Synthesis of N-methyl-5,6-dihydrobenzo[c]phenanthridine and its sp3 C(6)-H bond functionalization via oxidative cross-dehydrogenative coupling reactions

Article abstract of DOI:10.1016/j.tetlet.2015.10.018

An expeditious route involving a Pd-catalyzed intramolecular biaryl-coupling for the synthesis of the N-methyl-5,6-dihydrobenzo[c]phenanthridine scaffold has been developed. For the first time, we herein report the sp³ C(6)-H functionalization

Full text of DOI:10.1016/j.tetlet.2015.10.018

Accepted Manuscript
Synthesis of N-methyl-5,6-dihydrobenzo[c]phenanthridine and its sp3 C(6)–H
bond functionalization via oxidative cross-dehydrogenative coupling reactions
Adriana Romo-Pérez, Luis D. Miranda, Abraham García
PII:
S0040-4039(15)30215-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.10.018
TETL 46847
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
7 August 2015
2 October 2015
5 October 2015
Please cite this article as: Romo-Pérez, A., Miranda, L.D., García, A., Synthesis of N-methyl-5,6-
dihydrobenzo[c]phenanthridine and its sp3 C(6)–H bond functionalization via oxidative cross-dehydrogenative
coupling reactions, Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.10.018
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Graphical Abstract
Synthesis of N-methyl-5,6-
Leave this area blank for abstract info.
dihydrobenzo[c]phenanthridine and its sp3
C(6)±H bond functionalization via oxidative
cross-dehydrogenative coupling reactions
Adriana Romo-Pérez, Luis D. Miranda, and Abraham García

1
Tetrahedron Letters
Synthesis of N-methyl-5,6-dihydrobenzo[c]phenanthridine and its sp3 C(6)±H bond
functionalization via oxidative cross-dehydrogenative coupling reactions
Adriana Romo-Péreza, Luis D. Mirandab,ꢀ and Abraham Garcíaa,ꢀ
a Universidad Autónoma de Nuevo León, Facultad de Ciencias Químicas, Av. Universidad s/n, Ciudad Universitaria, Monterrey, Nuevo León, 66455, México
b Universidad Nacional Autónoma de México, Instituto de Química, Circuito Exterior s/n, Ciudad Universitaria, Coyoacán, México, D.F. O4510, México
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Available online
An expeditious route involving a Pd-catalyzed intramolecular biaryl-coupling for the synthesis
of the N-methyl-5,6-dihydrobenzo[c]phenanthridine scaffold has been developed. For the first
time, we herein report the sp3 C(6)-H functionalization of this heterocyclic scaffold through
DDQ-mediated cross-dehydrogenative coupling reactions with nitroalkanes, dialkyl malonates,
alkynes, dialkyl phosphites, carbonyl compounds, pyrrole, and indoles.
2009 Elsevier Ltd. All rights reserved.
Keywords:
Dihydrobenzo[c]phenanthridines
Cross-dehydrogenative coupling
sp3 C±H functionalization
Alkaloids
DDQ
nucleophiles.16 Using a similar strategy, Zheng et al. performed
the alkynylation of THIQs.17 Zhu et al.18 developed the
Introduction
The N-methyl-5,6-dihydrobenzo[c]phenanthridine (1, DHB)
represents a common scaffold of several bioactive alkaloids of
the benzophenanthridine family.1,2 Members of this family have
drawn the attention of researchers due to their broad spectrum of
pharmacological properties such as antimicrobial, antifungal, and
antiproliferative activities.1-4 Notwithstanding that several
synthetic strategies have been reported for natural and non-
natural compounds having the benzophenanthridine scaffold,5-9
the direct C±H functionalization of this heterocycle remains
unexplored as an alternative strategy to generate structural
diverse compounds in the quest for new drugs.10,11 As part of our
continued interest in the development or application of synthetic
methods to the functionalization of heterocyclic scaffolds that
occur in natural products,12 we recently became interested in the
direct sp3 C±H functionalization of DHB (1). Considering that
the sp3 C±H functionalization of 1 can not only occur at the
position 6 but also at the methyl group, we specifically explored
the sp3 C-H activation and functionalization at position 6 through
oxidative cross-dehydrogenative coupling (CDC) reactions with
suitable nucleophiles.
functionalization of THIQs via oxidative multicomponent
reactions using 2-iodoxybenzoic acid as oxidant, while Prabhu et
al.19 reported the same reaction using O2 as the oxidant and
different nucleophiles such as nitroalkanes, carbonyl compounds,
coumarins, and phosphites. Recent investigations have reported
the efficient application of the well-known oxidant, 2,3-dichloro-
5,6-dicyano-1,4-benzoquinone (DDQ), in C-C bond forming
reactions through benzylic C-H bond activation.20
Taking the previously described literature into consideration,
we postulated DHB (1) as an attractive heterocyclic scaffold to
explore the scope of the CDC reaction. Therefore, we herein
report an expeditious route for the synthesis of the heterocycle 1
followed by its sp3 C(6)-H functionalization through a Cu-
catalyzed cross-dehydrogenative coupling using DDQ as oxidant
and different nucleophiles (Scheme 1).
Considerable progress has been made in the development of
CDC reactions between diverse nucleophiles and nitrogen-
containing heterocycles such as tetrahydroisoquinolines (THIQs)
and benzylamine derivatives.13 Copper-catalyzed CDC reactions
between N-aryl-THIQ and indoles or activated methylenes have
been developed by Li et al.14,15 Niu et al. reported the
Scheme 1. Representative CDC reaction between N-methyl-5,6-
dihydrobenzo[c]phenanthridine (1) and nucleophiles.
functionalization of tertiary benzylamines using acetylides as
²²²
ꢀ Corresponding author. Tel.: +52 81 83294000 ext. 3463; fax: +52 81 83529025; e-mail: edgar.garciazp@uanl.edu.mx
ꢀ Corresponding author. Tel.: +52 55 56224440; fax: +52 55 56162203; e-mail: lmiranda@unam.mx

2
Tetrahedron
Table 1. Optimization for the preparation of N-methyl-5,6-dihydrobenzo[c]phenanthridine (1).a
Entry
1
Catalyst
Ligand
Base
Temperature (°C)
Time (h)
24
Isolated yields (%)
PdCl2
PPh3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
K3PO4
AcONa
t-BuOk
t-BuOk
t-BuOk
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
140
140
140
140
140
140
140
140
140
140
130
110
140
140
130
130
NR
NRb
NR
9c
16d
8d
2
PdCl2
PPh3
24
3
Pd(PPh3)4
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
Pd(OAc)2
Pd(OAc)2
-
24
4
Cy3P·HBF4
Cy3P·HBF4
P(o-tol)3
24
5
24
6
24
7
Cy3P·HBF4
Cy3P·HBF4
Cy3P·HBF4
Cy3P·HBF4
Cy3P·HBF4
Cy3P·HBF4
Cy3P·HBF4
Cy3P·HBF4
Cy3P·HBF4
Cy3P·HBF4
24
NR
NR
NR
18
8
24
9
24
10
11
12
13
14
15
16
12
12
25
36d,e
12
24
42
24
45d
40
79d,f
12
6
aReaction conditions: Compound 6 (1 equiv), catalyst (20 mol%), ligand (40 mol%), base (2 equiv), DMA (0.2 M).
bReaction carried out in dimethylformamide.
cCatalyst (10 mol%).
dBase (2.5 equiv).
eReaction carried out in toluene.
fCatalyst (30 mol%) and ligand (60 mol%).
equiv), DCM:MeOH, 0 °C to rt, 16 h. iii) a) NaH, THF, 0 °C to rt, 30 min,
CH3I, THF, rt, 16 h. iv) DHB (1 equiv), Pd(OAc)2 (30 mol%), Cy3P·HBF4
(60 mol%), Cs2CO3 (2.5 equiv), DMA (0.2 M), 130 °C, 6 h.
Results and Discussion
At the outset of our work, the DHB (1) was chosen as an
interesting scaffold to explore its sp3 C(6)-H functionalization, so
an expedient synthetic route was carried out as outlined in
Scheme 2. First, the 2-bromo-N-ꢀĮ-naphthyl)benzylamine (5) was
synthesized in excellent yield (94%) by reductive amination
between 1-naphthylamine (3) and 2-bromobenzaldehyde (4)
using NaBH3CN as the reducing agent. Next, the N-methyl-(2-
bromobenzyl)naphthylamine (6) was efficiently obtained by
methylation of 5 with NaI and CH3I in THF. In the final step the
cyclization of 6 into 1 was achieved by a palladium-catalyzed
intramolecular biaryl-coupling (Scheme 2) and the results of the
optimization experiments are summarized in Table 1.
Our initial efforts using PdCl2/PPh3 or Pd(PPh3)4 in the
presence of K2CO3 failed to give the desired product at 140 °C in
N,N-dimethylacetamide (DMA) or dimethylformamide (Table 1,
entries 1-3).21 However, the combination of Pd(OAc)2 and
Cy3P·HBF4 in the presence of K2CO3 gave the desired product in
low yields (entries 4-5), even when the Cy3P·HBF4 ligand was
replaced by P(o-tol)3 (entry 6). The replacement of K2CO3 by
other weak bases such as Na2CO3, K3PO4, and AcONa proved to
be inefficient to favor the coupling process (entries 7-9), but the
use of a stronger base like t-BuOK slightly improved the yield of
1, resulting a more efficient reaction when the temperature was
decreased to 130 °C or the solvent was replaced by toluene
(entries 10-12). Interestingly, compound 1 was achieved in better
yields (42% and 45%) by using 2 or 2.5 equiv of Cs2CO3 as the
base in DMA at 140 °C (entries 13-14). When the coupling
reaction was performed at 130 °C for 12 h, a slightly decrease in
yield from 45% to 40% was observed (entry 15). Further
experiments revealed that a shorter reaction time (6 h) was a
critical factor to increase yield of product 1 from 40% to 79%
(entry 16). Therefore, the optimal conditions for the
intramolecular biaryl-coupling reaction of compound 6 were
reached by using 1 equiv of 6, 30 mol% of Pd(OAc)2, and 60
mol% of Cy3P·HBF4 in DMA at 130 °C for 6 h.
With the heterocyclic scaffold 1 in hand; we carried out a set
of experiments to optimize the reaction conditions for the CDC
between 1 and indole, which was taken as the model reaction
(Table 2). Based on the reaction conditions reported by Prabhu et
Scheme 2. Synthesis of N-methyl-5,6-dihydrobenzo[c]phenanthridine (1).
Reaction Conditions: i) InCl3 (5 mol%), rt, 1 h, DCM. ii) NaBH3CN (3

3
al.,19 the use of I2 as catalyst in polar solvents (DCM:MeOH or
MeOH) under aerobic conditions failed to provide the desired
product 2a at 60 °C (Table 2, entries 1 and 2). To circumvent
this, we explored iron and ruthenium catalysts (FeCl2, FeCl3, or
RuCl3) in combination with tert-butyl hydroperoxide or hydrogen
peroxide, but the product 2a was obtained in low yields (entries
3-5). Considering that DDQ has been reported to be an efficient
reagent that promotes CDC reactions, our next experiment was
performed using this oxidant. At first we used DDQ as the sole
oxidant in toluene, but the desired compound 2a was obtained in
30% yield (entry 6). However, the combination of DDQ with 20
mol% of CuBr afforded the product in 45% yield (entry 7). To
circumvent the unsatisfactory dissolution of DDQ in all previous
experiments, a 1:1 mixture of CH3CN:toluene was attempted. To
our delight, the CDC between 1 and indole furnished the desired
product 2a in good yield (60%) once the solubility of DDQ and
the temperature were increased (entry 8). Additional experiments
were carried out to examine the use of CuBr in the absence of
DDQ and to determine the minimum loading of CuBr for the
desired CDC reaction. In the absence of DDQ, the copper
catalyst moderately promoted the coupling between 1 and indol
(entry 9). When the amount of CuBr was decreased to 10 and 3
mol%, the yields decreased dramatically (entries 10 and 11).
product 2g showed a double splitting pattern for two main
isomers (see supplementary material). The proton H-6 split (G 5.0
ppm) into a doublet with a coupling constant of J = 11.4 Hz,
indicating that the methine proton of the nucleophile (CH3-CO-
CH-CO2-CH2CH3) adopts an antiperiplanar rather than a gauche
conformation. Therefore, the CH3-CO- and -CO2-CH2CH3 groups
are gauche to H-6 and their positions can be interchanged to
explain the two main isomers in NMR. Geometry optimization of
all major conformers of 2g using molecular mechanic force fields
(MMX) as implemented in the PCMODEL software, resulted in
two minimum energy structures having the antiperiplanar
conformations.22 Then we turned our attention to the carbon±
phosphorous coupling reaction, which produced the D-
aminophosphonates 2i and 2j in low yields under the standard
conditions. We then extended the CDC reaction to nitroalkanes,
obtaining the nitro derivatives 2k-2m in low and moderate yields
(55%, 32%, and 25%), which suggested that the progress of the
coupling reaction decreases with increasing chain length of the
nitroalkanes. To our surprise, the 1H-NMR spectra of the
nitroethane and nitropropane derivatives (2l and 2m) exhibited
splitting patterns for
a single isomer (see supplementary
material). It should be noted that no other nitroethane and
nitropropane derivatives were observed on thin layer
chromatography or NMR. The proton H-6 split (G 4.58 ppm) into
a doublet with a coupling constant of J = 10.5 Hz, indicating that
the methine proton of the nucleophile (CH3-CH-NO2) adopts an
antiperiplanar conformation. According to the molecular
modeling by PCMODEL, the minimum energy structures of 2l
are those with the CH3- and -NO2 groups gauche to H-6, being
more stable the conformer with the -NO2 group oriented towards
the heterocyclic nitrogen (see supplementary material). A similar
outcome was observed for compound 2m, which exhibited a
doublet (G 4.60 ppm) with J = 10.5 Hz, characteristic of the
antiperiplanar conformation. On the other hand, the trimethylsilyl
cyanide reacted with compound 1 to give the nitrile 2n in
moderate yield. To our delight, the CDC reaction proceeded
smoothly by using alkynes and the desired products 2o and 2p
were afforded in good yields (60% and 70%, respectively).
Notwithstanding the range of yields, the described oxidative
CDC reaction can be extended to the synthesis of a structurally
diverse chemical library starting from the heterocyclic scaffold 1.
Table 2. Optimization for the synthesis of product 2a.a
Entry
Catalyst
Oxidant
Solvent
Isolated
yields (%)
1
I2
O2
CH2Cl2:CH3OH
CH3OH
-
2
I2
O2
-
3
RuCl3
FeCl3
FeCl2
-----
O2
CH3OH
20
13b
7
4
TBHP
H2O2
DDQ
DDQ
DDQ
-----
ClCH2CH2Cl
CH3OH
5
6
PhCH3
30
45
60c
31
31d
8e
A preliminary mechanistic proposal for the CDC reaction is
depicted in Scheme 3. Based on previous observations about
DDQ/Cu-mediated processes,20a the iminium ion 7 is assumed to
be the reaction intermediate, which further reacts with the
nucleophile to furnish the expected product (Scheme 3).
7
CuBr
CuBr
CuBr
CuBr
CuBr
PhCH3
8
CH3CN:PhCH3
CH3CN:PhCH3
CH3CN:PhCH3
CH3CN:PhCH3
9
10
DDQ
11
DDQ
aReaction conditions: Compound 1 (1 equiv), compound a (1.2 equiv),
oxidant (1.2 equiv), catalyst (20 mol%), solvent (0.2 M), 60 °C, 24 h. b2 equiv
c
e
of TBHP. Reaction carried out at 80 °C. dCatalyst (10 mol%). Catalyst (3
mol%).
Scheme 3. Plausible mechanism for the CDC of 1 with nucleophiles.
To explore the scope of this methodology, we incorporated
various types of nucleophiles into compound 1 (Table 3). The
CDC between 1 and 2-methylindole afforded the desired product
2b in 56% yield. However, performing the standard reaction with
pyrrole resulted in lower yields of product 2c (39%). It is worth
noting that methyl and ethyl malonates underwent moderate
coupling reaction with compound 1 to furnish derivatives 2d-2e
(40% yield), but the CDC reaction proved to be less efficient
ZLWKꢁ WKHꢁ 0HOGUXP¶Vꢁ DFLGꢁ GHVSLWHꢁ LWꢁ LVꢁ PRUHꢁ DFLGLFꢁ WKDQꢁ WKHꢁ
malonates (product 2f in 22% yield). Similarly, the coupling
reaction of 1 with ethyl acetoacetate and acetophenone gave
desired compounds 2g and 2h in low yields (20% and 18%,
Conclusions
In summary, the N-methyl-5,6-dihydrobenzo[c]phenanthridine
(1) was prepared in a novel and expedient three-step synthetic
sequence. Moreover, the sp3 C(6)±H bond functionalization of
the heterocyclic scaffold 1 was achieved through a CuBr/DDQ-
mediated cross-dehydrogenative coupling reaction, using a wide
variety of nucleophiles such as nitroalkanes, dialkyl malonates,
alkynes, dialkyl phosphites, carbonyl compounds, pyrrole, and
indoles. It is worth mentioning that these experiments represent
1
respectively). It is worth to mention that the H-NMR spectra of

4
Tetrahedron
the first example of sp3 C±H bond functionalization onto the
Supplementary data
5,6-dihydrobenzo[c]phenanthridine heterocyclic system. We are
currently extending this methodology to the sp3 C±H bond
Supplementary data (experimental procedures, spectroscopic
and spectrometric data for all new compounds) associated with
this article can be found, in the online version, at doi:
functionalization
of
natural
products
having
the
dihydrobenzo[c]phenanthridine scaffold.
Table 3. CDC reaction of DHB (1) with several nucleophiles.
Entry
1
2
a
b
Product
Yield
[%]b
Entry
1
2
Product
Yield
[%]b
9
60
56
30
1
1
2i
2a
2b
i
1
1
41
1
2
10
11
2j
j
55d
32d
1
1
39
2k
2l
1
1
k
3
4
5
c
d
2c
2d
12
13
40c
l
1
40c
25d
1
1
2m
m
n
2e
e
1
1
14
15
22
20
18
42
60
70
6
7
8
2n
2o
f
2f
1
1
g
2g
o
p
1
16
2p
2h
h
a
Reaction conditions: Compound 1 (1 equiv), nucleophile (1.2 equiv), DDQ (1.2 equiv), CuBr (20 mol%), 50:50 v/v CH3CN:PhCH3 (0.2 M), 80°C, isolated
yields in parenthesis. b Yields of isolated products based on DHB. cCs2CO3 (1.2 equiv.) was added. d2 equiv of nucleophile were added.
References and notes
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6
Tetrahedron
Table 1. Optimization for the preparation of N-methyl-5,6-dihydrobenzo[c]phenanthridine (1).a
Entry
1
Catalyst
Ligand
Base
Temperature (°C)
Time (h)
24
Isolated yields (%)
PdCl2
PPh3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
K3PO4
AcONa
t-BuOk
t-BuOk
t-BuOk
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
140
140
140
140
140
140
140
140
140
140
130
110
140
140
130
130
NR
NRb
NR
9c
16d
8d
2
PdCl2
PPh3
24
3
Pd(PPh3)4
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
Pd(OAc)2
Pd(OAc)2
-
24
4
Cy3P·HBF4
Cy3P·HBF4
P(o-tol)3
24
5
24
6
24
7
Cy3P·HBF4
Cy3P·HBF4
Cy3P·HBF4
Cy3P·HBF4
Cy3P·HBF4
Cy3P·HBF4
Cy3P·HBF4
Cy3P·HBF4
Cy3P·HBF4
Cy3P·HBF4
24
NR
NR
NR
18
8
24
9
24
10
11
12
13
14
15
16
12
12
25
36d,e
12
24
42
24
45d
40
79d,f
12
6
aReaction conditions: Compound 6 (1 equiv), catalyst (20 mol%), ligand (40 mol%), base (2 equiv), DMA (0.2 M).
bReaction carried out in dimethylformamide.
cCatalyst (10 mol%).
dBase (2.5 equiv).
eReaction carried out in toluene.
fCatalyst (30 mol%) and ligand (60 mol%).

7
Table 2. Optimization for the synthesis of product 2a.a
Entry
Catalyst
Oxidant
Solvent
Isolated
yields (%)
1
2
3
4
5
6
7
8
I2
O2
DCM:MeOH
MeOH
-
I2
O2
-
RuCl3
FeCl3
FeCl2
-----
CuBr
CuBr
O2
MeOH
20
13b
7
TBHP
H2O2
DDQ
DDQ
DDQ
DCE
MeOH
PhCH3
30
45
60c
PhCH3
CH3CN:PhCH3
aReaction conditions: Compound 1 (1 equiv), compound a (1.2 equiv),
oxidant (1.2 equiv), catalyst (20 mol%), solvent (0.2 M), 60 °C, 24 h.
b2 equiv of TBHP.
cReaction carried out at 80 °C.

8
Tetrahedron
Table 3. CDC reaction of DHB (1) with several nucleophiles.
Entry
1
2
Product
Yield
[%]b
Entry
1
2
Product
Yield
[%]b
9
60
56
30
1
1
2i
2a
2b
a
b
i
1
1
41
1
2
10
11
2j
j
55d
32d
1
1
39
2k
2l
1
1
k
3
4
c
d
2c
2d
12
13
40c
l
1
40c
25d
1
1
5
2m
m
n
2e
e
1
1
14
15
22
20
18
42
60
70
6
7
8
2n
2o
f
2f
1
1
g
2g
o
p
1
16
2p
2h
h
a
Reaction conditions: Compound 1 (1 equiv), nucleophile (1.2 equiv), DDQ (1.2 equiv), CuBr (20 mol%), 50:50 v/v CH3CN:PhCH3 (0.2 M), 80°C, isolated
yields in parenthesis. b Yields of isolated products based on DHB. cCs2CO3 (1.2 equiv.) was added. d2 equiv of nucleophile were added.