield and the reproducibility.[35] The yields
are strictly dependent on the temperature, with 858C being
the best conditions (Table 1, entries 3 and 5).
bocyclization as the secondary transformation. Nevertheless,
the reductive Heck reaction is a known process, has been used
to build the 3-benzazepine core[30] and tricyclic isoquinoline
core structures,[31] and is an unwanted side reaction in the pal-
ladium-catalyzed alkyne insertion/Suzuki reaction of aryl io-
dides.[32]
Also, the amount of formic acid is crucial. With three equiva-
lents, the reaction was faster but compound 17, the result of
deiodination and partial reduction of the triple bond of 8a,
was obtained as a by-product (Table 1, entry 4). Between 1 and
1.2 equivalents of formic acid are enough to afford a good
yield of 16a with minimal formation of 17 (Table 1, entry 5).
Another very important feature is the reaction time. If the re-
action was stopped after 8 h (Table 1, entry 6), a considerably
lower amount of 16a was obtained, whereas the yield of 17
was not significantly affected. The prevailing product in this
case was 15a (50%, as a 2:1 Z/E diastereomeric mixture, with
the configuration of the double bonds assigned through an
nOe experiment as described in the Supporting Information).
This suggests that the final aromatization is the rate-determin-
ing step of the whole sequence summarized in Scheme 3. To
achieve a faster rate, we tried different conditions (different
bases, acids, or buffers) and found a beneficial effect when
DBU was used as an ancillary base to be added after comple-
tion of the cyclization (Table 1, entry 10). In contrast, the addi-
3-Hydroxyisoquinolines are rather unexplored heterocycles,
although they have shown interesting biological properties.[33]
Moreover, preliminary analyses showed exciting fluorescence
properties, which made this scaffold very attractive for us.
We, therefore, worked on the optimization of the reaction,
focusing our attention on two main aspects: a) Which species
is responsible for the reduction of Pd? b) By which mechanism
does the isomerization/aromatization take place?
We first hypothesized Et3N to be the reducing agent, in ac-
cordance with literature data.[34] Actually Et3N plays a crucial
role in the Heck reaction and cannot be substituted; other
bases such as cesium carbonate[28] or diazabicycloundecene
(DBU; Table 1, entries 8 and 9) were unsuitable. However, the
reaction with this base turned out to be erratic anyway, with
the yields of isolated 16a even close to zero in some instances.
Also, the choice of solvent was crucial, because acetonitrile af-
forded 16a, albeit in low yield, whereas DMF did not allow the
formation of 16a, even in traces.
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tion of acids or a buffer system did not affect the reaction out-
come.
Table 2. Ugi reaction with ammonia followed by the reductive Heck reac-
tion.
Finally, to shorten the reaction time, we employed micro-
wave heating and obtained 16a with a comparable yield, by
using also less formic acid and DBU (Table 1, entry 11).
Scheme 4 describes a possible mechanism for the base-pro-
moted aromatization: the base is not only able to accept
Entry R1
R2 R3
R4
R5
8
16
(yield [%][a]) (yield [%][a])
1[b]
2[b]
3[b]
4[c]
5[c]
6[c]
7[d]
tBu
Ph
H
H
H
H
H
H
H
8a (70)
8b (51)
8c (51)
16a (64)
16b (17)
16c (40)
16d (66)
16e (44)
16 f (23)
16g (35)
2,6-dimethylphenyl nPr H
cyclohexyl
tBu
tBu
Me
nPr H
Ph
nPr H
Me
H
OCH2CH2O 8d (50)
OCH2CH2O 8e (46)
OCH2CH2O 8 f (39)
Scheme 4. Possible mechanism for the base-promoted aromatization.
B=base.
H
benzyl
Ph OMe OMe OMe 8g (49)
[a] Yield after isolation. [b] Aldehyde 5. [c] Aldehyde 21. [d] Aldehyde 22.
a proton from either 15a or 19 but acts twice as a proton
shuttle on intermediates 18 and 20. However, an aromatization
occurring through a hydride transfer from the C1 atom to the
exocyclic benzylic carbon atom cannot be completely ruled
out.[36]
The first attempts, by using the optimized conditions of
Scheme 2 and Table 1, were disappointing, with 16a being
formed just in traces. We attributed this to the contemporane-
ous presence of an excess of ammonia, which was mandatory
to avoid the formation of by-products, and the isocyanide
itself, because they may both act as ligands for palladium and
interfere with the catalytic cycle. Moreover, even when the
excess of ammonia was removed after the Ugi reaction, the
following cyclization was unsatisfactory.
With the optimized protocol (Table 1, entry 11) in hand, we
started to test the scope of the sequence. To this purpose, we
synthesized o-iodobenzaldehydes 21[37] and 22,[38] by improv-
ing the literature procedures, and used them in the Ugi reac-
tion with ammonia as previously described. As shown in
Table 2, the Ugi reaction occurred in satisfactory yields in most
of the reported examples to afford 8a–g.
For these reasons, we returned back to our initial idea and
substituted ammonia with 2,4-dimethoxybenzylamine in the
Ugi reaction. However, this time, our plan was to remove the
2,4-dimethoxybenzyl (DMB) group only after the reductive
Heck reaction to allow for the final aromatization. Once again,
we used the synthesis of 16a as a model.
We found the stoichiometric ratio of the components of the
Ugi reaction to be crucial, with the best conditions requiring
a slight excess (1.2 equivalents) of aldehyde 5 with respect to
the other reagents (Scheme 5). To test the overall sequence,
we first transformed 6 into 23 (a 10:1 mixture of diastereo-
mers) and, after intermediate isolation, converted 23 into 16a
by stepwise treatment with TFA, which causes deprotection,
and DBU, which promotes isomerization/aromatization. We
were pleased to isolate both 23 and 16a in excellent yield (92
and 84%, respectively) and observed again that the DMB
group can be efficiently removed in the absence of the triple
bond.
By contrast, the following reductive Heck reaction was more
problematic. With the exception of compounds 16a and 16d
(Table 2, entries 1 and 4), all of the other 3-hydroxyisoquino-
lines were obtained only in moderate or, in some cases, poor
yields. We demonstrated that the low yield for 16b (Table 2,
entry 2) was a consequence of incomplete aromatization be-
cause, after addition of DBU and heating for 2 h at 908C, 34%
of 15b was still present. Similar results were obtained in the
synthesis of 16c and 16 f (Table 2, entries 3 and 6, respective-
ly), in which cases heating up to 1108C was necessary to com-
plete the aromatization. This behavior seems to be peculiar for
compounds in which R2 is an alkyl group. In addition, during
the preparation of isoquinolines with R2 =Me or nPr, we also
isolated the oxidized analogues of 16 with an unsaturation in
the side chain, conjugated with the heterocyclic scaffold. Final-
ly, during the preparation of 16 f and 16g, we also found
a series of fluorescent by-products that have not been identi-
fied.
After demonstrating the feasibility of this two-step protocol
and knowing that a domino process is not consistent with the
different conditions required for the planned reactions, we fo-
cused our attention on the development of a one-pot proce-
To improve the step economy, we explored the possibility to
carry out the whole sequence to 16 as a domino reaction or,
at least, as a one-pot procedure.
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Table 3. Two-step synthesis of compounds 16 (R2: Ph).
Entry[a] R1
R3
R4
R5
15
16
(yield [%])[b] (yield [%])
1
2
tBu
2,6-dimethyl-
phenyl
cyclohexyl
benzyl
nBu
H
H
H
H
H
H
15a (92)
15h (56)
16a (84[b]
16h (92,[c]
54[b]
16i (60[b]
)
Scheme 5. One-pot synthesis of compound 16a.
)
3
4
5
H
H
H
H
H
H
H
H
H
15i (90)
15j (97)
15k (79)
)
dure. After completion of the Ugi reaction, the Pd catalyst,
formic acid, and the MeCN/Et3N (1:1) solution were directly
added and the mixture was heated in a microwave apparatus
to afford 23. After concentration of the mixture, the DMB
group was removed by means of TFA to give 15a, then DBU
in MeCN was added to promote the aromatization.
16j (95,[c] 59[b]
16k (91,[c]
)
52[b]
)
6
7
8
tBu
tBu
benzyl
H
OCH2CH2O 15d (88)
16d (66[b]
)
OMe OMe OMe 15l (45)
OMe OMe OMe 15g (63)
16l (79,[c] 64[b]
16g (88[c])
)
[a] Conditions for aromatization: Entry 1: DBU, RT, 2 h; entry 2: DBU/ZnI2,
1008C, MW, 30 min; entry 3: tBuOK, RT, 10 min; entry 4: tBuOK, RT,
30 min; entries 5 and 6: tBuOK, RT, 40 min; entry 7: DBU, 1008C, MW, 2 h;
entry 8: DBU/ZnI2, 1008C, MW, 45 min. [b] Yield after isolation. [c] HPLC
yield of the crude residue.
Apart from two very fast work-ups, the four-step sequence
was performed without isolating or purifying any intermediate.
The overall 77% yield (the same as that of the previously de-
scribed two-step procedure) is therefore excellent if we consid-
er the high degree of convergence of the protocol. From the
point of view of atom economy, this route is clearly less con-
venient; this drawback is compensated for by step economy,
by the operational simplicity, and by the higher overall yields.
Upon extending this protocol, under the same optimized
conditions, to the synthesis of other compounds 16, we found
again that the yields depended heavily on the nature of the
starting components. After a careful investigation, we realized
that the first three steps (Ugi/Heck/DMB removal) worked well
in all cases. By contrast, the crucial step is the final aromatiza-
tion, which requires a fine tuning of conditions for each sub-
strate.
(excitation at around 350 nm; Figure 1) and the photophysical
properties were, therefore, studied by UV/Vis and fluorescence
spectroscopy to determine the absorption and emission
maxima, molar extinction coefficients (e), Stokes shifts (Dn˜),
and relative fluorescence quantum yields (Ff; Table 4).
For enabling this tailored optimization, we preferred to iso-
late and purify intermediates 15 to search for the best condi-
tions for their conversion into 16, by changing the base, tem-
perature, and reaction times and possibly by adding a Lewis
acid. The results are summarized in Table 3 and show that, in
all cases, we were able to set up a satisfactory aromatization
step. The yields, based on the HPLC analyses of the crude
product, ranged from good to excellent. In contrast, the isolat-
ed yields after chromatography were usually less satisfactory. A
possible explanation may be the poor solubility of these com-
pounds, which crystallized on the silica and prevented com-
plete elution from the stationary phase.
Figure 1. Dichloromethane solutions (c=1ꢂ10À4 molLÀ1) of 3-hydroxyiso-
quinoline derivatives 16c, 16i, 16k, 16j, 16h, 16e, 16d, 16 f, 16l, and 16g
under a handheld UV lamp (lexcitation ꢀ350 nm).
In comparison to that of the unsubstituted 3-hydroxyisoqui-
noline (lmax,abs =340 nm),[39] the longest wavelength maxima of
all of the derivatives 16 are considerably redshifted and appear
between 358 and 383 nm. Also, the emission maxima of deriv-
atives 16 are bathochromically shifted, relative to that of the
parent system (lmax,em =370 nm) and are found in a range from
394.5 to 446.5 nm.
Photophysical properties
Even upon eyesight, the 3-hydroxyisoquinolines 16 exhibit a re-
markable deep-blue fluorescence under the handheld UV lamp
By considering the substitution pattern on the benzo moiety
of the 3-hydroxyisoquinoline core, three classes of moiety can
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the amide does not bear a sterically demanding substituent
(16h), neither the amide nor the 4-alkyl substitution influences
the electronic structure of the ground state (absorption
maxima) or the excited state (fluorescence maxima, quantum
yield).
Table 4. Selected photophysical properties of 3-hydroxyisoquinolines 16.
Compound
lmax,abs [nm][a]
(e [LmolÀ1 cmÀ1])
lmax,em [nm][b]
(Ff [a.u.])
Stokes shift
[c]
(Dn˜) [cmÀ1
]
16a
16c
16d
358.5 (9000)
282.5 (3400)
358.5 (8600)
286.5 (3500)
359.0 (9400)
314.0 (5600)
249.5 (47300)
358.5 (8200)
308.0 (4600)
249.5 (44700)
358.5 (7500)
317.0 (4200)
249.0 (42300)
382.5 (7600)
260.5 (34900)
361.5 (10100)
287.0 (3800)
359.0 (9600)
282.0 (3700)
359.5 (8700)
281.0 (3300)
358.5 (8900)
282.0 (3100)
380.0 (6800)
258.0 (33500)
395.5 (0.87)[d]
396.0 (0.79)[d]
396.0 (0.20)[d]
2600
The second series is represented by 3-hydroxy-1,3-dioxol[4,5-
g]isoquinoline derivatives (16e, 16d, and 16 f), of which all
three derivatives are fluorescent. In the absorption spectra,
three distinct maxima can be found. The highest and lowest
energy transitions are located in the very narrow ranges of
249.0 to 249.5 nm and 358.5 to 359.0 nm, with molar extinc-
tion coefficients (e) of 42300–44700 and 7500–
9400 LmolÀ1 cmÀ1, respectively. However, it is noticeable that
the intermediate absorption maxima appearing between 308.0
and 317.0 nm, with molar extinction coefficients between 4200
and 5600 LmolÀ1 cmÀ1, are clearly affected by the substitution
pattern. This is surprising because the structural variation
occurs at a position that is not in conjugation with the isoqui-
noline chromophore. Hence, it can be concluded that this tran-
sition is sensitive to minute inductive substituent effects. All of
the emission maxima appear at around 395 nm, which indi-
cates that the vibrationally relaxed excited S1 state is unaffect-
ed by the substitution pattern. Also, the quantum yields deter-
mined with anthracene as a relative standard (Ff =0.36) fall
within the range of 0.20 to 0.40, that is, with lower fluores-
cence efficiencies relative to those of the unsubstituted series
(16a, 16c, 16i, 16k, 16j, and 16h).
The third series consists of the trimethoxy-substituted deriv-
atives 16l and 16g, in which methoxy groups as +M and ÀI
substituents exert their effects on the electronic properties.
The donor substitution on the benzo core of the isoquinoline
shifts both the absorption and emission maxima bathochromi-
cally. Two distinct absorption maxima are found. The higher
energy transitions appear at around 260.0 nm with molar ex-
tinction coefficients (e) of 33500 and 34900 LmolÀ1 cmÀ1, re-
spectively, and the longest wavelength maxima are found at
around 381.0 nm with molar extinction coefficients of 6800
and 7600 LmolÀ1 cmÀ1, respectively. The emission maxima
appear at 443.5 and 446.5 nm, respectively. In comparison to
the second series (see above), the fluorescence quantum yields
(Ff) are significantly higher (0.62 and 0.65) and the lumines-
cence appears brighter to the eye (Figure 1).
2600
2600
16e
16 f
394.5 (0.25)[d]
394.5 (0.38)[d]
2600
2600
16g
16h
16i
446.5 (0.65)[e]
401.0 (<0.01)[d]
399.5 (0.79)[d]
397.0 (0.90)[d]
395.5 (0.84)[d]
443.5 (0.62)[e]
3800
2700
2800
2600
2600
3800
16j
16k
16l
[a] Recorded in CH2Cl2 at RT. [b] Recorded in CH2Cl2 at RT with lexcitation
=
350.0 nm. [c] Dn˜ =1/lmax,absÀ1/lmax,em
.
[d] Quantum yields were deter-
mined with anthracene as a standard in cyclohexane (Ff =0.36).[40,41]
[e] Quantum yields were determined with 9,10-diphenylanthracene as
a standard in cyclohexane (Ff =1.00).[40,42]
be distinguished: unsubstituted (16a, 16c, 16i, 16k, 16j, and
16h), dioxolannelated (16e, 16d, and 16 f), and 5,6,7-trime-
thoxy-substituted (16l and 16g) derivatives. With the excep-
tion of the 5,6,7-trimethoxy-substituted derivatives 16l and
16g, the Stokes shifts (Dn˜; that is, 1/lmax,absÀ1/lmax,em) lie at
around 2600–2800 cmÀ1 for all of the other 3-hydroxyisoquino-
lines 16, whereas derivatives 16l and 16g display considerably
larger Stokes shifts of 3800 cmÀ1. In comparison to the parent
system, 3-hydroxyisoquinoline, derivatives 16 are unlikely to
undergo hydrogen-bond-assisted dimerizations. Moreover, the
1-amide functionality offers an intramolecular hydrogen-bond
donor for the isoquinoline nitrogen atom to stabilize the mo-
nomer structure. Obviously, this intramolecular hydrogen
bonding is hampered by the steric demand of the 2,6-dime-
thylphenyl amide substituent in compound 16h, which causes
a radiationless deactivation of the excited state (see below).
The spectra of the series of unsubstituted derivatives, that is,
16a, 16c, 16h, 16i, 16j, and 16k, display two distinct absorp-
tion maxima. The first shorter wavelength band with weaker
intensity (e values ranging from 3100 to 3800 LmolÀ1 cmÀ1) ap-
pears between 281.0 and 287.0 nm and the intense longest
wavelength maximum is found at around 360.0 nm (e values
ranging 8600 to 10100 LmolÀ1 cmÀ1). With exception of 16h,
all of the compounds of this series are strongly luminescent
and the quantum yields determined with anthracene as a rela-
tive standard (Ff =0.36) fall in the range of 0.79 to 0.90. Unless
For scrutinizing the solvent effects on the photophysical
properties of the 3-hydroxyisoquinolines, derivative 16k was
considered to be an appropriate model and the absorption
and emission maxima, molar extinction coefficients (e), Stokes
shift (Dn˜), and fluorescence quantum yield (Ff) were deter-
mined in dichloromethane, acetonitrile, and DMSO (Table 5).
The absorption properties are only slightly affected upon
variation of the solvent polarity. With increasing polarity, a very
modest bathochromic shift of the longest wavelength maxi-
mum can be observed (358.5 nm for CH2Cl2 and acetonitrile
and 361.0 nm for DMSO). It should be noted that, in DMSO,
the second maximum at 271.5 nm is shifted hypsochromically
(relative to 281.0 nm for acetonitrile) and hyperchromically,
that is, the molar extinction coefficient almost doubles in mag-
nitude, relative to the corresponding bands in the other sol-
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This also matches with the pKa value of protonated 3-hydroxyi-
soquinoline (2.18).[43] The occurrence of an isosbestic point
(Figure 3) upon titration indicates an equilibrium between the
protonated and nonprotonated species without the formation
of further intermediates (Scheme 6).
Table 5. Solvent effects on selected photophysical properties of com-
pound 16k.
Entry Solvent
lmax,abs [nm][a]
lmax,em [nm][b] Stokes shift
[c]
(e [LmolÀ1 cmÀ1]) (Ff [a.u.])
(Dn˜) [cmÀ1
]
1
2
dichloromethane 358.5 (8900)
395.5 (0.84)[d] 2600
282.0 (3100)
358.5 (8600)
281.0 (3800)
230.5 (39800)
361.0 (7500)
271.5 (6500)
acetonitrile
DMSO
395.5 (0.60)[d] 2800
3
410.0 (0.22)[e] 3300
[a] Recorded in CH2Cl2 at RT. [b] Recorded in CH2Cl2 at RT with lexcitation
=
350.0 nm. [c] Dn˜ =1/lmax,absÀ1/lmax,em
.
[d] Quantum yields were deter-
mined with anthracene as a standard in cyclohexane (Ff =0.36).[40,41]
[e] Quantum yields were determined with 9,10-diphenylanthracene as
a standard in cyclohexane (Ff =1.00).[40,42]
vents. However, in the emission spectrum, a positive solvato-
chromism is clearly apparent (Figure 2). The modest batho-
chromic shift by 900 cmÀ1 suggests that the nature of the ex-
cited state should be slightly more polar and it thereby experi-
ences stabilization by DMSO.
Figure 3. Absorption spectra for the titration of compound 16j
(c=3.3ꢂ10À5 molLÀ1) with TFA in dichloromethane (recorded at T=293 K).
Scheme 6. Protonation equilibrium of compounds 16j and 16jÀH+.
Computations on the DFT and time-dependent (TD) DFT
level of the theory, with the B3LYP functional and the 6-31G*
basis set by using the SM8 solvent model for dichloromethane,
were carried out on the structures of free base 16j and its con-
jugated acid 16jÀH+.[44] The calculations qualitatively repro-
duce the trend of the absorption maxima. Upon protonation,
the longest wavelength maximum of 16j shifts from 339 nm
(lexp =360 nm) to 373 nm (lexp =390 nm) for 16jÀH+. The TD-
DFT computations indicate that these longest wavelength
bands arise from p–p* transitions, which are best represented
by highest occupied molecular orbital (HOMO)–lowest unoccu-
pied molecular orbital (LUMO) transitions in both cases
(Figure 4).
Figure 2. Normalized absorption and emission spectra of 16k in dichlorome-
thane, acetonitrile, and DMSO (recorded at T=293 K, lexcitation =350.0 nm).
3-Hydroxyisoquinoline derivatives 16 contain basic pyridyl-
type nitrogen atoms that can be protonated. Qualitative tests
indicated that the protonation of 3-hydroxyisoquinoline deriva-
tives opens a channel for nonradiative deactivation of the ex-
cited state. This behavior was more thoroughly investigated in
a titration experiment of compound 16j with trifluoroacetic
acid. The titration was easily quantified with absorption spec-
troscopy. In the absorption spectra, the appearance of a new
redshifted absorption maximum at 390 nm was observed upon
titration; this maximum can be attributed to the protochromic-
ity of the underlying isoquinoline chromophore. The pKa value
of 16j was determined to 2.24 in dichloromethane from the
measured data, with the assumption of complete dissociation
of TFA as a strong acid (c(H+)=c(TFA)). Most likely, the first
protonation occurs at the basic isoquinoline nitrogen atom.
Furthermore, protonation of the isoquinoline nitrogen atom
can be also observed in the emission behavior (Figure 5). The
emission of the chromophore is quenched with an increased
amount of TFA.
Based on the emission data, a Stern–Volmer plot was pro-
duced[45] (Figure 6), in which F0 is the emission intensity of
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Figure 6. Stern–Volmer plot of compound 16j (c0(16j)=1ꢂ10À6 m in di-
chloromethane, T=293 K; F0/F=0.933+432.96 [H+]; (r2 =0.979)).
4CR adduct has been discovered and methodologically ex-
plored.
Figure 4. Frontier molecular orbitals of 16j and 16jÀH+ (bottom: HOMOs;
top: LUMOs) contributing to the longest wavelength p–p* transitions (com-
puted frontier molecular orbital energies are given in eV).
The multiply substituted 3-hydroxyisoquinoline derivatives
16 display, in comparison with the parent system, remarkably
high fluorescence quantum yields, which renders them excel-
lent blue-light singlet emitters. Furthermore, neither the 4-alkyl
nor the 1-amide substituent causes major changes in the emis-
sion properties, which opens up additional points of diversity
for further functionalizations through the alkynyl and isonitrile
substrates. Much more pronounced effects on the electronics
of the ground and excited states can be exerted by the substi-
tution pattern of the benzo core of the isoquinoline. The fluo-
rescence efficiency is controlled by protonation, as unambigu-
ously supported by Stern–Volmer quenching, which indicates
that the protonated species is responsible for a static fluores-
cence quenching. As already shown by the trimethoxy-substi-
tuted derivatives, the redshift of both the absorption and emis-
sion maxima still maintains the intense blue luminescence and
makes this class of luminophores particularly interesting for
photonic applications. Studies directed toward more complex
3-hydroxyisoquinoline luminophores and their photophysical
and electronic characterization are currently underway.
Figure 5. Emission spectra for the titration of compound 16j
(c=1.8ꢂ10À8 molLÀ1) with TFA in dichloromethane (recorded at T=293 K;
lexcitation =350.0 nm).
Experimental Section
compound 16j and F is the emission intensity upon addition
of TFA as a quencher. The Stern–Volmer constant (KSV) for com-
pound 16j was determined to 432.96 LmolÀ1. The linear plot
supports a steady-state quenching with the Stern–Volmer con-
stant (KSV) representing the pKa value (2.67) of compound 16j
in the electronic ground state. This value matches reasonably
well with the pKa value determined from absorption spectros-
copy (2.24).
General conditions
NMR spectra were taken at room temperature in CDCl3 or
[D6]DMSO at 300 MHz (1H) and 75 MHz (13C) by using internal
standards: in CDCl3, tetramethylsilane (TMS) for H NMR spectros-
1
copy and the central peak of CDCl3 (at d=77.02 ppm) for 13C NMR
spectroscopy; in [D6]DMSO, the central peak of DMSO (at d=
2.506 ppm) for 1H NMR spectroscopy and the central peak of
DMSO (at d=39.429 ppm) for 13C NMR spectroscopy. Chemical
shifts (d) are reported in ppm and coupling constants (J) are re-
ported in Hertz. Peak assignments were also made with the aid of
gCOSY and gHSQC experiments. In an ABX system, proton A is
considered upfield and proton B is considered downfield. IR spec-
tra were recorded as solid, oil, or foamy samples, with the attenu-
ated total reflectance (ATR) technique, or as CHCl3 solutions. TLC
analyses were carried out on silica gel plates, viewed with UV light
Conclusions
In summary, a novel approach to the highly functionalized 3-
hydroxyisoquinoline scaffold through a convergent strategy in-
volving an MCR followed by a Pd-based cyclization of the Ugi
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(l=254 or 360 nm), and developed with Hanessian stain (dipping
into a solution of (NH4)4MoO4·4H2O (21 g) and Ce(SO4)2·4H2O (1 g)
in H2SO4 (31 mL) and H2O (469 mL) and warming). Rf values were
measured after an elution of 7–9 cm. Absorption spectra were re-
corded in CH2Cl2 or cyclohexane UVASOL at 293 K on a Perkin–
Elmer UV/Vis/NIR Lambda 19 spectrometer. Emission spectra were
recorded in CH2Cl2 or cyclohexane UVASOL at 293 K on a Perkin–
Elmer LS55 spectrometer. The molar extinction coefficients and
quantum yields were measured in a multipoint setup. The quan-
tum yields were measured relative to the noted standard. HRMS
was performed by employing an ESI+ ionization method. GC-MS
analyses were performed on an HP-1 column (12 m long, 0.2 mm
wide), with electron impact at 70 eV and a mass temperature of
about 1708C. Only m/z>33 were detected. All analyses were per-
formed (unless otherwise stated) with a constant He flow of
1.0 mLminÀ1 with an initial temperature of 1008C, initial time of
2 min, rate of 20 or 308CminÀ1, final temperature of 2908C, injec-
tion temperature of 2508C, and detection temperature of 2808C.
HPLC analyses (determination of the purity of compounds 16,
Table 3) were performed on a Gemini 3 mm C6-Phenyl 150ꢂ3 mm
column, at 268C with a flow of 0.3 mLminÀ1 and H2O/MeOH (from
90:10 to 0:100 in 15 min) as the eluent. Melting points are uncor-
rected. Column chromatography was done with the “flash” meth-
odology by using 220–400 mesh silica. Petroleum ether (40–608C)
is abbreviated as PE. All reactions employing dry solvents were car-
ried out under a nitrogen or argon atmosphere.
financial support, and the International Exchange Erasmus Stu-
dent Network for a grant to G.V.
Keywords: fluorescence · Heck reaction · isoquinolines ·
multicomponent reactions · photochromism
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Representative procedure for the one-step synthesis of com-
pounds 16
4-Benzyl-N-(tert-butyl)-3-hydroxyisoquinoline-1-carboxamide
(16a): A stirred solution of 5 (100 mg, 0.43 mmol) in dry MeOH
(1 mL) was treated with 2,4-dimethoxybenzylamine (54 mL,
0.36 mmol), phenylpropiolic acid (53 mg, 0.36 mmol), and tert-buty-
lisocyanide (41 mL, 0.36 mmol). The mixture was stirred at 408C
until consumption of the amine was complete (22 h). The mixture
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crude residue was diluted with CH2Cl2, washed with saturated
aqueous NaHCO3, dried (Na2SO4), and concentrated. The crude resi-
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0.72 mmol) was added. The reaction mixture was stirred at room
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100:2 to 100:4) to give 16a (93 mg, 77%) as a yellow solid. Com-
parable yields have been obtained by purifying 23 by chromatog-
raphy with PE/AcOEt (from 5:2 to 2:1) as the eluent (procedure (b)
in the Supporting Information) and submitting it to the following
deprotection and aromatization. The complete spectroscopic char-
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Published online on && &&, 0000
&
&
Chem. Eur. J. 2014, 20, 1 – 11
www.chemeurj.org
10
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Full Paper
FULL PAPER
&
Fluorescent Compounds
L. Moni, M. Denißen, G. Valentini,
T. J. J. Mꢀller,* R. Riva*
&& – &&
Diversity-Oriented Synthesis of
Intensively Blue Emissive 3-
Hydroxyisoquinolines by Sequential
Ugi Four-Component Reaction/
Reductive Heck Cyclization
Blue is the color: A library of highly
substituted 3-hydroxyisoquinolines was
prepared by coupling the isocyanide-
based Ugi four-component reaction
(Ugi-4CR) with an intramolecular reduc-
tive Heck reaction (see scheme). The
prepared compounds are intensively
blue emitting fluorophores, as support-
ed by high fluorescence quantum
yields.
Chem. Eur. J. 2014, 20, 1 – 11
www.chemeurj.org
11
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ