Domino Direct Arylation and Cross-Aldol for Rapid Construction of Extended Polycyclic π-Scaffolds

Article abstract of DOI:10.1021/jacs.7b03412

Five-membered aromatic heterocycles are a ubiquitous skeleton of π-conjugated organic compounds, and their incorporation requires synthetic protocols that are not easily industrially sustainable or scalable. Improved methodologies for their insertion into π-scaffolds are therefore necessary. We report an efficient and scalable protocol involving a one-pot cross-Aldol direct arylation reaction protocol for the rapid construction of thiophene- and furan-based π-extended organic materials.

Full text of DOI:10.1021/jacs.7b03412

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Communication
Domino Direct Arylation and Cross-Aldol for Rapid
Construction of Extended Polycyclic #-Scaffolds
Andrea Nitti, Gabriele Bianchi, Riccardo Po, Timothy M. Swager, and Dario Pasini
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Domino Direct Arylation and Cross-Aldol for Rapid
Construction of Extended Polycyclic -Scaffolds
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†


‡
†,
Andrea Nitti, Gabriele Bianchi, Riccardo Po, Timothy M. Swager, and Dario Pasini *
†
Department of Chemistry and INSTM Research Unit, University of Pavia, Viale Taramelli 10, 27100 Pavia, Italy

Research Center for Renewable Energies and Environment, Istituto Donegani, Eni Spa, Via Fauser 4, 28100 Novara, Italy
‡
Department of Chemistry, Massachusetts Institute of Technology, Cambridge 02139, United States
Supporting Information Placeholder
ABSTRACT: Five-membered aromatic heterocycles are a ubiq-
uitous skeleton of -conjugated organic compounds, and their in-
corporation requires synthetic protocols that are not easily indus-
trially sustainable or scalable. Improved methodologies for their
insertion into -scaffolds are therefore necessary. We report an
efficient and scalable protocol involving a one-pot cross-Aldol
direct arylation reaction protocol for the rapid construction of thi-
ophene- and furan-based -extended organic materials.
ide and the reactive C-H bond of the -thiophene or furan in the
DHA are kept unchanged, as this was found to be the best combi-
11
nation in order to ensure high regioselectivity in related systems.
Conjugated -extended organic compounds based on five-
membered aromatic heterocycles enjoy an increasing importance
1
in several major chemical sectors, including organic materials,
2
3
pharmaceuticals, agrochemicals. Complex -extended com-
pounds incorporating five-membered aromatic heterocycles have
proven to be effective at creating high performance materials;
lengthy synthetic sequences can however be a problem for indus-
Figure 1. Strategies for cross-Aldol-DHA annulation reactions.
EWG = Electron-withdrawing group. X = Sulfur or Oxygen.
4
trial scalability. In this context, the teachings from “classical”
As part of our continuing interest in isatin derivatives as new -
6
c,12
total synthesis wherein atom economical domino/cascade and/or
multicomponent reaction approaches are core principles, provide
a powerful strategy for materials production.
systems for organic electronics,
we initially investigated the
5
reaction of N-methyl-4-bromooxindole 1 (derived from isatin by
reduction at its C3 carbonyl) and 3-formylthiophene or 3-
formylfuran 2, to form annulated products 3 (Scheme 1).
Pd-catalyzed (Stille or Suzuki) coupling reactions, in sequence
with traditional CC or CN bond formation methodologies, such
Scheme 1. Synthesis of thiophene-and furan-fused compounds
3
6
7
as Aldol condensation or Michael reactions, have been recently
reported. However, Stille and Suzuki reactions require preactiva-
tion of the building blocks. Direct heteroarylation reactions
R
O
O
S
R
O
O
N
R
Pd(OAc)2
PPh3, AcOK
N
N
(DHA) are becoming increasingly popular as Pd-catalyzed car-
+
DMA, 150°C
bon-carbon forming methodologies in organic and macromolecu-
X
Br
8
Br
X
lar syntheses, since no such preactivation is required. Our atten-
tion has been further attracted by the fact that DHAs are conduct-
ed in aprotic polar organic solvents with relatively weak bases
similar to those that can be used for cross-Aldol reactions. As a
result, domino/cascade processes employing both direct arylation
4a R=CH3
b R=C8H17
1
a R=CH3 2a X=S
(46%)
(40%)
3a X=S R=CH3
4
1b R=C8H17
2b X=O
3b X=S R=C H
8
17
(
41%)
3c X=O R=C8H17
This reaction is schematically shown as option a) in Figure 1.
Using standard DHA conditions in moderately dilution conditions
200 mM), we were pleased to isolate the desired compound, 3a
Scheme 1), albeit in relatively low yield (26%, entry 1 in Table
S1). A screening of catalysts, bases and reaction conditions (Table
S1) afforded an improved yield of 46%. Compound 3a was char-
acterized by X-ray crystallography, NMR and UV/Vis spectros-
copy, and cyclic voltammetry (Figures S1-S4). Compounds 4a
9
and cross-Aldol methodologies are feasible. Annulation strategies
in the case of thiophene derivatives have been reported before,
under rather harsh conditions, involving the use of elemental sul-
(
(
1
0
fur. In this communication we report a regioselective and effi-
cient domino cross-Aldol-DHA strategy for construction of fully
-conjugated compounds wherein thiophene or furan rings are
fused to arene or heteroarene moieties.
and 4b were also isolated and characterized in the same reactions
Two alternative synthetic strategies (Figure 1) described herein
differ in the relative position of the aldehyde and the acidic pro-
tons involved in the Aldol condensation. The position of the hal-
1
(20-30% yields), appearing as single stereoisomers in the
H
NMR spectra. Although the precise stereochemistry of the carbon-
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Page 2 of 4
carbon double bond in either 4a or 4b could not be unequivocally
determined, it is likely to be the E-configuration, unfavorable for
subsequent cyclization. We did not observe C5 arylation byprod-
ucts in the crude reaction mixtures.
(Figure S9) upon heating at 110˚C in DMSO-d for 48 h, and,
when subjected to DHA conditions, afforded compound 10 in
6
1
2
3
4
5
6
7
8
9
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good yields. The control reaction between 7 and 13, followed by
esterification with ethyl bromide, gave no cross-Aldol product,
with the reaction containing unreacted 7 and esterification of 13 to
afford 8. On the basis of all the above data, we propose the mech-
anism illustrated in Scheme 3. It is clear that the different elec-
To demonstrate the scope of our cross-Aldol-DHA strategy, we
evaluated the use of simplified, commercially available reagents,
in conjunction with route a) depicted in Figure 1.
tron-withdrawing abilities of cyano, ester, and carboxylate groups
Scheme 2. Efficient construction of naphthothiophene-fused
compounds
13
(
Hammett’s  = 0.66, 0.45 and 0.00, respectively) influence the
p
acidity of the neighboring -hydrogens lowering the rate of the
Aldol condensation with respect to the DHA, and promoting the
synthetic Pathway 1 instead of 2.
COOR
O
Table S2
COOR
+
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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6
7
8
9
0
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8
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2
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4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Br
S
Scheme 3. Competing cross-Aldol and DHA Pathways
S
Pathway 1
Preferred for 14
5
a R=Et
2a
6a R=Et
6b R=H
5b R=H
O
S
R
[Pd]
-H2O
Pd(OAc)2
R
S
PPh3, K2CO3
14 R=H
O
+
HOOC
Not isolated
DMA, 150°C
COOR
Br
S
COOEt
O
S
Br
7
8 R=COOEt
10 R=COOEt (35%)
11 R=CN (0%)
12
Br
9
R=CN
S
COOEt
10 R=Et
HCl
COOH
-H2O
[Pd]
COOH
Br
Pd(OAc)2
S
PPh3, K2CO3
O
S
+
DMF, 110°C
14 (95%)
Br
Pathway 2
Preferred for 10
S
COOEt
The possibility of the carboxylate functionality present in the
reagent 13 to coordinate intramolecularly the Pd(II) catalyst, to
form the Ar-Pd-OOCR group attacking the CH in a metallocyclic
intermediate, is highly unlikely by geometrical considerations.
Furthermore, control experiments with 7 and 13, with all other
conditions equal except increasing amounts of pivalic acid (up to
100% mol with respect to the starting materials), had only minor
effects on the yield of compound 10 (yields dropped from 91% to
7
13
EtBr
One pot
91%
S
10
The reaction of ethyl 2-bromophenylacetate 5a, or the corre-
sponding acid 5b, and 3-formylthiophene 2a (Scheme 2), when
screened under a variety of conditions (Table S2), did not afford
the desired product 6. Both electronic and steric effects are likely
responsible for the different outcomes of reactions of aldehyde 2a.
The starting amide used in the synthesis of 3 enjoys aromatic sta-
bilization when deprotonated, whereas the conjugate base of the
ester in the attempted synthesis of 6 may be more prone to side
reactions. Additionally, a highly stereoselective preference for the
formation of the E-intermediate alkene formed in the Aldol reac-
tion could play a role since would inevitably preclude cyclization
in the subsequent DHA.
8
0%). Pivalic acid is known to coordinate to Pd(II) and should
compete with the carboxylic acid functionality of 13. The inter-
mediate in Pathway 1 could not be isolated. As a further confir-
mation of our proposed mechanism, Pd(PPh ) as the catalyst for
3
4
the synthesis of 10 through 13 worked well (Table S3, entry 8),
whereas the use of the same Pd(0) catalyst in the case of 1a failed
to produce product 3a (Table S1, entry 2). Whereas in the former
case DHA occurs first (Pathway 1), in the latter case the bulkier
Pd(0) catalyst is prevented entry into the catalytic cycle after the
Aldol reaction had occurred.
Reversing the positions of nucleophilic and electrophilic ele-
ments of the cross-Aldol reaction (Pathway b) in Figure 1), by
using reactants 7 and 8, produced 10 (Scheme 2) in 35% yield
after reaction optimization (Table S3). GC-MS experiments on the
crude reaction mixture revealed the presence of byproduct 12,
wherein the Aldol condensation had occurred without subsequent
DHA. Furthermore, in the case of cyano substituted substrate, 9,
none of the desired product 11 is detected. Gratifyingly, using 3-
thiopheneacetic acid 13 in place of the corresponding ester (8)
produced 14 in nearly quantitative yield after acidification and
simple filtration. The reaction could be carried forward, bypassing
the isolation of 14, by the addition of ethyl bromide at room tem-
perature one pot, giving -extended annulated ester 10 (91%).
In order to investigate the general utility of the domino DHA
and cross-Aldol strategy, so successful in the case of 13, we ex-
tended our procedures to the synthesis of compounds 15-19
(Scheme 4).
Scheme 4. Synthesis of compounds 15-19 with the optimized
DHA-Aldol cascade protocol
O
COOH
OR
X
Pd(OAc)2
1.
PPh3, K CO
DMF, 110°C
2
3
O
S
O
OR
Ar
15 (72%) R= C8H17
Ar
16 (76%) R= (2ethyl)hexyl
2
. RBr
Br
Room temp. or 40°C
In case of substrate 13, the cross-Aldol intermediate byproduct
was not observed in the crude reaction mixture. Control experi-
ments in the absence of the Pd(II) catalyst and the phosphine, with
all other conditions equal, revealed that reactants 7 and 8, produce
X
O
O
O
O
O
O
OEt
O
1
2 in 43% yield. The major stereoisomer could be separated by
S
chromatography, and NOESY NMR spectroscopy confirmed this
to be the (E)-12 adduct (Figures S5-S8). Furthermore, the stereo-
pure compound did not show any sign of (E)-(Z) interconversion
O
7 (81%)
S
S
1
18 (79%)
19 (89%)
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impart solubilty, is equally efficient and, by adding other alkyl-
bromides, 15 and 16 are produced in good yields. The introduc-
tion of a furan ring instead of thiophene occurred smoothly to
produce 17 (Figures S10-S11). Also important is that the intro-
duction of electron rich functional groups in the aryl-aldehydes
worked equally well to efficiently produce 18 and 19. It is worth
noting that 10 was previously reported as byproduct of the catalyt-
ic cyclization via ruthenium-carbene/oxidation, following a com-
1
4
plex procedure. Compound 19, an interesting and promising
building block for organic photovoltaic (OPV) devices, has been
1
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previously reported by Kirner et. al. using a seven-step synthetic
sequence rather than our single step sequence from commercially
available materials. Additionally a comparison between E-
(
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1
6
factors calculated for the last synthetic step of our synthetic
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duction for 10 and 19, respectively (see Supporting Information).
(
2
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gle step one pot method that provides for polycyclic extended π-
systems with pendant carboxylate or ester groups for use in de-
veloping chromophores and organic electronic materials. Previ-
ously known compounds are produced in dramatically simplified
procedures. Our annulations appear to work equally well for furan
and thiophene compounds. The ester moiety will not be a limita-
9
25943.
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1
7
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18
tive layers with a “frozen” and stable morphology.
Our strategy paves the way for efficient syntheses of other di-
thiophene, difuran or mixed thiophene-furan -extended annulat-
ed monomers, through easily scalable procedures, and may find
utility in creating industrially relevant OPV materials.
ASSOCIATED CONTENT
Supporting Information
(9) Previous examples of DHA combined with cross-Aldol did not tar-
get aromatic heterocycles: (a) Dhiman, S.; Pericherla, K.; Nandwana, N.
K.; Kumar, D.; Kumar, A. J. Org. Chem. 2014, 79, 73997404. (b) Fu,
M.; Lin, D.; Deng, Y.; Zhang, X. Q.; Liu, Y.; Lai, C.; Zeng, W. RCS Adv.
Additional experimental details and Tables about synthetic routes.
Additional Figures about UV-Vis spectroscopy, cyclic voltamme-
2
014, 4, 2359523603.
1
try and X-Ray crystallography for compound 3a. Copies of H,
(10) Meng, L.; Fujikawa, T.; Kuwayama, M.; Segawa, Y.; Itami, K. J.
1
3
C NMR, ESI-MS and GC-MS spectra for new compounds.
Am. Chem. Soc. 2016, 138, 10351–10355.
(11) (a) Nitti, A.; Po, R.; Bianchi, G.; Pasini, D. Molecules 2017, 22,
2
1. (a) Takeda, D.; Yamashita, M.; Hirano, K.; Satoh, T.; Miura, M.
AUTHOR INFORMATION
Corresponding Author
Chem. Lett. 2011, 40, 1015–1017. (b) Dong, J. J.; Doucet, H.; Eur. J. Org.
Chem. 2010, 611–615. (c) Glover, B.; Harvey, K. A.; Liu, B.; Sharp, M.
J.; Tymoschenko, M. F.; Org. Lett. 2003, 5, 301–304.
*E-mail: dario.pasini@unipv.it
(12) (a) Nitti, A.; Signorile, M.; Boiocchi, M.; Bianchi, G.; Po, R.; Pa-
sini, D. J. Org. Chem. 2016, 81, 11035–11042.
(13) C. Hansch, A. Leo and R. W. Taft, Chem. Rev. 1991, 91, 165–195.
Notes
The authors declare no competing financial interests.
(
14) Tsai, F. Y.; Lo, J. X.; Hsu, H. T.; Lin, Y. C.; Huang, S. L.; Wang,
J. C.; Liu, Y. H. Chem. Asian J. 2013, 8, 2833–12842.
15) Welker, M.; Turbiez, M. G. R.; Chebotareva, N.; Kirner, H. J.;
ACKNOWLEDGMENTS
(
We gratefully acknowledge funding by Eni S.p.A. through its
University contact branch Eni Corporate University (contract with
the University of Pavia No. C49/09/13) and through the MIT En-
ergy Initiative. We thank M. Boiocchi (Centro Grandi Strumenti,
University of Pavia) for the X-ray structural determination of
compound 3a.
Functionalized benzodithiophene polymers for electronic application, WO
2014086722.
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(17) PTB7, one of the most popular OPV donor polymers, bears an es-
ter group on the thienothiophene unit and it is obtained by Stille polycon-
densation. See for example: Lu, L.; Yu, L. Adv. Mater. 2014, 26, 4413–
4
430.
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vester-Hvid, K. O. ACS Appl. Mater. Interfaces 2009, 1, 2768–2777.
(
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