Regiospecific Minisci acylation of phenanthridine via thermolysis or photolysis

Article abstract of DOI:10.1016/j.tetlet.2014.10.068

In this study, a new type of Minisci reaction for regiospecific acylation of phenanthridine has been developed based on cross dehydrogenative coupling (CDC) strategy. Using substoichiometric amount of TBAB (tetrabutylammonium bromide, 30 mol %) and K₂S₂O₈ as an oxidant, acyl radicals generate from aldehyde substrates under thermal conditions followed by a regiospecific intermolecular acylation with phenanthridine. Furthermore, a preliminary research has indicated that the acylation reaction can be carried out at room temperature when K₂S₂O₈/TBAB is displaced by (NH₄)₂S₂O₈ and another 5 mol % of fac-Ir(ppy)₃ is used as photocatalyst under irradiation of visible light. This intermolecular acylation reaction provides an easy access to 6-acylated phenanthridine derivatives.

Full text of DOI:10.1016/j.tetlet.2014.10.068

Accepted Manuscript
Regiospecific Minisci acylation of phenanthridine via thermolysis or photolysis
Pi Cheng, Zhixing Qing, Sheng Liu, Wei Liu, Hongqi Xie, Jianguo Zeng
PII:
S0040-4039(14)01751-1
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.10.068
TETL 45297
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
12 July 2014
2 October 2014
10 October 2014
Please cite this article as: Cheng, P., Qing, Z., Liu, S., Liu, W., Xie, H., Zeng, J., Regiospecific Minisci acylation
of phenanthridine via thermolysis or photolysis, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.
2014.10.068
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Regiospecific Minisci acylation of phenanthridine
via thermolysis or photolysis
Pi Cheng a, b, Zhixing Qing c, Sheng Liu b, Wei Liu a, Hongqi Xie a, * and Jianguo
Zeng a, b, c *
aPre-State Key Laboratory for Germplasm Innovation and Utilization of Crop, Hunan
Agricultural University, Changsha, Hunan 410128, China
bNational Research Center of Engineering Technology For Utilization of Functional
Ingredients From Botanicals, Hunan Agricultural University, Changsha, Hunan
410128, China
cSchool of Pharmaceutical, Hunan University of Chinese Medicine, Changsha, Hunan
410208, China
*Corresponding authors:
Hongqi Xie: Tel: +86 731 84686560; E-mail address: xiehongqi2006@126.com;
Jianguo Zeng: Tel: +86 731 84673824; E-mail address: ginkgo@world-way.net
1

Graphic Abstract
Regiospecific Minisci acylation of phenanthridine via thermolysis or photolysis
Pi Cheng a, b, Zhixing Qing c, Sheng Liu b, Wei Liu a, Hongqi Xie a, *, Jianguo Zeng a, b, c, *
Using K2S2O8 as oxidant and TBAB as initiator, acyl radicals generate from aldehydes substrates
and couple with phenanthridine under thermal conditions at 110 °C. When K2S2O8/TBAB is
displaced by (NH4)2S2O8 and another 5 mol % fac-Ir(ppy)3 catalyst is added to the reaction system,
this type of coupling reaction proceeds slowly under visible light at room temperature.
2

Abstract: In this study, a new type of Minisci reaction for regiospecific acylation
of phenanthridine has been developed based on cross dehydrogenative coupling (CDC)
strategy. Using substoichiometric amount of TBAB (tetrabutylammonium bromide,
30 mol %) and K2S2O8 as an oxidant, acyl radicals generate from aldehydes substrates
under thermal conditions followed by a regiospecific intermolecular acylation with
phenanthridine. Furthermore, a preliminary research has indicated that the acylation
reaction can be carried out at room temperature when K2S2O8/TBAB is displaced by
(NH4)2S2O8 and another 5 mol % of fac-Ir(ppy)3 is used as photocatalyst under
irradiation of visible light. This intermolecular acylation reaction provides an easy
access to 6-acylated phenanthridine derivatives.
Key words: acylation, phenanthridine, Minisci reaction, photochemistry, fac-Ir(ppy)3
The phenanthridine is a common pharmacophore existed in a wide variety of
naturally occurring benzophenanthridine and phenanthridine alkaloids.1–4 Among
them benzo[c]phenanthridine alkaloid analogues such as NK109 exhibit
potentanti-tumor activity by the inhibition of DNA topoisomerase I,5–6 and are
considered as potential anti-tumor drugs. Phenanthridines also possess a wide variety
of interesting biological activities and potential pharmaceutical applications such as
antibacterial,7–8 DNA intercalator9–10 and enzyme inhibition.11–12 Substituted
phenanthridines are also used in material science due to their significant
optoelectronic properties.13
Because of the above reasons, diverse methods have been developed for
phenanthridine synthesis in the last decades.14–22 Along with the traditional methods,23
phenanthridines have recently been successfully prepared by radical chemistry using
cascades radical addition to 2-isocyanobiphenyls with subsequent homolytic aromatic
substitution (HAS). Based on this strategy, various radical species such as sp3 or sp2
28
29
C-radicals,24–27 P-radicals
and Si-radicals
reacted with 2-isocyanobiphenyls to
give the corresponding 6-substituted phenanthridines (A, Scheme 1). Recently,
Leifert30 reported a new method to synthesize 6-aroylated phenanthiridne using
aromatic aldehydes as C-radical precursor to react with 2-isocyanobiphenyls by HAS
3

strategy (B, Scheme 1). In this report, t-BuOOH (TBHP) was used as the oxidant and
FeCl3 as initiator. According to previous literature, the cross dehydrogenative
coupling (CDC) provided another facile route to generate acyl radical with aldehydes
as precursor for acylation of arenes.31–33 Based on CDC strategy, electron-deficient
heteroarenes34 such as pyridine, quinolone, isoquinoline and quinoxaline could be
acylated via intermolecular Minisci reaction with aldehydes.35–36 However, this
method has never been applied to synthesize 6-aroylated phenanthridine and generally
needs high reaction temperature. Guided by Leifert’s research, we thought that the
intermolecular cross dehydrogenative coupling of aromatic aldehydes with
phenanthridine could also provide corresponding 6-aroylated phenanthridines via
Minisci reaction to avoid using water sensitive and toxic 2-isocyanobiphenyls (C,
Scheme 1).
A
: Typical 6-substituted phenanthridine synthesis by somophinic isocyanide insertion
R
HAS
radical addition
N
R
N
N
R
C
B
: 6-Aroylated phenanthridine synthesis reported by Leifert
O
TBHP, FeCl3
+
O
H
N
MeCN, 90 C
N
C
C
: this work
O
Minisci reaction
+
O
H
N
N
Scheme 1. Synthesis of 6-aroylated phenanthridines via radical addition to
2-isocyanobiphenyls and Minisci reaction
31
According to previous literatures, diverse oxidants such as (NH4)2S2O8 ,
TBHP,32–34 PhI(OCOCF3)235 and K2S2O836 can be used for the CDC coupling reaction
of aldehyde with various arenes, thus our reaction condition optimization began with
oxidant screening. The reaction was optimized using 1.0 equiv of phenanthridine (1)
4

and 2.0 equiv of benzaldehyde (2a) as model substrates. In the most of times, CDC
reaction was carried out in the presence of TBHP. However, experimental results in
this study indicated that the intermolecular coupling of 1 and 2a only furnished target
compound 3a in poor isolated yield when 2.0 equiv of TBHP (6M solution in decane)
was used as oxidant (entry 1, Table 1). Small amount of FeCl3(1 mol %) added to the
reaction system could slightly improve the yield of 3a after 9 h reaction time (entry 2,
table 1). Increasing TBHP to 4.0 equiv promoted the reaction and gave 3a in moderate
yield under similar condition (entry 3–4, table 1). Although the reaction proceeded in
the presence of TBHP, high yield of 3a was not achieved.
Table 1. Optimization studies for coupling conditions a
oxidant
initiator
solvent
O
O
+
H
N
12 h, 110 C
N
3a
1
2a
entry
oxidant (equiv.)
catalyst
solvent
Yield(%)b
(mol%)
none
1
6M TBHP in decane(2.0)
6M TBHP in decane(2.0)
6M TBHP in decane(2.0)
6M TBHP in decane(4.0)
K2S2O8 (1.0)
DCE
DCE
DCE
DCE
DCE
DCE
MeCN
DMSO
toluene
DMF
DCE
DCE
DCE
DCE
DCE
DCE
15
2c
FeCl3 (1)
FeCl3 (1)
FeCl3 (1)
none
18
3
23
4
37
5
10
6
K2S2O8(2.0)
none
17
7
K2S2O8 (2.0)
none
NR
NR
NR
NR
41
8
K2S2O8 (2.0)
none
9
K2S2O8 (2.0)
none
10
11
12
13c
14
15
16
K2S2O8 (2.0)
none
K2S2O8 (2.0)
TBAB (10)
TBAB (30)
TBAB (30)
KBr (30)
none
K2S2O8 (2.0)
54
K2S2O8 (2.0)
69
K2S2O8 (2.0)
16
(NH4)2S2O8 (2.0)
(NH4)2S2O8 (2.0)
51
TBAB (30)
55
a 1a (0.5mmol) and 2a (1.0mmol) as model substrates in solvents (4 mL).
b isolated yield.
c 1a (0.5 mmol) and 2a (2.0 mmol) as model substrates in solvents (4 mL), 110 C for 9 h.
NR = not reaction.
DCE = dichloroethane.
TBAB = tetra-n-butylammonium bromide.
5

To continue oxidants screening, K2S2O8 was used as an alternative of TBHP in this
study. In the presence of 1.0 equiv of K2S2O8, 3a was obtained in 10% yield (entry 5,
Table 1). Increasing K2S2O8 to 2.0 equiv led to slightly promoted yield (entry 6, Table
1). After a screening of solvent, the experimental results suggested that MeCN,
DMSO, toluene were not suitable for the reaction (entries 7–10, Table 1), whereas
DCE was still the best suitable solvent for the reaction. When 10 mol% of TBAB was
used as catalyst, the reaction furnished 3a in 41% yield (entry 11, Table 1). Increasing
the amount of TBAB to 30 mol% led to slightly enhanced yield of 3a (entry 12, Table
1). To promote the reaction, when 4.0 equiv of benzaldehyde 2a was used as
C-radical precursor in the reaction, target compound 3a was obtained in 69% yield
(entry 13, Table 1). A further investigation of the role of TBAB in this type of Minisci
reaction showed that when the same amount of KBr was used to displace TBAB, only
16% isolated yield of 3a was achieved (entry 14, Table 1). According to previous
literatures,31, 36 TBAB possibly not only acted as a phase transfer catalyst in the
reaction to dissolve persulfate anion but also a special initiator to facilitate the
decomposition of K2S2O8 to generate sulfate radical anion. Bromide ion (Br-) of
TBAB or KBr couldn’t act as reductant to reduce persulfate to corresponding sulfate
radical anion to promote the reaction efficiency. As a contrast, when 2.0 equiv. of
(NH4)2S2O8 was used as oxidant, target compound 3a was obtained in 55% and 51%
yields with or without catalyst TBAB respectively (entry 15–16, Table 1). The
experimental results indicated that (NH4)2S2O8 could decompose easily37 or possibly
possessed better solubility in DCE than K2S2O8.
Although the optimized Minisci reaction in Table 1 could furnish 3a in good yield,
this type of acylation must be performed at high temperature using low boiling point
organic solvent such as DCE. According to previous literatures, the ability of complex
tris(2,2´-bipyridine) ruthenium(II) (Ru(bpy)3Cl2 4a, Table 2) and related transition
metal complexes such as Ru(phen)3Cl2 and fac-Ir(ppy)3 (4b–4c, Table 2) to function
as visible light phtotocatalysts has been extensively investigated for room temperature
organic synthesis in recent years.38 Extensive studies demonstrated that photocatalyst
can initiate single electron transfer (SET) processes and promote both reductive and
6

oxidative reaction under visible light irradiation. In present study, various
photocatalysts were added to the reaction system as an effort to reduce the reaction
temperature under irritation of 25W compact fluorescent lamp (CFL) (Table 2). After
a preliminary solvents screening, we found that TBHP (6M in decane) was not
suitable for the coupling reaction with 4a (Ru(bpy)3Cl2.6H2O) as photocatalyst in
DCE and MeCN (entry 1–2, Table 2). With K2S2O8 as oxidant and TBAB as phase
transfer catalyst, no target compound was generated under irradiation of visible light
in MeCN, DCE and DMSO respectively (entry 3–5, Table 2) and only trace of 3a
could be detected when the reaction was carried out in acetone after 48 h of reaction
time (entry 6, Table 2). To continue the oxidants screening, K2S2O8 was displaced by
(NH4)2S2O8. However, desire compound was not obtained when the reaction was
carried out in acetone and MeCN (entry 7–8, Table 2) in the presence of 4a under
irradiation of visible light. However, we were pleased to find that desire compound
could be obtained in 38% isolated yield when DMSO was used as solvent (entry 9,
Table 2). Thus, further photocatalysts screening was conducted which showed that
fac-Ir(ppy)3 (4c) possessed better catalytic ability than 4a and 4b (entry 10, Table 2)
and 44% isolated yield of desire compound was achieved under the irradiation of
visible light (entry 11, Table 2). To understand the role of visible light in the coupling
reaction, control experiment was conducted as showed in Table 2. Only trace of desire
compound could be detected when the reaction was carried out in darkness (entry 12,
Table) in the presence of 4c. It should be noted that (NH4)2S2O8 could decompose
slowly in DMSO under visible light without any photocatalyst to give target
compounds 3a in 18% isolated yield (entry 13, Table 2). Uploading photocacalyst 4c
to 5 mol % slightly improved yield of 3a from 44% to 52% (entry 14, Table 2).
Increasing the oxidant (NH4)2S2O8 from 2.0 equiv to 4.0 equiv led to 58% isolated
yield of 3a when 4c was used as photocatalyst under visible light at room temperature
(entry 15, Table 2).
7

Table 2. Photocatalytic Minisci synthesis of 3a a
O
oxidant
phase trasfer catalyst
+
O
H
N
4
photocalalyst (1 mol %)
N
solvent
room temperature
25W compact fluorescent lamp
1
2a (4.0 equiv)
3a
2Cl
2Cl
N
N
N
N
N
N
N
N
N
N
N
IrIII
RuII
N
RuII
N
N
N
Ru(bpy)3Cl2
4a
fac-Ir(ppy)3
4c
Ru(phen)3Cl2
4b
entry oxidant
(2.0 equiv.)
photocatalyst
(1 mol %)
phase transfer
catalyst
(0.3 equiv.)
none
solvent
time
yield
(%)b
1
TBHP
DCE
48 h
48 h
48 h
48 h
48 h
48 h
48 h
48 h
48 h
48 h
48 h
48 h
48 h
48 h
48 h
NR
NR
NR
NR
NR
trace
NR
NR
38
4a
4a
4a
4a
4a
4a
4a
4a
4a
4b
4c
4c
none
4c
4c
2
TBHP
none
MeCN
MeCN
DCE
3
K2S2O8
TBAB
TBAB
TBAB
TBAB
none
4
K2S2O8
5
K2S2O8
DMSO
acetone
acetone
MeCN
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
6
K2S2O8
7
(NH4)2S2O8
(NH4)2S2O8
(NH4)2S2O8
(NH4)2S2O8
(NH4)2S2O8
(NH4)2S2O8
(NH4)2S2O8
(NH4)2S2O8
(NH4)2S2O8
8
none
9
none
10
11
12c
13
14d
15e
none
31
none
44
none
trace
18
none
none
52
none
58
a 1a (0.5mmol) and 2a (1.0mmol) as model substrates in solvents (4 mL).
b isolated yield.
c reaction was carried out in darkness.
d 5 mol % of catalyst 4c was used.
e 5 mol % of catalyst 4c and 4.0 equiv. of oxidant were used.
With these optimized conditions in hand, we firstly surveyed the substrate scope
of aromatic aldehyde under thermal conditions. Initially, a variety of halogen
benzaldehydes were investigated by reaction with phenanthridine under standard
8

conditions. Phenanthridine underwent a smooth coupling reaction with chloro and
bromo substituted benzaldehydes. The halogen atoms on phenyl ring didn’t interfere
with the coupling reaction which gave corresponding 6-aroylated phenanthridines in
moderate yields (entry 2–5, Table 3). Interestingly, coupling reaction of 4-fluoro
benzaldehyde with phenanthridine afforded the target compound in 80% isolated yield
(entry 6, Table 3). Similarly, coupling reaction of 2-methyl and 4-methyl
benzaldehydes
with
phenanthridine
furnished
corresponding
aroylated
phenanthridines in 58 and 64% yields respectively (entries 7–8, Table 3). It was also
found that the reaction of ortho-substituted benzaldehydes with phenanthridine
resulted in lower yields compared with para-substituted benzaldehydes. Similar yields
of target compounds 3i (57% yield) and 3j (66% yield) were obtained
when1-naphthaldehyde and 2-naphthaldehyde were used in the coupling reaction.
Thus, it was suggested that the coupling reaction proceeded well with sterically less
hindered aldehydes. To further investigate tolerance to functional group on phenyl
ring of substrate under the optimized reaction conditions, 2-acetoxyl benzaldehyde
was applied in the coupling reaction and gave target compound 3k in 38%yield (entry
11, Table 3) with recovered substrates of pheanthridine and excess aldehyde detected
by TLC experiment. On the other hand, the number of methoxyl group on phenyl ring
didn’t generate significant effects on the yields of target compounds (entries 12–15,
Table 3). Generally, the electro-donating methoxyl group could facilitate the coupling
reaction and give target compounds in better yields. However, it was quite interesting
that reaction of 4-N,N-dimethylamino benzaldehyde with phenanthridine couldn’t
furnish target compound 3p (entry 16, Table 3). The lack of reactivity of
4-N,N-dimethylamino benzaldehyde could be due to the preferential oxidation of
tertiary amine in the substrate, which generated N-based radical or aryl radical which
competes with the desired aldehyde oxidation. It should be noted that the reaction
couldn’t proceed with electro-deficient 4-nitrobenzaldehyde as substrates (entry 17,
Table 3). Under optimized photocatalytic conditions as showed in Table 2, various
aromatic aldehydes could react with phenanthridine. However, target compounds
were generally obtained in lower isolated yields compared with thermolysis
9

conditions.
Table 3. Minisci reaction of phenanthridine with aromatic aldehydes
Yield (%)
Aldehyde
Products
entry
2
3
thermolysis photocatalysis
1
2
R = phenyl
R = 2-Cl-phenyl
69
54
64
50
65
80
58
64
57
66
38
53
70
81
77
0
58
40
44
35
60
59
37
49
45
51
27
47
68
73
63
0
3a
3b
3c
3d
3e
3f
3
R = 4-Cl-phenyl
R2 = 2-Br-phenyl
4
5
R = 4-Br-phenyl
6
R = 4-F-phenyl
7
R = 2-Me-phenyl
R = 4-Me-phenyl
R = 1-napthyl
3g
3h
3i
8
9
10
11
12
13
14
15
R = 2-napthyl
3j
R =2-acetoxylphenyl
R = 2-methxoylphenyl
R = 4-methoxylphenyl
R = 3,4-dimethoxylphenyl
R = 3,4,5-trimethoxylphenyl
3k
3l
3m
3n
3o
3p
3q
16
17
R= 4-N,N-dimethylaminophenyl
R2 = 4-NO2-phenyl
0
0
To further expand the scope of this coupling reaction, we also investigated whether
aliphatic aldehydeand α,β-unsaturated cinnamaldehyde work as substrate. When
n-enanthic aldehydeand n-butanal were applied in the thermal coupling experiments,
the reaction finished in 3 h under thermal conditions. Phenanthridine derivatives 3r
and 3s were obtained in 39% and 31% isolated yields respectively (Scheme 2).
However, the reaction of isopropanal with 1a furnished the mixture of acylated (3t)
and alkylated (3u) phenanthridine compounds as an inseparable mixture in a ratio of
81:19 (Scheme 2). The above experiments suggested that the stability of acyl radical
and alkyl radical is crucial in the formation of products.36 Under the optimized
conditions, reaction of cinnamaldehyde with phenanthridine couldn’t furnish target
10

compound 3v with unreacted substrates detected (Scheme 3).
O
O
K2S2O8 (2.0 equiv), TBAB (30 mol %)
N
+
(
)
H
n
(
)
n
110 C, 3 h
N
1a
aliphatic aldehyde
(4.0 equiv)
3r (n =1) 39%
3s (n =4) 31%
O
K2S2O8 (2.0 equiv), TBAB (30 mol %)
110 C, 3 h
+
+
O
H
N
N
N
isobutyraldehyde
(4.0 equiv)
1a
3t
3u
inseparable mixture of 3t + 3u
in ratio of 81:19 (by GCMS)
Scheme 2. Coupling reaction with aliphatic aldehydes
O
O
K2S2O8 (2.0 equiv), TBAB (30 mol %)
N
+
H
110 C, 12 h
N
3v (0%)
1a
cinnamaldehyde (4.0 equiv)
Scheme 3. Coupling reaction with cinnamaldehyde
On the basis of the literature precedence31–36 and our experimental results, a
possible photocatalytic mechanism was proposed in Scheme 4. Under photocatalytic
conditions as listed in Scheme 4, we believe that persulfate anion can be reduced by
visible light excited Ir(ppy)33+* to give sulfate and sulfate radical anion I 37–38 together
with Ir(ppy)34+. The aldehyde can then undergo H-atom abstraction by radical I to
give acyl radical II. Successively addition of acyl radical II to phenanthridine affords
the corresponding amidyl radical III. Because of the neighboring carbonyl group, the
α-proton in amidyl radical III is extremely acidic and can be deprotonated by the
sulfate anion and then generates radical anion (IV). Through a single electron transfer
(SET), a reductive quencher of Ir(ppy)34+ by radical anion (IV) generates Ir(ppy)33+ to
sustain the photocatalytic chain along with the formation of target compound 3. Under
thermal conditions, the reaction mechanism in present study was similar to that as
described in previous references. 31, 36
11

Scheme 4. Proposed photocatalytic mechanism
In summary, we have developed an efficient method for the synthesis of 6-acylated
phenanthridine derivatives through direct coupling of phenanthridine with various
aromatic aldehydes. In the presence of K2S2O8/TBAB, the CDC coupling of
aldehydes with phenanthridine underwent smoothly in DCE under thermal conditions.
When K2S2O8/TBAB were displaced by (NH4)2S2O8 and another 5 mol % Ir(ppy)3
catalyst was added to the reaction system, this type of coupling reaction proceeded
slowly under visible light at room temperature. Persulfate was found to be an
inexpensive and efficient reagent for this transformation. This Minisci reaction of
acylation of electro-deficient phenanthridine was highly regioselective and provided a
useful method for synthesis of functionalized phenanthridine derivatives with
potential pharmacological activities.
Acknowledgement
This research was financially supported by Natural Science Foundation of China
(No. 31402109), Natural Science Foundation of Hunan Province (No. 13JJ5044),
Research Fund for the Doctoral Program of Higher Education, Ministry of Education
of China (No. 20124320120006) and the Important Science & Technology Specific
Projects of Hunan province (No. 2012FJ1004 ).
12

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Graphic Abstract
Regiospecific Minisci acylation of phenanthridine via thermolysis or photolysis
Pi Cheng a, b, Zhixing Qing c, Sheng Liu b, Wei Liu a, Hongqi Xie a, *, Jianguo Zeng a, b, c, *
Using K2S2O8 as oxidant and TBAB as initiator, acyl radicals generate from aldehydes substrates
and couple with phenanthridine under thermal conditions at 110 °C. When K2S2O8/TBAB is
displaced by (NH4)2S2O8 and another 5 mol % fac-Ir(ppy)3 catalyst is added to the reaction system,
this type of coupling reaction proceeds slowly under visible light at room temperature.
15