Short and modular synthesis of tetraarylsalicylaldehydes

Article abstract of DOI:10.1039/d0cc00738b

In this study, we describe a novel strategy that allows the obtention of all 15 possible substitution geometries of perarylated salicylaldehydes with total control of the regioselectivity. This strategy entitles the formation of the salicylaldehyde core via a Claisen rearrangement of propargyl vinyl ethers, followed by bromination and Pd-catalyzed aryl-aryl cross-coupling reactions.

Full text of DOI:10.1039/d0cc00738b

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Short and modular synthesis of tetraarylsalicylaldehydes
David Tejedor,*a Samuel Delgado-Hernández,a,b Blanca Santamaría-Peláeza and Fernando García-
Tellado*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
a) Rh(III)-catalyzed C-H [4+2]C-annulation.
Herein we describe a novel strategy that allows the obtention of
all 15 possible substitution geometries of perarylated
salicylaldehydes with total control of the regioselectivity. This
strategy entitles the formation of the salicylaldehyde core via a
Claisen rearrangement of propargyl vinyl ethers, followed by
bromination and Pd-catalyzed aryl-aryl cross-coupling reactions.
OH
Ar1
O
Ar1
Ar2
O
[Rh/Ag]
Ar2
NMe2
Ar1
Ar1
b) This work
O
Ar2
Ar1
Multiply arylated -electron systems constitute important
molecular components in material science.1 Propeller-shaped
hexaarylbenzenes (HAB)2 constitute a good example of this
class of molecular structures, with important applications in
the field of molecular-scale devices.3 The regioselective
access to fully arylated -electron systems featuring tailor-
made peripheral substitution patterns constitutes a current
challenge in organic synthesis. Significant progress to this end
has been achieved by the groups of Yamaguchi4a and Jux4b
with the synthesis of perarylated benzenes endowed with six
different aryl substituents. These methodologies have
allowed the exploration of large areas of the chemical space
of HABs hitherto inaccessible by classical methodologies.2 The
chemical space of perarylated -extended systems based on
ring-cores other than benzene systems remains scarcely
explored. The access to these systems should allow the
mapping of their chemical spaces, bringing new opportunities
to the design and applications of novel molecular-devices. A
handful number of synthetic methodologies to access
perarylated nicotinates,5a indazoles,5b pyridines5c-e and
indoles5f have been recently reported in the bibliography.5
They use either consecutive sp2-sp2 Suzuki cross-coupling
R
Ar2
1
i-iii
Ar1
Ar4
CO2Me
Ref 13
Ar4
OHC
OH
5 R = H
6 R = Br
3
iv
2
Ar3
Ar2
v
Ar3
BH(OH)2
Ar4
Ar1
7
OHC
OH
8 (TASA)
Reactions. i: 1,2-Acetylide addition; ii: Propargyl vinyl ether formation; iii:
imidazole-catalyzed domino cyclization; iv: bromination; v: Pd-coupling.
c) Substrates used in this work
OH
OH
O
R
B
R
CH2Ph
2a R = H
2b R = F
2c R = OMe
7a R = H
7b R = F
7c R = OMe
7d R = CF3
7e R = tBu
R
1a R = H
1b R = F
reactions on the core ring,5c
condensation/halogenation/cross-coupling reactions,5a,b,d an
a
combination of
7f R = 3-furyl
enamine-ketone condensation5e or
a
programmed
Scheme 1. Strategy for the synthesis of tetraarylated salicycladehydes (TASA).
coupling/ring transformation strategy.5f The condensation
reaction allows using two arylated fragments to generate the
core ring and install the peripheral aromatic rings at specific
positions of the ring. A similar strategy has been recently
reported for the synthesis of multiarylated salicylaldehyde,6
through the Rh(III)-catalyzed C-H [4+2]C annulation of vinyl
enaminones with diaryl alkynes (Scheme 1a). The reaction
manifold generates the salicyladehyde ring endowed with
a. Instituto de Productos Naturales y Agrobiología, CSIC, Astrofísico Francisco
Sánchez 3, 38206 La Laguna, Tenerife, Spain. E-mail: fgarcia@ipna.csic.es
dtejedor@ipna.csic.es
b. Doctoral and Postgraduate School, Universidad de La Laguna, Avda. Astrofísico
Francisco Sánchez s/n, 38200 La Laguna, Tenerife, Spain.
Electronic Supplementary Information (ESI) available: Experimental procedures and
spectral data for all new compounds 5-8. See DOI: 10.1039/x0xx00000x
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three peripheral aromatic rings, two identical (Ar1) and one
distinct (Ar2). Although the reaction is efficient and selective,
it delivers salicylaldehydes endowed with a limited peripheral
diversity and a diminished reactivity toward halogenation for
the subsequent introduction of the fourth aryl substituent
(perarylation). The only available position for halogenation is
electronically deactivated, i.e. it is meta to the hydroxyl
group. The importance of the salicylaldehyde motive in
different areas of chemistry and related sciences,7 and the
absence of a real-world methodology for the perarylation of
these motives prompted us to face the challenge. At this end,
we designed the strategy outlined in Scheme 1b, which took
advantage of our experience in the modular synthesis of
salicylaldehydes8 to get a short (5 steps from the ketone 1)
and regioselective access to all 15 possible substitution
geometries of the salicylaldehyde core, spanning from the all-
the same A4-TASA to the all-different ABCD-TASA (Figure 1).
Herein, we describe this strategy using cheap and
commercially available benzylarylketones 1, arylacetylenes 2,
methyl propiolate (3) and aryl boronic acids 7 as the building
blocks (Scheme 1c). Last but not least, the strategy was
designed to be independent of the electronic nature of the
aromatic substituents, with the only restrictions coming from
the own reactivity demands of the aromatic bromination9 or
Suzuki coupling.10
isolated and it was engaged in the next reaction. In this
manner, the reaction mixture was heated under
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DOI: 10.1039/D0CC00738B
OH
OH
OH
OH
OH
OH
CHO
CHO
CHO
CHO
CHO
CHO
ABA2
A4
AB2
A
ABAB
A2BA
A3B
R1
R2
OH
OH
OH
OH
OH
CHO
CHO
CHO
CHO
CHO
R3
8
R4
TASA
A2B2
AB3
ABCA
OH
OH
OH
OH
OH
OH
CHO
CHO
CHO
CHO
CHO
CHO
AB2
C
A2BC
ABCB
ABCD
ABAC
ABC2
Figure 1. All possible substitution geometries of tetraarylsalicylaldehydes. The ABCD
nomenclature follows an anti-clockwise orientation starting from the hydroxyl group
and in the order A to D.
microwave irradiation to successfully deliver the desired
3,4,6-triphenyl salicylaldehyde (5aa) (50% yield in
3
steps)(Table 1, entry 1).13 Following this standardized
reaction sequence, we were able to prepare the five
trisubstituted salicylaldehyde derivatives 5 needed for the
purpose of completing all possible substitution geometries of
TASAs (Scheme S1; Table 1, entries 1, 5, 9, 12 and 15)
As previously identified by others, one of the main
difficulties associated to the construction of perarylated
aromatic ring systems is regioselectivity.2 It is a real challenge
to achieve the regioselective installation of an aromatic group
independent of the stereoelectronics of the other existing
peripheral substituents. Our strategy overcomes this
We next explored the bromination step, taking into
account that we anticipated that the desired salicylaldehyde
ring would be more prone to electrophilic aromatic
substitution than the appended aromatic rings. Indeed, while
bromination of 5aa delivered bromine 6aa in 90% yield (Table
1, entry 1) the remaining triarylated salicylaldehydes were
brominated with yields ranging from 84% to 95% (Table 1,
entries 5, 9, 12 and 15). We could only appreciate
overbromination of the electron rich aromatic substituents
when larger excesses of Br2 were used (see SI for details).
Finally, we explored the Suzuki coupling of substrate 6aa
with different boronic acids using typical coupling conditions
(Pd(Ph3)4 as the catalyst and Na2CO3 as the base in
dimethylformamide at 90ºC). To our delight, the first A4-TASA
(8aaa) was easily isolated in a satisfactory 64% yield when
using phenyl boronic acid (7a) as the coupling partner (Table
1, entry 1).14 Similarly, to prove the robustness of the coupling
step, three more boronic acids were used to prepare three
different A2BA-TASAs (8aab, 8aae and 8aaf) in moderate to
good yields (76%, 50% and 79% respectively) (Table 1, entries
2-4).14 Overall, the 3,4,6-triphenyl salicylaldehyde (5aa)
enabled us to form 2 of the 15 possible substitution
geometries of TASAs depicted in Figure 1.
difficulty by relying on
a modular approach for the
construction of the salicylaldehyde ring, which utilizes a non-
symmetrical ketone (aryl and benzyl substituents) and a
terminal arylacetylene. Additionally, and key to the success of
this strategy, is that the appending of the last aryl group takes
place at the only unsubstituted position of the ring which is
conveniently located at the para position with respect to the
hydroxyl group (and meta with respect to the formyl group).
We began this study investigating the synthesis of the
triphenyl salicylaldehyde derivative 5aa (Ar1 = Ar2 = Ar3 = Ph),
because although we had previous experience synthesizing
di- and trisubstituted salicylaldehydes,8 we had never tackled
specifically the synthesis of the triarylated substrate (Table 1).
Fortunately, we were able to obtain the desired product 5aa
with a slight modification of our previous synthetic protocol
(see SI for full details). Thus, 2-phenylacetophenone (1a)
reacted with phenylacetylene (2a) under standard reaction
conditions to deliver the corresponding propargylic alcohol.
This was subsequently treated with methyl propiolate (3) and
a catalytic amount of DABCO to obtain the propargyl vinyl
ether (PVE) 4aa.11 Because of the high propensity of highly
substituted PVEs to rearrange at room temperature
(propargyl Claisen rearrangement),12 product 4aa was not
Next, we continued with the Suzuki coupling of substrate
6ac which would allow us to prepare three more substitution
geometries of TASAs. By choosing the appropriate aryl
boronic acids, TASAs A3B (8aca), A2B2 (8acc) and two A2BC
(8acb and 8acf) were easily prepared using the same reaction
2 | J. Name., 2012, 00, 1-3
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Table 1. Synthesis of all 15 different substitution geometries of tetra-aryl salicylaldehydes
Ar1
Ar1
Ar1
Ar1
Ar1
Ar2
Ar2
Ar2
Ar2
Ar4
O
OH
OH
OH
2
O
iv
v
i,ii
iii
1
Br
CHO
CHO
CHO
CO2Me
CO2Me
Ar3
3
Ar2
Ar4
6
Ar4
5
Ar4
Ar4
4
8 (TASA)
(Not isolated)
Conditions. i: nBuLi, -50ºC,THF, Ar4CCH; ii: DABCO (10 mol%), HCCCO2Me, RT, 1h; iii: Imidazole (10 mol%), xylene, MW, 200 W,190 ºC; iv: Br2, CH2Cl2, RT; v: Na2CO3,
Pd(Ph3)4, Ar3-B(OH)2 (7), DMF, 90 ºC.
Entry
1
2
3
4
5
6
7
8
Ar1
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ar2
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-FC6H4
4-FC6H4
4-FC6H4
4-FC6H4
4-FC6H4
4-FC6H4
4-FC6H4
4-FC6H4
4-FC6H4
4-FC6H4
Ar3
Ph
4-FC6H4
4-tBuC6H4
3-furanyl
Ph
4-MeOC6H4
4-FC6H4
3-furanyl
Ph
4-FC6H4
4-CF3C6H4
Ph
4-FC6H4
4-MeOC6H4
Ph
4-FC6H4
4-MeOC6H4
3-furanyl
Ar4
Ph
Ph
Ph
Ph
5 (%)a
6 (%)
8 (%)
Type
A4
8aaa (64%)
8aab (76%)
8aae (50%)
8aaf (79%)
8aca (40%)b
8acc (43%)c
8acb (44%)d
8acf (53%)
8baa (57%)
8bab (41%)e
8bad (46%)f
8bba (37%)g
8bbb (33%)h
8bbc (84%)
8bca (85%)
8bcb (52%)
8bcc (50%)
8bcf (73%)
5aa (50%)
6aa (90%)
A2BA
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
Ph
A3B
A2B2
5ac (47%)
6ac (93%)
A2BC
9
ABA2
AB2A
ABCA
ABAB
AB3
ABCB
ABAC
AB2C
ABC2
ABCD
10
11
12
13
14
15
16
17
18
Ph
Ph
5ba (35%)
5bb (40%)
6ba (92%)
6bb (95%)
4-FC6H4
4-FC6H4
4-FC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
5bc (49%)
6bc (84%)
aOverall yield for three steps from ketone 1. b58% brsm. c69% brsm. d78% brsm. e81% brsm. f70% brsm. g46% brsm .h81% brsm. See Supporting Information for
experimental conditions and procedures.
conditions (Table 1, entries 5-8). Likewise, the brominated
salicylaldehyde 6ba gave rise to three substitution
geometries ABA2 (8baa), AB2A (8bab) and ABCA (8bad) (Table
1, entries 9-11). The brominated derivative 6bb gave rise to
the geometries ABAB (8bba), AB3 (8bbb) and ABCB (8bbc)
(Table 1, entries 12-14). Finally, 6bc delivered the last set of
possible geometries including ABAC (8bca), AB2C (8bcb),
ABC2 (8bcc) and the all-different ABCD (8bcf) (Table 1, entries
15-18). This last example is worth mentioning as it highlights
that the all-different ABCD-TASA was synthesized as any
other member of the set of TASAs in five synthetic steps using
commercially available building blocks.
The solutions of these perarylated salicylaldehydes 8
exhibited yellow-green fluorescence (486-573 nm) under
visible irradiation (403-424 nm) (see SI for the emission
spectra). Because the strategy depicted in this study allows
the access to an immense number of perarylated derivatives,
multiple batteries of potential emitters for use in material
science should be available by design. In addition, the
presence of fluorine atoms in the peripheral aromatic rings
should allow further diversification by reaction with different
nucleophiles (SNAr), which in turn, should allow the chemo-
modulation of the optical properties of these extended
motives.
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Chem. Eur. J., 2012, 18, 11937; g) Y.Tanaka, T. Koike, M.
In summary, we have developed
a modular and
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regioselective synthetic strategy for the access to all 15
different possible geometrical variants of perarylated
salicylaldehydes 8 (TASAs) using cheap and commercially
available benzylarylketones 1, arylacetylenes 2, methyl
propiolate (3) and aryl boronic acids 7 as the building blocks.
This strategy entitles the formation of the salicylaldehyde
core via a Claisen rearrangement of the corresponding
propargyl vinyl ether, followed by bromination and Suzuki
cross-coupling reactions. To demonstrate the efficacy of this
strategy we have synthesised at least one example of each
one of the 15 possible substitution geometries using the
minimum number of benzylarylketones and arylacetylenes
building blocks, and only five key 3,4,6-triarylated
salicylaldehyde intermediates. In all, we built a small library
of 18 different TASAs by using a small set of representative
aryl boronic acids for the last Suzuki coupling step.
4
5
6
7
Y. Zhao, Q. Zheng, C. Yu, Z. Liu, D. Wang, J. You, G. Gao, Org.
Chem. Front 2018, 5, 2875.
For selected reviews, see: a) A. Sebastian, V. Srinivasulu, I.
A. Abu-Yousef, O. Gorka, T. Al-Tel, Chem. Eur. J. 2019, 25,
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This research was supported by the Spanish Ministries of
Economy and Competitiveness (MINECO), Science,
Innovation and Universities (MICINN), Agencia Estatal de
Investigación (AEI) and the European Regional Development
Funds (ERDF) (CTQ2015-63894-P and PGC2018-094503-B-
C21). We acknowledge support of the publication fee by the
CSIC Open Access Publication Support Initiative through its
Unit of Information Resources for Research (URICI). We thank
Ms Estefanía Gámez and Mr Jesús Peyrac for experimental
assistance and La Laguna University for the use of SEGAI. S. D.
H. thanks La Laguna University and Cajasiete for a pre-
doctoral contract. We thank Dra. Verónica Pino for her
assistance in the fluorescence experiments, and Dr. Romen
Carrillo and Prof. Uwe Pitschel for critical comments on this
work.
8
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Conflicts of interest
There are no conflicts to declare.
13 See Scheme S2 in the Supporting Information for the
synthesis of propargyl vinyl ethers 4 from terminal alkynes
2 and ketones 1, and their microwave-assisted imidazole-
catalyzed domino transformation into salicylaldehydes 5.
14 Because the aim of this communication was to show the
power of this methodology to delivery each one of the 15
different peripheral geometries, the yields of the Suzuki
couplings were found convenient at this stage and they
were not optimized.
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4 | J. Name., 2012, 00, 1-3
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