Visible-light-promoted and one-pot synthesis of phenanthridines and quinolines from aldehydes and o -Acyl hydroxylamine

Article abstract of DOI:10.1021/acs.orglett.5b01096

A one-pot synthesis of phenanthridines and quinolines from commercially available or easily prepared aldehydes has been reported. O-(4-Cyanobenzoyl)hydroxylamine was utilized as the nitrogen source to generate O-acyl oximes in situ with aldehydes catalyzed by Bronsted acid. O-Acyl oximes were then subjected to visible light photoredox catalyzed cyclization via iminyl radicals to furnish aza-arenes. A variety of phenanthridines and quinolines have been prepared assisted by Bronsted acid and photocatalyst under visible light at room temperature with satisfactory yields.

Full text of DOI:10.1021/acs.orglett.5b01096

Letter
pubs.acs.org/OrgLett
Visible-Light-Promoted and One-Pot Synthesis of Phenanthridines
and Quinolines from Aldehydes and O‑Acyl Hydroxylamine
Xiao-De An and Shouyun Yu*
State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University,
22 Hankou Road, Nanjing 210093, China
*
S Supporting Information
ABSTRACT: A one-pot synthesis of phenanthridines and
quinolines from commercially available or easily prepared
aldehydes has been reported. O-(4-Cyanobenzoyl)-
hydroxylamine was utilized as the nitrogen source to generate
O-acyl oximes in situ with aldehydes catalyzed by Brønsted
acid. O-Acyl oximes were then subjected to visible light
photoredox catalyzed cyclization via iminyl radicals to furnish aza-arenes. A variety of phenanthridines and quinolines have been
prepared assisted by Brønsted acid and photocatalyst under visible light at room temperature with satisfactory yields.
N-Containing 6-membered arenes, such as quinolines and
efficiency of this transformation, we would like to investigate
the possibility of a one-pot procedure for the synthesis of aza-
arenes from carbonyl compounds and a nitrogen source. In this
regard, selection of the nitrogen source is crucial to this
transformation. The nitrogen source must be able to generate
phenanthridines, are ubiquitous in natural products, pharma-
1
ceuticals, and other biologically active molecules. Traditional
methods to prepare these heterocycles primarily rely on ionic
transformations from amines and carbonyl compounds, such as
2
,3
8
Combes, Povarov, and Skraup reactions. Transition-metal-
mediated reactions have also been developed prosperously to4
achieve these motifs from diverse precursors for recent years.
Compared to the flourish of ionic condensation and
transition-metal catalysis, there are fewer reported method5s
using radical approaches in the construction of aza-arenes.
Very recently, we have developed a visible-light-promoted
synthesis of N-containing 6-membered arenes from O-acyl
O-acyl oximes with carbonyl compounds in situ. It was found
that O-acyl hydroxylamines, which could easily be prepared
from readily available hydroxylamine and the corresponding
acyl chlorides, could condense with aldehydes to give O-acyl
oximes. Thus, we believed that O-acyl hydroxylamines could
serve as the nitrogen source in the one-pot synthesis of aza-
arenes from aldehydes under visible light photoredox catalysis
9
(
Scheme 1b).
6
oximes via an iminyl radical (Scheme 1a). This strategy affords
Our initial efforts toward this goal focused on the use of O-
(
4-cyanobenzoyl)hydroxylamine (2a) as the nitrogen source.
Scheme 1. Visible-Light-Promoted Synthesis of Aza-arenes
Reaction of biphenyl-2-carbaldehyde (1a) with 2a (3.0 equiv)
under our previously established conditions gave desired
phenanthridine 3a in 37% yield based on H NMR spectros-
6
1
copy analysis (Table 1, entry 1). The poor yield was due to low
conversion of aldehyde 1a to the corresponding acyl oxime. To
accelerate the formation of the acyl oxime, a variety of additives
were examined (entries 2−9). Organic base, such as Et N,
3
could not improve this reaction (entry 2). To our delight,
Brønsted acids were efficient additives to this transformation
(
entries 3−9). p-Cl-benzenesulfonic acid (CBSA) was proven
to be the best additive with 72% NMR yield of 3a (entry 9).
The dosage of the nitrogen source was then investigated. The
use of less 2a did not affect the yield of this reaction
significantly (entries 10−11), and 1.5 equiv of 2a gave the
optimal result with 74% NMR yield (72% isolated yield) (entry
1
0). The solvent effect was then evaluated (entries 12−17). No
an efficient method for the exclusive 1 e reduction of acyl
oximes under mild conditions, which can furnish a class of
ubiquitous aza-arenes in high yields, including pyridines,
quinolines, and phenanthridines. However, O-acyl oximes
must be preformed from corresponding ketones or aldehydes
in two steps (oximation and acylation). To improve the overall
7
solvent was superior to DMF. O-(4-CF -benzoyl)-
hydroxylamine (2b) was investigated as the nitrogen source,
3
Received: April 15, 2015
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01096
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization of Reaction Conditions
Scheme 2. Scope of Aldehydes Leading to
ab
,
Phenanthridines
b
entry
additive
solvent
yield/%
1
2
3
4
5
6
7
8
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
NMP
toluene
37
<10
55
Et N
3
AcOH
TsOH
64
TfOH
41
Cl CCO H
3
57
2
oxalic acid
CSA
46
70
9
CBSA
CBSA
CBSA
CBSA
CBSA
CBSA
CBSA
CBSA
CBSA
CBSA
72
c
f
1
1
1
1
1
1
1
1
1
0
74 (72 )
72
d
1
2
3
4
5
6
7
8
c
c
c
c
c
c
e
71
68
trace
trace
trace
trace
16
CH CN
3
MeOH
THF
DMF
a
Reaction condition: A solution of 1a (0.2 mmol), 2a (0.6 mmol), fac-
Ir(ppy) (0.004 mmol, 2.0 mol %) and additive (0.02 mmol) in the
3
indicated solvent (2.0 mL) was irradiated by white LED strips for 10 h.
b
1
c
d
H NMR yield. 1.5 equiv of 2a (0.3 mmol) was used. 1.2 equiv of
e
2
a (0.24 mmol) was used. 2b (0.3 mmol) was used instead of 2a.
f
Isolated yield. CSA = camphorsulfonic acid; CBSA = p-Cl-
benzenesulfonic acid.
and it turned out to be much less efficient than 2a. The
corresponding O-acyl oxime could be generated smoothly, but
visible-light-promoted cyclization was sluggish and the desired
product was isolated in 16% yield after 10 h (entry 18).
With the optimized conditions in hand, the synthetic
potential of this one-pot procedure was then investigated and
the results are summarized in Schemes 2 and 3. To find the
scope of aldehydes leading to phenanthridines, a variety of
biaryl aldehydes were then subjected to the optimized
conditions (Scheme 2). Generally, acceptable to good isolated
yields (39−89%) were obtained no matter the substituents on
the biphenyl moiety (3a−3m). Aza-arenes with more than one
nitrogen atom (3n−3p) were also prepared by means of this
method. Pyridine-derived aldehydes were also tolerated in this
reaction, and several interesting aza-arenes 3n−3p were
prepared in 51−66% yields. Functional groups such as hydroxyl
a
Reaction conditions: A solution of 1 (0.2 mmol), 2a (0.3 mmol) fac-
Ir(ppy) (0.004 mmol, 2.0 mol %) and CBSA (0.02 mmol) in dry
3
b
DMF (2.0 mL) was irradiated by white LED strips. Isolated yields.
c
The major product is shown and the asterisk indicates the position of
the C−N bond to this ring in the minor isomer.
blue LED strips instead of white LEDs could suppress the
formation of side products.
To demonstrate the practicability of this newly established
method, a gram scale and two-step synthesis of alkaloid
10
trisphaeridine (8), which possessing excellent antitumor
11
effects and antiretroviral activity, was conducted (Scheme
4). Suzuki coupling of commercially available aldehyde 6 with
phenyl boronic acid gave biphenyl aldehyde 7 in nearly
quantitative yield. Irradiation of 7 (1.81 g) under white LEDs in
(3q), keto carbonyl (3r), amide (3s), which could not be
tolerated in our previous stepwise procedure, could go through
this one-pot transformation. To our disappointment, biaryl
ketones were not compatible with these conditions and all
ketones we tried were fully recovered (for more unsuccessful
examples, see Supporting Information).
the presence of fac-Ir(ppy) and CBSA allowed the preparation
3
of trisphaeridine (8, 1.43 g) in 80% yield. The route described
here represents the shortest route for trisphaeridine with
highest overall yield to date.
In summary, we have described a one-pot synthesis of
phenanthridines and quinolines from commercially available or
easily prepared aldehydes. O-(4-Cyanobenzoyl)hydroxylamine
was utilized as the nitrogen source to generate O-acyl oximes in
situ, which was then subjected to photoredox catalyzed
cyclization. Various phenanthridines and quinolines have been
We next sought to explore the applicability of this strategy to
other important functionalized N-containing arenes such as
quinoline derivatives (Scheme 3). We found that cinnamalde-
hyde-type substrates could also go through this one-pot
transformation to give quinolines 5a−5h in acceptable yields
(
45−63%) irradiated by blue LED strips. It is noteworthy that
the light source was important to these reactions. The use of
B
DOI: 10.1021/acs.orglett.5b01096
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Scope of Aldehydes Leading to Quinolines ,
a b
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AUTHOR INFORMATION
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4
Corresponding Author
*E-mail: yushouyun@nju.edu.cn.
(
7
Notes
The authors declare no competing financial interest.
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DOI: 10.1021/acs.orglett.5b01096
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