Radical alkylation of isocyanides with amino acid-/peptide-derived Katritzky salts via photoredox catalysis

Article abstract of DOI:10.1039/C8OB02786B

An efficient and mild method was developed for the synthesis of 6-alkylated phenanthridines upon visible light irradiation. Bench-stable and easily handled redox-active Katritzky pyridinium salts derived from abundant amino acids/peptides were used as radical precursors for the alkylation of isocyanobiphenyl species. The reaction displays an excellent functional group tolerance and a potential utility for peptide functionalization, allowing access to desired products in good to excellent yields.

Full text of DOI:10.1039/C8OB02786B

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Biomolecular Chemistry
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Radical alkylation of isocyanides with amino acid-/
peptide-derived Katritzky salts via photoredox
catalysis†
Cite this: DOI: 10.1039/c8ob02786b
a
a
a,b
Ze-Fan Zhu, Miao-Miao Zhang and Feng Liu
*
An efficient and mild method was developed for the synthesis of 6-alkylated phenanthridines upon visible
light irradiation. Bench-stable and easily handled redox-active Katritzky pyridinium salts derived from
abundant amino acids/peptides were used as radical precursors for the alkylation of isocyanobiphenyl
species. The reaction displays an excellent functional group tolerance and a potential utility for peptide
functionalization, allowing access to desired products in good to excellent yields.
Received 8th November 2018,
Accepted 23rd January 2019
DOI: 10.1039/c8ob02786b
rsc.li/obc
reactions, it is important to note that there is no systematic
investigation on the use of Katritzky pyridinium salts derived
Introduction
α-Amino acids and their derivatives are not only ubiquitous in from naturally abundant amino acids in radical alkylation.
organic molecules and natural products but also widely On the other hand, phenanthridines are extensively found
1
9
10
present as structural motifs in bioactive agents. Notably, they in natural products and bioactive molecules with a wide
1
frequently serve as building blocks in organic synthesis.
range of pharmacological properties including antitumor, anti-
Recently, redox-active esters, as electron acceptors, have been fungal, and antiviral activities. Therefore, the development of
2
,3
extensively used in radical alkylation, especially via photo- efficient and practical methods for construction of phenanthri-
3
11,12
redox catalysis. Moreover, the use of redox-active esters dine skeletons has received considerable attention.
Among
derived from amino acids as precursors of α-aminoalkyl rad- these protocols, the isonitrile insertion of 2-isocyanobiphenyls
4
icals is also well established (Scheme 1). In contrast, the gene- via a radical process has emerged as a general strategy for the
3
12
ration of alkyl radicals via C(sp )–N bond activation remains synthesis of 6-substituted phenanthridines. For instance, we
5
largely under-explored. Bench-stable and easily handled have recently reported a mild and effective method for the syn-
Katritzky pyridinium salts which are readily prepared from thesis of 6-fluoroalkylated phenanthridines from isocyanobi-
6
primary amines in one step can act as a class of alkyl radical
7
source for further transformation. Of the few relevant reports,
Watson and co-workers developed a nickel-catalyzed cross-
coupling of redox-activated Katritzky salts with boronic acids
7
a,b
via the formation of an alkyl radical species.
Furthermore,
Glorius et al. reported a visible-light-mediated Minisci-type
reaction involving a single-electron-transfer (SET) reduction of
8
Katritzky salt (E1/2 = −0.93 V vs. SCE in DMF) and then a frag-
mentation to give an alkyl radical and a pyridine ring via
7
c
photoredox catalysis. Despite these reports on deaminative
a
Jiangsu Key Laboratory of Neuropsychiatric Diseases and Department of Medicinal
Chemistry, College of Pharmaceutical Sciences, Soochow University, 199 Ren-Ai
Road, Suzhou, Jiangsu 215123, People’s Republic of China.
E-mail: fliu2@suda.edu.cn
b
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032,
People’s Republic of China
†
Electronic supplementary information (ESI) available: Experimental details,
1
13
19
characterization data, and copies of H, C and F NMR spectra for all com-
pounds. See DOI: 10.1039/c8ob02786b
Scheme 1 Radical-mediated transformations of redox-active α-amino
acid derivatives.
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1
3
phenyls via organic photoredox catalysis. In this context, we (entries 15 and 16). To examine the heat effect, we conducted
would like to report a general visible-light-mediated protocol the reactions in the dark at 60 °C, finding that they gave the
for the synthesis of 6-alkylated phenanthridines using redox- desired product 3a in much lower yields (entries 17 and 18).
active Katritzky pyridinium salts derived from amino acids/
With the optimized conditions in hand, the substrate scope
peptides as the alkylating agents under mild reaction con- of the reaction was studied. At first, the reactions of phenyl-
ditions (Scheme 1).
alanine-derived Katritzky salt (2a) with various 2-isocyanobi-
phenyls (1) were explored. As shown in Scheme 2, a variety of
substituted phenanthridines were readily obtained in good to
excellent yields (3a–k). This protocol could accommodate a
range of substituents on arenes regardless of their electronic
and/or steric properties (3b–k). In particular, the reactions of
the substrates (1) bearing either electron-withdrawing or elec-
tron-donating functional groups at the para-position on the
Results and discussion
We commenced our investigations on the model reaction of
2
-isocyanobiphenyl 1a with Katritzky salt 2a which can be
readily prepared from phenylalanine methyl ester on a gram
scale in one step.
1
4
Best results were obtained with
2
-phenyl rings (R ) proceeded smoothly, achieving the corres-
2
Ru(bpy) Cl as the photocatalyst (PC), K CO /Cs CO as the
2
2
2
3
2
3
ponding products in satisfied yields (3d–g). Moreover, the reac-
tion also gave the desired phenanthridines in good yields
when substituents such as a fluorine or methyl group were
installed on the meta-position (3h–i), though poor regio-
selectivity was observed in the case of substrate 1k, providing
the separable isomers 3k and 3k′ in 44% and 40% yields
respectively. It should be noted that an aryl isonitrile with a
nitrogen-containing heterocycle was also compatible with this
protocol, affording the desired product in excellent yield (3j).
Importantly, the reaction can be readily scaled up to gram
level, furnishing the desired product 3a without compromising
the chemical yield.
To test the further practicability of this deaminative reac-
tion, we investigated the reaction of 2-isocyanobiphenyl (1a)
with different natural and unnatural amino acid-/dipeptide-
derived redox-active Katritzky salts (2). As depicted in
Scheme 3, a series of Katritzky salts were suitable substrates
for this radical cascade reaction, providing the desired 6-sub-
3
base, and CH CN as the solvent (Table 1, entries 1 and 11).
Upon irradiation with household blue LEDs (22 W) at ambient
temperature for 12 h, the desired phenanthridine product 3a
was furnished in 94% isolated yield when using much more
2 3 2 3
inexpensive inorganic base K CO (compared to Cs CO ). A
brief survey of organic solvents showed that CH CN was the
3
best one in terms of chemical yield (entries 1–6). Other com-
monly used photocatalysts, such as Ir complexes and Eosin Y,
gave the product 3a in lower yields (entries 7–9). A series of
bases including common organic base DIEA (N,N-diisopropyl-
ethylamine) were examined, showing that both K
2 3
CO and
Cs CO gave the highest chemical yields (entries 1 and 11).
2
3
Control experiments revealed that the photocatalyst and visible
light were both essential for the success of the reaction
a
Table 1 Optimization of reaction conditions
b
Entry
Solvent
CH CN
Acetone
THF
DCE
DMF
Photocatalyst
Base
Yield (%)
1
2
3
4
5
6
7
8
9
3
Ru(bpy)
2
Cl
Cl
Cl
Cl
Cl
Cl
2
2
2
2
2
2
K
K
K
K
K
K
K
K
K
2
2
2
2
2
2
2
2
2
CO
CO
CO
CO
CO
CO
CO
CO
CO
3
3
3
3
3
3
3
3
94
89
68
5
Ru(bpy)
Ru(bpy)
Ru(bpy)
Ru(bpy)
Ru(bpy)
2
2
2
2
2
78
<5
91
61
91
82
95
80
52
65
<5
0
PhCH
3
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
3
CN
3
CN
3
CN
3
CN
3
CN
3
CN
3
CN
3
CN
3
CN
3
CN
3
CN
3
CN
2 6
Ir[(ppy) (dtbbpy)]PF
Ir(ppy)
Eosin Y
Ru(bpy)
Ru(bpy)
Ru(bpy)
Ru(bpy)
Ru(bpy)
—
3
3
10
11
12
13
14
15
16
17
18
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
2
2
2
2
Na
Cs
KHCO
PO
DIEA
2
CO
3
2
CO
3
3
K
3
4
K
2
K
2
K
2
K
2
CO
3
3
3
3
c
Ru(bpy)
Ru(bpy)
—
2
Cl
Cl
2
2
CO
CO
CO
c,d
c,d
2
14
13
a
Scheme 2 Substrate scope of 2-isocyanobiphenyls. Reaction con-
Reaction conditions: 1a (0.15 mmol), 2a (0.30 mmol), photocatalyst
ditions: 1 (0.15 mmol), 2a (0.30 mmol), Ru(bpy)
2 2 2 3
Cl (5 mol%), K CO
(
PC, 5 mol%), base (0.30 mmol), solvent (2 mL), room temperature,
b c
irradiation with household blue LEDs (22 W), 12 h. Isolated yield. In (0.30 mmol), CH CN (2 mL), room temperature, irradiation with blue
3
d
a
the dark. 60 °C.
LEDs (22 W), 12 h. Isolated yield. 1 g (5.6 mmol) scale of 1a.
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Scheme 4 Proposed mechanism.
To gain insights into the possible mechanism of this
visible-light-mediated reaction, the luminescence quenching
1
5
experiments were conducted (Fig. S1†).
As might be
expected, the results showed that phenylalanine-derived
Katritzky salt (2a) could quench the photoexcited Ru(bpy) Cl
2
2
2
+ 16
(
*[Ru] ) effectively but 2-isocyanobiphenyl (1a) did not.
Performing the reaction in the presence of radical scavenger
TEMPO ((2,2,6,6-tetramethylpiperidin-1-yl)oxyl), did lead to no
desired product 3a formation. Moreover, a TEMPO-trapped
product was also determined by MS analysis and NMR
1
5
(
Fig. S2†), indicating that an alkyl radical intermediate could
be generated. Furthermore, an on/off light experiment was
conducted to investigate more mechanistic details, showing
that the reaction proceeded smoothly upon irradiation with
light but no further conversion was observed when removing
1
5
the light source (Fig. S3†). It verified the necessity of light,
Scheme 3 Substrate scope of Katritzky salts. Reaction conditions: 1a and strongly supports that the reaction is a non-chain process.
0.15 mmol), 2 (0.30 mmol), Ru(bpy) Cl (5 mol%), K CO (0.30 mmol),
CH CN (2 mL), room temperature, irradiation with blue LEDs (22 W),
2 h. Isolated yield. The dr value was determined by H NMR.
(
2
2
2
3
12,13
On the basis of the observations and previous reports,
3
the proposed mechanistic details of the transformation are
depicted in Scheme 4. The initial step involves a single electron
a
1
1
2
+
reduction of a redox-active Katritzky salt 2 by *[Ru] , yielding a
dihydropyridine radical A, followed by a fragmentation process
driven by the reformation of an aromatic pyridine ring to afford
an alkyl radical B. Then, the radical B adds to isocyanide 1a to
give an imidoyl radical C which undergoes intramolecular cycli-
zation to form intermediate D. Finally, the single electron oxi-
stituted phenanthridines in good to excellent yields (4a–o).
The accommodated amino acids include alanine (4a), valine
(
4
(
4b), leucine (4c), isoleucine (4d), methionine (4e), tyrosine (4f,
j), homophenylalanine (4g), aspartic acid (4h), glutamic acid
4i), and phenylalanine (3a, 4k–m). This protocol demonstrates
excellent functional group compatibility, for instance, sulfide
4e), ester (4h–i), and amide (4l–m), especially the unmasked
3+
dation of the D by [Ru] produces the desired product 4 by an
aromatization and deprotonation process, as well as the
(
II
ground-state Ru complex to close the photoredox cycle.
hydroxyl group (4j), being well tolerated. Importantly, we have
found that dipeptide-derived redox-active Katritzky salts could
be successfully used in the deaminative radical reaction,
giving the desired products in good yields (4m–n). In addition,
the diastereoselectivity of this reaction is poor as most of
Conclusions
radical reactions (4d, 4n). It is of note that this protocol could In summary, we have described an efficient visible-light-
offer a powerful complementary strategy for the use of amino mediated protocol for the synthesis of 6-alkylated phenanthri-
acids that were also employed in photoredox-catalyzed decar- dine derivatives. The readily available redox-active Katritzky
4
boxylative reactions.
pyridinium salts derived from abundant amino acids/peptides
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were used as radical precursors for the alkylation of isocyano-
biphenyl species. The reaction displays an excellent functional
group tolerance and is able to be applicable to the peptide
transformation. The reaction proceeds at room temperature
without any external strong oxidant and could be readily scal-
able, furnishing the desired products in good to excellent
chemical yields.
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