Synthesis of 5,6-dihydrophenanthridines via N,O-acetal TMS ethers

Article abstract of DOI:10.1016/j.tetlet.2013.07.037

A concise and high-yielding protocol for the synthesis of 5,6-dihydrophenanthridines is disclosed. The key feature includes a sequential reduction-cyclization reaction of N-acylcarbamates via N,O-acetal TMS ethers as a stable N-acyliminium ion precursor.

Full text of DOI:10.1016/j.tetlet.2013.07.037

Tetrahedron Letters 54 (2013) 5167–5171
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of 5,6-dihydrophenanthridines via N,O-acetal TMS ethers
Won-Il Lee a, Jong-Wha Jung b, Jaebong Jang a, Hwayoung Yun a, Young-Ger Suh a,
⇑
a College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 151-742, Republic of Korea
b College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 701-702, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
A concise and high-yielding protocol for the synthesis of 5,6-dihydrophenanthridines is disclosed. The
key feature includes a sequential reduction-cyclization reaction of N-acylcarbamates via N,O-acetal
TMS ethers as a stable N-acyliminium ion precursor.
Received 24 April 2013
Revised 1 July 2013
Accepted 5 July 2013
Available online 15 July 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
5,6-Dihydrophenanthridine
N,O-Acetal TMS ether
N-Acyliminium ion
Intramolecular aromatic substitution
Phenanthridine and 5,6-dihydrophenanthridine alkaloids are
found throughout a wide range of natural resources, exhibiting var-
ious biological activities including antibiotic, anti-inflammatory,
and anticancer activity.1 Thus, there have been continuous endeav-
ors to secure the classes of phenanthridines and 5,6-dihydrophe-
nanthridines occupying biologically relevant chemical spaces. For
instance, phenanthridines including aza-phenanthridines and
benzophenathridines have been reported to be promising candi-
dates for drug development and the related biological studies2
although 5,6-dihydrophenanthridines were less explored. A recent
report revealed that the natural alkaloid-based 5,6-dihydrophenan-
thridines possess potent inhibitory activities against acetylcholine
esterase.3 In addition, development of the 5,6-dihydrophenanthri-
dine derivatives as bradykinin B1 antagonist has been reported.4
5,6-Dihydrophenanthridines as potassium channel inhibitors and
as immunosuppressants were also reported.1h Figure 1 Notably
5,6-dihydrophenanthridines often exhibited distinct biological
properties compared to the structurally related phenanthridines
owing to the absence of electrophilic C@N double bond.5
OMe
OMe
OMe
OMe
CHO
N
N
O
O
assoanine
acetylcholine esterase inhibitor
dihydrochelerythrinylacetaldehyde
cytotoxic
N
N
N
O
N
H
O
O
5,6-dihydrophenanthridine
Compared to the well developed phenanthridine syntheses,6
only a few synthetic methods for the preparation of 5,6-dihydr-
ophenanthridines were reported. In addition, the 5,6-dihydrophe-
nanthridine syntheses often suffered from low yields due to the
limited functional group tolerance7 and the undesirable in situ oxi-
dation.8 Modified Pictet-Spengler reaction for the synthesis of 5,6-
dihydrophenanthridine-6-carboxylates,9 a sequential multicompo-
nent reaction involving intramolecular C–H functionalization10 and
potassium channel inhibitor
MeO
O
O
N
O
N
SO2
N
H
Cl
Cl
N
Et
Et
bradykinin B1 antagonist
acetylcholine esterase inhibitor
⇑
Corresponding author. Tel.: +82 2 880 7875; fax: +82 2 888 0649.
E-mail address: ygsuh@snu.ac.kr (Y.-G. Suh).
Figure 1. Selected 5,6-dihydrophenanthridines.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.07.037

5168
W.-I. Lee et al. / Tetrahedron Letters 54 (2013) 5167–5171
Table 1
R2
R2
Optimization of reaction conditions
X
N
X
N
2
OMe
OMe
[H]
R1
R1
CO2Me
R3
CO2Me
R3
Amidation
Conditions
O
TMSO
R
N
N
R
Me
1
TMSO
Me
4a
2a
R2
R3
R2
Yielda (%)
X
N
Entry
R
Lewis acid
Solvent
Temp. (°C)
X
N
Lewis
Acid
1
2
3
4
5
6
7
8
9
10
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
Ts
TiCl4
SnCl4
TFA
TMSOTf
BF3ÁOEt2
BF3ÁOEt2
BF3ÁOEt2
BF3ÁOEt2
BF3ÁOEt2
BF3ÁOEt2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Toluene
CH3CN
THF
À78
À30
À30
À30
À30
À30
À30
À30
À30
À30
98
98
98
98
99
97
99
75
98
99
R1
R1
R3
CO2Me
CO2Me
3
4
Figure 2. Synthetic strategy.
CH2Cl2
CH2Cl2
Ms
a
Isolated yield.
a biomimetic hydrogenation for the syntheses of 6-aryl-5,6-
dihydrophenanthridines have been developed very recently.11
Recently, we reported an efficient synthesis of Calycotomine,12
in which construction of the tetrahydroisoquinoline scaffold using
a Pictet-Spengler type cyclization of N,O-acetal TMS ether was in-
cluded as a key step. Kuhakarn et al. also reported synthesis of a
series of 1-substituted tetrahydroisoquinoline derivatives employ-
ing a similar strategy, namely a sequential reduction-cyclization
reaction of N-acylcarbamates.13 Considering the limited scope of
the precedent procedures to 1-substituted tetrahydroisoquino-
lines, the efficient and widely applicable procedures for dihydro-
synthetic procedure for 5,6-dihydrophenanthridines utilizing elec-
trophilic cyclization of N-acyliminium ions via N,O-acetal TMS
ethers as stable and easily accessible precursors.14
As shown in Figure 2, we envisioned that 5,6-dihydrophenathri-
dines would be easily provided from the corresponding amide pre-
cursors. The amide precursors are conveniently prepared by the
standard amidation reaction. Partial reduction followed by in situ
silylation of the resulting aluminum alkoxide would provide N,O-
acetal TMS ethers. Finally, N-acyliminium ions are generated from
isoquinolines are currently required. We herewith report
a
O
O
O
Br
Br
NH2
a
b
c
d
R
R
NH
CO2Me
R
R
R
CO2Me
Me
CO2Me
Me
N
NH
CO2Me
N
5
6
O
TMSO
R
R
1
2
7a:
H
7h: 4-Me
b
c
d
e
f
g
4-Cl
5-Cl
4-CF3
i
4-CN
t
j
k
l
4-CO2 Bu
5-NO2
5-CF3
5-(3'-MeO-Ph)
6-Me
m
4-OEt
5-OMe
h
O
O
F
OH
NO2
F
OTf
Br
NO2
f
g
e
f
F
NO2
Br
R
8
9
NO2
10
NO2
12
11a
b
: R = 4-OEt
: 5-(3`-MeO-Ph)
Scheme 1. Reagents and conditions: (a) ClCO2Me, EtOAc, 80 °C, 92–98%; (b) 3-methoxyphenylboronic acid, Pd(PPh3)4, K3PO4, 1,4-dioxane, 98 °C, 75–86%; (c) LHMDS or n-
BuLi, acetyl chloride, THF, À78 °C to rt, 88–96%; (d) DIBAL-H or LiEt3BH, pyridine, TMSOTf, CH2Cl2, À78 °C, 56–75% except for 2i (18%), 2j (26%) and 2k (15%); (e) Tf2O, DIPEA,
CH2Cl2, rt, 95%; (f) 3-methoxyphenylboronic acid, Pd(PPh3)4, K3PO4, 1,4-dioxane, 98 °C, 92% for 10, 85% for 11b; (g) NaOEt, EtOH, 80 °C, 85%; (h) H2(g), Pd/C, MeOH, rt;
ClCO2Me, EtOAc, 80 °C, 92% for 7f, 92% for 7l (2 steps).

W.-I. Lee et al. / Tetrahedron Letters 54 (2013) 5167–5171
5169
Table 2
Scope of cyclization
N,O-acetal TMS ether 2a was prepared as shown in Scheme 1.
The commercially available aniline 5a was treated with methyl
chloroformate to provide carbamate 6a, which was coupled with
3-methoxyphenylboronic acid in the presence of Pd(PPh3)4 and
then followed by the acylation of carbamate to give amide 1a.
Amide 1a was finally reduced with DIBAL-H, and the resulting
N,O-acetal was trapped with TMSOTf in situ to afford the desired
N,O-acetal TMS ether 2a. As shown in Table 1, the desired 5,6-
dihydrophenanthridine 4a was successfully obtained in high yield
by treatment of N,O-acetal TMS ether 2a with various Lewis acids
at À30 °C except for TiCl4. The cyclization proceeded smoothly in
various solvents although THF was not appropriate in terms of
chemical yield. We also found that the sulfonamide precursors
could also be utilized as alternative to carbamates (entries 9, 10).15
Having successfully established the optimized reaction condi-
tions,16 we turned our attention to scope and limitation of our
strategy for the synthesis of 5,6-dihydrophenanthridines. We first
explored various functional groups on the benzene ring. The requi-
site N,O-acetal TMS ethers were prepared by analogy to the prepa-
ration of 2a (Scheme 1). Syntheses of 7f and 7l required a few more
steps because the corresponding o-bromoanilines were not com-
mercially available. All substrates were prepared in high chemical
yields except for 7i, 7j, and 7k. In the preparation of N,O-acetal TMS
ethers,17 most of amides 1 showed moderate to good yields except
for 7i,18 7j and 7k19 in which the C–N bond cleavage consistently
occurred as a side reaction. Cyclization of all N,O-acetal TMS ethers
successfully provided the corresponding 5,6-dihydrophenanthri-
dines in high yields under the optimized conditions (Table 2). Sub-
strates including both electron withdrawing and donating groups
on the benzene ring system provided the desired cyclization prod-
OMe
OMe
BF3·OEt2
R
R
CO2Me
Me
N
N
Me
CO2Me
CH2Cl2, -30 o
C
TMSO
2a-j
4a-j
Entry
R
Yielda (%)
1
2
3
4
5
6
7
8
H (2a)
4-Cl (2b)
5-Cl (2c)
4-CF3 (2d)
5-CF3 (2e)
4-OEt (2f)
5-OMe (2g)
4-Me (2h)
4-CN (2i)
99
98
98
97
97
99
99
99
82
98
78
99
98
9
10
11
12
13
4-CO2tBu (2j)
5-NO2 (2k)
5-(3’-Methoxy)phenyl (2l)
6-Me (2m)
a
Isolated yield.
N,O-acetal TMS ethers in the presence of appropriate Lewis acid
resulting in formation of 5,6-dihydrophenanthridines via electro-
philic cylcization.
Table 3
Scope of cyclization
R1
R1
X
X
BF3·OEt2
CO2Me
R2
CH2Cl2, -30 o
C
N
N
R2
CO2Me
TMSO
OMe
2k-p
4k-p
Entry
Substrate
Product
Yielda (%)
Entry
Substrate
Product
Yielda (%)
NHBoc
OMe
NHBoc
CO2Me
4r
2a
4a
2r
1
99
6b
8c
CO2Me
N
N
Me
N
N
CO2Me
CO2Me
TMSO
TMSO
Me
OTBS
OTBS
2s
4s
4t
O
N
O
2n
4n
4o
CO2Me
Me
N
Me
2
3
98
98
7
95
CO2Me
CO2Me
N
Me
CO2Me
N
TMSO
TMSO
Me
OMe
OMe
2t
S
N
S
OMe
OMe
2o
CO2Me
Me
8d
N
Me
88e
CO2Me
Me
CO2Me
N
N
Me
CO2Me
TMSO
TMSO
(continued on next page)

5170
W.-I. Lee et al. / Tetrahedron Letters 54 (2013) 5167–5171
Table 3 (continued)
Entry
Substrate
Product
Yielda (%)
Entry
Substrate
Product
Yielda (%)
OMe
OMe
4u
2u
2p
4p
CO2Me
Me
e
4b
72c
9
-
OMe
CO2Me
OMe
OBn
N
N
Me
CO2Me
N
N
N
Me
TMSO
CO2Me
TMSO
Me
OMe
OMe
Cl
Cl
2q
4q
2v
4v
e
5
97
10
-
CO2Me
OBn
CO2Me
Me
N
N
N
Me
CO2Me
CO2Me
TMSO
TMSO
a
b
c
Isolated yield.
N,O-acetal TMS ether was used as a crude mixture.
Yield for two steps (N,O-acetal TMS ether was used as a crude mixture).
d
e
TFA was used instead of BF3ÁOEt2.
See text.
ucts regardless of substitution position.20 The reactions of N,O-ace-
tal TMS ethers containing 4- or 5-chloro substituent required long-
er reaction time to be completed although they were completed
within 1.5 h.
We also explored the benzene ring systems possessing various
functional groups including heterocycles, which functioned as an
internal nucleophile. The requisite N,O- acetal TMS ethers 2n–2v
were prepared by analogy to the previous precursors.
Acknowledgment
This work was supported by the National Research Foundation
of Korea Grant funded by the Korean Government (MEST) (NRF-
C1ABA001-2011-0018561).
References and notes
As shown in Table 3, all the substrates that contain activating
groups on the benzene ring gave high yields. (entries 1–5) In par-
ticular, the N,O-acetal TMS ether 2n possessing a para-siloxy group,
which is readily deprotectable, provided 4p in an excellent yield.
This supports extensive synthetic utility of the protocol. The ortho-
and para-disubstituted 5,6-dihydrophenanthridine 4p was suc-
cessfully provided too.21 The N,O-acetal TMS ether 2q derived from
the benzyloxylacetyl amide was well tolerable and afforded the
corresponding 5,6-dihydrophenanthridine as anticipated (entry
5). As shown in entry 6, effect of the protected amine substituent
as an activating group was investigated. The N,O-acetal TMS ether
2r was used as a crude mixture due to its instability. Effects of het-
erocycles such as furan (entry 7) and thiophene (entry 8) were also
examined. While furan 2s afforded the desired 5,6-dihydrophena-
thridine in high yield, thiophene 2t provided poor yield under the
standard conditions (<10%). However, TFA was found to be much
more effective than BF3ÁOEt2 after extensive efforts (entry 8). Com-
pared to the furan moiety, higher aromatic character of thiophene
is known to attribute to the lower reactivity in electrophilic substi-
tution.22 However, the non-substituted benzene 2u (entry 9) and
3-chlorobenzene 2v (entry 10) did not provide the desired 5,6-
dihydrophenanthridines.
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In summary, we have developed a high-yielding method for the
preparation of 5,6-dihydrophenanthridines via
a sequence of
reduction and cyclization of N-acylcarbamtes. The key feature in-
volved convenient preparation of N,O-acetal TMS ethers as N-acyli-
minium ion precursors, which were easily derived from amides,
and
efficient
intramolecular
aromatic
substitution
of
N-acyliminium ion under mild conditions. This procedure
would be widely applicable for the synthesis of 5,6-
dihydrophenanthridines.
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7.74 (dd, J = 7.8, 1.3 Hz, 1H), 7.60 (br s, 1H), 7.34–7.30 (m, 1H), 7.29 (d,
J = 2.5 Hz, 1H), 7.25–7.21 (m, 1H), 7.14 (d, J = 8.3 Hz, 1H), 6.85 (dd, J = 8.3,
2.5 Hz, 1H), 5.63 (m, 1H), 3.86 (s, 3H), 3.78 (s, 3H), 1.19 (d, J = 6.9 Hz, 3H); 13C
NMR (100 MHz, CDCl3) d 159.2, 154.3, 134.5, 131.6, 131.2, 127.9, 127.6, 126.6,
125.8, 124.9, 123.6, 113.4, 108.9, 55.4, 53.0, 51.8, 20.7; HRMS (ESI+) calcd for
C
17H17NO3 (M+) 283.1208, found 283.1203.
17. In most case, DIBAL-H gave slightly higher yield than LiEt3BH.
18. LiEt3BH was used for the more elaborate control of the amount of reducing
agent.
19. 7k was prepared using only LiEt3BH. When DIBAL-H was used, only C–N bond
cleavage occurred.
15. The Boc or Cbz protected amides were unstable under a basic condition to give
the deacylated carbamates (7), which were obtained as sole product after NH-
silica gel chromatography.
16. Representative procedure: To a solution of 2a (86 mg, 0.23 mmol) in dry CH2Cl2
(1 mL) at À30 °C was added BF3ÁOEt2 (0.085 mL, 0.69 mmol). The reaction
mixture was stirred for 1 h and quenched with triethylamine. Water was
added to the organic solution, and the resulting mixture was extracted with
CH2Cl2. The combined organic layer was dried over Na2SO4, filtered, and
concentrated in vacuo. The residue was purified by SiO2 column
20. In 7i and 7k, the yields for cyclization slightly decreased because they slowly
decomposed at room temperature.
21. Because the N,O-acetal TMS ether 2p could not be isolated with the by-product
which resulted from the C–N bond cleavage, it was used as a crude mixture in
cyclization reaction. On the analysis of LC-Mass data, it was judged that the
cyclization reaction proceeded well. In addition, the yield for two steps was
almost same to the yield of 4a from 1a.
22. Eicher, T.; Hauptmann, S.; Speicher, A. In The Chemistry of Heterocycles:
Structure, Reactions, Syntheses, and Applications, 2nd ed.; Wiley-VCH GmbH &
Co. KGaA, 2003; pp 71–74.
chromatography (EtOAc
: hexane = 1:3) to afford 64.5 mg (99%) of 4a as