Synthesis of para-aryl-substituted salicyldialdehydes

Article abstract of DOI:10.1002/ejoc.201500228

para-Substituted salicyldialdehydes are versatile molecular building blocks for porous organic cages, fluorescent dyes, spirobenzopyrans, homooxacalixarenes, dinuclear metal complexes, macrocycles, and cryptands. To date, no procedures for the synthesis of para-aryl-substituted salicyldialdehydes have been reported, which would broaden the scope of the above-mentioned topics, especially in the field of sensors and dyes, because the aromatic π systems can be enlarged and absorption or fluorescent events can be fine-tuned by various substituents. Herein, two synthetic routes to para-aryl-substituted salicyldialdehydes with both electron-withdrawing and -donating aromatic units are reported.

Full text of DOI:10.1002/ejoc.201500228

FULL PAPER
DOI: 10.1002/ejoc.201500228
Synthesis of para-Aryl-Substituted Salicyldialdehydes
Dennis Reinhard,[a] Ludger Schöttner,[a] Victor Brosius,[a] Frank Rominger,[a] and
Michael Mastalerz*[a]
Keywords: Synthetic methods / Cross-coupling / Formylation / Aldehydes / Phenols / Cage compounds
para-Substituted salicyldialdehydes are versatile molecular
building blocks for porous organic cages, fluorescent dyes,
spirobenzopyrans, homooxacalixarenes, dinuclear metal
complexes, macrocycles, and cryptands. To date, no pro-
cedures for the synthesis of para-aryl-substituted salicyldi-
aldehydes have been reported, which would broaden the
scope of the above-mentioned topics, especially in the field
of sensors and dyes, because the aromatic π systems can be
enlarged and absorption or fluorescent events can be fine-
tuned by various substituents. Herein, two synthetic routes to
para-aryl-substituted salicyldialdehydes with both electron-
withdrawing and -donating aromatic units are reported.
of para-substituted salicyldialdehydes with triptycene
triamine.[8a] This [4+6] cage has been used for further trans-
formations in the interiors of cavities[11] and as a soluble
porous unit to decorate quartz microcrystal balances with
thin films of these cages to create gravimetric sensors for
airborne analytes.[12] For these [4+6] cages it has been dem-
onstrated that the peripheral substituents have a significant
impact on the crystal packing and, thus, the accessible sur-
face areas.[8d,8e] A similar observation has been made for
the Cooper cages.[13] However, to date the para-substituted
salicyldialdehydes used in the cage synthesis were restricted
to aliphatic chains and a trityl unit, which is also connected
to the 4-position of the salicyldialdehyde through an sp3-
centered carbon atom.[8d,8e]
Introduction
Organic cage compounds have gained a large amount of
interest from the synthetic community since the concept of
dynamic covalent chemistry was introduced as a powerful
synthetic tool to achieve rather complex structures from
readily accessible building blocks.[1] Although Quan and
Cram described the synthesis of a large carcerand by eight-
fold imine condensation in 1991,[2] most cages at that time
were synthesized by irreversible reactions under dilute con-
ditions, which often gave the compounds in low yields.[3]
Warmuth et al., for instance, used imine condensation in a
broader sense to realize shape-persistent organic cage com-
pounds with different geometries and sizes.[4] In 2009, the
group of Cooper demonstrated that [6+4] cages, synthesized
by 12-fold imine condensation of 1,3,5-triformylbenzene
and chiral diamines, could be freed from enclathrated solv-
ate molecules in the crystalline state to give materials with
specific surface areas of 624 m2 g–1, according to the
Brunauer–Emmett–Teller model.[5] Since then, this new re-
search area has been developing very quickly,[6] and besides
imine condensation reactions[7–9] other types of reversible
reactions, such as that of boronic acids and diols, have been
applied to synthesize shape-persistent organic cages that
can be used to create porous materials with mesopores and
specific surface areas of 3758 m2 g–1.[10]
Those alkyl-substituted dialdehydes were accessible by
twofold Duff formylation according to a protocol of
Svenstrup, in which trifluoroacetic acid (TFA) and hexa-
methylenetetramine (HMTA) are used as reagents under
elevated temperatures.[14]
It is known for cage compounds that aromatic moieties
in the periphery can influence the packing of cages in the
crystalline state by π–π stacking, and therefore, salicyldi-
aldehydes that are para-substituted with an aromatic unit
would be desired as molecular building blocks for the con-
struction of [4+6] cages.[15] Considering that salicyldi-
aldehydes are used for the synthesis of [4+6] cages, larger
[8+12] cages,[16] water-soluble fluorescent dyes,[17] spiro-
benzopyrans as sensors,[18] homooxacalixarenes,[19] smaller
macrocycles as ligands for dinuclear metal complexes,[20]
larger macrocycles,[21] and cryptands,[22] it is surprising that
there is no general protocol for the synthesis of para-aryl-
substituted salicyldialdehydes.[23] Herein, we describe the
development of two synthetic routes to make a variety of
para-aryl-substituted salicyldialdehydes readily available.
Still, one of the most porous cages with a very high sur-
face area of 2071 m2 g–1 is based on the [4+6] condensation
[a] Organisch-Chemisches-Institut,
Heidelberg,
Ruprecht-Karls-Universität
Im Neuenheimer Feld 273, 69120 Heidelberg, Germany
E-mail: Michael.Mastalerz@oci.uni-heidelberg.de
http://www.uni-heidelberg.de/fakultaeten/chemgeo/oci/
mastalerz/index.html
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500228.
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Synthesis of para-Aryl-Substituted Salicyldialdehydes
to increase the yield of 2 from 35 to 52%, but we were never
were able to reproduce the reported yields.
Results and Discussion
The formylation of phenols by the procedure first investi-
gated by Duff and Bills is a useful method to synthesize
salicylaldehydes.[24] Besides other methods that regioselec-
tively introduce formyl groups to phenols such as the Re-
imer–Tiemann reaction[25] or the magnesium-mediated
ortho-selective formylations described by Casiraghi,[26] the
major advantage of the Duff reaction in its modification by
Svenstrup[14] is that it gives the opportunity to synthesize
doubly formylated phenols under harsh conditions within
one step, which was not possible to date by other form-
ylation methods in a broader sense, with the exception of
one protocol, which described a twofold Reimer–Tiemann
reaction on para-hydroxyacetophenone.[27]
The Duff formylation is a key step for the preparation of
4-substituted salicyldialdehydes, and in principle, there are
two different reaction sequences leading to the target 4-aryl-
substituted compounds (Scheme 1). Reaction pathway A
starts from 4-bromophenol (1), which is known to undergo
a twofold Duff formylation reaction;[14] this is followed by
a Suzuki–Miyaura cross-coupling reaction with various
arylboronic acids.[28] Alternatively, pathway B, in which the
reverse order of reactions is applied is a possibility. In this
case, the first step is a Suzuki–Miyaura cross-coupling reac-
tion to get 4-hydroxybiphenyls 5, followed by Duff for-
mylation under Svenstrup conditions.
The second step in route A is the Suzuki–Miyaura cross-
coupling reaction with arylboronic acids or esters. To the
best of our knowledge, no such reactions have been de-
scribed with the use of brominated salicyldialdehyde 2 as
the electrophile. In contrast, para-bromosalicylmonoal-
dehydes have been described to undergo cross-coupling re-
actions with arylboronic acids in high yields if Pd(dppf)Cl2
[dppf = 1,1Ј-bis(diphenylphosphino)ferrocene] is used as
the catalyst in a mixture of 1,2-dimethoxyethane (DME)/
water under reflux conditions.[29]
First these conditions [Pd(dppf)Cl2 (5 mol-%)] were
adopted for the reaction of bromide 2 with anisylboronic
acid (3a; Table 1, entry 1; see also Scheme 2). Desired para-
substituted salicyldialdehyde 4a was isolated in 25% yield.
Changing the palladium source to Pd2(dba)3 (dba = dibenz-
ylideneacetone) and by using HP(tBu)3BF4 as a precursor
for the corresponding phosphine ligand (Table 1, en-
try 2),[30] 4a was isolated in a much higher yields of 86%.
In this case, THF was used as the solvent instead of DME,
which can be more easily removed, and only 1 mol-% of
the catalyst was necessary. With these optimized conditions,
other electron-rich boronic acids were cross-coupled to give
4-tert-butylphenyl- (4b, Table 1, entry 3), thienyl- (4c,
Table 1, entry 4), and 9-anthracenyl-coupled (4d, Table 1,
entry 5) salicyldialdehyde in yields between 68 and 93%.
However, if para-hydroxyphenylboronic acid (3e, Table 1,
entry 6) was used, the yields dropped to 37%. 3,5-Dimeth-
oxyphenylboronic acid (3f; Table 1, entry 7) gave corre-
sponding salicylaldehyde 4f in 52% yield, which is in agree-
ment with the fact that methoxy substituents in the meta
position do not influence the reactivity of the boronic acid
through mesomeric effects.
Phenylboronic acid (3g) has neither an electron-with-
drawing nor an electron-donating substituent, and it gave
an even somewhat lower yield of 34% for the product of the
Suzuki–Miyaura cross-coupling reaction (Table 1, entry 8).
The yields dropped if electron-poor arylboronic acids were
used (Table 1, entries 11, 14, and 17) under these condi-
tions. With the exception of aldehyde-substituted phenyl-
boronic acid 3h, the yield decreased to 11% for bis(tri-
fluoromethyl)-substituted boronic acid 3i and to 20% for
acid ester 3j. Another catalyst system based on Pd(OAc)2
and triphenylphosphine gave slightly higher yields for the
reaction of electron-poor boronic acids with bromide 2
(Table 1, entries 12, 13, and 15).[31] However, no catalyst
system was reactive enough to give a cross-coupling prod-
uct in the reaction of (pentafluorophenyl)boronic acid (3l)
Scheme 1. Two possible routes (A and B) towards 4-aryl-substi-
tuted salicyldialdehydes 4. Route A: First Duff formylation (i);
then, Suzuki–Miyaura cross-coupling (ii). Route B: First Suzuki–
Miyaura cross-coupling (iii); then, Duff formylation (iv).
First, route A was investigated. It started with the syn- with bromide 2.[32]
thesis of 4-bromosalicyldialdehyde (2), which was achieved
It is noteworthy that in the analysis of the crude products
in about 35% yield by twofold Duff formylation by using by ultra performance liquid chromatography (UPLC)–MS
HMTA (2.3 equiv.) and TFA (solvent) as the reactants at for all cross-coupling reactions with electron-poor boronic
100 °C for 24 h according to the method of Svenstrup et al., acids a small peak with a m/z ratio corresponding to a two-
as previously reported.[14] A more recent publication de- fold coupled product was always observed. For bis(fluoro-
scribes a slightly different protocol, for which under harsher methyl)-substituted compound 3i, byproduct 6 was isolated
conditions (110 °C, 48 h, 20 equiv. HMTA) 2 can be iso- in 4% yield (and 9% yield on 2 mmol reaction scale,
lated in 92% yield.[23] Following this protocol, we were able Scheme 3) and was identified by NMR spectroscopy as well
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D. Reinhard, L. Schöttner, V. Brosius, F. Rominger, M. Mastalerz
Table 1. Conditions and yields for the Suzuki–Miyaura cross-coupling reactions depicted in Scheme 2 performed on a 1 mmol scale.
FULL PAPER
Entry
Ar-B(OH)2
Catalyst system[a] (mol-% Pd)
Conditions[b]
Yield[c] [%] (4)
1
2
3
4
5
6
7
8
3a
3a
3b
3c[d]
3d
3e
3f
Pd(dppf)Cl2 (5)
K2CO3, DME/H2O, 105 °C
KF, THF/H2O, 80 °C
KF, THF/H2O, 80 °C
KF, THF/H2O, 80 °C
KF, THF/H2O, 80 °C
KF, THF/H2O, 80 °C
KF, THF/H2O, 80 °C
KF, THF/H2O, 80 °C
KF, THF/H2O, 80 °C
K2CO3, DME/H2O, 105 °C
KF, THF/H2O, 80 °C
K2CO3, DME/H2O, 105 °C
K2CO3, DME/H2O, 105 °C
KF, THF/H2O, 80 °C
K2CO3, DME/H2O, 105 °C
K2CO3, DME/H2O, 105 °C
KF, THF/H2O, 80 °C
K2CO3, DME/H2O, 105 °C
CsF, Ag2O, DMF, 105 °C
25 (4a)
86 (4a)
82 (4b)
68 (4c)
93 (4d)
37 (4e)
52 (4f)
34 (4g)
55 (4h)
14 (4i)
11 (4i)
55 (4i)
53 (4i)
20 (4j)
31 (4j)
29 (4k)
–(4l)
Pd2(dba)3/P(tBu)3 (1)
Pd2(dba)3/P(tBu)3 (1)
Pd2(dba)3/P(tBu)3 (1)
Pd2(dba)3/P(tBu)3 (1)
Pd2(dba)3/P(tBu)3 (1)
Pd2(dba)3/P(tBu)3 (1)
Pd2(dba)3/P(tBu)3 (1)
Pd2(dba)3/P(tBu)3 (1)
Pd(dppf)Cl2 (5)
Pd2(dba)3/P(tBu)3 (1)
Pd(OAc)2/PPh3 (2)
Pd(OAc)2/PPh3 (2)
Pd2(dba)3/P(tBu)3 (1)
Pd(OAc)2/PPh3 (2)
Pd(OAc)2/PPh3 (2)
Pd2(dba)3/P(tBu)3 (1)
Pd(OAc)2/PPh3 (2)
Pd2(dba)3/P(tBu)3 (1)
3g
3h
3i
9
10
11
12[e]
13[e,f]
14
15
16
17
18
19
3i
3i
3i
3j
3j
3k
3l
3l
3l
–(4l)
–(4l)
[a] P(tBu)3 was generated in situ from HP(tBu)3/BF4. [b] Reaction time: 16 h. [c] Isolated yield after column chromatography. [d] The
corresponding pinacol ester of (5-hexylthienyl)boronic acid was used. [e] In addition, byproduct 6 was isolated in 4 or 9% yield, respec-
tively, depending on the reaction scale. [f] Scale of reaction: 2 mmol.
of the singlet of the Hc proton (of compound 4i) into two
doublets, Hc*Ј at δ = 8.19 ppm and Hc*ЈЈ at δ = 8.06 ppm,
was observed; this can be explained by the unsymmetric
chemical environment originating from the two bis(3,5-tri-
fluoromethyl)phenyl substituents. Furthermore, in the
13C NMR spectrum an additional chemical shift of δ =
193.3 ppm, which is typical for a carbonyl group of a keto
functionality, was found. The formation of 6 was also
proven by single-crystal X-ray structure analysis (Figure 2
and the Supporting Information). Byproduct
6 was
probably formed through an oxidation step, which might
stem from trace amounts of oxygen or by homodimeriza-
tion of 2.[33–37]
Scheme 3. Suzuki–Miyaura cross-coupling of 2 with 3i to give
salicyldialdehyde 4i and diaryl ketone 6, yields are given for reac-
tions of substrate 2 on a 1 or 2 mmol scale.
Scheme 2. Syntheses of salicyldialdehydes 4a–l by Suzuki–Miyaura
cross-coupling. For reaction conditions and yields, see Table 1. In
the case of compound 3c, the corresponding pinacol ester of 5-
hexylthienylboronic acid was used.
Regarding the low to moderate yields for electron-poor-
substituted salicyldialdehydes following cross-coupling
as by single-crystal X-ray diffraction. Whereas the route A, investigation of route B was undertaken first with
1H NMR spectrum of compound 4i shows a characteristic electron-poor hydroxybiphenyls 5i–l (Scheme 4) to see
set of singlets deriving from the aldehyde Hb proton (δ = whether route B was superior to route A for electron-poor
10.35 ppm) and the aromatic protons between δ = 8.22 to compounds. The hydroxybiphenyls were commercially
7.92 ppm, the spectrum of 6 contains an additional set of available or easily synthesized from (4-hydroxyphenyl)-
signals (Figure 1) that can be assigned to an unsymmetrical boronic acid and appropriate aryl bromides through
substituted salicylaldehyde. Besides a lower integral value Suzuki–Miyaura cross-coupling reactions in very good to
for the aldehyde Hb* proton at δ = 10.28 ppm, the splitting quantitative yields.[38] The first synthetic target was salicyl-
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Synthesis of para-Aryl-Substituted Salicyldialdehydes
1
Figure 1. Comparison of the H NMR spectra of 4i (top) and 6 (bottom) in CDCl3. Only sections of the aromatic regions are depicted.
For the full spectra, see the Supporting Information.
yield of the diformylated product increased from 25 to 73%
(Table 2, entries 4 and 5). Nitro compound 4k was isolated
in 33% yield beside 30% of monoaldehyde 7k. Even penta-
fluorophenyl-substituted salicyldialdehyde 4l was accessible
in 57% yield (Table 2, entry 7), which could not be realized
at all by route A.
Scheme 4. Duff formylation of electron-poor substituted 4-
hydroxybiphenyls as the second step of route B. For conditions and
yields, see Table 2.
Figure 2. ORTEP plot of 6 with 50% probability; carbon: gray,
oxygen: red, hydrogen: white, fluorine: green.
dialdehyde 4j. Upon applying the standard conditions
If 5g without an electron-donating or electron-with-
(4 equiv. HMTA, 100 °C, 3 days), 5j was diformylated in drawing group was treated with a slight excess amount of
10% yield to give 4j in addition to 70% of monoaldehyde HMTA (2.1 equiv.) for 3 h at 100 °C, monoformylated
7j (Table 2, entry 1). By using higher temperatures (4 equiv. product 7g dominated with a yield of 74% besides 4% of
HMTA, 125 °C), the yield of desired twofold formylated 4g. By using 6 equiv. of HMTA (Table 2, entry 9) 4g was
product 4j increased to 27% (Table 2, entry 2); by doubling then again isolated in 49% yield besides 13% yield of the
the amount of HMTA to 8 equiv., the yield was slightly monoaldehyde. Åkermark has previously reported that 4g
raised to 35% (Table 2, entry 3). For 5i, we observed an can be synthesized in 92% yield by using 20 equiv. of
even larger effect upon using harsher conditions, and the HMTA.[23] Indeed, by following the reported procedure
Eur. J. Org. Chem. 2015, 3274–3285
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FULL PAPER
Table 2. Duff reactions of 5g–b,i–k.
Entry
Substrate
HMTA
T
t
Yield[a] [%]
[equiv.] [°C] [h]
dialdehyde monoaldehyde
4
7
1
2
3
4
5
6
7
8
5j
5j
5j
5i
5i
4
4
8
4
8
8
8
2.1
6
20
4
100 72
125 72
125 72
100 72
125 72
125 72
125 72
10 (4j)
27 (4j)
35 (4j)
25 (4i)
73 (4i)
33 (4k)
57 (4l)
4 (4g)
70 (7j)
– (7j)
– (7j)
57 (7i)
– (7i)
30 (7k)
– (7l)
74 (7g)
13 (7g)
Ͻ3 (7g)
26 (7g)
– (7a)
5k
5l
5g
5g
5g
5g
5a
100
3
9
100 16
110 72
125 36
49 (4g)
47 (4g)
6 (4g)
10[23]
11[b]
12[c]
2.2
100
3
– (4a)
[a] Yield of isolated product. [b] Triformylated substrate 4h (6%)
was also formed. [c] Other diformylated regioisomer 8 was isolated
(33%).
Scheme 5. Duff formylation reactions of electron-rich substituted
4-hydroxybiphenyl derivatives 5a and 5g.
strictly it was nearly possible to reach the reported yield of
92% (crude yield in our case: 85%). It has to be mentioned
that after purification by column chromatography only 47% comes poorer than that of the unsubstituted anisyl ring,
of desired dialdehyde 4g was isolated (Table 2, entry 10). which makes the anisyl ring more reactive. This clearly
Upon using higher temperatures, we observed that instead demonstrates that route A has to be used for the synthesis
of increasing the yield of 4g, another regioisomer was of electron-rich salicyldialdehydes.
formed in 6% yield, for which the para position of the sec-
ond phenyl ring was formylated (4h; Table 2, entry 11; see the synthesis of [4+6] cages were performed (Scheme 6).[39]
also Scheme 5).
For instance, in the reaction of triamine 9[40] with an-
Preliminary tests for the use of the new dialdehydes in
If electron-rich hydroxybiphenyl 5a was treated under thracenyl-substituted dialdehyde 4d, an orange-colored pre-
Duff conditions, salicyldialdehyde 4a was not formed. cipitate was formed after stirring the mixture in THF at
1
Instead, a second electrophilic aromatic substitution took room temperature. Analysis of the solid by H NMR and
place on the anisyl ring to give compound 8. This can be IR spectroscopy and by mass spectrometry revealed that
explained by the fact that after the first formylation of the the orange solid mainly corresponded to imine cage 10. In
1
phenol ring, the electron density of this phenyl ring be- the H NMR spectrum, the imine protons resonate at δ =
Scheme 6. Imine condensation reaction of 4g and 7 to cage compound 10.
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Synthesis of para-Aryl-Substituted Salicyldialdehydes
Figure 3. Aromatic region of the 1H NMR spectrum (400 MHz, 70 °C, C2D2Cl4) of cage compound 10. A full-range spectrum is available
in the Supporting Information.
9.09 ppm (Figure 3). Also characteristic are two sharp sing- by us to enlarge the family of periphery-substituted [4+6]
lets of the bridgehead protons Hbr at δ = 5.73 and imine cages. Besides that, these are versatile precursors for
5.45 ppm. The HR MALDI mass spectrum shows a pro- fluorescent dyes, new homooxacalixarenes, spiropyrans, and
nounced base peak at m/z = 2940.04186 [M + H]+ with an macrocycles.
isotopic pattern that fits well to the one expected (see the
Supporting Information). In addition, in the IR spectrum
a characteristic band of the formed imine bond can be
Experimental Section
found at ν = 1621 cm–1. However, small residual signals of the
˜
aldehyde protons can be detected in the 1H NMR spectrum
General Remarks: All reagents and solvents were obtained from
Chempur, Fisher Scientific, Alfa Aesar, Sigma–Aldrich, TCI
at approximately δ = 10.25 and 10.75 ppm, which corre-
Chemicals, or VWR and were used without further purification
spond to minor impurities of a not fully closed cage com-
unless otherwise noted. 4-Hydroxy-1,1Ј-biphenyl derivatives 5 were
commercially available or were synthesized according to literature
pound. Indeed, in the IR spectrum this can be seen as well
(band at ν = 1688 cm–1) and in the MALDI MS (m/z =
˜
procedures.[38] Triaminotriptycene (9) was synthesized according to
the protocol of Zhang and Chen.[40] For thin-layer chromatography,
Silica gel 60 F254 plates from Merck were used, which were exam-
ined under UV-light irradiation (254 and 365 nm). Flash column
chromatography was performed on silica gel from Sigma–Aldrich
(particle size: 0.04–0.063 mm) by using petroleum ether, ethyl acet-
ate, and glacial acetic acid. Melting points (not corrected) were
measured with a Büchi Melting Point B-540 device. IR spectra were
recorded with a Bruker Lumos spectrometer by using a Ge ATR
crystal. NMR spectra were taken with a Bruker Avance III 600
2958).
Conclusions
In conclusion, we developed two complementary routes
(routes A and B) to synthesize 4-aryl-substituted salicyldi-
aldehydes. For electron-rich aryl substituents, route A (first
Duff formylation, then cross-coupling) turned out to be the
preferred method. On the other hand, for phenols substi- (1H NMR: 600 MHz, 13C NMR: 151 MHz), Avance III 500
(1H NMR: 500 MHz, 13C NMR: 125 MHz), Avance III 400
tuted with electron-poor aryl rings, route B was favored,
(1H NMR: 400 MHz, 13C NMR: 100 MHz), Avance DRX 300 and
which even allowed the formation of pentafluorophenylsal-
Avance III 300 (1H NMR: 300 MHz, 13C NMR: 75 MHz) spec-
icyldialdehyde 4l in 57% yield, whereas by route A forma-
trometers at 298 K, unless otherwise mentioned. Chemical shifts
tion of this product was not observed.
(δ) are reported relative to trace amounts of CHCl3 (δH = 7.26 ppm,
The new aryl-substituted salicyldialdehydes are versatile
δC = 77.0 ppm), DMSO (δH = 2.50 ppm, δC = 39.5 ppm), or tetra-
chloroethane (δH = 5.96 ppm, δC = 73.8 ppm) in the corresponding
deuterated solvent. HRMS (ESI) as well as HRMS (MALDI) ex-
periments were performed with a Fourier Transform Ion Cyclotron
Resonance (FT-ICR) mass spectrometer Bruker ApexQe hybrid
precursors for imine cages. Indeed, preliminary results on
the reaction of anthracenyl-substituted salicyldialdehyde 4d
with triamine 9 showed the formation of corresponding
cage 10. With the herein presented methods, a variety of
new salicyldialdehydes can be obtained, which will be used 9.4 T FT-ICR equipped with a 9.4 T superconducting magnet and
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3
interfaced to an Apollo II MTP Dual ESI/MALDI source, whereas
HRMS (EI+) spectra were recorded under usage of a JEOL JMS-
700 Magnetic Sector Instrument. MALDI mass spectra were mea-
sured in positive mode with DCTB as matrix. Elemental analysis
was performed by the Microanalytical Laboratory of the University
of Heidelberg by using an Elementar Vario Micro Cube. Crystal
structure analysis was accomplished with a Bruker APEX-II Qua-
H, -OH), 10.31 (s, 2 H, -CHO), 8.14 (s, 2 H, 2,6-H), 7.52 (d, J =
8.7 Hz, 2 H, 2Ј,6Ј-H), 7.00 (d, 3J = 8.7 Hz, 2 H, 3Ј,5Ј-H), 3.87 ppm
(s, 3 H, -OCH3). 13C NMR (100.1 MHz, CDCl3): δ = 192.4
(-CHO), 162.6 (-COH), 159.8 (C-4Ј), 135.5 (C-2,6), 133.4 (C-1Ј),
130.7 (C-1), 127.8 (C-2Ј,6Ј), 123.5 (C-3,5), 114.7 (C-3Ј,5Ј),
55.5 ppm (-OCH ). FTIR (ATR): ν = 2897 (w), 2853 (w), 1686 (s),
˜
3
1660 (s), 1601 (s), 1517 (m), 1452 (s), 1395 (m), 1356 (m), 1311 (m),
1276 (s), 1248 (s), 1177 (m), 1015 (s), 979 (s), 824 (s), 793 (m), 767
(m), 734 (m), 624 cm–1 (s). HRMS (ESI): calcd. for C15H11O4 [M –
H]– 255.06628; found 255.06588; Δ = 1.6 ppm. C15H12O4·0.1H2O:
calcd. C 69.82, H 4.77; found C 69.82, H 4.77.
zar diffractometer with
a molybdenum source [λ(MoKα =
0.71073 Å].[41]
CCDC-1049101 (for 4d) and -1049102 (for 6) contain the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
4Ј-tert-Butyl-4-hydroxy-1,1Ј-biphenyl-3,5-dicarbaldehyde
(4b):
According to GP1, 2 (229 mg, 1.00 mmol) and (4-tert-butylphenyl)-
boronic acid (3b; 196 mg, 1.10 mmol) were dissolved in THF
(2 mL) and mixed with a solution of KF (174 mg, 3.00 mmol) in
H2O (0.7 mL) under an argon atmosphere. Pd2(dba)3 (9.5 mg,
0.01 mmol) and HP(tBu)3BF4 (11.0 mg, 0.04 mmol) were added,
and the mixture was stirred for 16 h at 80 °C. After workup and
flash column chromatography on silica gel (light petroleum ether/
EtOAc, 20:1), 4b was obtained as a yellow solid (231 mg, 82%);
m.p. 97–98 °C. 1H NMR (600 MHz, CDCl3): δ = 11.61 (s, 1 H,
-OH), 10.30 (s, 2 H, -CHO), 8.18 (s, 2 H, 2,6-H), 7.53 (d, 3J =
8.5 Hz, 2 H, 3Ј,5Ј-H), 7.49 (d, 3J = 8.5 Hz, 2 H, 2Ј,6Ј-H), 1.37 ppm
[s, 9 H, -C(CH3)3]. 13C NMR (151 MHz, CDCl3): δ = 192.3
(-CHO), 162.8 (-C-OH), 151.4, (C-4Ј), 135.8 (C-1Ј), 135.2 (C-2,6),
133.5 (C-1), 126.4 (C-2Ј,6Ј), 126.2 (C-3,5Ј), 123.5 (C-3,5), 34.7
4-Bromo-2,6-diformylphenol (2): 4-Bromophenol (1; 13.5 g,
70.0 mmol) and HMTA (22.3 g, 160 mmol) were dissolved in an-
hydrous TFA (100 mL), and the mixture was heated to 100 °C for
24 h under an argon atmosphere. After cooling to room tempera-
ture, the brownish solution was poured into 4 m HCl and left to
crystallize overnight. The yellow crystalline solid was filtered off,
dried in vacuo, and purified by flash column chromatography on
silica gel (light petroleum ether/CH2Cl2, 5:2) to give two fractions.
First fraction (Rf = 0.40): monoaldehyde (3.71 g, 25%), white solid;
m.p. 104 °C. 1H NMR (300 MHz, CDCl3): δ = 10.93 (s, -OH), 9.85
(s, -CHO), 7.68 (d, J = 2.5 Hz, H-3), 7.61 (dd, J = 8.9 Hz, J =
2.5 Hz, H-5), 6.91 ppm (d, 3J = 8.9 Hz, H-6) ppm. Second fraction
(Rf = 0.13): Dialdehyde 2 (5.86 g, 35%), pale yellow crystalline
solid; m.p. 139 °C. 1H NMR (500 MHz, CDCl3): δ = 11.54 (s, 1
H, -OH), 10.19 (s, 2 H, -CHO), 8.06 ppm (s, 2 H, 3,5-H). The
analytical data are in accordance with those previously pub-
lished.[14,23]
Alternative Procedure:[23] Compound 1 (1.47 g, 8.50 mmol) and
HMTA (9.52 g, 67.9 mmol) were dissolved in anhydrous
CF3COOH (25 mL), and the mixture was heated at 110 °C for 48 h.
After cooling to room temperature, the mixture was poured into
4 m HCl (50 mL) and stirred for 5 h. The yellow solid was filtered
off and washed with H2O (3ϫ 15 mL). Purification by flash col-
umn chromatography on silica gel (light petroleum ether/CH2Cl2,
5:2) gave, after drying in vacuo, 2 (1.01 g, 52%). The analytical data
are in accordance with those previously published.[14,23]
4
3
4
[-C(CH ) ], 31.4 ppm [-C(CH ) ]. FTIR (ATR): ν = 3034 (w), 2967
˜
3 3
3 3
(m), 2867 (w), 1682 (s), 1666 (s), 1660 (s), 1599 (s), 1454 (s), 1391
(s), 1364 (m), 1346 (m), 1321 (m), 1287 (m), 1266 (s), 1213 (s), 1199
(s), 1115 (w), 1066 (w), 975 (s), 901 (m), 830 (m), 750 (s), 695 (s),
612 (s) cm–1. HRMS (ESI): calcd. for C18H17O3 [M – H]–
281.11832; found 281.11778; Δ = 1.9 ppm. C18H18O3 (282.34):
calcd. C 76.57, H 6.43; found C 76.10, H 6.08.
4-(5Ј-Hexylthiophen-2Ј-yl)-2-hydroxy-1,3-benzenedicarbaldehyde
(4c): According to GP1, 2 (229 mg, 1.00 mmol) and (5-hexylthi-
enyl)boronic ester (3c; 324 mg, 1.10 mmol) were dissolved in THF
(2.0 mL) and mixed with a solution of KF (174 mg, 3.00 mmol)
in H2O (0.7 mL) under an argon atmosphere. Pd2(dba)3 (4.5 mg,
0.005 mmol) and HP(tBu)3BF4 (5.8 mg, 0.02 mmol) were added,
and the mixture was stirred for 16 h at 80 °C After workup and
flash column chromatography on silica gel (light petroleum ether/
EtOAc, 20:1), 4c was obtained as a yellow waxy solid (214 mg,
General Procedure for the Synthesis of Electron-Rich Salicyldi-
aldehydes by Suzuki–Miyaura Cross-Coupling (GP1): 4-Bromo-2,6-
diformylphenol (2, 1 equiv.) and arylboronic acid 3 (1.1 equiv.)
were dissolved in THF and mixed with a solution of KF (3 equiv.)
in H2O under an argon atmosphere. Pd2(dba)3 (0.5–1.0 mol-%) and
HP(tBu)3BF4 (1.0–2.0 mol-%) were added, and the mixture was
heated for 16 h at 70–80 °C. After cooling to room temperature,
the resulting mixture was quenched with satd. aq. NH4Cl (20 mL)
and extracted with THF (3ϫ 20 mL). The combined organic layer
was washed with brine and dried with MgSO4. After removal of
the solvent under reduced pressure, the crude product was purified
by flash column chromatography and dried in vacuo to give the
desired dialdehyde.
1
68%); m.p. 63 °C. H NMR (400 MHz, CDCl3): δ = 11.54 (s, 1 H,
OH), 10.26 (s, 2 H, CHO), 8.08 (s, 2 H, 3,5-H), 7.11 (d, 3J = 3.5 Hz,
3
3
1 H, 3Ј-H), 6.75 (d, J = 3.5 Hz, 1 H, 4Ј-H), 2.82 [t, J = 7.5 Hz,
3
2 H, C-5Ј-CH2CH2(CH2)3CH3], 1.70 [quint., J = 7.3 Hz, 2 H, C-
5Ј-CH2CH2(CH2)3CH3], 1.45–1.28 [m, 6 H, C-5Ј-CH2CH2(CH2)3-
CH3], 0.90 ppm [t, 3J = 6.9 Hz, 3 H, C-5Ј-CH2CH2(CH2)3CH3].
13C NMR (101 MHz, CDCl3):
δ = 192.1 (-CHO), 162.4
(-COH), 146.8 (C-5Ј), 138.4 (C-3,5), 134.1 (C-2Ј), 127.8 (C-4),
125.5 (C-3Ј), 123.5 (C-4Ј), 123.5 (C-2,6), 31.7 (2 C, C-5Ј-
CH2CH2CH2CH2CH2CH3), 30.4 [C-5Ј-CH2CH2(CH2)3CH3], 28.9
4-Hydroxy-4Ј-methoxy-1,1Ј-biphenyl-3,5-dicarbaldehyde
(4a): (C-5Ј-CH2CH2CH2CH2CH2CH3), 22.7 [C-5Ј-CH2(CH2)3CH2-
According to GP1, 2 (229 mg, 1.00 mmol) and (4-methoxyphenyl)- CH ], 14.2 ppm [C-5Ј-CH CH (CH ) CH ]. FTIR (ATR): ν =
˜
3
2
2
2 3
3
boronic acid (3a; 167 mg, 1.10 mmol) were dissolved in THF
(2 mL) and mixed with a solution of KF (174 mg, 3.00 mmol) in
3046 (w), 2956 (w), 2917 (m), 2871 (w), 2848 (m), 1738 (w), 1684
(s), 1657 (s), 1600 (m), 1551 (w), 1489 (w), 1466 (m), 1405 (w), 1379
H2O (0.7 mL) under an argon atmosphere. Pd2(dba)3 (4.6 mg, (w), 1355 (w), 1337 (w), 1312 (m), 1291 (w), 1273 (w), 1224 (m),
0.005 mmol) and HP(tBu)3BF4 (5.8 mg, 0.02 mmol) were added, 1184 (w), 1101 (w), 1060 (w), 977 (s), 928 (s), 905 (w), 887 (w), 870
and the mixture was stirred for 16 h at 80 °C. After workup and (w), 806 (s), 745 (m), 703 (w), 632 (w) cm–1. HRMS (ESI): calcd.
flash column chromatography on silica gel (light petroleum ether/
for C18H19O3S [M – H]– 315.10604; found 315.10524; Δ = 2.5 ppm.
EtOAc, 9:1 to 7:1), 4a was obtained as a yellow solid (220 mg,
C18H20O3S (316.41): calcd. C 68.33, H 6.37, S 10.13; found C 68.57,
86%); m.p. 131 °C. 1H NMR (400 MHz, CDCl3): δ = 11.57 (s, 1 H 6.16, S 9.69.
3280
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 3274–3285

Synthesis of para-Aryl-Substituted Salicyldialdehydes
4-(Anthracen-9-yl)-2-hydroxy-1,3-benzenedicarbaldehyde (4d): Ac-
cording to GP, 2 (458 mg, 2.00 mmol) and 9-anthraceneboronic
acid (3d; 489 mg, 2.20 mmol) were dissolved in THF (2.6 mL) and
1442 (s), 1403 (s), 1358 (m), 1315 (m), 1297 (m), 1266 (m), 1215
(s), 1199 (s), 1176 (s), 1152 (s), 1062 (s), 1042 (s), 983 (s), 924 (m),
899 (m), 834 (m), 748 (s), 730 (m), 699 (s), 626 (m) cm–1. HRMS
mixed with a solution of KF (349 mg, 3.00 mmol) in H2O (1.4 mL) (ESI): calcd. for C16H13O5 [M – H]– 285.07685; found 285.07633;
under an argon atmosphere. Pd2(dba)3 (18.3 mg, 0.02 mmol) and
Δ = 1.8 ppm. C16H14O5 (286.28): calcd. C 67.13, H 4.93; found C
HP(tBu)3BF4 (23.2 mg, 0.08 mmol) were added, and the mixture 66.76, H 5.16.
was stirred for 16 h at 80 °C. After workup and flash column
4-Hydroxy-1,1Ј-biphenyl-3,5-dicarbaldehyde (4g): According to GP,
chromatography on silica gel (light petroleum ether/EtOAc, 20:1),
4d was obtained as a yellow solid (608 mg, 93%); m.p. 165 °C
(dec.). 1H NMR (400 MHz, CDCl3): δ = 11.81 (s, 1 H, -OH), 10.35
(s, 2 H, -CHO), 8.56 (s, 1 H, 10Ј-H), 8.08 (d, J = 8.5 Hz, 2 H, 4Ј,5Ј-
H), 8.05 (s, 2 H, 2,6-H), 7.59–7.54 (m, 2 H, 1Ј,8Ј-H), 7.53–7.46 (m,
2 H, 2Ј,7Ј/3Ј,6Ј-H), 7.43–7.37 ppm (m, 2 H, 2Ј,7Ј/3Ј,6Ј-H). 13C
NMR (101 MHz, CDCl3): δ = 192.3 (-CHO), 163.2 (-C-OH), 140.4
(C-2,6), 133.2 (C-1), 131.5 (C-4aЈ,5aЈ/1aЈ,8aЈ), 130.9 (C-9Ј), 130.5
(C-4aЈ,5aЈ/1aЈ,8aЈ), 128.9 (C-4Ј,5Ј), 127.9 (C-10Ј), 126.4 (C-2Ј,7Ј/
3Ј,6Ј), 125.9 (C-1Ј,8Ј), 125.5 (C-2Ј,7Ј/3Ј,6Ј), 123.5 ppm (C-3,5).
2 (229 mg, 1.00 mmol) and phenylboronic acid (3g; 134 mg,
1.10 mmol) were dissolved in THF (1.3 mL) and mixed with a solu-
tion of KF (174 mg, 3.00 mmol) in H2O (0.7 mL) under an argon
atmosphere. Pd2(dba)3 (4.6 mg, 0.005 mmol) and HP(tBu)3BF4
(5.8 mg, 0.02 mmol) were added, and the mixture was stirred for
16 h at 80 °C. After workup and column chromatography on silica
gel (light petroleum ether/EtOAc/HOAc, 95:4:1), 4g was obtained
as a pale yellow solid (77 mg, 34%); m.p. 112 °C. 1H NMR
(400 MHz, CDCl3): δ = 11.61 (s, 1 H, -OH), 10.31 (s, 2 H, -CHO),
8.18 (s, 2 H, 2,6-H), 7.60–7.55 (m, 2 H, 3Ј,5Ј-H), 7.52–7.44 (m, 2
H, 2Ј,6Ј-H), 7.42–7.37 ppm (m, 1 H, 4Ј-H). 13C NMR (101 MHz,
CDCl3): δ = 192.3 (-CHO), 163.0 (-COH), 138.2 (C-1Ј), 135.9 (C-
2,6), 133.7 (C-1), 129.3 (C-2Ј,6Ј), 128.2 (C-4Ј), 126.7 (C-3Ј,5Ј),
FTIR (ATR): ν = 3052 (w), 2861 (w), 1686 (s), 1656 (s), 1599 (m),
˜
1460 (m), 1419 (w), 1395 (m), 1362 (w), 1295 (m), 1262 (w), 1211
(m), 1134 (w), 1009 (w), 979 (m), 889 (w), 846 (w), 818 (w), 797
(w), 734 (s), 708 (m), 640 (w), 622 (m) cm–1. HRMS (ESI): calcd.
for C22H13O3 [M – H]– 325.08702; found 325.08649; Δ = 1.6 ppm.
C22H14O3 (326.35): calcd. C 80.97, H 4.32; found C 80.60, H 4.58.
123.6 ppm (C-3,5). FTIR (ATR): ν = 3032 (w), 2877 (w), 2850 (w),
˜
1666 (s), 1594 (s), 1456 (s), 1417 (m), 1395 (m), 1321 (m), 1285 (s),
1266 (m), 1213 (s), 1070 (w), 975 (s), 899 (m), 763 (m), 752 (m),
697 (s), 648 (s) cm–1. HRMS (ESI): calcd. for C14H9O3 [M – H]–
225.05572; found 225.05515; Δ = 0.2 ppm. C14H10O3 (226.23):
calcd. C 74.33, H 4.46; found C 74.62, H 4.45. The analytical data
are in accordance with those previously published.[41]
4,4Ј-Dihydroxy-1,1Ј-biphenyl-3,5-dicarbaldehyde (4e): According to
GP, 2 (143 mg, 0.62 mmol, 1.00 equiv.) and (4-hydroxyphenyl)bo-
ronic acid (3e; 95.0 mg, 0.69 mmol, 1.10 equiv.) were dissolved in
THF (1.5 mL) and mixed with an aq. K2CO3 solution (1 m,
0.7 mL) under an argon atmosphere. Pd2(dba)3 (10 mg, 0.01 mmol)
and HP(tBu)3BF4 (10 mg, 0.04 mmol) were added, and the mixture
was stirred for 16 h at 80 °C. After workup and flash column
chromatography on silica gel (light petroleum ether/EtOAc, 20:1),
4e was obtained as an orange solid (73 mg, 0.32 mmol, 52%); m.p.
4-Hydroxy-1,1Ј-biphenyl-3,5,4Ј-tricarbaldehyde (4h): According to
GP, 2 (229 mg, 1.00 mmol) and (4-formylphenyl)boronic acid (3h;
165 mg, 1.10 mmol) were dissolved in THF (2 mL) and mixed with
a solution of KF (174 mg, 3.00 mmol) in H2O (0.7 mL) under an
argon atmosphere. After the addition of Pd2(dba)3 (4.6 mg,
0.005 mmol) and HP(tBu)3BF4 (5.9 mg, 0.02 mmol), the mixture
was stirred for 16 h at 80 °C. After workup and flash column
chromatography on silica gel (light petroleum ether/EtOAc, 7:1 to
2:1), 4h was obtained as an off-white solid (87 mg, 0.34 mmol,
34%); m.p. 176 °C. 1H NMR (600 MHz, [D6]DMSO): δ = 11.73 (s,
1 H, -OH), 10.30 (s, 2 H, -CHO), 10.05 (s, 1 H, -C-4Ј-CHO), 8.42
1
227 °C. H NMR (400 MHz, [D6]DMSO): δ = 11.50 (s, 1 H, C-4-
OH), 10.28 (s, 2 H, -CHO), 9.60 (s, 1 H, C-4Ј-OH), 8.22 (s, 2 H, 2,6-
3
H), 7.52 (d, J = 8.5 Hz, 2 H, 2Ј,6Ј-H), 6.87 ppm (d, 3J = 8.5 Hz, 2
H, 3Ј,5Ј-H). 13C NMR (101 MHz, [D6]DMSO): δ = 192.4 (-CHO),
160.7 (C-4-OH), 157.4 (C-4Ј-OH), 134.2 (C-2,6), 132.2 (C-1Ј), 128.3
(C-1), 127.4 (C-2Ј,6Ј), 123.7 (C-3,5), 115.9 ppm (C-3Ј,5Ј). FTIR
(ATR): ν = 3468 (br. s), 3071 (w), 2889 (w), 1666 (s), 1592 (s), 1523
˜
3
3
(s, 2 H, 2,6-H), 8.01 (d, J = 8.5 Hz, 2 H, 3Ј,5Ј-H), 7.95 ppm (d, J
= 8.5 Hz, 2 H, 2Ј,6Ј-H). 13C NMR (151 MHz, [D6]DMSO): δ =
192.7 (C-4Ј-CHO), 192.2 (C-3,5-CHO), 162.1 (-COH), 143.2
(-C-1Ј), 135.4 (C-4Ј), 135.3 (C-2,6) 130.3 (C-3Ј,5Ј), 130.3 (C-1),
(m), 1462 (m), 1446 (s), 1421 (m), 1401 (s), 1364 (m), 1319 (m),
1305 (w), 1274 (s), 1264 (s), 1211 (s), 1179 (s), 1066 (m), 979 (s),
899 (m), 832 (s), 795 (m), 734 (s), 646 (m), 620 (s) cm–1. HRMS
(ESI): calcd. for C14H9O4 [M – H]– 241.05063; found 241.05020; Δ
= –0.4 ppm. C14H10O4 (242.23): calcd. C 69.42, H 4.16; found C
69.02, H 4.45.
126.9 (C-2Ј,6Ј), 124.1 ppm (C-3,5). FTIR (ATR): ν = 3050 (w),
˜
2899 (w), 2865 (w), 1729 (w), 1686 (s), 1654 (s), 1605 (s), 1597 (s),
1572 (s), 1456 (s), 1391 (s), 1323 (m), 1289 (s), 1266 (m), 1197 (s),
1174 (s), 977 (s), 901 (m), 826 (s), 740 (s), 722 (m), 665 (m), 608
(m) cm–1. HRMS (ESI): calcd. for C15H10O4 [M – H]– 253.05063;
found 253.05014; Δ = 1.9 ppm. C15H10O4·0.3H2O: C 69.39, H 4.12;
found C 69.38, H 4.36.
4-Hydroxy-3Ј,5Ј-dimethoxy-1,1Ј-biphenyl-3,5-dicarbaldehyde (4f):
According to GP,
2 (229 mg, 1.00 mmol) and (3,5-dimeth-
oxyphenyl)boronic acid (3f; 200 mg, 1.10 mmol) were dissolved in
THF (2 mL) and mixed with a solution of KF (174 mg, 3.00 mmol)
in H2O (0.7 mL) under an argon atmosphere. Pd2(dba)3 (9.5 mg,
0.01 mmol) and HP(tBu)3BF4 (11.0 mg, 0.04 mmol) were added,
General Procedure for the Synthesis of Electron-Poor Salicyldi-
and the mixture was stirred for 16 h at 80 °C. After workup and aldehydes by Suzuki–Miyaura Cross-Coupling (GP2): 4-Bromo-2,6-
flash column chromatography on silica gel (light petroleum ether/
diformylphenol (2, 1 equiv.), arylboronic acid 3 (1.1 equiv.), and
K2CO3 (3 equiv.) were suspended in DME/H2O (1:1 v/v) under an
argon atmosphere. Pd(OAc)2 and PPh3 were added, and the mix-
ture was stirred for 16 h at 105 °C. The reaction was quenched by
EtOAc, 9:1 to 6:1), 4f was obtained as a yellow solid (121 mg,
1
0.42 mmol, 43%); m.p. 175 °C. H NMR (300 MHz, CDCl3): δ =
11.63 (s, 1 H, -OH) 10.30 (s, 2 H, -CHO), 8.15 (s, 2 H, 2,6-H), 6.68
(d, 4J = 2.2 Hz, 2 H, 2Ј,6Ј-H), 6.49 (t, 4J = 2.2 Hz, 1 H, 4Ј-H), the addition of satd. aq. NH4Cl (20 mL) followed by extraction
3.85 ppm (s, 6 H, -OCH3). 13C NMR (75 MHz, CDCl3): δ = 192.2 with EtOAc (3ϫ 50 mL). The organic extract was washed with
(-CHO), 163.1 (-COH), 161.6 (C-3Ј,5Ј), 140.3 (C-1Ј), 136.0 (C-2,6), brine and dried with MgSO4, and the solvent was removed under
133.6 (C-1), 123.4 (C-3,5), 105.1 (C-2Ј,6Ј), 99.9 (C-4Ј), 55.7 ppm reduced pressure to give the crude product as a yellow to orange
(-OCH ). FTIR (ATR): ν = 3081 (w), 3012 (w), 2983 (w), 2946 (w), residue. Purification by flash column chromatography gave the
˜
3
2842 (w), 1682 (s), 1650 (s), 1599 (s), 1590 (s), 1472 (m), 1446 (s),
biaryl.
Eur. J. Org. Chem. 2015, 3274–3285
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3281

D. Reinhard, L. Schöttner, V. Brosius, F. Rominger, M. Mastalerz
C16H12O5 (284.27): calcd. C 67.60, H 4.26; found C 66.91,
FULL PAPER
4-Hydroxy-3Ј,5Ј-bis(trifluoromethyl)-1,1Ј-biphenyl-3,5-dicarbalde-
hyde (4i) and 5-[3,5-Bis(trifluoromethyl)benzoyl]-4-hydroxy-3Ј,5Ј-
bis(trifluoromethyl)-1,1Ј-biphenyl-3-carbaldehyde (6): According to
GP2, 2 (229 mg, 1.00 mmol), [3,5-bis(trifluoromethyl)phenyl]-
boronic acid (3i; 284 mg, 1.10 mmol), and K2CO3 (415 mg,
3.00 mmol) were suspended in DME/H2O (1:1 v/v, 2.4 mL) under
an argon atmosphere. After the addition of Pd(OAc)2 (4.5 mg,
0.02 mmol) and PPh3 (10.5 mg, 0.04 mmol), the mixture was stirred
for 16 h at 105 °C. After workup, purification by flash column
chromatography on silica gel (light petroleum ether/EtOAc/HOAc,
95:4:1) gave two fractions. First fraction (Rf = 0.28): Carb-
aldehyde 6 (21 mg, 4%), off-white solid; m.p. 148 °C. 1H NMR
(600 MHz, CDCl3): δ = 11.82 (s, 1 H, -OH), 10.28 (s, 2 H, -CHO),
H 4.68.
4-Hydroxy-4Ј-nitro-1,1Ј-biphenyl-3,5-dicarbaldehyde (4k): Accord-
ing to GP2, 2 (229 mg, 1.00 mmol), (4-nitrophenyl)boronic acid
(3k; 184 mg, 1.10 mmol), and K2CO3 (415 mg, 3.00 mmol) were
suspended in DME/H2O (1:1 v/v, 2.4 mL) under an argon atmo-
sphere. After the addition of Pd(OAc)2 (4.5 mg, 0.02 mmol) and
PPh3 (10.5 mg, 0.04 mmol), the mixture was stirred for 16 h at
105 °C. After workup, purification by flash column chromatog-
raphy on silica gel (light petroleum ether/EtOAc, 5:1 to 3:2) gave 4k
1
as a pale yellow solid (78 mg, 29%); m.p. 241 °C (dec.). H NMR
(400 MHz, CDCl3): δ = 11.74 (s, 1 H, -OH), 10.34 (s, 2 H, -CHO),
8.34 (d, J = 8.8 Hz, 2 H, 3Ј,5Ј-H), 8.24 (s, 2 H, 2,6-H), 7.76 ppm
(d, J = 8.8 Hz, 2 H, 2Ј,6Ј-H). 13C NMR (101 MHz, CDCl3): δ =
191.8 (-CHO), 163.9 (-COH), 147.7 (C-4Ј), 144.5 (C-1Ј), 136.0 (C-
2,6), 131.1 (C-1), 127.5 (C-2Ј,6Ј), 124.7 (C-3Ј,5Ј), 123.9 ppm (C-
4
8.27 (s, 2 H, 2ЈЈ,6ЈЈ-H), 8.19 (d, J = 2.3 Hz, 1 H, 2-H), 8.14 (s, 1
4
H, 4ЈЈ-H), 8.06 (d, J = 2.4 Hz, 1 H, 6-H), 8.00 (s, 2 H, 2Ј,6Ј-H),
7.92 ppm (s, 1 H, 4Ј-H). 13C NMR (151 MHz, CDCl3): δ = 194.0
(-CHO), 193.3 (-C=O), 161.4 (-COH), 140.4 (C-1Ј), 138.9 (C-1ЈЈ),
136.7 (C-2), 135.8 (C-6), 132.9 (C-2Ј,6Ј), 132.5 (C-2ЈЈ,6ЈЈ), 130.9 (C-
1), 129.6 (C-3ЈЈ,5ЈЈ), 127.0 (C-3Ј,5Ј), 126.7 (C-4ЈЈ), 125.9 (C-3),
123.1 (-CЈF3, -CЈЈF3), 123.0 (C-5), 122.0 ppm (C-4Ј). FTIR (ATR):
3,5). FTIR (ATR): ν = 3116 (w), 3085 (w), 2869 (w), 1694 (s), 1660
˜
(s), 1605 (s), 1519 (s), 1458 (s), 1395 (m), 1378 (m), 1350 (s), 1323
(m), 1281 (m), 1221 (m), 1111 (w), 985 (s), 905 (w), 854 (m), 759
(m), 697 (w), 683 (w), 614 (m) cm–1. HRMS (ESI): calcd. for
C14H8NO5 [M – H]– 270.04080; found 270.04033; Δ = 1.7 ppm.
C14H9NO5·0.2H2O: C 61.18, H 3.45, N 5.10; found C 61.06, H
3.75, N 4.81.
ν = 3089 (w), 1666 (m), 1603 (w), 1480 (w), 1454 (w), 1411 (w),
˜
1382 (m), 1356 (w), 1311 (m), 1276 (s), 1248 (m), 1221 (w), 1195
(s), 1166 (s), 1138 (s), 1124 (s), 1107 (s), 1083 (s), 1034 (m), 950
(w), 920 (m), 895 (s), 881 (w), 846 (w), 783 (m), 748 (w), 736 (m),
–1
General Procedure for Duff Formylation of 4-Arylsubstituted Phen-
ols (GP3): 4-Hydroxybiphenyl 5 (1 equiv.) and hexamethylenetetra-
mine (HMTA, 4–8 equiv.) were dissolved under an argon atmo-
sphere in anhydrous trifluoroacetic acid (TFA), and the mixture
was stirred at 100–125 °C in a closed vessel for 16–72 h. The dark
yellow to brownish solution was cooled to room temperature and
poured into a mixture of 4 m HCl/CH2Cl2 (1:1 v/v). The resulting
mixture was vigorously stirred for 4 h at room temperature. The
layers were separated, and the aqueous layer was extracted with
CH2Cl2 (2ϫ). The combined extract was washed with H2O and
brine and dried with MgSO4. The crude product was obtained as
a yellow residue after solvent removal under reduced pressure and
was purified by flash column chromatography to give, after drying
in vacuo, the formylated products.
701 (m), 683 (s), 659 (w), 622 cm (m). HRMS (EI+): calcd. for
C24H10F12O3 [M]·+ (46%) 574.0438; found 574.0421; Δ = –3.0 ppm;
calcd. for C23H10F12O2 [M – CO]·+ (100 %) 546.0489; found
546.0493; Δ = 0.6 ppm. Second fraction (Rf = 0.15): Dialdehyde 4i
(198 mg, 55%), pale yellow solid; m.p. 170 °C. 1H NMR (400 MHz,
CDCl3): δ = 11.75 (s, 1 H, -OH), 10.35 (s, 2 H, -CHO), 8.22 (s, 2
H, 2,6-H), 8.02 (s, 2 H, 2Ј,6Ј-H), 7.92 ppm (s, 1 H, 4Ј-H). 13C NMR
(101 MHz, CDCl3): δ = 191.9 (-CHO), 163.9 (-COH), 140.5 (C-1Ј),
135.9 (C-2,6), 132.9 (C-3Ј,5Ј), 130.5 (C-1), 126.9 (C-2Ј,6Ј), 124.0
(C-3,5), 123.4 (-CF ), 121.9 ppm (C-4Ј). FTIR (ATR): ν =
˜
3
3067 (w), 2873 (w), 1682 (m), 1662 (m), 1599 (m), 1452 (w), 1376
(s), 1346 (m), 1303 (s), 1274 (s), 1223 (m), 1176 (s), 1148 (s), 1121
(s), 1113 (s), 1079 (s), 977 (s), 940 (m), 895 (s), 846 (m), 789 (m),
771 (m), 730 (m), 703 (m), 683 (s), 667 (m) cm–1. HRMS (ESI):
calcd. for C16H8F6O3 [M – H]– 361.03049; found 361.02996; Δ =
1.5 ppm. C16H8F6O3 (362.23): calcd. C 53.05, H 2.23; found C
53.20, H 2.42.
4-Hydroxy-4Ј-methoxy-1,1Ј-biphenyl-3,3Ј-dicarbaldehyde (8): Ac-
cording to GP3, 4-(4Ј-methoxyphenyl)phenol (5a; 100 mg,
0.50 mmol) was treated with HMTA (154 mg, 1.00 mmol) in TFA
(1.1 mL) and stirred for 3 h at 100 °C. After workup, the crude
product was purified by flash column chromatography on silica gel
(light petroleum ether/EtOAc, 4:1; Rf = 0.25) to give dicarb-
aldehyde 8 (43 mg, 33%) as an off-white solid; m.p. 114 °C. 1H
NMR (400 MHz, CDCl3): δ = 10.99 (s, 1 H, -OH), 10.53 (s, 1 H, -
CHЈO), 9.98 (s, 1 H, -CHO), 8.04 (d, 4J = 2.5 Hz, 1 H, 2Ј-H), 7.78–
7.73 (m, 3 H, 2,6,6Ј-H), 7.11–7.08 (m, 1 H, 5Ј-H), 7.09–7.06 (m, 1
H, 5-H), 3.99 ppm (s, 3 H, -OCH3). 13C NMR (101 MHz, CDCl3):
δ = 196.7 (-CHO), 189.7 (-CЈHO), 161.5 (C-4Ј), 161.2 (C-4), 135.4
(C-6), 133.8 (C-6Ј), 132.2 (C-1Ј), 131.9 (C-1), 131.6 (C-2), 126.4 (C-
2Ј), 125.3 (C-3Ј), 121.0 (C-3), 118.5 (C-5), 112.6 (C-5Ј), 56.08 ppm
(-OCH3). HRMS (ESI): calcd. for C15H11O4 [M – H]– 255.06628;
found 255.06586; Δ = –0.9 ppm. Analytical data are in accordance
with those previously published.[42]
4-Hydroxy-4Ј-methyloxycarbonyl-1,1Ј-biphenyl-3,5-dicarbaldehyde
(4j): According to GP2, 2 (229 mg, 1.00 mmol), (4-methoxycarb-
onylphenyl)boronic acid (3j; 198 mg, 1.10 mmol), and K2CO3
(415 mg, 3.00 mmol) were suspended in DME/H2O (1:1 v/v,
2.4 mL) under an argon atmosphere. After the addition of Pd-
(OAc)2 (4.5 mg, 0.02 mmol) and PPh3 (10.5 mg, 0.04 mmol), the
mixture was stirred for 16 h at 105 °C. After workup, purification
by flash column chromatography on silica gel (light petroleum
ether/EtOAc, 8:1 to 3:2) gave 4j as an off-white solid (87 mg, 31%);
m.p. 190 °C. 1H NMR (300 MHz, CDCl3): δ = 11.69 (s, 1 H, -OH),
3
10.33 (s, 2 H, -CHO), 8.23 (s, 2 H, 2,6-H), 8.15 (d, J = 8.5 Hz, 2
3
H, 3Ј,5Ј-H), 7.67 (d, J = 8.5 Hz, 2 H, 2Ј,6Ј-H), 3.96 ppm (s, 3 H,
-COOCH3). 13C NMR (76 MHz, CDCl3): δ = 196.8 (-CHO), 166.8
(-COOCH3), 163.5 (-COH), 142.5 (C-1Ј), 134.8 (C-2,6), 132.4 (C-
1), 130.6 (C-3Ј,5Ј), 129.8 (C-4Ј), 126.7 (C-2Ј,6Ј), 123.7 (C-3,5), 52.4 4-Hydroxy-3Ј,5Ј-bis(trifluoromethyl)-1,1Ј-biphenyl-3,5-dicarbalde-
(-COOCH ) ppm. FTIR (ATR): ν = 3044 (m), 2958 (m), 2889 (m),
1927 (w), 1705 (s), 1686 (s), 1654 (m), 1600 (m), 1571 (s), 1514 (w),
hyde (4i) and 4-Hydroxy-3Ј,5Ј-bis(trifluoromethyl)-1,1Ј-biphenyl-3-
carbaldehyde (7i): According to GP3, 4-hydroxy-3Ј,5Ј-bis(trifluoro-
˜
3
1453 (w), 1430 (m), 1409 (w), 1389 (w), 1320 (w), 1277 (s), 1214 methyl)-1,1Ј-biphenyl (3i; 100 mg, 0.33 mmol) was treated with
(w), 1199 (w), 1185 (w), 1110 (m), 1070 (w), 1015 (w), 1006 (w), HMTA (183 mg, 1.31 mmol) in TFA (1.5 mL) and heated for 72 h
978 (s), 929 (w), 909 (m), 857 (m), 826 (w), 772 (m), 751 (m), 722
at 105 °C. After workup, purification by flash column chromatog-
raphy on silica gel (light petroleum ether/EtOAc/HOAc, 94:5:1)
gave two fractions. First fraction (Rf = 0.36): Monoaldehyde 7i
–1
(m), 703 (w), 677 (m), 611 cm
(w). HRMS (ESI): calcd. for
C16H11O3 [M – H]– 283.06120; found 283.06075; Δ = –1.4 ppm.
3282
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© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 3274–3285

Synthesis of para-Aryl-Substituted Salicyldialdehydes
1
3
(62 mg, 57%), pale yellow solid; m.p. 74 °C. H NMR (400 MHz, 8.24 (s, 2 H, 2,6-H), 7.76 ppm (d, J = 8.9 Hz, 2 H, 2Ј,6Ј-H). The
CDCl3): δ = 11.12 (s, 1 H, -OH), 10.03 (s, 1 H, -CHO), 7.98 (s, 2
H, 2Ј,6Ј-H), 7.87 (s, 1 H, 4Ј-H), 7.83–7.77 (m, 2 H, 2,6-H),
7.16 ppm (d, J = 8.4 Hz, 1 H, 5-H). 13C NMR (101 MHz, CDCl3):
δ = 196.4 (-CHO), 162.3 (-COH), 141.7 (C-1Ј), 135.6 (C-6), 132.7
(C-3Ј,5Ј), 132.3 (C-2), 130.4 (C-1), 126.8 (C-2Ј,6Ј), 123.5 (-CF3),
analytical data are in accordance with those reported above.
4-Hydroxy-2Ј,3Ј,4Ј,5Ј,6Ј-pentafluoro-1,1Ј-biphenyl-3,5-dicarbalde-
hyde (4l): Following GP3, 4-hydroxy-2Ј,3Ј,4Ј,5Ј,6Ј-pentafluoro-1,1Ј-
biphenyl (3l; 167 mg, 0.64 mmol, 1.00 equiv.) was treated with
HMTA (720 mg, 5.14 mmol, 8.00 equiv.) in TFA (2.2 mL) and
heated for 72 h at 125 °C. After workup, purification by flash col-
umn chromatography on silica gel (light petroleum ether/EtOAc,
20:1 to 2:1) followed by drying in vacuo gave dialdehyde 4l (120 mg,
57%) of as an off-white solid; m.p. 150–161 °C (dec.). 1H NMR
(500 MHz, CDCl3): δ = 11.82 (s, 1 H, -OH), 10.30 (s, 2 H, -CHO),
8.04 ppm (s, 2 H, 3,5-H). 13C NMR (101 MHz, CDCl3): δ = 191.6
(-CHO), 164.0 (-COH), 139.1 (C-2,6), 123.7 (C-3,5), 118.7 ppm (C-
121.2 (C-4Ј), 121.1 (C-3), 119.1 ppm (C-5). FTIR (ATR): ν = 3350–
˜
3050 (br.,w), 2971 (w), 2857 (w), 1739 (w), 1658 (s), 1623 (w), 1588
(w), 1495 (w), 1466 (w), 1382 (m), 1315 (w), 1278 (s), 1219 (m),
1160 (s), 1132 (s), 1064 (m), 930 (m), 889 (s), 840 (m), 750 (m), 703
(m), 683 (m), 642 (w) cm–1. HRMS (EI+): calcd. for C15H8F6O2
[M]·+ 334.0428; found 334.0426; Δ = –0.8 ppm. C15H8F6O2
(334.22): calcd. C 53.91, H 2.41; found C 53.93, H 2.59. Second
fraction (Rf = 0.13): Dialdehyde 4i (29 mg, 25%), pale yellow solid;
m.p. 167 °C. The analytical data are in accordance with those re-
ported above.
4). FTIR (ATR): ν = 3500–3200 (w), 2928 (w), 2853 (w), 1692 (s),
˜
1664 (m), 1603 (m), 1529 (m), 1497 (s), 1468 (m), 1242 (m), 1144
(w), 1087 (s), 997 (s), 967 (s), 928 (m), 913 (m), 754 (w), 736 (w),
689 (m), 671 (w), 608 (m) cm–1. HRMS (ESI): calcd. for C14H4F5O3
[M – H–] 315.00861; found 315.00852, Δ = 0.3 ppm. C14H5F5O3
(316.18): calcd. C 53.18, H 1.59; found C 53.07, H 2.32.
4-Hydroxy-1,1Ј-biphenyl-3,5-dicarbaldehyde (4g) and 4-Hydroxy-
1,1Ј-biphenyl-3-carbaldehyde (7g): Following GP3, 4-phenylphenol
(5g; 255 mg, 1.50 mmol) was treated with HMTA (1.26 g,
9.00 mmol) in TFA (3 mL) and stirred for 16 h at 100 °C. After
workup, purification by flash column chromatography on silica gel
(light petroleum ether/EtOAc/HOAc, 95:4:1) gave two fractions.
First fraction (Rf = 0.29): Monoaldehyde 7g (40 mg, 13%), pale
Anthracenyl-Substituted Cage Compound (10): Triamine 7 (30.0 mg,
0.10 mmol, 4.00 equiv.) and salicyldialdehyde 4d (49.1 mg,
0.15 mmol, 6.00 equiv.) were dissolved in dry THF under an atmo-
sphere of argon. 0.1 m TFA in THF (2 mol-%) was added. The
solution was stirred for 12 d at room temperature, and the resulting
precipitate was collected by suction filtration, washed with NEt3/
THF (50 μL NEt3 in 5 mL THF), dry THF (2ϫ 5 mL), and n-
pentane (2ϫ 5 mL), and dried in vacuo to give 10 as an orange
solid (52 mg, 65%); m.p. Ͼ 410 °C. 1H NMR (400 MHz, 343 K,
C2D2Cl4): δ = 14.09 (s, 6 H, -OH), 9.09 (s, 12 H, –N=CH), 8.51 (s,
1
yellow solid; m.p. 102 °C. H NMR (600 MHz, CDCl3): δ = 11.01
(s, 1 H, -OH), 9.98 (s, 1 H, -CHO), 7.83–7.72 (m, 2 H, 2,6-H), 7.56
(d, J = 7.4 Hz, 2 H, 2Ј,6Ј-H), 7.46 (t, J = 7.7 Hz, 2 H, 3Ј,5Ј-H),
7.37 (t, J = 7.4 Hz, 1 H, 4Ј-H), 7.08 ppm (d, J = 8.4 Hz, 1 H, 5-
H). Analytical data are in accordance with those previously pub-
lished.[43,44] Second fraction (Rf = 0.13): Dialdehyde 4g (167 mg,
49%), pale yellow solid; m.p. 113 °C. The analytical data are in
accordance with those reported above.
3
6 H, anthracenyl-10-H), 8.05 (d, J = 8.5 Hz, 12 H, Ar-H), 8.01 (s,
12 H, salicyl-H), 7.78–7.73 (m, 24 H, Ar-H), 7.48–7.35 (m, 36 H,
Ar-H), 7.06 (d, 3J = 6.8 Hz, 12 H, Ar-H), 5.73 (s, 4 H, bridgehead-
4-Hydroxy-4Ј-methyloxycarbonyl-1,1Ј-biphenyl-3,5-dicarbaldehyde
(4j): Following GP3, 4-hydroxy-4Ј-methyloxycarbonyl-1,1Ј-bi-
phenyl (3j; 200 mg, 0.88 mmol) was treated with HMTA (983 mg,
7.01 mmol) in TFA (3 mL) and heated for 72 h at 125 °C. After
workup, purification by flash column chromatography on silica gel
(light petroleum ether/EtOAc/HOAc, 94:5:1) gave 4j as an off-white
H), 5.45 ppm (s, 4 H, bridgehead-H). FTIR (ATR): ν = 3048 (w),
˜
2955 (w), 1621 (m), 1578 (s), 1519 (w), 1466 (s), 1411 (m), 1385
(w), 1358 (w), 1301 (m), 1283 (m), 1260 (m), 1215 (w), 1174 (w),
1162 (w), 1134 (w), 1109 (w), 1087 (w), 1015 (w), 973 (w), 952 (w),
883 (m), 848 (m), 818 (w), 789 (m), 763 (w), 734 (s), 687 (w), 659
(w), 648 (w), 620 (w) cm–1. HRMS (MALDI): calcd. for
1
solid (88 mg, 35%); m.p. 190 °C. H NMR (300 MHz, CDCl3): δ
C
212H128N12O6 [M]+ 2937.00743; found 2937.01014, Δ = –0.9 ppm.
= 11.69 (s, 1 H, -OH), 10.33 (s, 2 H, -CHO), 8.24 (s, 2 H, Ar-2,6-
H), 8.15 (d, J = 8.4 Hz, 2 H, Ar-2Ј,6Ј-H), 7.67 (d, J = 8.4 Hz, 2 H,
Ar-3Ј,5Ј-H), 3.96 ppm [s, 3 H, -C(O)OCH3]. The analytical data
are in accordance with those reported above.
C212H128N12O6·6H2O (3047.46): calcd. C 83.55, H 4.63, N 5.52;
found C 83.05, H 4.56, N 5.91.
Acknowledgments
4-Hydroxy-4Ј-nitro-1,1Ј-biphenyl-3,5-dicarbaldehyde (4k) and 4-
Hydroxy-4Ј-nitro-1,1Ј-biphenyl-3-carbaldehyde (7k): Following
GP3, 4-Hydroxy-4Ј-nitrobiphenyl (3k; 150 mg, 0.70 mmol) was
treated with HMTA (782 mg, 5.58 mmol) in TFA (3 mL) and
heated for 72 h at 125 °C. After workup, purification by flash col-
umn chromatography on silica gel (light petroleum ether/EtOAc/
HOAc, 94:5:1) followed by drying in vacuo gave two fraction. First
fraction (Rf = 0.11): monoaldehyde 7k (73 mg, 30%) as a colorless
solid; m.p. 201 °C. 1H NMR (600 MHz, CDCl3): δ = 11.14 (s, 1
H, -OH), 10.02 (s, 1 H, -CHO), 8.32 (d, 3J = 8.8 Hz, 2 H, 3Ј,5Ј-
H), 7.84 (d, 4J = 2.2 Hz, 1 H, 2-H), 7.82 (dd, 3J = 8.6 Hz, 4J =
2.4 Hz, 1 H, 6-H), 7.72 (d, 3J = 8.8 Hz, 2 H, 2Ј,6Ј-H), 7.14 ppm (d,
3J = 8.6 Hz, 1 H, 5-H). 13C NMR (151 MHz, CDCl3): δ = 196.5
(-CHO), 162.3 (-COH), 147.2 (C-4Ј), 145.8 (C-1Ј), 135.8 (C-6),
132.5 (C-2), 130.9 (C-1), 127.3 (C-2Ј,6Ј), 124.5 (C-3Ј,5Ј), 121.0 (C-
3), 119.0 ppm (C-2). HRMS (EI+): calcd. for C13H9NO4 [M]·+
243.0532; found 243.0529; Δ = –1.2 ppm. Second fraction (Rf =
0.08): Dialdehyde 4k (63 mg, 33 %) as an off-white solid; m.p.
241 °C (dec.). 1H NMR (300 MHz, CDCl3): δ = 11.75 (s, 1 H,
-OH), 10.34 (s, 2 H, -CHO), 8.35 (d, 3J = 8.9 Hz, 2 H, 3Ј,5Ј-H),
The authors would like to thank the Deutsche Forschungsgemein-
schaft (DFG) (project number MA4061/5-1) and Fonds der Chem-
ischen Industrie (FCI) for financial support. ChemPur and Solvay
Fluor are thanked for the donation of chemicals.
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Received: February 16, 2015
Published Online: April 8, 2015
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