Synthesis of heteroarenes via radical cyclisation onto nitriles

Article abstract of DOI:10.1055/s-2001-14592

A new protocol for the synthesis of tetracyclic nitrogen heteroarenes using cascade radical cyclisation has been developed. The key steps involve 5-exo vinyl radical cyclisation onto nitriles to yield intermediate iminyl radicals which cyclise onto an arene rings. Rings A-D of the anticancer alkaloids camptothecin, mappicine and nothapodytines A and B have been synthesised using this protocol.

Full text of DOI:10.1055/s-2001-14592

LETTER
765
Synthesis of Heteroarenes via Radical Cyclisation onto Nitriles
W. Russell Bowman,* Colin F. Bridge, Martin O. Cloonan, David C. Leach
Department of Chemistry, Loughborough University, Loughborough, Leicestershire LE11 3TU, UK
Fax +44-1509 223 925; E-mail: w.r.bowman@lboro.ac.uk
Received 22 March 2001
radicals to the arene rings and the driving force to aroma-
tisation are important in facilitating these reactions. We
now report our studies of the development of a new proto-
col for the synthesis of tetracyclic heteroarenes using
Abstract: A new protocol for the synthesis of tetracyclic nitrogen
heteroarenes using cascade radical cyclisation has been developed.
The key steps involve 5-exo vinyl radical cyclisation onto nitriles to
yield intermediate iminyl radicals which cyclise onto an arene rings.
Rings A-D of the anticancer alkaloids camptothecin, mappicine and [4+2] radical annulation via cyclisation of intermediate
nothapodytines A and B have been synthesised using this protocol.
iminyl radicals, generated by vinyl radical cyclisation
onto nitriles, onto arenes. The synthesis of rings A-D of
the alkaloids camptothecin 1, mappicine 2, nothapodytine
B 3 (mappicine ketone) and nothapodytine A 4 has been
achieved in good yield using this protocol. The retrosyn-
thetic analysis is shown in Scheme 1.
Key words: radical cyclisation, nitriles, tandem reactions, vinyl
radicals, camptothecin
The application of radical cyclisation to the synthesis of
heterocycles has become commonly used and important.1
In contrast, the radical synthesis of heteroarenes has been
surprisingly little studied.1 Some exceptions include the
synthesis of indoles,2 pyridines,3,4 quinoxalines5 and
camptothecin and analogues.6,7 The studies on the radical
synthesis of camptothecin by Curran and co-workers have
demonstrated the potential for the use of cascade radical
cyclisations in the synthesis of heteroarenes.6 Cascade
radical cyclisations have also been applied to the synthesis
of other complex polycyclic natural products.8 Radical
cascade reactions facilitate ‘one-pot’ reactions which cut
out purification at each step thereby facilitating higher
overall yields and less waste.
R1
O
O
N
N
N
N
Me
R2
R3
O
Et
HO
Et
O
mappicine 2, R1 = R3 = H, R2 = OH
nothapodytine B 3, R1 = H, R2 R3 = O
nothadpoytine A 4, R1 = OMe, R2 R3 = O
camptothecin 1
R
R
O
Most radical cyclisations have involved the formation of
C-C bonds. Our studies have also shown the utility of
N-centred radicals in synthesis for the generation of C-N
bonds. For instance, aminyl radicals, either generated
from sulfenamides9 or by cyclisation of C-centred radicals
onto imines, have proved useful in tandem cyclisations.10
Recently, we have extended our studies to iminyl radicals,
generated by cyclisation of C-centred radicals onto ni-
triles, which can undergo tandem cyclisations onto suit-
ably placed alkenes.11 Radical cyclisation onto nitriles has
proved enigmatic with as many failures as successes.12
One of the reasons for the enigmatic behaviour is the slow
rate of cyclisation, e.g. the rate of cyclisation of 4-cy-
anobutyl radicals [•CH2(CH2)3CN] is only 4 103 s-1 at 25
°C.13 The problem of these slow rates can be overcome by
choice of starting materials or altering the reaction condi-
tions to avoid faster competing reactions. Cyclisations of
iminyl radicals have been successfully exploited by
Zard14 and the rate of 5-exo cyclisation onto alkenes is one
order of magnitude slower than for C-centred radicals.15
O
N
N
X
N
NC
5a, R = H
5b, R = OMe
6a, R = H, X = Br; 6b, R = H, X = I
6c, R = OMe, X = I
O
R
HN
Br
X
NC
7a, R = H, X = Br
7b, R = H, X = I
7c, R = OMe, X = I
8
Scheme 1
Camptothecin 1 and the related alkaloids, mappicine 2,
nothapodytine B 3 and nothapodytine A 4, are potent an-
ticancer and antiviral alkaloids in current medicinal use
and have been popular targets of synthesis and a wide va-
riety of methods have been used.16 Recent syntheses have
used hetero Diels-Alder reactions17 and a biomimetic syn-
thesis.18 Two radical protocols have been reported. Curran
and co-workers have synthesised camptothecin and
analogues6a-f and mappicine6f via bimolecular radical
A few reports in the literature indicated that 6-endo cycli-
sation of iminyl radicals onto arenes (or 5-exo cyclisation
followed by a neophyl rearrangement) is possible, thereby
forming new pyridine rings by [4+2] radical annula-
tion.4,5,6c,6d The proximity and orientation of the iminyl
Synlett 2001 No. 6, 765–768 ISSN 0936-5214 © Thieme Stuttgart · New York

766
W. R. Bowman et al.
LETTER
additions of radicals derived from 6-iodo-1H-pyridin-2- tion times used up the starting material but did not in-
one onto aryl-isonitriles. A synthesis using radical cycli- crease the yield of 5a. The bromovinyl precursor 6b was
sation of 2-quinolinyl radicals onto pyridones has also reacted under the same conditions as the iodo analogue
been recently reported.7
and yielded only 20% of the tetracycle 5a with a large
amount of unaltered starting material (80%). The differ-
ence in yield between the bromo- and iodo-precursors is
obviously related to the difference in bond strengths. The
cascade radical cyclisation using the methoxy precursor
6c was also carried out to synthesise the A-D ring skeleton
(1-methoxy-11H-indolizino[1,2-b]quinolin-9-one 5b) of
the alkaloid nothapodytine A 4. The same reaction condi-
tions were used and only one isomer 5b was obtained in
45% yield (un-optimised) (Scheme 4).
The synthesis of the precursors is shown in Schemes 2 and
3. The cinnamaldehydes 9a and 9b were converted to the
corresponding -halogenocinnamyl bromides 7a-c in
high yield by standard procedures (Scheme 2). 2,6-Dibro-
mopyridine was converted to 6-oxo-1,6-dihydropyridine-
2-carbonitrile 8 (Scheme 3). The conversion of 2-cyano-
6-methoxypyridine to the cyanopyridone 8 was carried
out using a literature procedure.6a The cyanopyridone 8
was alkylated with the -halogenocinnamyl bromides 7a-
c using a literature procedure which favours N-regioselec-
tivity.6a,19 The radical precursors 6a-c were obtained in
good yield [6a (71%), 6b (63%), 6c (45%, non-opti-
mised)]. A small amount of product resulting from
O-alkylation was observed in each alkylation reaction.
The Z-stereochemistry of each radical precursor was de-
termined by nOe difference spectroscopy. However, the
stereochemistry of the precursors is not important because
vinyl radicals interconvert rapidly between E- and Z-ste-
reochemistry.
heat
(Me3Sn)2
2
Me3Sn•
hυ
R
O
5-exo
Me3Sn•
N
6a, R = H, X = Br
6b, R = H, X = I
6c, R = OMe, X = I
•
N
11
R
R
O
O
5-exo
N
N
•
N
N
•
R
R
13a, R = H
12
CHO
CHO
X = Br (Br2, Et3N, CH2Cl2)
X = I (ICl, pyr, CH2Cl2)
13b, R = OMe
X
6-endo
N
neophyl
3-exo
rearrangement
9a, R = H
9b, R = OMe
10a, R = H, X = Br (90%)
10b, R = H, X = I (80%)
10c, R = OMe, X = I (95%)
R
R
•
O
O
i. NaBH4, CeCl3
N
7a, i. 100%, ii. 100%
7b, i. 100%, ii. 80%
7c, i. 85%, ii. 80%
•
N
N
H
ii. CBr4, PPh3, MeCN
H
14
15a, R = H
15b, R = OMe
(– H•)
Scheme 2
5a, R = H
5b, R = OMe
NaOMe, N2
CuCN, DMF
Scheme 4
MeOH, reflux
73%
reflux, 48 h, N2
OMe
Br
N
Br
Br
N
62%
The full mechanism of the cascade reaction is not clear.
Hexamethylditin cleaves under the influence of heat and/
or light to yield trimethyltin radicals which abstract the io-
dine atom from the vinyl iodide of 6b to yield the interme-
diate vinyl radical 11. The reactive vinyl radical
undergoes 5-exo-cyclisation onto the nitrile. In the ab-
sence of potential competing reactions the attack on the
nitrile is favoured. The resulting iminyl radical intermedi-
ate 12 undergoes cyclisation onto the aryl ring by either a
6-endo or 5-exo cyclisation followed by a neophyl rear-
rangement to yield the stable aromatic -radical 14. This
-radical is shown in Scheme 4 as a localised radical but
is stabilised by delocalisation over the whole ring system,
i.e. the quinoline and pyridone rings. In normal iodine
atom abstraction reactions the final radical abstracts io-
dine from the starting material and hexamethylditin is
only required in sub-equivalent amounts. Abstraction of
6a (71% from 7a)
6b (63% from 7b)
6c (45% from 7c)
TMSCl, NaI
MeCN, 82%
OMe
7a-c
8
NaH, LiCl
DME/DMF
NC
N
Scheme 3
The cascade radical cyclisations using the radical precur-
sors 6a-c were carried out under a range of conditions us-
ing hexamethylditin to generate the intermediate radicals
(Scheme 4). The radical reaction using the iodo radical
precursor 6b gave the best yield of the tetracycle 11H-in-
dolizino[1,2-b]quinolin-9-one 5a. Optimised conditions
[hexamethylditin (7.9 equiv), t-butylbenzene, 155 °C, 48
h, sunlamp irradiation, under nitrogen] gave 73% of 5a
with some unaltered starting material 6b (15%).20 Large
amounts of organotin polymers were also observed but
they did not interfere with the purification. Longer reac-
Synlett 2001, No. 6, 765–768 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Synthesis of Heteroarenes via Radical Cyclisation onto Nitriles
767
iodine from the starting material by this stable -radical is (7.9 equiv), 120 °C, 48 h]. The use of di-t-butyl peroxide
extremely energetically unfavourable and hence can be without hexamethylditin led to extensive decomposition.
ruled out. Homolytic cleavage of the vinyl-iodine bond is The use of di-t-butyl peroxide with hexamethylditin al-
unlikely to initiate the radical reaction. A blank reaction lowed for milder conditions and/or higher yields.
with 6b without the addition of hexamethylditin gave re-
covered starting material (99%) with only traces of the tet-
racycle 5a. The blank reaction also rules out a possible
heat
(Me3C–O)2
2 Me3C–O •
Diels Alder mechanism followed by elimination of HI as
a major pathway.
(Me3Sn)2 + Me3C–O •
Me3Sn • + Me3C–O–SnMe3
The mechanism of the oxidative step (14 to 5a) is unclear.
The most likely route is abstraction of the 4a-hydrogen
but the identity of the H-abstractor is unknown. There is a
strong driving force towards aromatisation of 14 to yield
the product 5a. Disproportionation can be ruled out be-
cause no dihydro products were obtained and the yields
for 5b were higher than 50%. Traces of oxygen will rap-
idly react with trimethyltin radicals to yield peroxy radi-
cals (Me3SnOO•) which are good H-abstractors. We
believe that this possibility can be ruled out because traces
of oxygen in these reactions lead to another product and
also the reactions were carefully deoxygenated using
freeze-thaw techniques. Methyl radicals, generated by
breakdown of the trimethyltin radicals to methyl radicals
and dimethylstanylene 16 in the formation of the organo-
tin polymer 17, are obvious H-abstractors (Scheme 5).22
This oxidative cyclisation mechanism mediated by hex-
amethylditin,6a-f or by tributyltin hydride,23 has been dis-
cussed in the literature.
O
very fast
N
6a, 6b
5a
– Me3COH
N
H
14
•O CMe3
Scheme 6
We also investigated the use of acetone as a triplet sensi-
tiser to facilitate splitting of the Sn-Sn bond in triplet
hexamethylditin21 in order to improve yields and to cut
down on the formation of organotin polymers. This proto-
col gave 5a in 19% yield with unaltered 6a (40%) [ace-
tone, (Me3Sn)2 (10 equiv), 350 nm UV irradiation, 4
days]. Yields could not be improved.
The intermediacy of the spirodienyl radicals 13a and 13b
is likely but not proven and is important if substituted are-
nes are to be used in the protocol. The synthesis of the tet-
racycle 5b, rings A-D of nothapodytine A, gave only one
isomer suggesting 6-endo rather than 5-exo cyclisation,
followed by a neophyl rearrangement. However, the se-
lectivity towards isomer 5b could be explained by inter-
mediate radical stability, i.e. 3-exo cyclisation of the -
radical intermediate 13b to the neophyl intermediate 15b
gives a radical stabilised by both the pyridone and the alk-
ene, whereas the alternative cyclisation onto the alkene
would yield a radical only stabilised by the imine. Revers-
ibility between the spirodiene 13 and the iminyl radical in-
termediate 12 is possible but ring opening of 13 to an
alternative vinyl radical is energetically unlikely. There is
evidence in the literature for both 6-endo-cyclisation5 and
for 5-exo cyclisation followed by a neophyl rearrange-
ment.6d-f In related cyclisations onto arenes by vinyl radi-
cals, arenes with o-fluorine substituents6f and a range of
m- and p-substituents give both regioisomers6d-f indicating
5-exo cyclisations, followed by neophyl rearrangements
to both isomers.
heat
Me2Sn
Me• +
Me3Sn•
hυ
16
Me
Me2Sn
(Me3Sn)2
Scheme 5
Me3Sn Sn SnMe3
n
Me
17
In order to overcome the problem of the organotin poly-
mer formation, to provide an efficient abstracting radical
and to lower the reaction temperature and time, we inves-
tigated the use of di-t-butyl peroxide (Scheme 6). t-Butox-
yl radicals rapidly cleave the Sn-Sn bond providing
trimethyltin radicals at a lower temperature and will also
efficiently abstract the 4a-hydrogen from the -radical in-
termediate 14 (Scheme 6). For the conversion of the iodo
precursor 6b to the tetracycle 5a, the optimum conditions
[(t-BuO)2 (1.7 equiv), (Me3Sn)2 (2.2 equiv), 120 °C, 24 h
under nitrogen in a sealed Schlenk tube] gave 5a (60%)
and unaltered starting material 6a (10%). The yield of the
tetracycle from the bromo-precursor 6a [5a (21%) and un-
altered 6b (35%)] was similar to the reaction with hexam-
ethylditin alone. However, when 6a was reacted with
more of both reagents and a longer reaction time, the yield
of 5a increased to 50% [(t-BuO)2 (8.6 equiv), (Me3Sn)2
Our protocol has given good yields of the rings A-D skel-
eton of camptothecin and nothapodytin A and provides a
facile synthetic route to a range of other polycyclic bio-
logically active natural products.
Acknowledgement
We thank the EPSRC for Research Associate grants (M.O.C. and
C.F.B.) and the EPSRC Mass Spectrometry Unit, Swansea Univer-
sity, Wales for mass spectra.
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768
W. R. Bowman et al.
LETTER
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atmosphere of nitrogen and irradiated with two 150 W
sunlamps for 48 h. The reaction was cooled to room
temperature, diluted with methanol, and the solution
evaporated to dryness. The residue was placed on a silica gel
column and eluted with CH2Cl2 to remove t-butylbenzene.
Further elution gave unaltered 1-[(Z)-2-iodo-3-phenylprop-2-
enyl]-6-oxo-1,6-dihydropyridine-2-carbonitrile (25 mg, 15%)
and 11H-indolizino[1,2-b]quinolin-9-one (80 mg, 73%). m.p.
253-254 °C (EtOH) (lit.,24 265 °C). 1H NMR 5.28 (s, 2 H,
11-CH2), 6.73-6.77 (m, 1 H, 8-H), 7.27-7.34 (m, 2 H, 6,7-H),
7.69 (m, 1 H), 7.90 (m, 1 H), 7.93 (m, 1 H), 8.23 (m, 1 H), 8.37
(m, 1 H); 13C NMR 49.91 (11-CH2), 100.88, 120.53, 127.66,
128.02, 128.07, 140.36, 128.57, 129.65, 130.33,
130.84,146.13, 148.83, 152.97, 161.55; m/z (EI) 234, 205,
178, 151, 140, 128, 115, 105, 91, 75, 63, 55, 49 and 43. HRMS
C15H19N2O+H requires: 235.0871; found: 235.0870.
C15H10N2O (234.26) calcd. C 76.91, H 4.30, N 11.96%; found
C 76.5, H 4.1, N 11.9.
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Synlett 2001, No. 6, 765–768 ISSN 0936-5214 © Thieme Stuttgart · New York