3-amino-fluorene-2,4-dicarbonitriles (AFDCs) as photocatalysts for the decarboxylative arylation of α-amino acids and α-oxy acids with arylnitriles

Article abstract of DOI:10.1021/acs.orglett.9b00443

1-(4-(9H-Carbazol-9-yl)phenyl)-3-amino-9H-fluorene-2,4-dicarbonitrile as a new photocatalyst for the decarboxylative cross-coupling reaction of α-amino acids or α-oxy carboxylic acids with arylnitriles is described. This light-driven reaction enables a va

Full text of DOI:10.1021/acs.orglett.9b00443

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
3‑Amino-fluorene-2,4-dicarbonitriles (AFDCs) as Photocatalysts for
the Decarboxylative Arylation of α‑Amino Acids and α‑Oxy Acids
with Arylnitriles
Yiyang Chen, Ping Lu,* and Yanguang Wang*
Department of Chemistry, Zhejiang University, Hangzhou 310027, P. R. China
S
* Supporting Information
ABSTRACT: 1-(4-(9H-Carbazol-9-yl)phenyl)-3-amino-9H-
fluorene-2,4-dicarbonitrile as a new photocatalyst for the
decarboxylative cross-coupling reaction of α-amino acids or α-
oxy carboxylic acids with arylnitriles is described. This light-
driven reaction enables a variety of benzylic amines and ethers
to be prepared from readily available starting materials under
mild conditions.
ith growing environmental awareness, the past decade
3-Amino-9H-fluorene-2,4-dicarbonitrile and derivatives
Whas witnessed tremendous advancement in the develop- (AFDCs), such as 1a, 2a, and 3a (Figure 1), are a typical
ment of chemical reactions triggered by light through
photocatalysis, accompanied by intensive research in the field
of photocatalyst design. The light-driven reaction systems
typically comprise transition-metal complexes1 and small
molecular organic dyes as molecular photocatalysts,1a,2 both
of which have been demonstrated to be efficient in
homogeneous catalysis for a variety of organic photoredox
reactions. Additionally, the macromolecular heterogeneous
photocatalysts based on the conjugated organic dyes have also
been developed for photocatalysis in metal-free alternatives.3
Desired photophysical properties including both optimal redox
windows and long-lived excited states have made polypyridyl
Figure 1. Structure of the AFDC-based photocatalysts.
complexes of ruthenium and iridium the most commonly used
photocatalysts.1 Small molecular organic photocatalysts have
been adopted as alternatives, as they are more economical,
class of acceptor−donor−acceptor (A−D−A) systems which
structurally variable, and environmentally friendly.2,4 However,
have been found to exhibit strong fluorescence in our previous
studies.11 This class of stable fluorophores were measured to
a narrower redox window, photobleaching tendency, pH
dependence, low solubility in common organic solvent, and a
narrower redox window render most of the traditional organic
photocatalysts such as fluorescein, Rose Bengal (RB), Eosin Y,
and phenothiazines impractical.
possess excited state redox potentials of E1/2(PC+/PC*) =
−1.71 to − 1.96 V and E1/2(PC*/PC−) = +1.00 to +1.30 V vs
SCE (see Supporting Information (SI), Table S1) favoring a
variety of redox processes.
Encouraged by these results and inspired by Zhang’s work,10
we investigated the photocatalytic activities of AFDCs as
photoredox catalysts for organic synthesis. Herein, we report
our success in using AFDC-based A−D−A fluorophores as
photocatalysts for the direct transformation of readily available
α-amino acids, α-oxy acids, and arylnitriles into high-value
benzylic amines or ethers.
Therefore, it has been our goal to develop novel and
effective organic photocatalysts with easily modified molecular
structures. Elegant examples for recent advances in this field
include the development of a series of new acridinium salts,4
acridones,5 bodipy derivatives,6 and phenoxazines,7 bifunc-
tional photocatalyst bearing a chiral bisoxazoline ligand,8 and a
dicyanopyrazine derived chromophore (DPZ).9
Recently, Zhang and co-workers reported carbazolyl
dicyanobenzene (CDCB)-based donor−acceptor (D-A) fluo-
rophores as efficient photoredox catalysts for photoredox/Ni
dual catalytic decarboxylative coupling of carboxylic acids and
alkyltrifluoroborates using aryl halides.10a Alkylation of imines
were also achieved using this class of organic photocatalysts.10b
AFDCs 1a, 2a, and 3a as well as their derivatives 1b, 2b, and
3b were synthesized according to our previous methods.11
Their photophysical properties were measured in order to
Received: February 1, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00443
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
select suitable photocatalytic reaction and irradiation. Upon
light excitation, the photoexcited state of these compounds
shows both strong oxidative (E1/2(PC*/PC−) = +1.00 to +1.40
V vs SCE) and reductive (E1/2(PC+/PC*) = −1.67 to − 2.11
V vs SCE) capabilities that parallel or surpass those of many
metal complexes and organic dyes (see SI, Table S1).
Modifying the donor moieties or substituents on the 3-
amino-9H-fluorene-2,4-dicarbonitrile core can easily afford the
wide range photoredox potentials.
Since our AFDC-based photocatalysts demonstrated strong
photoredox potentials, we deemed them suitable to facilitate
reactions with a high energy barrier such as the decarboxylative
C−C bond forming reactions. Decarboxylation is a critical step
in biological systems and extremely useful in synthetic
molecule construction. Discovering transformations that
selectively target carboxylic acids as leaving groups is valuable
for C−C bond forming reactions.12 Elegant examples for the
photocatalytic decarboxylative C−C coupling reactions of α-
amino acids using iridium complex photocatalyst were
reported by MacMillan and co-workers.13 Therefore, we
selected the decarboxylative aryl coupling reaction of protected
α-amino acids 4 with aryl nitriles 5 to evaluate our small
molecular photocatalysts.
Table 1. Screening of Reaction Conditions
entry catalyst
light (nm)
base
solvent
DMSO
yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
1a
1b
2a
2b
3a
3b
2a
2a
−
390−395
390−395
390−395
390−395
390−395
390−395
390−395
−
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
CsF
NR
NR
73
45
10
NR
47
NR
NR
NR
60
69
67
33
27
68
67
NR
NR
NR
79
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
MeCN
THF
b
c
c
−
−
390−395
375−380
385−390
395−400
390−395
390−395
390−395
390−395
390−395
390−395
390−395
390−395
390−395
390−395
390−395
390−395
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
DMF
DMAc
toluene
2,4-dioxane
acetone
DMSO
DMSO
DMSO
DMSO
DMSO
Our work mechanism is proposed in Figure 2. First,
irradiation of photocatalyst (PC) with light was intended to
K2CO3
Cs2CO3
NaOAc
66
62
76
67
NaHCO3
a
Reaction conditions: 4a (0.4 mmol), 5a (0.2 mmol), catalyst (2 mol
%), base (0.4 mmol), irradiation from 10 W LED, N2 atmosphere,
room temperature, 24 h; isolated yield. Under an air atmosphere. At
b
c
90 °C.
5). However, no reaction was observed when 1a, 1b, and 3b
were used as catalysts (Table 1, entries 1, 2, and 6). When the
reaction was performed under an air atmosphere, a lower yield
was obtained (Table 1, entry 7). Control experiments
demonstrated that both the photocatalyst and light were all
indispensable ingredients to achieve a successful coupling
reaction (Table 1, entries 8−10). Then, we fixed 2a as the
catalyst to screen other reaction conditions. Both decreasing
and increasing the light wave led to a reduction in the yield
(Table 1, entries 11−13). Changing the solvent from DMSO
to acetonitrile, THF, DMF, or DMAc did not further improve
the reaction (Table 1, entries 14−17), while the reaction did
not take place when toluene, 2,4-dioxane, and acetone were
used as solvent (Table 1, entries 18−20). Finally, several other
bases, such as CsF, K2CO3, Cs2CO3, NaOAc, and NaHCO3,
were screened (Table 1, entries 21−25), and the optimal result
was obtained when CsF was used as the base (Table 1, entry
21).
After establishing the optimal reaction conditions, we next
investigated the scope of amino acids for their reaction with
1,4-dicyanobenzene (5a). As shown in Scheme 1, all amino
acid derivatives 4a−n reacted smoothly with 5a to give the
corresponding products 6a−n in good to high yields (59−
82%). The protecting groups, such as Cbz (product 6a), Boc
(products 6b−l), trityl (product 6i), and benzyl (products 6k
and 6h), could tolerate the reaction conditions. The α-carbon
Figure 2. Design plan based on mechanistic considerations.
produce a photoexcited state PC* that is a strong oxidant (for
2a, E1/2(PC*/PC−) = +1.30 V vs SCE). We presumed that the
α-amino acid component (for Cbz-Pro-OCs, E1/2red = +1.00 V
vs SCE)13 would be oxidized by PC* to form the
corresponding carboxyl radical species, which should produce
the α-amino radical intermediate A with loss of CO2. Then, the
reduced photocatalyst (PC−) (for 2a, E1/2(PC/PC−) = −1.70
V vs SCE) would reduce aryl nitriles such as 1,4-
dicyanobenzene (5a) (E1/2 = −1.53 V vs SCE)14 via single
red
electron transfer to form the radical anion intermediate B.
Finally, the radical−radical coupling of A with B and
subsequent aromatization with release of cyanide would deliver
the benzylic amine.
Evaluation of the decarboxylative cross-coupling reaction
was first investigated using Cbz-protected proline (4a), 1,4-
dicyanobenzene (5a) and six AFDC-based photocatalysts 1−3
in the presence of K2HPO4 under irradiation from 10 W LED
(390−395 nm) at room temperature (Table 1). To our
delight, compounds 2a, 2b and 3a could catalyze the model
reaction to give a decarboxylative coupling product 6a in 73%,
45% and 10% isolated yields, respectively (Table 1, entries 3−
B
DOI: 10.1021/acs.orglett.9b00443
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Letter
a
a
Scheme 1. Scope of Amino Acids 4
Scheme 2. Scope of Aryl Nitriles 5
a
Reaction conditions: 4a (0.4 mmol), 5 (0.2 mmol), 2a (2 mol %),
CsF (0.4 mmol), DMSO (2 mL), irradiation from 10 W LED (390−
395 nm), room temperature, N2, 24 h; isolated yield.
a
Scheme 3. Direct Arylation with α-Oxy Carboxylic Acids 7
a
Reaction conditions: 7 (0.4 mmol), 5a (0.2 mmol), 2a (2 mol %),
a
Reaction conditions: 4 (0.4 mmol), 5a (0.2 mmol), 2a (2 mol %),
CsF (0.4 mmol), DMSO (2 mL), irradiation from 10 W LED (390−
CsF (0.4 mmol), DMSO (2 mL), 10 W LED (390−395 nm), room
temperature, N2, 24 h; isolated yield.
b
395 nm), room temperature, N2, 24 h; isolated yield. Reaction was
conducted at 1 mmol scale.
methoxy-2-phenylacetic acid (7c) with 5a provided the
corresponding products 8a−c in 65−85% yields. Moreover,
treatment of 7c with 4-cyanopyridines 5f and 5g under the
standard conditions led to the desired products 8d and 8e with
higher levels of efficiency, respectively.
We next explored the mechanism of this decarboxylative
cross-coupling reaction. The Stern−Volmer experiments
showed no measurable luminescence quenching of PC* (2a)
by 1,4-dicyanobenzene (5a). However, cesium salt of 4a could
significantly quench the emission of PC* (see Supporting
Information, Figure 7). This result supports the proposed
photocatalytic cycle that is triggered from a single-electron-
transfer reduction of PC* by carboxylate (Scheme 1).
In conclusion, we have demonstrated that 1-(4-(9H-
carbazol-9-yl)phenyl)-3-amino-9H-fluorene-2,4-dicarbonitrile,
one of AFDC-based fluorophores, is a novel and efficient
photocatalyst that promotes the decarboxylative aryl coupling
reaction of α-amino acids or α-oxy carboxylic acids with
arylnitriles. The reaction is general for a remarkable range of
of the amino acid derivative could bear two methyl groups
(product 6m) and the nitrogen atom of the α-amino could be
substituted by a phenyl (product 6n), although a relatively
lower yield (59%) was obtained in the last case. It is
noteworthy that this reaction could be scaled up as
demonstrated by the preparation of 6a at 1 mmol scale
(75% isolated yield).
Subsequently, we examined the scope of arylnitriles under
established conditions. As shown in Scheme 2, 2,5-dimethyl-
terephthalonitrile (5b), methyl 4-cyanobenzoate (5c), 4-
(phenylsulfonyl)benzonitrile (5d), 1-oxo-1,3-dihydroisobenzo-
furan-5-carbonitrile (5e), 4-cyanopyridine (5f), and 4-cyano-2-
methylpyridine (5g) smoothly reacted with 4a to give the
corresponding products 6o−t in 61−81% yields.
As an extension of our method, the established procedure
was used for the direct arylation with α-oxy carboxylic acids 7
(Scheme 3). The reaction of tetrahydrofuran-2-carboxylic acid
(7a), tetrahydro-2H-pyran-2-carboxylic acid (7b), and 2-
C
DOI: 10.1021/acs.orglett.9b00443
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00443.
Experimental procedures and characterization data for
all new compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: pinglu@zju.edu.cn.
*E-mail: orgwyg@zju.edu.cn.
ORCID
Ping Lu: 0000-0002-3221-3647
Yanguang Wang: 0000-0002-5096-7450
Notes
(12) For a review on decarboxylations, see: Gooβen, L. J.; Gooβen,
K.; Rodríguez, N.; Blanchot, M.; Linder, C.; Zimmermann, B. Pure
Appl. Chem. 2008, 80, 1725.
(13) The reduction potential of Cbz-Pro-OCs was measured in THF
following the methods in: (a) Andrieux, C. P.; Gonzalez, F.; Saveant,
J. J. Electrochem. Soc. 2001, 498, 171. (b) Galicia, M.; Gonzalez, F. J. J.
Electrochem. Soc. 2002, 149, D46.
(14) The reduction potential of 1,4-dicyanobenzene was measured
in THF following the methods in: Mori, Y.; Sakaguchi, W.; Hayashi,
H. J. Phys. Chem. A 2000, 104, 4896.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by National Natural Science
Foundation of China Grants Nos. 21871229 and 21632003
to P.L. and Y.G.W. The authors thank Jiarui Wang for language
editing.
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DOI: 10.1021/acs.orglett.9b00443
Org. Lett. XXXX, XXX, XXX−XXX