A new entry to the phenanthridine ring system

Article abstract of DOI:10.1016/j.tetlet.2011.12.095

A new synthesis of phenanthridine derivatives having three-point diversity has been developed based on the sequential application of three-atom economic processes viz. aza-Claisen rearrangement, ring-closing enyne metathesis and Diels-Alder reaction as key steps. An unexpected isomerisation was observed during aza-Claisen rearrangement of N-allylanilines which may open up new opportunities in heterocyclic synthesis.

Full text of DOI:10.1016/j.tetlet.2011.12.095

Tetrahedron Letters 53 (2012) 1328–1331
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A new entry to the phenanthridine ring system
⇑
Poulomi Mondal, Latibuddin Thander, Shital K. Chattopadhyay
Department of Chemistry, University of Kalyani, Kalyani 741235, West Bengal, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A new synthesis of phenanthridine derivatives having three-point diversity has been developed based on
the sequential application of three-atom economic processes viz. aza-Claisen rearrangement, ring-closing
enyne metathesis and Diels–Alder reaction as key steps. An unexpected isomerisation was observed dur-
ing aza-Claisen rearrangement of N-allylanilines which may open up new opportunities in heterocyclic
synthesis.
Received 19 October 2011
Revised 20 December 2011
Accepted 22 December 2011
Available online 12 January 2012
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
aza-Claisen rearrangement
Catalysis
Ring-closing enyne metathesis
Diels–Alder reaction
Isomerisation
Phenanthridine
Heterocycle
Phenanthridines represent important core structures of a variety
of both naturally occurring (1–3, Fig. 1) and synthetic molecules
having biological activities ranging from antibacterial, antiproto-
zoal activities to antitumor property through DNA intercalation.1
They are also currently receiving attention in material science
applications.2 Therefore, reports in the development of a new syn-
thetic route to such ring systems continue to appear.3 Although
diverse and elegant approaches have been reported, the need for
a simple but efficient protocol from easily available starting mate-
rials with selective control in the substitution pattern does exist.
Herein, we report a new synthesis of the phenanthridine ring
system using sequential applications of three-atom economic pro-
cesses viz. aza-Claisen rearrangement, ring-closing enyne metathe-
sis reaction (RCEYM) and Diels–Alder reaction.4
Our retro-synthetic analysis of the phenanthridine ring system
4 relied on the construction of the ring C through a Diels–Alder
reaction-aromatisation sequence of an appropriate 3-vinylquino-
line derivative 5, which was thought to be obtainable from ring-
closing enyne metathesis (RCEYM) reaction of the N-tethered eny-
ne 6. Further functional group manipulation sequence brought to
us the 2-vinyl aniline derivative 7 as an appropriate precursor
which we sought to prepare from isomerisation of the easily
obtainable 2-allylaniline derivative 8 (Scheme 1).
resulting 10a–f under conventional conditions (Scheme 2). The 4-
nitro-N-allylaniline 11g was however prepared by direct allylation
of 4-nitroaniline. The thermal aza-Claisen rearrangement of N-ally-
lanilines usually require drastic conditions.5,6 On the other hand,
Lewis or protic acid mediated aza-Claisen rearrangement of N-ally-
lanilines is known to proceed with significant rate enhancements
under either thermal7 or microwave conditions.8 However, the
reaction is more general and more predictable with N-alkyl-N-ally-
lanilines. During the rearrangement of simple N-allylanilines with-
out additional substituent on the nitrogen atom or in the N-allyl
moiety, cyclisation leading to undesired indoline derivatives has
also been reported.9 After some experimentation, we have found
that the aza-Claisen rearrangement of the unsubstituted N-allylan-
iline 11a proceeded better in refluxing chlorobenzene in the pres-
ence of BF3ÁOEt2 (1.5 equiv) within a reasonable short period of
time (6 h) to provide the rearranged aniline 13a in good yield
(71%). Attempted optimisation of the reaction using high boiling
O
O
O
NH2
O
Thus, we prepared the N-allylanilines 11a–f from straightfor-
ward N-allylation of the corresponding Boc-protected anilines
9a–f followed by acid mediated removal of the Boc-group in the
N
H2N
N
N
Me
Et
1: Trispheridine
2: Bicolorine
3
: Ethidium
⇑
Corresponding author. Fax: +91 33 25828282.
E-mail address: skchatto@yahoo.com (S.K. Chattopadhyay).
Figure 1. Some phenanthridine derivatives of importance.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.12.095

P. Mondal et al. / Tetrahedron Letters 53 (2012) 1328–1331
1329
R
R
R
R
R1
C
R1
R1
RCEYM
Diels-Alder
aromatise
B
N
A
N
N
Ts
Ts
4
5
6
R1
R1
FGI
Isomerise
NH2
NH2
8
7
Scheme 1. Retrosynthetic analysis of the phenanthridine ring system.
Boc
N
H
N
NHBoc
6N, HCl
rt, 15 h
NaH, allyl bromide
THF, 0 °C to rt,
15 h
R
R
R
9a-f
11 a-f
(81-93%)
10 a-f (77-96%)
H
N
NH2
allyl bromide, Et3N
O2N
MeCN, reflux, 24 h
78%
O2N
11 g
12
NH2
NH2
BF3-OEt2 (1.5 equiv)
PhCl, reflux, 6 h
BF3-OEt2 (5-10 equiv)
PhCl, reflux, 24 h
11
a-g
R
R
14 a-g (59-80%)
13 a-g (71-85%)
BF3-OEt2 (5 equiv)
PhCl, reflux,12-24 h
Scheme 2. Preparation of the starting materials 14a–g.
solvent and prolonged reaction time, either singly or in combina-
tion, met with limited success. However, during one such optimi-
sation study we noticed that the use of five equivalents of
BF3ÁOEt2 and longer reaction time (24 h) led to the formation of
the rearranged and isomerised product 14a as E-isomer. The con-
current isomerisation, although unexpected and unplanned at this
stage, was a fortunate outcome since this was projected in the ret-
ro-synthetic analysis as a subsequent step. To test the generality of
the process, we subjected N-allylanilines 11b–g to a similar course
of reaction and found that all of these undergo facile rearrange-
ment and isomerisation to provide either the rearranged anilines
13b–g (71–85%) or the rearranged and isomerised anilines 14b–g
(69–80%) depending on the amount of Lewis acid and reaction
time. Moreover, the rearranged 2-allylanilines 13a–g could also
be converted to the isomerised products 14a–g separately, if de-
sired, indicating that perhaps these are intermediates in the direct
conversion of 11a–g to 14a–g.
propargyl bromide under conventional conditions to obtain the
enyne derivatives 16a–f in good overall yield. Ring-closing enyne
metathesis reaction (RCEYM)10 of olefins other than terminal ole-
fins has been studied less compared to that of the terminal ole-
fins.10 In a few instances studied, interesting mechanistic and
stereochemical observations have been made.11 However, hetero-
atom tethered enynes have been reported to show poor stereose-
lectivity.12 Pleasingly, we observed that RCEYM of the compounds
16a–f proceeded well in the presence of Grubbs’ 2nd generation
catalyst 17 to provide each of the dienes 18a–f as a single diaste-
reomer in good yield. Mechanistically, the reaction may follow
(Fig. 2) either of the ‘ene-then-yne’ or ‘yne-then-ene’ pathways12
(Fig. 2). The ruthenium carbene complex may coordinate with
the alkyne of the substrate i (path A), to produce the intermediate
carbene complex ii which subsequently would cyclise to the prod-
uct v where the product would be expected to exhibit stereoselec-
tivity similar to that of the cross enyne metathesis reaction. On the
other hand, the ruthenium carbene complex III produced during
the reaction at the ‘ene’-site would cyclise to IV and then may react
with the olefin part of another substrate molecule leading to the
1,3-diene product V (path B).
Having access to the required 2-vinylaniline derivatives 14a–g,
we focused on their conversion to the phenanthridine derivatives
along the projected pathway. Thus, the corresponding N-tosyl
derivatives 15a–f (Scheme 3) were prepared and N-alkylated with

1330
P. Mondal et al. / Tetrahedron Letters 53 (2012) 1328–1331
R
R
R
i
ii
iii
14 a-f
NHTs
N
Ts
N
Ts
15 a-f
16 a-f
18 a-f
CO2R1
CO2R1
R1O2C
R1O2C
Mes N N Mes
v
iv
R
R
Cl
Ru
PCy3
Cl
N
N
Ts
17
19 a-f
20 a-f
Scheme 3. Preparation of the phenanthridine derivatives 20a–f. Reagents and conditions: (i) p-TsCl, pyridine, rt, 1–2 h, 70–90%; (ii) propargyl bromide, K2CO3, acetone,
reflux, 6 h, 74–94%; (iii) catalyst 17 (5 mol %), toluene, 90 °C, 24–48 h, 66–87%; (iv) dimethyl acetylenedicarboxylate (or diethyl acetylenedicarboxylate), toluene, reflux, 48 h,
66–81%; (v) DBU (2 equiv), toluene, reflux, 24 h, 66–90%.
Ru
A
N
N
N
Ts
Ts
Ts
II
V
Ru
I
B
Me
Ru
Ru
N
Ts
III
N
N
Ts
Ts
IV
V
Figure 2. Representation of possible catalytic pathways: ‘yne-then-ene’ pathway (A) and ‘ene-then-yne’ pathway (B).
We next studied the Diels–Alder reaction of the dienes 18a–f.
in the aza-Claisen rearrangement may also prove to be useful in
Separate treatment of each of these dienes with diethyl acetylene-
dicarboxylate or dimethyl acetylene dicarboxylate proceeded slug-
gishly in refluxing toluene to provide the cycloadducts in moderate
to good yields. These were mostly obtained as single diastereomers
but the compounds proved to be slightly contaminated with par-
tially oxidised product/s formed during chromatographic purifica-
tion. Compounds 19c and 19d proved to be exceptions and these
could be obtained as pure and single diastereomers. Base-mediated
elimination13 of the tosyl group from the adducts 19a–f proceeded
with concomitant aromatisation to deliver the desired phenanthri-
dine derivatives 20a–f in an overall yield of 16–25% over six steps
from the starting N-allylanilines 11a–g.14
In brief, we have developed aza-Clasien rearrangement of N-
allylanilines in two different modes depending on the use of
amount of Lewis acid and reaction time. The observed isomerisa-
tion15 has been utilised to develop a simple protocol for the syn-
thesis of phenanthridine derivatives having diversity in rings A
and C, a pattern which is usually found in most of the known bio-
logically active phenathridine derivatives. The procedure involves
use of readily available precursors and operationally easy reactions
which are highly atom economic. These attributes may aid to gen-
erate other phenanthridine derivatives of biological interest. The
methodology may therefore complement the existing methodolo-
gies for the preparation of such compounds. The diversity observed
the synthesis of other heterocyclic systems of interest.
Acknowledgements
We are thankful to DST, Govt. of India (Grant No. SR/S1/OC-35/
2009) for financial support and CSIR, New Delhi. P.M. is thankful to
University of Kalyani, and L.T. is thankful to CSIR, New Delhi for
fellowships.
Supplementary data
Supplementary data (list of compounds along with their yield,
melting points, and copies of 1H NMR and 13C NMR spectra are in-
cluded) associated with this article can be found, in the online ver-
sion, at doi:10.1016/j.tetlet.2011.12.095.
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