Pd-catalyzed assembly of phenanthridines from aryl ketone O-acetyloximes and arynes through C-H bond activation

Article abstract of DOI:10.1016/j.tetlet.2013.12.075

Pd-catalyzed annulation of aryne and aryl ketone O-acetyloxime via C-H bond activation was realized. Through the C-H bond activation/insertion/cyclization/ elimination reaction sequence, phenanthridines are successfully constructed, providing an attractiv

Full text of DOI:10.1016/j.tetlet.2013.12.075

Tetrahedron Letters 55 (2014) 1036–1039
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Pd-catalyzed assembly of phenanthridines from aryl ketone
O-acetyloximes and arynes through C–H bond activation
⇑
Chen-Yu Tang, Xin-Yan Wu, Feng Sha , Fei Zhang, Hao Li
Key Laboratory for Advanced Materials and Institute of Fine Chemicals, East China University of Science and Technology, Shanghai 200237, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Pd-catalyzed annulation of aryne and aryl ketone O-acetyloxime via C–H bond activation was realized.
Through the C–H bond activation/insertion/cyclization/elimination reaction sequence, phenanthridines
are successfully constructed, providing an attractive strategy to approach substituted heterocycle
without preactivation of starting materials.
Received 6 October 2013
Revised 9 December 2013
Accepted 20 December 2013
Available online 25 December 2013
Crown Copyright Ó 2013 Published by Elsevier Ltd. All rights reserved.
Keywords:
Arynes
Palladium
C–H bond activation
Phenanthridines
Aryl ketone O-acetyloximes
Transition-metal catalyzed annulation reaction represents a
powerful methodology for the assembly of complex polycyclic
skeletons in organic chemistry.1 For example, Larock-type hetero-
cycle synthesis has been well developed to construct indoles, iso-
quinolines, and other heterocycles (A, Scheme 1, Eq. 1).2
However, the application is limited by the availability of the preac-
tivated substrates since most of these methodologies start from the
oxidation addition of metal to C–X bond. In contrast, the C–H bond
activation strategy utilizing a directing group to aid the ortho C–H
metalation can be a perfect solution due to its highly atom- and
step-economic property.3 During the last decade, the C–H activa-
tion involving alkynes and aromatics with directing groups has
been significantly developed.4 Pyridine4a–g,5 and pyrrole4h–j deriva-
tives could be successfully obtained by following the C–H activa-
tion/insertion/cyclization sequence (Scheme 1, Eq. 2).
Similar with ordinary alkynes, arynes are highly reactive and
easily available molecules and have been applied in transition-me-
tal catalyzed annulation reactions to approach various polycyclic
aromatic hydrocarbons,2a,6,7 such as phenanthrene6 and fluorenone
derivatives.7 In most of the known approaches, however, the
utilization of preactivated aryl or vinylic halides and triflates is
inevitable. Inspired by the previous work,8,7c we envisioned that
if the C–H activation strategy can be introduced to realize the
annulation of aryne, desirable fused rings would be formed from
easily accessible starting materials (Scheme 1, Eq. 3). Herein, we
report a Pd-catalyzed C–H activation of aryl ketone O-acetyloximes
and arynes to synthesize phenanthridines.
Initially, the reaction of acetophenone O-acetyl oxime (1a) with
2-(trimethylsilyl)phenyl trifluoromethanesulfonate (2a) was car-
ried out in the presence of PdCl2, CuCl2, Cs2CO3, and CsF in mixed
solvent toluene/CH3CN (v/v 2:1) at 80 °C. Desired product phenan-
thridine 3a was obtained in 21% yield (Table 1, entry 1). Then we
tried to optimize the reaction conditions (Table 1). After an initial
screening of several palladium catalysts, Pd(OAc)2 was found to be
the best choice, giving product 3a in 45% yield (entry 4). Effects of
Larock-type
R1
NR
Pd(0)-cat, -XR/XH
+
(1)
R2
C-X bond cleavage
X
X = I, Br
N
C-H bond activation
R2
R1
R1
NR
+
[M]-cat, -HR
(2)
(3)
A
R2
H
This stragegy
N
R1
NR
R1
[Pd]-cat, -HR
C-H bond activation
+
H
B
⇑
Corresponding author. Tel.: +86 021 64252011; fax: +86 021 64252758.
E-mail address: shaf@ecust.edu.cn (F. Sha).
Scheme 1. Heterocycle formation via transition-metal catalyzed annulation
reactions.
0040-4039/$ - see front matter Crown Copyright Ó 2013 Published by Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.12.075

C.-Y. Tang et al. / Tetrahedron Letters 55 (2014) 1036–1039
1037
Table 1
Table 2
Optimization of the reaction conditionsa
Synthesis of phenanthridines
3
from aryl ketone O-acetyloximes
1
and aryne
precursors 2a
NOAc
R3
[Pd]/ligand
N
R3
TMS
Me
base/additive, CsF
+
sol.(toluene/MeCN)
Me
H
NOAc
R2
Pd(OAc)2/PPh3
TMS
R3
R3
H
OTf
80 oC
N
Cs2CO3/CuCl2, CsF
+
1a
2a
3a
toluene/MeCN (3:1)
OTf
R2
R1
80 oC, 36 h
R1
1a-g
2a-b
Entry
[Pd]/ligandb
Base/additive
Sol.c
Time (h)
Yieldd
3a-h
1
2
3
PdCl2
Cs2CO3/CuCl2
Cs2CO3/CuCl2
Cs2CO3/CuCl2
Cs2CO3/CuCl2
Cs2CO3/CuCl2
Cs2CO3/CuCl2
Cs2CO3/Cu(OTf)2
Cs2CO3/Cu(OAc)2
K2CO3/CuCl2
Na2CO3/CuCl2
Li2CO3/CuCl2
DBU/CuCl2
CsOAc/CuCl2
t-BuOK/CuCl2
K3PO4/CuCl2
Cs2CO3/CuCl2
Cs2CO3/CuCl2
Cs2CO3/CuCl2
Cs2CO3/CuCl2
Cs2CO3/CuCl2
Cs2CO3/CuCl2
Cs2CO3/CuCl2
Cs2CO3/—
2:1
2:1
2:1
2:1
3:1
1:0
3:1
3:1
3:1
3:1
3:1
3:1
3:1
3:1
3:1
3:1
3:1
3:1
3:1
3:1
3:1
3:1
3:1
3:1
3:1
3:1
3:1
24
24
24
36
36
36
36
36
36
36
36
12
24
12
36
36
36
36
36
36
36
36
36
36
36
36
36
21%
23%
Trace
45%
50%
0%
Trace
23%
21%
13%
Trace
0%
Pd(MeCN)2Cl2
Pd(PPh3)2Cl2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Entry
1
2
Yieldb (%)
R1
H
OMe
Me
Cl
R2
R3
4
5
1
2
3
4
5
6
7
8
Me (1a)
Me (1b)
Me (1c)
Me (1d)
Me (1e)
1b
H (2a)
2a
2a
2a
2a
Me (2b)
2a
2a
59 (3a)
62 (3b)
60 (3c)
40 (3d)
61 (3e)
55 (3f)
41 (3g)
39 (3h)
6e
7
8
9
F
10
11
12
13
14
15
16
17
18
19
20
21
22f
23g
24h
25i
26j
27k
OMe
H
H
Et (1f)
–(CH2)3– (1g)
Trace
0%
a
Reaction conditions: 1.0 equiv of 1 (0.3 mmol), 2.0 equiv of 2, 8 mol % of
Pd(OAc)2, 16 mol % of PPh3, 2.1 equiv of CuCl2, 2.0 equiv of Cs2CO3 and 4.0 equiv of
Pd(OAc)2
10%
Trace
54%
44%
49%
50%
59%
30%
Trace
0%
Pd(OAc)2/bipy
Pd(OAc)2/dppe
Pd(OAc)2/dppp
Pd(OAc)2/dppf
Pd(OAc)2/binap
Pd(OAc)2/PPh3
Pd(OAc)2/PPh3
Pd(OAc)2/PPh3
—/PPh3
CsF in 0.9 mL of MeCN and 2.7 mL of toluene at 80 °C for 36 h.
b
Isolated yield of 3 based on 1.
observed (entry 27). Thus, the optimal reaction conditions were
confirmed as that described in entry 21.
With the optimized conditions in hand, we next explored the
application scope of this reaction with a series of aryl ketone
O-acetyloximes 1 and aryne precursors 2 (Table 2). Reactions of
O-acetyloximes 1a–e with the symmetrical arynes (from 2a–b)
proceeded smoothly, giving corresponding phenanthridines 3a–f
in 40–62% yields (entries 1–6). Employment of 1f bearing the ethyl
group (R2) gave product 3g in a relatively lower yield (41%, entry
Cs2CO3/CuCl2
Cs2CO3/CuCl2
Cs2CO3/CuCl2
Cs2CO3/CuCl2
Pd(OAc)2/PPh3
Pd(OAc)2/PPh3
Pd(OAc)2/PPh3
0%
38%
0%
a
Reaction conditions: 1.0 equiv of 1a (0.3 mmol), 2.0 equiv of 2a, 8 mol % of [Pd],
16 mol % of ligand, 2.1 equiv of additive, 2.0 equiv of base and 4.0 equiv of CsF in
3.6 mL of solvent at 80 °C.
b
Abbreviations:
bpy = 2,20-bipyridine;
dppe = 1,2-bis(diphenylphosphino)
7). Moreover, a-tetralone O-acetyloxime 1g could also be success-
fully applied to construct the tetracyclic phenanthridine 3h in 39%
ethane; dppf = 1,10-bis(diphenylphosphino)ferrocene; dppp = 1,3-bis(diphenyl-
phosphino) propane;
DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene.
binap = 2,20-bis(diphenylphosphino)-1,10-binaphthyl;
yield (entry 8).
When 1h bearing m-tolyl was introduced, isomeric products
3ia9 and 3ib were obtained in 50% and 6% yields, respectively
(Eq. (4)). The observed regiochemistry may be explained by the
steric hindrance of the methyl substituent. On the contrary, 1i with
m-chloro phenyl afforded regioisomers 3ja9 and 3jb in 25% and
20% yields, respectively.
c
The ratio of mixed solvent (v/v).
Isolated yields.
The reaction was carried out utilizing 3.6 mL of toluene.
The reaction was carried out utilizing 4 mol % of Pd(OAc)2 and 8 mol % of PPh3.
d
e
f
g
The reaction was carried out utilizing 100 mol % of Pd(OAc)2 and 200 mol % of
PPh3 without CuCl2.
h
The reaction was carried out without Pd(OAc)2.
Performed at 60 °C.
The reaction was carried out utilizing 0.9 mL of DMSO and 2.7 mL of toluene at
i
j
NOAc
105 °C.
N
Pd(OAc)2/PPh3
N
k
The reaction was carried out utilizing O-benzoyloxime 1a0 instead of O-acety-
Me
+
+
Cs2CO3/CuCl2, CsF
Me
loxime 1a.
R
2a
Me
toluene/MeCN (3:1)
80 oC, 36 h
ð4Þ
R
R
1h
, R = Me;
solvents, additives, bases, ligands, and reaction temperature were
then examined. Employing the mixed solvent toluene/CH3CN (v/v
3:1) could slow down the generation of the benzyne, resulting 3a
in a higher yield (50% vs 45%, compare entry 5 with 4). However,
when the reaction was carried out by using only toluene as solvent,
no desired product 3a was obtained (entry 6). Utilization of other
additives Cu(OTf)2, Cu(OAc)2 (entries 7 and 8) or other bases (en-
tries 9–15) did not give better yields. Ligands bpy, dppe, dppp,
dppf, binap, and PPh3 were also examined (entries 16–21) with
PPh3 giving a better yield of 3a (entry 21). The reactions conducted
with different loads of Pd(OAc)2 and PPh3 furnished lower yields of
3a (entries 22–24). Notably, Pd(OAc)2 and CuCl2 are inevitable in
this reaction (entries 23 and 24). Trials under different tempera-
tures gave no better results (entries 25 and 26). In addition,
reaction with the employment of O-benzoyloxime 1a0 instead of
O-acetyloxime 1a was also conducted and no product 3a was
1i, R = Cl
3ia
3ib (6%);
3jb (20%)
R = Me,
(50%)
R = Cl, 3ja (25%)
Regioselectivity of this Pd-catalyzed annulation reaction was
examined by employing the non-symmetric arynes. Introduction
of aryne precursor 2c gave regioisomers 3ka9 and 3kb in 35%
and 30% yields, respectively (Eq. (5)).
F
F
1a
+
Pd(OAc)2/PPh3
N
F
TMS
OTf
N
Cs2CO3/CuCl2, CsF
ð5Þ
+
Me
toluene/MeCN (3:1)
80 oC, 36 h, 65%
Me
2c
3ka
3kb
(30%)
(35%)

1038
C.-Y. Tang et al. / Tetrahedron Letters 55 (2014) 1036–1039
When aryne precursor 2d was applied, a 1:1 mixture of regioi-
bered ring and the long distance between the a0-position and the
directing group; 3nb was not observed either due to the low C–H
reactivity at the b-position (Scheme 2, Eq. 8).10
somers 3la and 3lb was observed in 46% combined yield (Eq. (6)).
The ratio of isomers was determined by the 1H NMR analysis of the
crude product.
Notably, phenanthridine derivatives are important core struc-
tures found in natural products and biologically active com-
pounds.11 Especially, 6-aryl-substituted phenanthridines are
widely applied in material science and as DNA-intercalating
agents.12 Thus, the scope of the reaction was further explored
(Table 3). A series of 6-aryl phenanthridines could be synthesized
in good yields. Equipped with a strong electron-donating group –
OMe, 1m furnished corresponding product 3p in higher yield
(79% vs 66%, compare entry 2 with entry 3). Interestingly, up to
81% yield of product 3r was observed with the employment of flu-
oro substituted 1o. In addition, other aryne precursor 2b could also
be successfully applied, giving corresponding products 3s and 3t in
good yields.
Me
Me
1b
+
Pd(OAc)2/PPh3
N
TMS
OTf
N
Me
Cs2CO3/CuCl2, CsF
+
Me
toluene/MeCN (3:1)
80 oC, 36 h, 46%
Me
MeO
2d
MeO
3la
3lb
(1:1)
:
ð6Þ
Moreover, we are interested in investigating the different C–H
bond reactivities of naphthalene at the - and b-positions. The
a
reaction of naphthalenylethanone O-acetyloxime 1j with 2a pro-
vided phenanthridine 3ma9 in 41% yield as the sole isomer, with
no regioisomer 3mb observed (Scheme 2, Eq. 7). This result
Interestingly, the reaction of non-symmetric diarylmethanone
O-acetyloxime 1p with benzyne (from 2a) gave 60% of 3u as the
sole product (Eq. (9)).
indicated that the C–H bond at the a-position was more reactive.
However, the reaction utilizing 1k did not afford the preconceived
product 3na, which may lie in the high strain of the seven-mem-
NOAc
Pd(OAc)2/PPh3
N
Cs2CO3/CuCl2, CsF
ð9Þ
toluene/MeCN (3:1)
80 oC, 36 h, 60%
MeO
Cl
1p
+
MeO
Cl
2a
3u
NOAc
α
The structure of 3u was established by the 1H NMR analysis and
NOESY study (Fig. 1). The annulation occurred on the -OMe substi-
tuted aryl ring, indicating that the C–H bond on the electron-rich
aryl ring is more likely to be activated.
N
Me
N
Me
Me
β
1j
(7)
Me +
3ma
41%
According to our knowledge of Pd-catalyzed reaction,13 the
insertion may occur on two sites of O-acetyloxime 1: the oxidative
addition may occur to the N–O bond;13c on the other hand, N-con-
taining functional group may act as the directing group to aid the
C–H bond activation at the ortho position,4c leading to a Pd-con-
tained cyclic specie to undergo the subsequent insertion with
aryne. To shed light on the mechanism of this Pd-catalyzed
annulation, control experiments were conducted. As shown in Eq.
(10), we tried to trap the intermediate by adding H2O to the reac-
tion. Other than heterocyclic product 3a (24% yield), compounds 4
and 5, both with benzyne inserting to the C–H bond at the ortho
position of the oxime group, were isolated in 31% and 7% yields.
Meantime, the decomposed product 6 from 1a was also observed
in 20% yield. The reaction of CH3OD and 1a was explored under
the optimal reaction conditions (Eq. (11)) and the product 1a–d
was isolated in 92% yield in 65% deuterated ratio as detected by
the 1H NMR analysis. We believe that the above observation sup-
ports the hypothesis that the Pd-catalyzed reaction starts from
the C–H bond activation at the ortho position by the direction of
the oxime group.
3mb
not observed
2a
Me
α'
NOAc
N
N
Me
β
1k
+
(8)
3nb
3na
not observed
not observed
Scheme 2. Reactions of naphthalenylethanone O-acetyloximes 1j and 1k with
benzyne.
Table 3
Synthesis of 6-aryl phenanthridines 3 from diarylmethanone O-acetyloximes 1 and 2a
NOAc
R2
R2
R1
R1
Pd(OAc)2/PPh3
1l-o
+
N
Cs2CO3/CuCl2, CsF
R2
R2
TMS
OTf
toluene/MeCN (3:1)
80 oC,36 h
R1
R1
3o-t
single peak
N
2a-b
H
NOE
Entry
1
2
Yieldb (%)
MeO
Cl
R1
R2
H
3u
1
2
3
4
5
6
H (1l)
OMe (1m)
Cl (1n)
F (1o)
1m
H (2a)
72 (3o)
79 (3p)
66 (3q)
81 (3r)
71 (3s)
80 (3t)
2a
2a
2a
Me (2b)
2b
Figure 1. NOESY study of 3u.
NOAc
Me
NOH
Me
NOH
Me
Pd(OAc)2/PPh3
1a
+
2a
1o
Cs2CO3/CuCl2, CsF
3a +
+
+
a
toluene/MeCN (3:1)
H2O, 80 oC, 36 h
Reaction conditions: 1.0 equiv of 1 (0.3 mmol), 2.0 equiv of 2, 8 mol % of
Pd(OAc)2, 16 mol % of PPh3, 2.1 equiv of CuCl2, 2.0 equiv of Cs2CO3 and 4.0 equiv of
CsF in 0.9 mL of MeCN and 2.7 mL of toluene at 80 °C for 36 h.
Ph
(31%)
Ph
5 (7%)
4
6 (20%)
24%
b
ð10Þ
Isolated yield of 3 based on 1.

C.-Y. Tang et al. / Tetrahedron Letters 55 (2014) 1036–1039
1039
D
NOH
Me
D (65% D)
NOAc
Me
Acknowledgments
Pd(OAc)2/PPh3
Cs2CO3/CuCl2, CsF
ð11Þ
toluene/MeCN (3:1)
MeOD, 80 oC, 36 h
We are grateful for the financial support from National Natural
Science Foundation of China (Project Nos. 21102043), the China
Postdoctoral Science Foundation (Project Nos. 20110490070, and
2012T50401) and the Fundamental Research Funds for the Central
Universities.
1a
1a d
-
(92%)
3a
[CuI]
NOAc
Me
Supplementary data
[CuII]
[CuI]
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.12.
075.
AcO
Me
H
[PdII]
1a
N
[Pd0]
3a
HOAc
Me
References and notes
F
Me
Me
O
O
N
Me
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OAc
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[PdII]
[PdII]
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E
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2a
D
Scheme 3. Proposed mechanism.
On the basis of the above experimental facts and the known
chemistry of arynes,2a,14 the possible mechanism of this transfor-
mation was proposed (Scheme 3). With the aid of the sp2 oxime
nitrogen atom, the activation of ortho-C–H leads to intermediate
C, which then inserts to the aryne generated in situ from 2-(tri-
methylsilyl)aryl triflate 2 to afford palladium specie D. The final
product 3 may be furnished through two possible reaction paths
(path I and path II) via path I,4c,15 seven-membered ring palladacy-
clic iminium cation intermediate E may be formed. Following C–N
reductive elimination would provide N-acetoxyphenanthridinium
cation F, along with regeneration of the Pd(II) catalyst by the oxi-
dation of Cu(II). The resulting Cu(I) species would take part in
the reduction of F to furnish final product 3. Alternatively, the con-
certed C–N bond formation/N–O bond cleavage sequence via the
transient intermediate G may occur as the direct formation of
phenanthridine 3 (path II).
In summary, we have developed a Pd-catalyzed reaction of aryl
ketone O-acetyloximes and arynes to construct phenanthridines.
Our strategy of Pd-catalyzed C–H bond activation is successfully
realized in the aryne participated heterocycle construction. There-
fore, preactivation of starting materials could be avoided, providing
a novel and efficient approach to synthesize substituted phenan-
thridines. Due to the potential utilization of the products and the
easy availability of the starting materials, this methodology may
be of great potential value.
8. (a) Sha, F.; Huang, X. Angew. Chem., Int. Ed. 2009, 48, 3458; (b) Sha, F.; Wu, L.;
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9. Compounds 3ia, 3ja, 3ka and 3ma were synthesized according to known
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2010, 1674. thus structures of these compounds could be unambiguously
determined by the NMR analysis to confirm the regiochemsitry of the reaction.
10. The reaction of 1k and 2a was carried out by using CH3OD as the trapping
reagent. No deuterated was observed.
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