Expeditious approach to pyrrolophenanthridones, phenanthridines, and benzo[ c ]phenanthridines via organocatalytic direct biaryl-coupling promoted by potassium tert -butoxide

Article abstract of DOI:10.1021/jo400890k

A methodology involving a "transition metal-free" intramolecular biaryl-coupling of o-halo-N-arylbenzylamines has been developed in the presence of potassium tert-butoxide and an organic molecule as catalyst. The reaction appears to proceed through KO^tBu-promoted intramolecular homolytic aromatic substitution (HAS). Interestingly, this biaryl coupling also works in the presence of potassium tert-butoxide as sole promoter. On extending our approach further, we found that N-acyl 2-bromo-N-arylbenzylamines undergo a one-pot N-deprotection/biaryl coupling followed by oxidation, thus offering an expeditious route to the phenanthridine and benzo[c]phenanthridine skeletons. The strategy has been applied to a concise synthesis of Amaryllidaceae alkaloids viz. oxoassoanine (1b), anhydrolycorinone (1d), 5,6-dihydrobicolorine (2d), trispheridine (2b), and benzo[c]phenanthridines alkaloids dihydronitidine (3b), dihydrochelerythidine (3d), dihydroavicine (3f), nornitidine (3h), and norchelerythrine (3j).

Full text of DOI:10.1021/jo400890k

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Article
Expeditious Approach to Pyrrolophenanthridones, Phenanthridines,
and Benzo[c]phenanthridines via Organocatalytic Direct
Biaryl-Coupling Promoted by Potassium tert-Butoxide
Subhadip De, Sourabh Mishra, Badrinath N. Kakde, Dhananjay Dey, and Alakesh Bisai
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo400890k • Publication Date (Web): 23 Jul 2013
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Expeditious Approach to Pyrrolophenanthridones, Phenanthridines,
and Benzo[c]phenanthridines via Organocatalytic Direct Biaryl-
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Coupling Promoted by Potassium tert-Butoxide
Subhadip De, Sourabh Mishra, Badrinath N. Kakde, Dhananjay Dey, and Alakesh Bisai*
Department of Chemistry, Indian Institute of Science Education and Research (IISER)
Bhopal, MP – 462 023, India
Corresponding Author’s Email Address: alakesh@iiserb.ac.in
£
This article is dedicated to Professor Satinder V. Kessar, Punjab University, India, on the occasion of
th
his 80 birthday.
TOC GRAPHIC
ꢀ
ABSTRACT
A methodology involving a 'transition metal-free' intramolecular biaryl-coupling of ortho-
halo-N-aryl-benzylamines has been developed in the presence of potassium tert-butoxide and
t
an organic molecule as catalyst. The reaction appears to proceed through KO Bu-promoted
intramolecular homolytic aromatic substitution (HAS). Interestingly, this biaryl-coupling also
works in the presence of just potassium tert-butoxide as sole promoter. On extending our
approach further, we found that N-acyl 2-bromo-N-arylbenzylamines undergo a one-pot N-
deprotection, biaryl-coupling followed by oxidation thus offering an expeditious route to the
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phenanthridine and benzo[c]phenanthridine skeletons. The strategy has been applied to a
concise synthesis of Amaryllidaceae alkaloids viz. oxoassoanine (1b), anhydrolycorinone
(
1d), 5,6-dihydrobicolorine (2d), trispheridine (2b) and benzo[c]phenanthridines alkaloids
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dihydronitidine (3b), dihydrochelerythidine (3d), dihydroavicine (3f), nornitidine (3h), and
norchelerythrine (3j).
INTRODUCTION
1
Carbon-carbon (C-C) bond-forming reactions through selective functionalization of
aromatic compounds via C–H bond activation have emerged as an extremely attractive tool in
2
, 3, 4
contemporary organic synthesis for atom- and step-economical pathways.
Significant
efforts have already been made for the direct C–H bond transformation through traditional
demetalhalide cross-coupling utilizing transition metal catalysts. Direct cross-coupling
5
6
7
8
methods such as demetal hydride, demetal hydroxide, dehydrative, dehydrohalide, and
9
dehydrogenative cross-couplings, have received considerable attention to accomplish this
target. In fact, these new strategies facilitate the C–C bond formations via activation of either
7
9
C–H or C–OH bond by replacing one, or in some cases both, of the expensive unstable
coupling partners (C–X or C–M) with inexpensive and unreactive molecules.
The synthesis of biaryls through direct C-H bond functionalization is particularly of
significant interest because of their wider abundanceꢀinꢀnaturalꢀproducts,ꢀpharmaceuticals,ꢀ
andꢀmaterialsꢀandꢀthusꢀrequiresꢀanꢀextensiveꢀstudy.ꢀIn this regard, the transition metal
catalysis has played a vital role to make use of ArX for substitution reactions. Especially,
palladium catalysis is found to be versatile for the coupling reaction of ArX with nucleophiles
10
such as arenes. ꢀ However, one of the straightforward methods to construct biphenyl
frameworks is the homolytic aromatic substitution (HAS) with aryl radicals, which is defined
as replacement of a leaving group (in general halogen) by an aryl radicals on an aromatic ring
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followed by elimination of a hydrogen radical. But, its utility has been hampered by
laborious procedure involved in the generation of aryl radicals. Aromatic compounds such as
arenediazonium salts and diaroyl peroxides having an Ar-X bond that readily undergoes
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homolytic cleavage are although efficient precursors, but are not always easily accessible.
Use of readily available aryl halides as precursors of aryl radicals, requires a stoichiometric
1
3a
13b
3 3 3
amount of a radical source such as Bu SnH and (Me Si) SiH or special conditions such
1
3c
as irradiation.
A major breakthrough came in the field when Itami and co-workers for the first time
t
described an unprecedented account on KO Bu-mediated biaryl-coupling of aryl halides and
1
4
electron deficient heterocyclic substrates in the absence of any transition metal catalyst.
Although the scope of their methodology was strictly limited to the electron-deficient 6-
membered N-heteroarenes such as pyrazine and microwave irradiation was required for high
2
2
yields, but the work is of significant interest because of the C(sp )-C(sp ) coupling taking
1
5a
place without the aid of transition metals.ꢀIn 2010, independently, Lei-Kwong et al, Shi et
15b
15c
al, and Shirakawa-Hayashi et al revealed that the biaryl-couplings could be promoted in
t
the presence of KO Bu and a bidentate ligand. While Lei-Kwong and Shi reported biaryl-
t
coupling promoted by KO Bu in combination with DMEDA (N,N'-dimethyl
1
5a
15a
ethylenediamine) and 1,10-phenanthroline derivatives, respectively, Shirakawa-Hayashi
t
15c
reported NaO Bu-1,10-phenanthroline-mediated biaryl-coupling at 155 ˚C. In these reports,
it has been shown that aryl and heteroaryl halides of various electronic character reacted with
benzene and other arenes to give biaryls in moderate to high yields.ꢀFollowing these reports,
t
few other reports also revealed that KO Bu-could efficiently promote the biaryl-coupling in
16
the absence of any transition-metal. In fact, the combination of an inorganic base and a
catalytic amount of an organic molecule, preferably a diamine, under heating is enough to
synthesize a wide range of biaryls. These pairs presumably initiate single electron transfer
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17a
(
SET) to a C-X bond at elevated temperatures, initially providing a radical anion that gives
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rise to a radical species for further propagation. The preliminary experimental data from
aforementioned reports strongly suggest the involvement of radical intermediate, as their
propagation chains were essentially terminated by the addition of common radical
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scavengers.
ꢀ
The impetus for syntheses of biaryl compounds lies in their exhaustive use as building
blocks of many alkaloids and natural products. In this regard, the indole based alkaloids of
Amaryllidaceae family having a biaryl connection drew our attention. In general
phenanthridinone derivatives (Figure 1) are common structural motifs of several bioactive
1
8
nitrogen
containing
natural
products.
Especially,
those
containing
the
pyrrolophenanthridinone core (Figure 1) have been the subject of many synthetic endeavors
due to their interesting biological activities, such as cytotoxicity and inhibition of male
1
9
fertility.
ꢀ
Figure 1: Alkaloids sharing pyrrolophenanthridine, phenanthridine, and benzo[c]phenanthridine structures.
On the other hand, phenanthridines represent an important substructure of a variety of
natural products, particularly those having benzo[c]phenanthridine skeleton (3a-j, Figure 1).
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Members of this family possess antimicrobial and antiviral properties. In addition, few
members of this class are considered as potential antitumor drugs inhibiting DNA
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topoisomerase I.
Owing to their interesting architecture and important biological
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activities, this family of alkaloids gained considerable synthetic interest in contemporary
organic synthesis. Traditional methods known so far, either involve longer synthetic routes or
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2
suffer from limited substrate generality and functional group tolerance. Alternative methods
using palladium-catalyzed approaches are comparatively popular in recent years, due to
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relatively mild reaction conditions and high functional group tolerance involved. Direct
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arylation methods allow the use of simplified starting materials and offer a atom
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economical approach compared to traditional metal-catalyzed cross-coupling reactions. In
present perspective, it would be challenging to realize these transformations under 'transition
metal-free' conditions.
Recently, our group demonstrated organocatalytic biaryl-coupling via a homolytic
1
1
t
aromatic substitution (HAS) using KO Bu as sole coupling promoter in the absence or
26
presence of catalytic amount of organic molecules. We have used N-dihydroindolyl/ benzyl
amine derivatives having a halogen at the ortho-position for intramolecular biaryl-coupling.
Employing our strategy, we were able to synthesize several pyrrolo- and
dihydrophenanthridines comprising vital building blocks of several alkaloids of
Amaryllidaceae family. In this article, we disclose the scope and limitations of
organocatalytic biaryl-coupling as well as our investigations towards the utility of
organocatalytic biaryl-coupling for the synthesis of natural products sharing
benzo[c]phenanthridine based structures. Applying this methodology, recently we
accomplished the total synthesis of Amaryllidaceae alkaloids oxoasoanine (1b),
anhydrolycorinone (1d) sharing pyrrolophenanthridone structure, 5,6-dihydrobicolorine (2d),
trispheridine (2b) sharing a phenanthridine core, various dihydrobenzo[c]phenanthridines viz
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dihydronitidine
(3b),
dihydrochelerythrine
(3d),
dihydroavicine
(3f),
and
benzo[c]phenanthridines such as nornitidine (3h), norchelerythrine (3j) through the
intramolecular direct arylation strategy of unactivated arenes.
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RESULTS AND DISSCUSION
Initially, we chose 2-bromobenzoylindoline (5a) as substrate in the presence of 4a-j
and potassium tert-butoxide to access corresponding pyrrolophenanthridine 6a. After
extensive optimization (table 1), we found that 40 mol% of DMEDA 4a in the presence of 3
t
equiv. of KO Bu in mesitylene (condition A) as solvent afforded the required product in 63%
yield (entry 3, table 1). We found that mesitylene was comparatively better solvent than
toluene and benzene, and thus, mesitylene was chosen for further optimization studies
(
entries 1-3). Under similar condition ligand 4c afforded products in 52% yields (entry 5).
However, ligands 4b and 4d-g afforded products in the range of 21-36% yields (entries 4 and
-9). The reaction could be performed with almost similar efficiency using 40 mol% of 1,10-
6
phenanthroline 4h (condition B) and bipyridine 4j (entries 10 and 13, respectively). However,
dppp 4i was found to be inferior to 4a and 4h in terms of catalytic activity (entry 12). It was
t
t
found that more basic KO Bu is superior as compared to NaO Bu (entries 15-17), whereas the
t
reaction was much more sluggish by use of less basic LiO Bu. It was also observed that the
reactions were associated with 18-20% of indoline probably due to the cleavage of amide
linkage of the substrate in the presence of potassium tert-butoxide. An interesting and
noteworthy observation made here was that, the reaction could also be done just in presence
of potassium tert-butoxide (condition C) without using any organic ligand to afford products
t
in almost similar efficiency (67% yields, entry 18). This clearly demonstrated that KO Bu is
solely responsible for the biaryl-coupling facilitating the reaction through homolytic aromatic
t
substitution (HAS) with aryl radical generated in the presence of KO Bu.
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Table 1. Optimization of organocatalytic biaryl-coupling.
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ꢀ
ꢀ
a
t
Reactions were carried out on a 0.25 mmol of 5a in presence of 0.10 mmol of catalyst and 0.75 mmol of KO Bu in 2 mL of
b
solvent in a sealed tube at 80 °C- 100 °C for specified time, unless otherwise stated. In most of the cases the reactions were
c
d
e
associated with the cleavage of amides, yielding 18-20% of indoline. Condition A. Condition B. Condition C.
With the optimized conditions in hand (table 1), we then examined the reaction scope.
t
A set of three reaction conditions were chosen viz. KO Bu in the presence of 4a (condition A)
t
and 4h (condition B) as well as KO Bu alone (condition C) in mesitylene and the results are
summarized in figure 2. It was gratifying to see that all the three conditions facilitated
intramolecular biaryl-coupling in moderate to good yields. Noticeably, 2-haloarylamides
prepared from indoline (5a-b, 5e-f, 5i-j, and 5m) and 1,2,3,4-tetrahydroquinoline (5c-d, 5g-h,
5
k-l, and 5n) underwent smooth reactions to afford a wide range of products (figure 2).
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Notably, the biaryl-coupling with aromatic bromides and iodides (5a-n) were equally
efficient. In order to make our strategy practically viable, one of the reactions was conducted
with 8 mmol. of 5a in the presence of 40 mol% of 1,10-phenanthroline and 3 equivalent of
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KO Bu (condition B), which afforded 6a in 55% yields along with 20% of indoline as by
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product due to the cleavage of N-arylamide in the presence of KO Bu under elevated
temperature.
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a
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t
t
mmol of KO Bu in 6 mL of solvent in a sealed tube at 100 °C for specified time. Condition C = 3.0 mmol of KO Bu only.
Figure 2: Initial exploration of the substrate scope.
As a preview of the usefulness of this methodology, we could successfully carry out
the total syntheses of oxoassoanine (1b) starting from 2-halobenzoylindolines 5i-j and
anhydrolycorinone (1d) from 5m (Figure 2). The naturally occurring dihydrophenanthridones
oxoassoanine (1b) and anhydrolycorinone (1d) are in fact the advanced intermediates for the
19m
synthesis of pratosine (1f) and hippadine (1g), respectively (Scheme 1).
Thus, the
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methodology presented here offers an opportunity to further explore its applicability in the
context of complex alkaloids of Amaryllidaceae family after further synthetic elaborations.
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ꢀ
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Scheme 1: Formal synthesis of pratosine (1f) and hippadine (1g).
In search for an advanced intermediate aiming to the total synthesis of other
pyrrolophenanthridones (figure 1), the methodology was further explored. For this purpose,
few N-(2-bromobenzyl) 2-oxindoles 7a-b and N-(2-bromobenzyl) isatins 7c-d were subjected
to the optimized conditions to carry out the biaryl-coupling as shown in scheme 2. However,
contrary to our assumption, 7a-b afforded tetracyclic O-arylated products 8a-b in moderate to
good yields instead of C-arylated products. In these cases, O-arylation took place presumably
due to the presence of sufficiently acidic proton at the 3-position of 2-oxindole substrates 7a-
b. The X-ray crystal structure of tetracyclic compound 8a (see, Supporting Information for
ORTEP) provided us an unambiguous proof for this unusual O-arylation process. This clearly
demonstrates that an organocatalytic O-arylation could be realized depending upon the
substrate structures, which should, in principle, leads to the formation of various phenol
derivatives. To our surprise, under optimized conditions A, B, and C, compounds 7c and 7d
yielded a mixture of products, from where neither products nor starting materials were
isolated.
ꢀ
a
Reactions were carried out on a 1.0 mmol of 7a-d in presence of 0.40 mmol of 4a (condition A), 4h (condition B) and 3.0
mmol of KO Bu in 6 mL of solvent in a sealed tube at 100 °C for specified time. Condition C = 3.0 mmol of KO Bu only.
t
t
Scheme 2: Substrate scope of organocatalytic biaryls syntheses.
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The organocatalytic biaryl-coupling reaction was further extended to a variety of
substrates 2-halo-N-aryl-benzylamines 9a-l for the synthesis of dihydrophenanthridines,
which are structurally similar to a number of Amaryllidaceae alkaloids (see, 2b-d; Figure 1).
Under the optimized conditions, 2-bromo-N-phenyl-benzylamine 9a afforded products 10a in
24% (condition A), 62% (condition B), and 52% (condition C) yields, and thus conditions B
and C were chosen for further substrate studies.
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t
mL of solvent in a sealed tube at 100 °C for 24 h. Condition C = 3.0 mmol of KO Bu only.
Figure 3: Substrate scope of dihydrophenanthridine synthesis.
To our delight, under optimized conditions B and C, the N-aryl-2-bromobenzylamines
(
9a-l) afforded various dihydrophenanthridines (10a-h) in moderate to good yields (up to
t
7
0% yield) as shown in figure 3. Interestingly, just the presence of KO Bu was sufficient to
affect this coupling (condition C; figure 3) in these cases as well. The strategy provides one
step total synthesis of 5,6-dihydrobicolorine (2d, figure 1) in 59-70% yield starting from 2-
halo-N-(3,4-methylenedioxyphenyl) benzylamines 9f and 9h. The reaction was applied to the
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substrates containing an electron-withdrawing group, such as 9k and 9l (figure 3). We found
that 9k afforded product 10h in 34% yield under condition B. However, condition C was
found not suitable, where 42% of starting material 9k was isolated along with decomposition
of the rest of the mass balance. Surprisingly, compound 9l simply leads to decomposition
under optimized conditions B and C (figure 3), indicating the process might be facilitated by
the presence of electron-donating groups.
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We then set forth to investigate the utility of organocatalytic biaryl-coupling by
applying it to the synthesis of natural products sharing benzo[c]phenanthridine structures. We
were especially interested to check the regioselective outcome of benzo[c]phenanthridines.
The substrate of the type 2-bromo-N-(α-naphthyl)benzylamine 11a (Table 2) is challenging
in the sense that it could lead to two possible regioisomeric products depending upon two
different C-H activation pathways. In one pathway, it could react at C-2 position to afford
more stable dihydrophenanthridine 12a or alternatively it could also react at the C-8 position
27
to afford naphthobenzazepine structures 12aa (Table 2). Thus, we thought substrates of the
type 11a would provide us an interesting platform to check the regioselectivity issues in the
homolytic aromatic substitutions (HAS). So, we performed our studies with N-(2-bromo-4,5-
t
dimethoxybenzyl) α-naphthyl-N-methylamine 11a in presence of 3 equiv of KO Bu and 40
2
6
mol% of bidentate ligands 4 (Table 2) in mesitylene at 110 ˚C in a sealed tube.
Optimization studies revealed that when the reactions were carried out in presence of
4
0 mol% of 4h (condition B) and 4j (condition D), the biaryl-coupling product
dihydrobenzo[c]phenanthridine 12a could be achieved in 75% and 72% yield (entries 13 and
1
5), respectively. The coupling can also be promoted in 66% yield only in the presence of
t
KO Bu (condition C) in benzene and without using any organic ligands (entry 23).
Noticeably, no naphthobenzazepine was formed under our optimized conditions. It was also
found that 40 mol% of DMEDA 4a (condition A) afforded 12a in just 22% of yields (entry
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). Thus, based on our studies, three sets of reaction conditions were chosen viz KO Bu in
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presence of 4h (condition B) and 4j (condition D) in mesitylene as well as KO Bu as sole
promoter in benzene (condition C) for further studies and the results so obtained are
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summarized in Figure 4.
Table 2. Optimization of 'transition metal-free' biaryl-couplings.
ꢀ
ꢀ
ꢀ
a
t
Reactions were carried out on a 0.50 mmol of 11a in presence of 0.20 mmol of organic ligands 4 and 1.5 mmol of KO Bu in
mL of solvent in a sealed tube at 100 °C-110 °C for specified time. Isolated yield after column chromatography.
b
3
c
d
e
f
g
Condition A. Condition B. Condition D. Starting material was isolated in 88-92%. Condition C.
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Under the optimized conditions B, C, and D, we then explored the substrate scope
using various N-2-bromo-N-(α-naphthyl)benzylamines 11b-e (Table 2). In all cases, the
biaryl-coupling was found to be quite general and proceeds without event to afford
dihydrobenzo[c]phenanthridines 12b-e in moderate to high yields (45-75% yields, see: Figure
10
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2
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4). Further, the X-ray crystal structure of 12a unambiguously proved the formation of
dihydrobenzo[c]phenanthridine structure (see, Supporting Information for ORTEP).
Figure 4: Substrates scope of dihydrobenzo[c]phenanthridine synthesis.
ꢀ
Next, we sought-after the synthetic viability of this protocol by applying it to the
synthesis of diversely substituted dihydrobenzo[c]phenanthridines. In order to materialize
this, we prepared α-tetralones 13c-d starting from aldehydes 13a-b via Wittig olefination,
hydrogenation followed by Friedel-Crafts acylations (Scheme 3). α-Tetralones 13c-d were
then converted into α-naphthylamines 14a-b in three step procedure (viz formation of oxime,
tosylation followed by detosylation/aromatization sequence). The latter were then converted
into 15a-b in two step sequence involving reaction with chloromethylformate followed by
4
reduction using LiAlH (Scheme 3). Few 2-bromo-N-(α-naphthyl)benzylamines 11f-i were
prepared from 15a-b following a simple N-benzylation (Scheme 3) and tested in
organocatalytic biaryl-coupling reaction.
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ꢀ
Scheme 3: Synthesis of 2-bromo-N-(α-naphthyl)amines 11f-i.
Interestingly, conditions B, C, and D afforded dihydrobenzo[c]phenanthridines 12f,
b, 3d, and 3f in 30-68% yields (Figure 5), thus accomplishing the total synthesis of alkaloids
3
dihydronitidine (3b), dihydrochelerythrine (3d), and dihydroavicine (3f).
ꢀ
Figure 5: Synthesis of dihydro-nitidine, avicine, and chelerythrine.
We then looked into the substrate scope of biaryl-coupling reactions with the
substrates having different protecting group on nitrogen such as N-acyl or N-tosyl-2-bromo-
N-(α-naphthyl)benzylamines. A series of N-protected-2-bromo-N-(α-naphthyl)benzylamines
3
17a-c and 18a-f were synthesized in two steps viz N-protection in the presence of Et N from
α-naphthylamines 14b-c followed by N-benzylations with 2-bromobenzyl bromides in the
presence of NaH (Scheme 4).
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ꢀ
Scheme 4. Synthesis of α-naphthyl-N-protected-benzylamines (18a-f).
In case of dihydropyrrolophenanthridone synthesis (Figure 2), we observed that the
yields were typically in the range of 45-55% because of the N-arylamide cleavage in the
t
presence of KO Bu at elevated temperature. This led us to think for sequential N-deprotection
followed by biaryl-coupling to afford 5,6-dihydrobenzo[c]phenanthridine having secondary
amine (Scheme 5). Interestingly, when 17a-c and 18a were reacted in the presence of 40
t
mol% of 4h in combination with 4 equivalent of
KO Bu (condition B),
benzo[c]phenanthridine 19a was achieved in 39%, 21%, 42%, and 46%, respectively, along
with 20-26% of debrominated compound 20a (Scheme 5). No traces of 5,6-
dihydrobenzo[c]phenanthridine 19aa was observed which indicated that the reaction might be
t
following a one-pot N-deprotection, organocatalytic biaryl-coupling in presence of KO Bu,
2
8
and concomitant oxidation. In fact, this result is interesting in the context of the synthesis of
benzo[c]phenanthridine alkaloids (Figure 1). The results of biaryl-coupling from substrates
1
7a-c and 18a led us to choose N-benzoyl substrates of the type 18a for further studies.
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ꢀ
Scheme 5. Optimization of one-pot N-deprotection, biaryl-coupling followed by oxidation sequence.
Under optimized conditions B, C, and D, N-benzoyl-2-bromo-N-(α-
naphthyl)benzylamine 18a afforded 19a in the range of 40-51% yields along with
debrominated secondary amine 20a in 16-27% yields (Figure 6). The one-pot methodology
was further applied to various N-benzoyl substrates 18b-f and found that the one-pot
deprotection, biaryl-coupling, and oxidation sequence is quite general and
benzo[c]phenanthridines 19b-c, 3h, and 3j were synthesized in up to 60% yields (Figure 6),
thus accomplishing one-pot total synthesis of nornitidine (3h) and norchelerythrine (3j)
starting from 18e and 18f, respectively. The X-ray structure of norchelerythrine 3j
unambiguously proved the formation of benzo[c]phenanthridine structure (see, Supporting
Information for ORTEP).
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ꢀ
Figure 6. One-pot debenzoylation, biaryl-coupling followed by oxidation sequence.
Further, in search for a straightforward approach to various phenanthridines such as
Amarylidaceae alkaloid trispheridine 2b and related structures, a variety of N-protected-2-
bromo-N-arylbenzylamines such as 22a-c, 23a-c, and 24a-c were synthesized via N-
benzylations of three different N-acylanilines 21a-c (Scheme 6).
ꢀ
Scheme 6. Synthesis of N-phenylbenzylamines (22a-c, 23a-c and 24a-c).
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Delightfully, our organocatalytic one-pot sequence was quite efficient to afford
phenanthridines 2a and 25 in high yields (up to 79%, see: figure 7) without observing the
debrominated products in most of the cases. We also achieved the total synthesis of
trispheridine 2b in up to 77% yields. The phenanthridine skeleton was further confirmed by
the X-ray crystal structure of trispheridine 2b (see, Supporting Information of ORTEP).
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Figure 7. One-pot deprotection, biaryl-coupling followed by oxidation.
To further check the regioselective outcome of the organocatalytic biaryl-coupling,
few N-acyl-2-bromo-N-(m-methoxyaryl)benzylamines such as 27a-b and 28a-b were
synthesized from 26a-b (Scheme 7). These compounds could provide a regioisomeric
mixture, where it could form a biaryl product either reacting at C-2 or C-6 position of m-
anisidine derivative (Scheme 8). We hypothesized that, the major product from the biaryl-
coupling would be possible at C-6 rather than C-2 in the HAS process, as position C-6 is
comparatively more electron-rich than C-2. In fact, our results also supported this hypothesis.
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ꢀ
ꢀ
Scheme 7. Synthesis of 2-bromo-N-(3-methoxyphenyl)benzylamines (27a-b, and 28a-b).
As shown in scheme 9, under the optimized conditions B and C, 27a-b and 28a-b
undergo an organocatalytic one-pot N-deprotection, biaryl-coupling followed by oxidation to
afford products 29a-b and 29c-d, where 29a and 29c were found to be the major products,
presumably arising from the coupling at the more electron-rich C-6 position of m-anisidine
derivatives.
ꢀ
Scheme 8: Regioselective one-pot deprotection, biaryl-coupling followed by oxidation.
In our hypothesis, we thought that the one-pot organocatalytic approach to
phenanthridines and benzo[c]phenanthridines undergoes a N-deprotection, biaryl-coupling
followed by oxidation events. If this is true, then secondaryamines 31a-b would also lead to
the phenanthridines 25 and trispheridine 2b. We were happy to find that, under optimized
conditions B and C, secondary amines 31a-b afforded only phenanthridines 25 and 2b in up
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to 68% yields and no biaryl-coupling products having secondary amines such as 25a-b were
isolated (Scheme 9). This might be due to the high stability of the phenanthridines with a
fully aromatic structure.
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Scheme 9: One-pot biaryl-coupling followed by oxidation.
2
6
Previously, we proposed a tentative mechanism based on mechanistic proposals by
t
Shirakawa-Hayashi, where after the initiation step in the presence of 32a (or KO Bu), an
1
7b
electron transfer (ET) takes place prior to proton transfer (PT). However, according to
1
7b
29
Studer and Curran hypothesis (which is well accepted by Shirakawa-Hayashi ), because
of powerful reducing nature of a radical anion as compared to radical, a direct electron
transfer (ET) from the intermediate radical anion is quite reasonable than the radical.
Therefore, a base promoted HAS must follow a proton transfer (PT) prior to the electron
transfer (ET).
In general, the mechanism of base promoted HAS follows a chain reaction mainly
involving three steps, viz the addition of aryl radical to arenes to form arylcyclohexadienyl
radical (step 1), which then gets deprotonated by a very strong base (potassium tert-butoxide)
to form a radical anion (step 2). The biaryl radical anion being highly conjugated, could act as
30
31
a powerful reducing agent and, thus, transfers an electron to the starting aromatic halide to
provide biaryl-coupling product, potassium halide, and the regeneration of aryl radical (step
t
3
). As shown in figure 8, an initial single electron transfer (SET) from 32a (or KO Bu) onto 5
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provides a radical anion intermediate 33a, which is the initiation step of biaryl-coupling
reaction. The radical anion 33a is then converted into aryl radical 33b, which could then
th
undergo propagation steps, to add intramolecularly at the 7 position of indoline derivatives,
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providing cyclohexadienyl radical 33c (step 1). At this point, a proton transfer (PT) from 33c
t
t
+
in the presence of 32a (or KO Bu) leads to the formation of radical anion 33d, BuOH and K
(step 2). The intermediate radical anion, 33d then transfers an electron to the starting aryl
halide 5 (step 3) to afford pyrrolophenanthridones 6 or 1, potassium halide and a new
arylradical 33b (via the intermediacy of 33a), which then continues the catalytic cycle
(Figure 8).
Figure 8: Revised mechanism of the sysnthesis of pyrrolophenanthridines.
t
On the other hand, a single electron transfer (SET) from 32a (or KO Bu) onto 7a-b
(Figure 9) provides a radical 34b through the intermediacy of radical anion 34a, which is the
initiation step of O-arylation. The latter then subsequently follows a O-arylation (8a-b,
scheme 2) with neighbouring carbonyl group to form radical 34c (step 1). At this point, a
t
proton transfer (PT) from 34c in presence of 32a (or KO Bu) leads to the formation of radical
t
+
anion 34d, BuOH and K (step 2). Finally, a radical anion transfer from 34d to the starting
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material 7a-b affords O-arylated product 8a-b and radical anion 34a (step 3), which then
continues the catalytic cycle (Figure 9).
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Figure 9: Revised mechanism of intramolecular O-arylation of 7a-b.
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A similar SET from 32a (or KO Bu) onto 11a-i (Figure 10) provides a radical 35b
through the intermediacy of radical anion 35a, which could then follow a propagation step
providing arene annulated cyclohexadienyl radical 35c (step 1). A similar proton transfer
t
(PT) from 35c in presence of 32a (or KO Bu) leads to the formation of radical anion 35d,
t
+
BuOH and K (step 2). Eventually, a radical anion transfer from 35d to the starting material
1a-i to afford dihydrobenzo[c]phenanthridines 12 or 3 and the radical anion 35a (step 3),
1
thus continuing the catalytic cycle (Figure 10). A similar mechanism could also operate in the
case of dihydrophenanthridines 10a-h and 2d (see: figure 3).
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ꢀ
Figure 10: Proposed mechanism of the synthesis of benzo[c]phenanthridines.
In case of N-benzoyl substrate 18a-f (Scheme 5 and figure 6), we believe that
t
cleavage of benzoyl group in the presence of KO Bu forms potassium amide, which
undergoes a biaryl-coupling to afford intermediate 36a (Figure 10). The latter upon
28
32
oxidation may form nitrogen centered radical 36b (Figure 10), which in turn could afford
final benzo[c]phenanthridines 19a-c, 3h and 3j after α-elimination reaction. Similar kind of
mechanism might also be operating in case of the synthesis of phenanthridines (Figure 7,
+
Schemes 8-9). The possible reason for a smooth one electron oxidation of 36a.K to afford
benzo[c]phenanthridine 19a (Scheme 5) might be the formation of highly stable aromatic
structure. In addition, the very high stabilty of benzo[c]phenanthridine could easily be
visualized from the crystal packing of natural product norchelerythrine 3j (see, Supporting
33
Information), clearly depicting the intermolecular H-bonding and π-π stacking.
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It is well accepted that single electron reduction of aryl halides enable them to the
aromatic nucleophilic substitution (SRN1) with various nucleophiles. In a similar fashion, base
promoted aromatic homolytic substitution (HAS) requires an initial SET from 32a (or
0
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0
t
KO Bu) onto halo arene of the type 11a providing a radical anion intermediate 35a under
elevated temperature, which is then converted into an aryl radical 35b (initiation step of
biaryl-coupling). Thus, it can be assumed that a small amount of reducing agent (such as Na
t
metal) could facilitate the first electron transfer step than 32a (or KO Bu) alone. In order to
provide additional experimental support, we carried out the intramolecular biaryl-coupling of
1
1a in the presence of Na-metal and the results are summarized in scheme 10.
ꢀ
a
t
Reactions were carried out on a 0.50 mmol of 11a in presence of 0.20 mmol of organic ligands 4h and 1.5 mmol of KO Bu
b
in 3 mL of solvent in a sealed tube at 100 °C-110 °C. Isolated yield after column chromatography.
Scheme 10: Biaryl-coupling in presence of Na-metal as a reducing agent.
t
In fact, when biaryl-coupling was done by KO Bu-40 mol% 4h in combination with
0
.5 equiv. of Na metal (entries 2 and 3), it afforded biaryl-coupling 12a in 57-62% yields
3
4
only in 8 h, thereby indicating a reducing agent facilitated the biaryl-coupling. However,
these reactions were also associated with debrominated product 37 in 15-19% yields (entries
2
and 3). Interestingly, when reactions were conducted only in the presence of 2.0 equiv. of
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Na-metal in combination with 40 mol% 4h, we obtained 12a in 45-58% along with
debrominated product 37 in 15-31% (entries 4 and 5). On the other hand, if these reactions
were carried out only in the presence of 2.0 equiv. of Na-metal under elevated temperature, it
provided 47-51% yields of debrominated product 37, in addition to the 36-41% of starting
material 11a due to incomplete reactions. These results shown in entries 2 and 3 clearly
depicted the biaryl-coupling would be facile in the presence of reducing agent which could
10
11
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60
3
4
undergo the first electron transfer step faster.
CONCLUSIONS
In summary, we have demonstrated an operationally simple, inexpensive and
t
environmentally friendly KO Bu mediated intramolecular homolytic aromatic substitution
(HAS) reaction with the aid of a catalytic amount of bidentate organic ligands. Interestingly,
t
the method also works just in the presence of KO Bu, without the use of organic molecule as
ligand. A mechanism has been proposed for the biaryl-coupling reaction where an aryl radical
intermediate seems to be involved in homolytic aromatic substitution (HAS). The
methodology provides a concise and straightforward total synthesis of Amaryllidaceae
alkaloids viz. oxoassoanine (1b), anhydrolycorinone (1d), 5,6-dihydrobicolorine (2d), and
dihydrobenzo[c]phenanthridines
alkaloids
such
as
dihydronitidine
(3b),
dihydrochelerythidine (3d), dihydroavicine (3f). Extending further, we have also shown a
short total synthesis of phenanthridine alkaloid such as trispheridine (2b),
benzo[c]phenanthridines viz. nornitidine (3h), and norchelerythrine (3j) following a one-pot
biaryl-coupling, deprotection followed by oxidation. Thus, it is reasonable to assume that the
rapid one-pot construction of molecular complexity using the straightforward biaryl-coupling
strategy will soon find more applications in complex natural product synthesis.
EXPERIMENTAL SECTION
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Material. Unless otherwise stated, reactions were performed in oven-dried glassware fitted
with rubber septa under a nitrogen atmosphere and were stirred with Teflon-coated magnetic
stirring bars. Liquid reagents and solvents were transferred via syringe using standard
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Schlenk techniques. Tetrahydrofuran (THF), diethyl ether (Et O) was distilled over
sodium/benzophenone ketyl. Dichloromethane (CH Cl ), toluene, and benzene were distilled
2
2
over calcium hydride. All other solvents such as DMF, mesitylene, 1,2-dimethoxyethane,
acetonitrile, chloroform, methanol, ethanol, and reagents were used as received. Thin layer
chromatography was performed using silicagel 60 F-254 precoated plates (0.25 mm) and
visualized by UV irradiation, anisaldehyde stain and other stains. Silicagel of particle size
1
13
1
4
00-200 mesh was used for flash chromatography. H and C NMR spectra were recorded
1
3
00, 500 MHz spectrometers with C operating frequencies of 100, 125 MHz, respectively.
) signal (δ =
.26 for H NMR and δ = 77.0 for C NMR). Data for H NMR spectra are reported as
Chemical shifts (δ) are reported in ppm relative to the residual solvent (CDCl
3
1
13
1
7
follows: chemical shift (multiplicity, coupling constants, number of hydrogen). Abbreviations
are as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad). IR
spectra were recorded on a FT-IR system (Spectrum BX) and are reported in frequency of
-
1
absorption (cm ). Only selected IR absorbencies are reported. High-Resolution Mass
Spectrometry (HRMS) and Low-Resolution Mass Spectrometry (LRMS) data were recorded
on MicrOTOF-Q-II mass spectrometer using methanol as solvent.
General Procedure for the synthesis of N-(2-bromobenzyl)-N-methylnaphthylamine
derivatives (11a-e): In an oven-dried sealed tube, N-methyl-α-naphthylamine (3.00 mmol;
1
.0 equiv) was taken in N, N-dimethylformamide (10 mL) under argon atmosphere. To this
reaction mixture was added K CO (4.50 mmol; 1.5 equiv) and 2-bromobenzylbromides
2
3
(3.30 mmol; 1.1 equiv) at room temperature. The reaction mixture was stirred for 10 h at 80
ºC. Upon completion of the reactions, (TLC showed complete consumption of starting
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material) the reaction mixture was quenched with ice-water (5 mL) and then diluted with 20
mL of EtOAc. The whole reaction mixture was taken in a separatory funnel and extracted
2 4
with 15 mL of water. The organic filtrate was dried over anhydrous Na SO and concentrated
10
11
12
13
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15
16
17
18
19
20
21
22
23
24
25
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37
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59
60
in a rotary evaporator under vacuum. The crude products were purified by flash
chromatography (10:1 hexanes/EtOAc) to afford 11a-e.
N-(2-Bromo-4,5-dimethoxybenzyl)-N-methylnaphthalen-1-amine (11a): The product was
1
obtained as yellow gel (950 mg, 82%), R
f
= 0.27 (5% EtOAc in hexane). H NMR (400 MHz,
CDCl
3
) δ: 8.28-8.26 (m, 1H), 7.85-7.83 (m, 1H), 7.55 (d, J = 8.2 Hz, 1H), 7.89-7.45 (m, 2H),
7
3
1
5
1
.39 (t, J = 7.7 Hz, 1H), 7.14 (d, J = 7.4 Hz, 1H), 7.11 (s, 1H), 7.02 (s, 1H), 4.35 (s, 2H),
1
3
3
.86 (s, 3H), 3.71 (s, 3H), 2.88 (s, 3H); C NMR (100 MHz, CDCl ) δ 149.6, 148.4, 148.39,
34.9, 129.7, 129.2, 128.5, 125.8, 125.7, 125.5, 123.5, 123.4, 115.9, 115.4, 113.6, 112.3,
9.9, 56.1, 55.9, 42.3; IR (film) υmax 2998, 2935, 2845, 1577, 1507, 1459, 1439, 1396, 1380,
-
1
+
260, 1208, 1159, 1032, 961, 928, 799, 775 cm ; LRMS (ESI) m/z 386.0792 [M + H] ;
+
calculated for [C20
H20BrNO
2
+ H] : 386.0750.
N-(2-Bromo-5-methoxybenzyl)-N-methylnaphthalen-1-amine (11b): The product was
1
obtained as yellow color gel (823 mg, 77%), R
MHz, CDCl
.30 (m, 4H), 7.25 (d, J = 2.7 Hz, 1H), 7.09 (d, J = 7.4 Hz, 1H), 6.30 (dd, J = 8.7, 3.0 Hz,
f
= 0.61 (5% EtOAc in hexane). H NMR (400
3
) δ: 8.15 (d, J = 8.3 Hz, 1H), 7.76-7.74 (m, 1H), 7.47 (d, J = 8.2 Hz, 1H), 7.37-
7
1
3
1H), 4.25 (s, 2H), 3.65 (s, 3H), 2.80 (s, 3H); C NMR (100 MHz, CDCl
3
) δ: 159.2, 149.8,
38.9, 134.9, 133.2, 129.1, 128.4, 125.8, 125.7, 125.5, 123.6, 123.4, 115.5, 114.9, 114.3,
14.1, 60.9, 55.4, 42.2; IR (film) υmax 3046, 2937, 2835, 1594, 1576, 1509, 1471, 1437,
1
1
1
-
1
397, 1292, 1272, 1238, 1160, 1121, 1045, 1016, 800, 775 cm ; HRMS (ESI) m/z 356.0648
+
+
[
M + H] ; calculated for [C19H18BrNO + H] : 356.0645.
N-(2-Bromo-3,5-dimethoxybenzyl)-N-methylnaphthalen-1-amine (11c): The product was
1
obtained as yellow gel (996 mg, 86%), R
f
= 0.4 (10% EtOAc in hexane). H NMR (400 MHz,
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CDCl
3
) δ: 8.23 (d, J = 8.0 Hz, 1H), 7.84-7.82 (m, 1H), 7.54 (d, J = 8.1 Hz, 1H), 7.47-7.38
(m, 3H), 7.17 (d, J = 7.5 Hz, 1H), 7.00 (d, J = 2.1 Hz, 1H), 6.44 (d, J = 2.4 Hz, 1H), 4.38 (s,
1
3
2
1
H), 3.88 (s, 3H), 3.73 (s, 3H), 2.90 (s, 3H); C NMR (100 MHz, CDCl
3
) δ: 159.0, 156.7,
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8
9
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2
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49.9, 140.0, 134.9, 129.1, 128.5, 125.8, 125.7, 125.4, 123.6, 123.3, 115.4, 105.5, 103.9,
98.4, 61.2, 56.3, 55.5, 42.2; IR (film) υmax 2958, 2922, 2848, 1621, 1520, 1463, 1404, 1384,
-
1
1
3
253, 1202, 1169, 1141, 1086, 1048, 1027, 812, 790, 771, 755 cm ; HRMS (ESI) m/z
+
+
2
86.0746 [M + H] ; calculated for [C20H20BrNO + H] : 386.0750.
N-(6-Bromo-2,3-dimethoxybenzyl)-N-methylnaphthalen-1-amine (11d): The product was
1
obtained as colorless gel (938 mg, 81%), R
MHz, CDCl
f
= 0.53 (10% EtOAc in hexane). H NMR (400
3
) δ: 8.41-8.38 (m, 1H), 7.82-7.80 (m, 1H), 7.56 (d, J = 8.2 Hz, 1H), 7.45-7.43
m, 3H), 7.30-7.27 (m, 2H), 6.75 (d, J = 8.8 Hz, 1H), 4.47 (s, 2H), 3.85 (s, 3H), 3.83 (s, 3H),
(
13
2
1
3
.79 (s, 3H); C NMR (100 MHz, CDCl ) δ: 152.2, 151.1, 149.4, 134.8, 131.9, 129.7, 128.1,
28.07, 125.9, 125.7, 125.0, 124.7, 123.3, 117.1, 116.3, 112.7, 61.4, 55.9, 53.7, 43.1; IR
-
(film) υmax 2934, 2853, 1731, 1575, 1471, 1396, 1292, 1271, 1232, 1079, 1024, 801, 776 cm
1
+
+
;
2
HRMS (ESI) m/z 386.0770 [M + H] ; calculated for [C20H20BrNO + H] : 386.0750.
N-((6-Bromobenzo[d][1,3]dioxol-5-yl)methyl)-N-methylnaphthalen-1-amine (11e): The
1
product was obtained as colorless solid (944 mg, 85%), R
f
= 0.58 (5% EtOAc in hexane). H
NMR (400 MHz, CDCl
3
) δ: 8.23-8.22 (m, 1H), 7.85-7.83 (m, 1H), 7.56 (d, J = 8.2 Hz, 1H),
7.48-7.45 (m, 2H), 7.41 (t, J = 8.0 Hz, 1H), 7.25 (s, 1H), 7.17 (d, J = 7.5 Hz, 1H), 7.03 (s,
13
1
1
1
1
3
H), 5.98 (s, 2H), 4.28 (s, 2H), 2.85 (s, 3H); C NMR (100 MHz, CDCl ) δ: 149.8, 147.6,
47.2, 134.9, 131.2, 129.1, 128.4, 125.8, 125.7, 125.4, 123.6, 123.4, 115.5, 113.9, 112.7,
09.4, 101.6, 60.5, 42.2; IR (film) υmax 3049, 2892, 2852, 1594, 1576, 1503, 1477, 1397,
-1
369, 1240, 1106, 1074, 1039, 963, 935, 867, 832, 774 cm ; HRMS (ESI) m/z 370.0464 [M
+
+
2
+ H] ; calculated for [C19H16BrNO + H] : 370.0437, MP 105−107 ºC.
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General procedure for organocatalytic biaryl-coupling: In an oven-dried Schlenk flask,
N-bromobenzyl-N-methylnaphthylamines (0.50 mmol; 1.0 equiv.) and DMEDA (0.20 mmol;
4
2
0 mol %) [Condition A] or 1, 10-phenanthroline (0.20 mmol; 40 mol %) [Condition B] or
, 2'-bipyridine (0.20 mmol; 40 mol %) [Condition D] were taken in mesitylene (5 mL)
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under argon atmosphere. Potassium tert-Butoxide (1.5 mmol; 3.0 equiv) or in some cases (2.0
mmol; 4.0 equiv) was added to the reaction mixture and the Schlenk flask was closed and
heated at 100-110 ºC for indicated time. Then the reaction mixture was allowed to cool at
room temperature then filtered through celite and washed with dichloromethane (2 x 5 mL).
The combined organic layers were concentrated in a rotary evaporator under vacuum. The
crude products were purified by flash chromatography (2:1 hexanes/EtOAc) to afford biaryl-
coupling products (2, 3, 12, 19 and 25). [Condition C]: In absence of any organic ligands and
dry benzene as a solvent.
8
,9-Dimethoxy-5-methyl-5,6-dihydrobenzo[c]phenanthridine (12a): The product was
f
obtained as yellow crystalline solid [115 mg, 75% (condition B)], R = 0.17 (10% EtOAc in
1
hexane). H NMR (400 MHz, CDCl
3
) δ: 8.35 (d, J = 8.4 Hz, 1H), 7.87-7.83 (m, 2H), 7.68 (d,
J = 8.6 Hz, 1H), 7.56-7.52 (m, 1H), 7.48-7.45 (m, 1H), 7.36 (s, 1H), 6.83 (s, 1H), 4.20 (s,
1
3
2
1
H), 4.02 (s, 3H), 3.97 (s, 3H), 2.70 (s, 3H); C NMR (100 MHz, CDCl
3
) δ: 149.1, 148.6,
43.2, 133.8 129.4, 128.2, 126.1, 125.7, 125.3, 124.9, 124.6, 124.6, 123.9, 121.5, 110.2,
106.6, 56.2, 56.1, 54.7, 41.4; IR (film) υmax 3055, 2937, 2835, 1607, 1520, 1503, 1367, 1353,
-1
1
3
8
328, 1284, 1253, 1246, 1212, 1152, 1142, 1042, 1021, 815, 764 cm ; HRMS (ESI) m/z
+
+
2
06.1495 [M + H] ; calculated for [C20H19NO + H] : 306.1489; MP 143−145 ºC.
-Methoxy-5-methyl-5,6-dihydrobenzo[c]phenanthridine (12b): The product was obtained
1
as yellow gel [80 mg, 58% (condition B)], R
MHz, CDCl
.75 (d, J = 8.6 Hz, 1H), 7.67 (d, J = 8.6 Hz, 1H), 7.55-7.52 (m, 1H), 7.47-7.44 (m, 1H), 6.95
f
= 0.30 (5% EtOAc in hexane). H NMR (400
3
) δ: 8.34 (d, J = 8.4 Hz, 1H), 7.87 (d, J = 8.6 Hz, 1H), 7.83 (d, J = 8.1 Hz, 1H),
7
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