Synthesis of heteroarenes using cascade radical cyclisation via iminyl radicals

Article abstract of DOI:10.1039/b501509j

Cascade radical cyclisation involving homolytic aromatic substitution has been used to synthesise new tetracycles. Treatment of vinyl iodide radical precursors with Me₃Sn radicals (from hexamethylditin) yielded intermediate vinyl radicals which

Full text of DOI:10.1039/b501509j

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A R T I C L E
Synthesis of heteroarenes using cascade radical cyclisation
via iminyl radicals†
W. Russell Bowman,* Martin O. Cloonan, Anthony J. Fletcher and Tobias Stein
Department of Chemistry, Loughborough University, Loughborough, Leicestershire,
UK LE11 3TU. E-mail: w.r.bowman@lboro.ac.uk; Fax: +44 (0)1509 223925;
Tel: +44 (0)1509 22256
Received 31st January 2005, Accepted 23rd February 2005
First published as an Advance Article on the web 10th March 2005
Cascade radical cyclisation involving homolytic aromatic substitution has been used to synthesise new tetracycles.
Treatment of vinyl iodide radical precursors with Me3Sn• radicals (from hexamethylditin) yielded intermediate vinyl
radicals which undergo 5-exo cyclisation onto suitably placed nitrile groups to yield intermediate iminyl radicals. The
iminyl radicals undergo aromatic homolytic substitution via 6-endo cyclisation (or 5-exo cyclisation followed by
neophyl rearrangement) with loss of hydrogen (H•) in a H-abstraction step. We propose that this abstraction was
facilitated by tert-butoxyl (t-BuO•) radicals from di-tert-butyl peroxide or methyl radicals, generated from breakdown
of trimethylstannyl radicals (Me3Sn•). The biologically active alkaloids mappicine and luotonin A were synthesised
using the new methodology. A novel radical conversion of nitriles to primary amides is proposed.
of syntheses. For example, the rate cyclisation of 4-cyanobutyl
Introduction
◦
radicals [•CH2(CH2)3CN] is slow (4 × 103 s−1 at 25 C).13 We
Tetracyclic and pentacyclic alkaloids with the 2,3-dihydro-1H-
pyrrolo[3,4-b]quinoline ring system making up rings A–C have
showed that 5-exo cyclisation of reactive aryl and vinyl radicals
was faster than alkyl radicals thus providing more suitable
been of intense interest in recent years. In particular, interest has
reactions for synthesis and that cyclisation onto nitriles to
centred around the anticancer and antiviral camptothecin 1 and
generate intermediate iminyl radicals could be used for further
analogues mappicine 2 and mappicine ketone (nothapodytine
tandem cyclisations onto alkenes.12 We have developed these
B) 3.1 The chemistry and pharmacology of camptothecins
studies to a new protocol for the synthesis of the 2,3-dihydro-1H-
and analogues have been fully reviewed.1 Camptothecin1,2 and
pyrrolo[3,4-b]quinoline ring system 7 which depends on several
mappicine1,2f ,3 have been popular targets of synthesis and a
radical reactions in a cascade sequence (Scheme 1).14
wide variety of protocols have been reported including hetero
Diels–Alder reactions, condensation to form the pyridone ring
in the synthesis and biomimetic synthesis. Few of these studies
have used radical methodology. The major studies using radical
synthesis have been reported by Curran and co-workers who
have synthesised camptothecin and analogues4–6 and mappicine7
via bimolecular radical additions of radicals derived from 6-
iodo-1H-pyridin-2-ones onto aryl-isonitriles. A synthesis of
camptothecin using cyclisation of 2-quinolinyl radicals onto
pyridones has also been reported.8 Synthetic studies towards
mappicine using radical cyclisation onto enamides have also
been reported.9
Another group of alkaloids containing the 2,3-dihydro-1H-
pyrrolo[3,4-b]quinoline ring system are the recently discovered
pyrroloquinazolinoquinoline alkaloids, luotonins A 4, B 5
and E 6 and other congeners.10 Although the compounds
were only isolated four years ago10 there are already several
syntheses of luotonin A, which has proved a popular synthetic
target.11 None of the syntheses have used radical protocols.
The luotonins are used in traditional Chinese medicine and
are reported to exhibit activity against a range of ailments
including rheumatism, inflammation, influenza, hepatitis and
luekemia.10,11 More recently, luotonin A has shown great promise
as an antitumour compound and is a poison for human DNA
topoisomerase I.10b
In our studies of radical reactions of nitriles we showed
that the cyclisation onto the nitrile group could be used in
synthesis with understanding of the reactivity and rates of
reactions.12 The rates of cyclisation onto nitriles are slow, and
Scheme 1
faster, competing reactions need to be avoided in the design
In this synthetic protocol, the first of the radical cyclisations
in the cascade sequence is 5-exo cyclisation of vinyl radicals onto
nitriles, i.e. 9 to 8. Vinyl6,14,15 and imidoyl16 radical cyclisations
onto nitriles have been reported in a few examples. In the second
† Electronic supplementary information (ESI) available: preparation
and analytical details for heteroarene compounds. See http://www.rsc.
org/suppdata/ob/b5/b501509j/
1 4 6 0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 4 6 0 – 1 4 6 7
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
©

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step of the cascade process (8 to 7), the newly formed iminyl
radical intermediate 8 undergoes 6-endo (or 5-exo cyclisation
followed by neophyl rearrangement) cyclisation onto the arene.
The cyclisation reactions of the iminyl radical have been
extensively studied by Zard and co-workers.17 The final step
is formally an aromatic homolytic substitution in which the
iminyl radical substitutes for a hydrogen radical (H•). Aromatic
homolytic substitution is a much under-used and maligned
synthetic reaction but importantly is usefully regioselective when
intramolecular.18 In recent years many of the aromatic homolytic
substitutions have been facilitated using tributyltin hydride to
excellent synthetic application.19 While these reactions can be
formally described as aromatic homolytic substitution, the exact
mechanism is unclear.19
to be due to some hydrolysis to 2-cyano-6-methoxypyridine-
4-carboxylic acid which binds to the copper in the reaction.
Conversion of 13 to the cyanopyridone 14 was carried out
using a literature procedure.5,14 The cyanopyridone 14 was
alkylated with the a-iodocinnamyl bromide14 15 using conditions
that normally favour N-alkylation of pyridones.14,23 The radical
precursor 16 was obtained in only a 32% yield. The low
yield was due to O-alkylation (17, 30%) and the formation of
small amounts of methyl 6-cyano-1,2-dihydro-1-methyl-2-oxo-
4-pyridine-carboxylate. The reasons for the low N-selectivity are
not obvious.
The radical precursor 16 was reacted under similar conditions
to those reported in our earlier paper,14 i.e. hexamethylditin
(7.5 equiv.) in tert-butylbenzene with sun lamp irradiation
(Scheme 3). Hexamethylditin was used in order to prevent
trapping of intermediate radicals with a reagent such as
tributyltin hydride. Irradiation and heating at 150 ◦C gave
considerable decomposition with an isolated yield of methyl 9-
oxo-9,11-dihydroindolizino[1,2-b]quinoline-7-carboxylate 21 of
only 15%. Reaction at a lower temperature of 85 ◦C with a
smaller amount of hexamethylditin (2 equiv.) gave a better
yield of 21 (50% crude, 21% purified). These lower yields were
disappointing compared with yields of up to 80% in earlier
studies but indicate that the ester group makes the substrate
16 more reactive.14 The use of di-tert-butyl peroxide as an
initator14 largely resulted in decomposition with only a trace
of 21. This may be related to the presence of the methoxy
functional group, as decomposition under these conditions was
also observed in the synthesis of the tetracyclic rings A–D of
nothapodytine A which contains a 1-methoxy substituent.14
Hydrogen-abstraction from methoxy groups is unfortunately
common due to the formation of a stable radical.
With the dual aim of further studying cyclisation onto nitriles
and investigating its use in synthesis, we report the application
of the methodology to the synthesis of mappicine (2) and
mappicine ketone (nothapodytine B; 3) and luotonin A (4).
Results and discussion
Mappicine 2 and nothapodytine B 3
Our first investigation was the synthesis of mappicine 2 and
mappicine ketone 3. We sought to synthesise the simplest
relay 21 which has been used in the synthesis of mappicine,
thereby constituting a formal synthesis.2e,20 The use of the
electron-withdrawing substituent also provides an interesting
test for the chemistry. The interconversion between the ketone of
nothapodytine B and the alcohol of mappicine are facile so both
present a formal synthesis of each other.
The radical precursor 16 was synthesised as shown in
Scheme 2 using a similar procedure to our earlier study.14
2,6-Dibromopyridine-4-carboxylic acid was synthesised from
the commercially available citrazinic acid 11 in an 80%
yield.21 SNAr substitution with methoxide yielded 2-bromo-
6-methoxypyridine-4-carboxylic acid 12 in a 96% yield.14,22
The usual procedure14 for the introduction of the nitrile
group using CuCN and decomposition of the resultant copper
complex to liberate the aryl nitrile proved problematic and
black tars were observed. Therefore, the copper(I)-catalysed
cyanation was carried out on the methyl ester, methyl 2-bromo-
6-methoxypyridine-4-carboxylate, instead of the free carboxylic
acid. Various alternative procedures were attempted but the
yield of 40% could not be further maximised, indicating that
the ester group hinders the reaction. The product 13 was only
obtained when methanol was used in place of water in the
decomposition of the copper complex. The low yield is likely
Scheme 3 Reagents and conditions: i, (Me3Sn)2, tert-BuPh, hm, 85 ◦C,
24 h, 21% (21).
Scheme 3 shows the putative mechanism of the cascade
reaction.14 Abstraction of iodine by the trimethyltin radical
(Me3Sn•) yields the vinyl radical which undergoes 5-exo cycli-
sation onto the nitrile group to yield an intermediate iminyl
radical 18. The rate of bromine abstraction by Bu3Sn• radicals
of bromine from vinyl bromides is fast (106–107 M−1 s−1),24 and
therefore, abstraction of iodine by Me3Sn• will be faster and is
unlikely to be rate determining in the reaction sequence. Both
the 5-exo cyclisation onto the nitrile to yield 18 and cyclisation of
the iminyl radical intermediate onto the phenyl ring (5-exo to 19
or 6-endo to 20) are slow. The abstraction of the hydrogen from
20 is the second step of the aromatic homolytic substitution. The
mechanism of this step is not clear but we have proposed that the
abstracting species are methyl radicals from the breakdown of
Scheme 2 Reagents and conditions: i, POBr3, 180 ◦C, 80%; ii, NaOMe,
MeOH, 60 ◦C, 96% (12); iii, MeOH, conc. H2SO4, 87%; iv, CuCN, DMF,
reflux, 48 h, 40% (13); v, TMSCl, NaI, MeCN, 63% (14); vi, 15, NaH,
LiCl, DME, DMF, 32% (16), 30% (17).
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 4 6 0 – 1 4 6 7
1 4 6 1

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trimethyltin radicals.14 Blank reactions without hexamethylditin
gave traces of 21 indicating iodine-homolysis or Diels–Alder
cyclisation as possible minor mechanisms.
(to 31) were largely eliminated. Unfortunately, the yields for
alkylation with 1-[(Z)-3-bromo-2-iodoprop-1-enyl]benzene14 15
were poor and the two regio-isomers could not be separated even
after extensive chromatography.
We therefore developed a protocol which would be regioselec-
tive to the required 3-N product. Ethyl 2-[(4-chloro-5H-1,2,3-
dithiazol-5-yliden)amino]benzene-1-carboxylate 24 was reacted
with the required cinnamylamines 32 and 33 (Scheme 5). The
cinnamylamines were prepared by standard methodology. Both
cinnamylamines gave moderate yields of the required products
27 and 28. The quinazoline 28 was synthesised as a possible
product of unsuccessful cascade cyclisation for comparison and
identification purposes. The yields could not be optimised but
are similar to reported reactions of similar compounds in the
literature.25,26 An excess (1.5 equiv.) of Appel’s salt was used
to ensure complete conversion of ethyl 2-aminobenzoate 22
because it co-elutes with the product 24 creating yet further
separation problems. The advantage of the Rees method in the
synthesis of the radical precursor is that it avoids the possibility
of alkylation at oxygen and 1-N. The Z-stereochemistry of the
alkene 27 and the E-stereochemistry of 28 were determined by
NOE difference NMR spectroscopy.
Luotonin A (4)
Our initial aim for the synthesis of luotonin A 4 was to use
the same methodology, i.e. to alkylate a suitable a-cyano NH-
heteroarene (Scheme 4) and carry out the [4 + 2] cascade
radical cyclisation as exemplified in Scheme 3 for the synthesis
of mappicine and our earlier studies.14 To this end we decided to
use 4-oxo-3,4-dihydroquinazoline-2-carbonitrile 25 (Scheme 4).
This model would allow study of the quinazoline ring system in
the radical cascade protocol.
Scheme 5 Reagents and conditions: i, THF, rt, 48 h, 32 gave 42% (27);
33 gave 40% (28).
The radical precursor 27 was reacted under the general
reaction conditions14 using hexamethylditin (14 equiv.) in tert-
butylbenzene with sun lamp irradiation at 150 ◦C for 46 h
(Scheme 6). Luotonin A 4 was formed as predicted in 21% yield
along with other products (30%, an E/Z isomeric mixture).
We initially assumed that the other product was the reduced
uncyclised compound 28. However, after independent syntheses
of potential products, we realised that the unknown products
were an E/Z isomeric mixture of the primary amides 38 and 39.
No unaltered starting material or other products were observed
in the radical reactions except for large amounts of a polymeric
organotin compound.14
Scheme 4 Reagents and conditions: i, pyridine, DCM, rt, 24 h, 92%
(24); ii, NH3, dioxane, rt, 5 d, 98% (25); iii, NaH, LiCl, DME, DMF,
rt, 5 h: 15 gave 16% (27), 0% (29, X = I), 6% (30) and 26 gave 45% (28),
9% (29, X = H), <1% (31); NaH, DMF, 60 ◦C, 20 h, 26 gave 44% (28),
trace (29, X = H), 0% (31).
4-Oxo-3,4-dihydroquinazoline-2-carbonitrile 25 was synthe-
sised in high yield (98%) from ethyl 2-[(4-chloro-5H-1,2,3-
dithiazol-5-yliden)amino]benzene-1-carboxylate 24 and ammo-
nia. This represents a new route to quinazoline-2-carbonitriles.
This unusual reaction between amines and the (4-chloro-5H-
1,2,3-dithiazol-5-yliden)amino ring system, developed by Rees
and co-workers,25 proved useful in our studies. A similar
application has been reported by Kim and Mohanta for the 2-
cyanoquinazoline system.26 The protocol relies on the reaction
between Appel’s salt27 23 and anthranilate esters (e.g. 22) to yield
24.25
The procedure for regioselective N-alkylation over O-
alkylation which has been successfully applied to 6-cyano-
pyridones14 and to 6-iodopyridones23 again gave only small
amounts of O-alkylation (Scheme 4). In contrast, O-alkylation
can be selectively facilitated over N-alkylation by using the
Mitsunobu reaction with alcohols instead of halides for quina-
zolines and isoquinolines based on low (hard) polarisabil-
ity factors.28 We have observed the same O-selectivity with
the Mitsunobu reaction when attempting alkylation of 6-
oxo-1,6-dihydro-pyridine-2-carbonitrile with 1-[(Z)-3-bromo-2-
iodoprop-1-enyl]benzene 15 and DEAD.29 However, in this
study the protocol was largely N-selective but it was not
completely selective between alkylation at the 1-N and 3-N and
the isomers were difficult to separate. At ambient temperatures,
alkylation of 25 with cinnamyl bromide 26 gave a moderate yield
of the required 3-N alkylated product 28. When the temperature
was raised, O-alkylation (to 29, X = H) and 1-N alkylation
Scheme 6 Reagents and conditions: i, (Me3Sn)2, tert-BuPh, hm.
In order to improve the yield of luotonin A, milder conditions
using di-tert-butyl peroxide were studied.14 tert-Butoxyl radicals
1 4 6 2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 4 6 0 – 1 4 6 7

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are formed by thermal or photochemical homolysis at lower
temperatures and react rapidly with hexamethylditin to yield
trimethyltin radicals. The use of tert-butylperoxyl radicals also
has the advantage of providing a reactive and efficient H-
abstractor for the final rearomatisation step (Scheme 6, 36 to
4). The reaction was carried out with 27 (6.33 × 10−2 M) and
fewer equivalents of hexamethylditin (3.8 equiv.) and di-tert-
butyl peroxide (2.0 equiv.) in a sealed tube at 120 ◦C and for a
shorter reaction time (24 h) and yielded luotonin A (30%) and
38/39 (16%). The reaction was repeated at lower dilution (1.47 ×
10−2 M) to encourage cyclisation over potential bimolecular
reactions. None of the unwanted products 38/39 were observed
but the yield of luotonin A dropped to 22%. This result indicates
a bimolecular reaction in the formation of 38 and 39. However, it
was not clear whether formation of 38 and 39 had been prevented
or whether there were subtle differences in the conditions of the
reaction, e.g. traces of oxygen. All the starting material was con-
sumed in these reactions, therefore, it may be possible to improve
the yield under milder conditions and shorter reaction times.
The proposed mechanism of the cascade cyclisation is shown
in Scheme 6. 5-exo-Cyclisation of the vinyl radical 34 onto
the nitrile yields the iminyl intermediate 35 which undergoes
cyclisation onto the phenyl ring (5-exo followed by a neophyl
rearrangement, or 6-endo, to 36). In this case both 5-exo and 6-
endo routes yield the same product. We have provided evidence
in previous examples of cyclisation proceeding via initial 5-exo
cyclisation to a spirodienyl intermediate.14 The abstraction of the
hydrogen from the p-radical intermediate 36 to yield luotonin
A 4 is formally the second step of the aromatic homolytic
substitution. The mechanism of this step is not clear but we have
proposed that the abstracting species are methyl radicals from
the breakdown of trimethyltin radicals or tert-butoxyl radicals
when di-tert-butyl peroxide was used.14 The synthesis provides
a further example, albeit in moderate yield, of our cascade
methodology indicating that cyanoquinazolines can also be used
and furthermore represents the first synthesis of luotonin A
using radical methodology.
Scheme 7 RCN = 38/37.
radicals add to the electrophilic nitrile. The resulting iminyl
radicals undergo 1,5-hydrogen abstraction or H-abstraction
from p-radical intermediates to yield unstable intermediates
which rearrange under the high temperature conditions. The
rearranged products rapidly hydrolyse on work-up to yield the
primary amides. A precedent has been reported for an analogous
compound which has an acyl group in place in the iminyl group.31
The characterisation of the unknown products 38/39 isolated
from the radical reactions was ambiguous and the purification
was hindered by two geometrical isomers which co-eluted on
chromatography. In order to be certain of the assignment of the
structures, possible products were synthesised by unoptimised
but unambiguous routes (Scheme 8).
In order to gain further mechanistic understanding of the
radical reactions of 27, blank reactions were carried out with
the radical precursor 27 and also the equivalent non-iodo 3-
alkylated compound 28 in which the hexamethylditin (and di-
tert-butyl peroxide) were omitted. Both reactions gave near
quantitative recovery of unaltered starting materials with only
traces of luotonin A (<1%). These blank reactions served several
purposes. Firstly, the reaction with 27 proved that the radical
reagents were required and hence that the reaction was radical
mediated. A putative mechanism initiated by iodine-homolysis
is also eliminated by the lack of reaction under these conditions.
Secondly, a mechanism involving a purely thermal Diels–Alder
reaction followed by loss of hydroiodic acid for the synthesis
of luotonin A 4 could be envisaged for 27 but is ruled out
by the blank reaction. There is literature precedence for an
intramolecular Diels–Alder reaction in which a nitrile functional
group behaves as the 2p component, the product in this case was
also luotonin A.11a
The mechanism of formation of the primary amide by-
products 38 and 39 is difficult to explain. The products are
clearly formed by a radical mechanism because they are not
formed in the blank reaction. The most likely scenario is a
competing reaction whereby the initial intermediate radical 34
can either undergo cyclisation onto the nitrile or H-abstraction
to yield 28 and 37 (Scheme 6). The isomerism to an E/Z
mixture can be explained by the radical intermediate 34. We
have previously observed the formation of primary amides from
reactions between nitriles and hexamethylditin under radical
conditions. The mechanism is not obvious but we propose
that the most likely explanation is that traces of oxygen react
with the trimethylstannyl radicals as shown in Scheme 7.30
Even with careful freeze–thaw techniques traces of oxygen
are difficult to eliminate completely. The nucleophilic peroxyl
Scheme 8 Reagents and conditions: i, NaH, DMF, DME, LiBr; ii,
cinnamyl bromide, 2 h; iii, cinnamaldehyde, EtOH, reflux, 15 min (46%);
iv, NaBH4, MeOH, 30 min, 94% (44); v, methyl oxalyl chloride, Et3N
followed by H+, 83% (45); vi, NH4OH, EtOH, 64% (46); vii, EDCI,
HOAT (1-hydroxy-7-azabenzotriazole) (catalytic), DCM, reflux, 3 d,
36% (31); viii, NaH, DMF; cinnamyl bromide, 50% (47); ix, NH3, EtOH,
69% (38).
The absence of a nitrile absorption in the IR spectrum and
the absence of a molecular ion including the nitrile in the mass
spectrum suggested a product without a nitrile group. 2-[(E)-
3-Phenylprop-2-enyl]-3H-quinazolin-4-one 41 was synthesised
from anthranilamide 40 and the acid chloride of cinnamic
acid using a protocol adapted from the literature.32,33 Radical
abstraction of iodine and the nitrile group presents another
possibility to yield 3-[(E)-3-phenylprop-2-enyl]-3H-quinazolin-
4-one 43. The 3-cinnamyl derivative 43 was prepared by
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 4 6 0 – 1 4 6 7
1 4 6 3

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alkylation of 3H-quinazolin-4-one 42. The data for 41 and 43
were similar to the unknown 38 but clearly different, thereby
ruling out these structures.
1283, 1243, 1198, 1024, 993, 947, 909, 884, 775 and 759; dH (d7-
DMF) 3.91 (3 H, s, OMe), 7.31 (1 H, s, 5-H), 7.74 (1 H, s, 3-H)
and 12.38 (1 H, br s, NH); dC (d6-DMSO) 51.45 (OMe), 163.14
=
Although unlikely, we considered that a radical rearrange-
ment to the 1-N-substituted 4-oxo-1-[(E)-3-phenylprop-2-enyl]-
3,4-dihyroquinazoline-2-carbonitrile 31 may be possible. The
nitrile 31 was prepared by an adapted literature procedure
for the synthesis of 1-N-substituted 2-cyano-3H-quinazolin-
4-ones (Scheme 8).33,34 The conversion of the primary amide
to the nitrile proved troublesome. The use of phosphorus
oxychloride for dehydrating the primary amide to the nitrile led
to removal of the cinnamyl group by SN2 substitution by chloride
on the cinnamyl methylene group. An alternative method of
dehydration using EDCI [1-(3-dimethylaminopropyl)-3-ethyl-
carbodiimide] proved satisfactory for converting 46 to 31.35
Again, the data for 46 and 31 were similar to 38 but not identical.
Finally, we synthesised the unexpected primary amide 38 as
shown in Scheme 8. The synthesised primary amide 38 was
identical to the E-isomer of the isomeric mixture of unknown
compounds isolated from the radical reactions.
and 161.83 (C O ester and 2-C), 139.70 (4-C), 128.05 (6-C),
117.49 (3-C), 114.77 (5-C) and 114.27 (CN); m/z (EI) 178 (M+,
93%, Found: 178.0381. C8H6N2O3 requires 178.0378), 147 (75),
119 (100), 110 (15), 91 (45), 76 (10) and 64 (18).
Methyl 6-cyano-1-[(Z)-2-iodo-3-phenylprop-2-enyl]-2-oxo-1,2-
dihydropyridine-4-carboxylate 16
60% NaH (0.445 g, 11.13 mmol) was added portion-wise
to a solution of methyl 6-cyano-2-oxo-1,2-dihydropyridine-4-
carboxylate 14 (1.894 g, 10.64 mmol) in 1,2-dimethoxyethane
(monoglyme) (21 cm3) and dimethylformamide after 10 min.
The mixture was stirred for 15 min at room temperature, 1-[(Z)-
3-bromo-2-iodoprop-1-enyl]benzene14 15 (1.6 g, 4.97 mmol)
added, and the reaction heated at 65 ◦C for 20 h. The
mixture was cooled to room temperature and poured into brine
(50 cm3), extracted with EtOAc and dried. The solution was
evaporated under reduced pressure to give an orange solid which
was purified by column chromatography using EtOAc/DCM
as eluent to give methyl 6-cyano-1-[(Z)-2-iodo-3-phenylprop-
2-enyl]-2-oxo-1,2-dihydro-pyridine-4-carboxylate 16 (1.398 g,
Our studies report novel cascade radical reactions and have in-
dicated that the methodology shown in Scheme 1 can be applied
to a range of radical precursors. Further studies are underway
to apply the general protocol to a wider range of syntheses.
◦
31%), mp 122–123 C (DCM/light petroleum) (Found: M+,
419.9971. C17H13IN2O3 requires 419.9971); mmax (DCM)/cm−1
=
2230 (CN), 1736, 1674 (C O, pyridone), 1605, 1543, 1219, 1080,
Experimental
988, 864, 772 and 694; dH 3.95 (3 H, s, CO2Me), 5.22 (2 H, d,
J = 1.2Hz, CH2N), 7.07 (1 H, s, vinylic 3-H), 7.27 (3 H, d,
J 2.0, pyridone 5-H), 7.32–7.38 (3 H, m, phenyl 3,4-H) and
7.48–7.50 (3 H, m, phenyl 2,6-H and pyridone 3-H); dC 53.41
(OMe), 58.20 (CH2N), 95.70 (vinylic 2-C), 163.13, 160.34 (ester
Commercial dry solvents were used in all reactions except for
light petroleum and ethyl acetate which were distilled from CaCl2
and dichloromethane (DCM) which was distilled over phos-
phorus pentoxide. Light petroleum refers to the bp 40–60 ◦C
fraction. Sodium hydride was obtained as a 60% dispersion in
oil and was washed with light petroleum. Mps were determined
on an Electrothermal 9100 melting point apparatus and are
uncorrected. Elemental analyses were determined on a Perkin
Elmer 2400 CHN Elemental Analyser in conjunction with a
Perkin Elmer AD-4 Autobalance. IR spectra were recorded
on a Perkin Elmer Paragon 1000 FT-IR spectrophotometer on
NaCl plates. 1H (250 MHz) and 13C (62.5 MHz) NMR spectra
were recorded on a Bruker AC-250 spectrometer as solutions of
CDCl3 with tetramethylsilane (TMS) as the internal standard
=
=
C O, pyridone C O), 139.33, 136.63 (pyridone 4-C, phenyl 1-
C), 139.18 (vinylic 3-C), 128.96 (phenyl 4-C), 128.61 (phenyl 3-
C), 128.59 (pyridone 3-C), 128.19 (phenyl 2-C), 121.67 (pyridone
6-C), 114.40 (pyridone 5-C) and 112.32 (CN); m/z 420 (M+,
77%), 388 (3), 328 (7), 293 (13), 281 (4) 268 (30), 192 (7), 181 (6),
133 (9), 115 (14), 91 (100), and 65 (5). Methyl 2-cyano-6-{[(Z)-
2-iodo-3-phenylprop-2-enyl]oxy}pyridine-4-carboxylate 17 was
also eluted (1.37 g, 30%), Found: M+, 419.9973. C17H13IN2O3
requires 419.9971; dH 3.97 (3 H, s, CO2Me), 5.25 (2 H, d,
J = 1.1 Hz, CH2O), 7.21 (1 H, s, vinylic 3-H), 7.33–7.37 (3
H, m, phenyl 4- and 3-H), 7.54–7.56 (2 H, m, phenyl 2-H),
7.64 (1 H, d, J 1.1, 5-H) and 7.85 (1 H, d, J 1.1, 3-H); dC
53.23 (ester OMe), 75.71 (CH2O), 97.48 (vinylic 2-C), 116.51
(CN), 116.67 (5-C), 121.78 (pyridine 3-C), 128.17 (phenyl CH),
128.52 (phenyl CH), 128.62 (phenyl CH), 131.01 and 136.55 (2-
C, phenyl 1-C), 137.74 (vinylic 3-C), 141.55 (4-C) and 163.43 and
1
for H NMR spectra and deuteriochloroform the standard for
13C NMR spectra unless otherwise specified. Chemical shifts
are given in parts per million (ppm) and J values in hertz
(Hz). Mass spectra were recorded on a JEOL SX102 mass
spectrometer or carried out by the EPSRC Mass Spectrometry
Service at University of Wales, Swansea. GC–MS was carried
out on a Fisons 8000 series GC–MS using a 15 m × 0.25 mm
DB-5 column and an electron impact low resolution mass
spectrometer. TLC using silica gel as adsorbent was carried
out with aluminium-backed plates coated with silica gel (Merck
Kieselgel 60 F254). Silica gel (Merck Kieselgel 60 H silica) was
used for column chromatography unless otherwise specified.
=
163.69 (ester C O, 6-C). Methyl 6-cyano-1,2-dihydro-1-methyl-
2-oxo-4-pyridine-carboxylate was eluted (0.2133 g), mp 144–
145 ◦C (DCM/light petroleum) (lit.,36 143–144 ◦C) (Found: M+,
192.0536. C9H8N2O3 requires 192.0535); mmax (DCM)/cm−1
2233, 1737 (C O, ester), 1675 (C O, pyridone), 1603, 1543,
1220, 1128, 1081, 1000, 992, 964, 909 and 856; dH 3.73 and 3.95
(3 H each, s, CO2Me, N–Me), 7.22 (1 H, d, J = 2.0 Hz, 5-H),
7.43 (1 H, d, J 2.0, 3-H); dC 34.83 (NMe), 53.36 (ester OMe),
=
=
Methyl 6-cyano-2-oxo-1,2-dihydropyridine-4-carboxylate 14
112.27 (6-C), 113.63 (5-C), 122.08 (CN), 128.31 (3-C), 139.12
Chlorotrimethysilane (0.560 g, 5.16 mmol) was added slowly to
a mixture of methyl 2-cyano-6-methoxypyridine-4-carboxylate
13 (0.323 g, 1.681 mmol) and sodium iodide (0.773 g, 5.16 mmol)
in acetonitrile (2.5 cm3) and the mixture stirred at 80 ◦C for 6 h.
The solution was cooled to room temperature, evaporated under
reduced pressure and water was added (2 cm3). This suspension
was purified by column chromatography using DCM/light
petroleum as eluent to yield methyl 2-cyano-6-methoxypyridine-
4-carboxylate 13 (0.12 g, 37%). Elution with a gradient mixture
of DCM/EtOAc gave the product methyl 6-cyano-2-oxo-1,2-
dihydropyridine-4-carboxylate 14 (0.189 g, 63%), mp 201–
203 ◦C (Found: C, 53.8; H, 3.35; N, 15.51. C8H6N2O3 requires C,
53.94; H, 3.39; N, 15.73%); mmax (Nujol)/cm−1 3100–2400 (broad
+
=
=
(4-C), 163.29, 161.00 (ester C O, pyridine C O); m/z 192 (M ,
63%), 153 (8), 136 (8), 133 (100), 115 (16), 105 (18), 91 (10), 89
(14), 77 (36), 67 (25), 63 (9), 59 (19), 51 (18) and 43 (17).
Methyl 9-oxo-9,11-dihydroindolizino[1,2-b]quinoline-7-
carboxylate 21 using a 300 W sun lamp
A solution of methyl 6-cyano-1-[(Z)-2-iodo-3-phenylprop-
2-enyl]-2-oxo-1,2-dihydropyridine-4-carboxylate 16 (0.10 g,
0.24 mmol) in tert-butylbenzene (6.5 cm3) in a flat-bottomed,
two-necked flask (Pyrex, 5 × 1 × 20 cm3, wall thickness 1 mm)
was purged with nitrogen for 20 min. Hexamethylditin (0.156 g,
0.48 mmol) was added by syringe and the resultant solution
purged with nitrogen for a further 30 min. The mixture was
=
NH); 2245 (CN), 1721, 1658 (C O, pyridone), 1615, 1573, 1343,
1 4 6 4
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 4 6 0 – 1 4 6 7

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irradiated with two 150 W sun lamps at 85 ◦C for 24 h.
The reaction was cooled to room temperature, diluted with
methanol and evaporated under reduced pressure. Analysis
by LCMS and 1H NMR spectroscopy showed 21 (50%)
along with a number of unidentified products. The residue
was purified using column chromatography with an eluent
gradient of DCM/EtOAc/MeOH and gave methyl 9-oxo-9,11-
dihydroindolizino[1,2-b]quinoline-7-carboxylate 21 (14.6 mg,
21%), mp 184–186 ◦C (lit.,37 185–187 ◦C) (Found: M+, 292.0848.
C17H12N2O3 requires 292.0848); dH 3.99 (3 H, s, CO2Me), 5.30
(2 H, s, 11-H), 7.37 (1 H, s, 6-H), 7.66 (1 H, ddd, J = 7.5, 7.8,
1.0 Hz, 2-H), 7.81 (1 H, s, 8-H), 7.83 (1 H, ddd, J 7.5, 7.8, 1.2,
3-H), 7.93 (1 H, dd, J 7.8, 1.0, 1-H), 8.24 (1 H, dd, J 7.8, 1.2,
4-H), 8.39 (1 H, s, 12-H); dC 50.59 (11-C), 53.39 (OMe), 100.09
(6-C), 122.45 (8-C), 128.37, 128.53 (1-C, 2-C), 128.59, 129.01
(12a-C, 11a-C), 130.24, 130.97, 131.46 (12-C, 4-C, 3-C), 142.36
J 6.7, 15.8, propenyl 2-H), 6.81 (1 H, d, J 15.8, propenyl 3-H),
7.24–7.31 (3 H, m, phenyl 3,4,5-H), 7.36–7.38 (2 H, m, phenyl
2,6-H), 7.63 (1 H, dd, J 7.9, 7.9, 6-H), 7.78–7.83 (2 H, m, 7- and
8-H) and 8.32 (1 H, d, J 7.9, 5-H); values were assigned using
NOE difference spectroscopy; important NOEs were observed
between the methylene protons and the propenyl 2-H (2.6%)
and propenyl 3-H (3.6%) indicating the E-stereochemistry but
not with 8-H indicating the 3-N isomer; dC 48.11 (CH2), 111.64
(CN), 120.91 (propenyl 2-C), 122.79 (4a-C), 126.75 (phenyl 2,6-
C), 127.11 (8-C), 128.45 and 128.49 (propenyl 3-C, phenyl 4-C),
128.63 (phenyl 3,5-C), 130.02 (6-C), 131.32 (phenyl 1-C), 135.09
(5-C), 135.58 (8a-C), 136.13 (7-C), 146.37 (2-C), and 159.72
+
+
=
(C O); m/z 287 (M , 37%, Found: M , 287.1058. C18H13N3O
requires 287.1058), 258 (2), 196 (43), 117 (100), 102 (4), 91 (14),
77 (5) and 76 (4).
29 (X = H) (Found: M+, 287.1058. C18H13N3O requires
287.1059); dH 5.25 (2 H, d, J = 6.2 Hz, OCH2), 6.6.4–6.61 (1
H, dt, J 6.2, 15.9, propenyl 2-H), 6.83 (1 H, d, J 15.9, propenyl
3-H), 7.24–7.31 (3 H, m, phenyl 3, 4, 5-H), 7.41–7.43 (2 H, m,
phenyl 2, 6-H), 7.68 (1 H, dd, J 7.9, 7.9, 6-H), 7.85 (1 H, dd,
J 7.9, 7.9, 7-H), 7.98 (1 H, d, J 7.9, 8-H) and 8.21 (1 H, d,
J 7.9, 5-H); dC 68.83 (OCH2), 116.27 and 116.94 (CN, 4a-C),
122.08 (propenyl 2-C), 139.60 (2-C), 123.71, 129.68, 135.03 and
135.55 (5,6,7,8-C), 150.50 (8a-C), 166.90 (4-C), the remaining
resonances overlap with those of 28; m/z 244 (31%), 230 (9), 171
(4), 153 (4), 131 (49) and 84 (18). 31 was not fully characterised
but exhibited a similar mass spectrum using GC–MS.
The alkylation was repeated◦with 25 (0.275 g) using only NaH
and DMF with heating at 65 C for 20 h after the addition of
cinnamyl bromide. 28 (0.203 g, 44%) was obtained with only a
trace of the O-alkyl 29 and none of the N-1 alkylated product
was observed.
(7-C), 147.13, 149.37 (4a-C, 5b-C), 152.93 (5a-C), 161.58 (9-C)
+
=
and 165.50 (ester C O); m/z 292 (M , 100%), 277 (8), 263 (6),
249 (2), 233 (12), 205 (27), 177 (6), 140 (8), 121 (6), 115 (14), 105
(7), 95 (11), 84 (30), 77 (14), 69 (29), 57 (23) and 49 (31).
The reaction was carried out under similar conditions at
150 ◦C with a larger excess of hexamethyditin (3.66 mmol) and
16 (0.048 mmol) in tert-butylbenzene (6.5 cm3) which yielded
21 (15%). The reaction was also repeated with the addition of
di-tert-butyl peroxide in a sealed tube and heated which yielded
21 in less than 5%.
4-Oxo-3,4-dihydroquinazoline-2-carbonitrile 25
Ethyl 2-[(4-chloro-5H-1,2,3-dithiazol-5-yliden)amino]benzene-
1-carboxylate 24 (4.453 g, 14.84 mmol) was added to an
ammonia solution (0.5 M) in 1,4-dioxane (100 cm3, 0.05 mol).
The solution was sealed under nitrogen and stirred at room tem-
perature for 5 d. The brown precipitate was filtered and washed
with light petroleum to give 4-oxo-3,4-dihydroquinazoline-2-
carbonitrile 25 (2.48 g, 98%). (Found: [M + NH4]+ 189.0772,
C9H5N3O+NH4 requires 189.0776; Found: M+, 171.0432.
C9H5N3O requires 171.0433); mmax (Nujol)/cm−1 3134 (NH),
3-[(Z)-2-Iodo-3-phenylprop-2-enyl]-4-oxo-3,4-
dihydroquinazoline-2-carbonitrile 27 using amine 32
(Z)-2-Iodo-3-phenylprop-2-en-1-amine
32
(0.7856
g,
3.03 mmol) was added to a solution of ethyl 2-[(4-chloro-
5H-1,2,3-dithiazol-5-yliden)amino]benzene-1-carboxylate 24
(0.2275 g, 0.76 mmol) in anhydrous tetrahydrofuran (20 cm3).
The mixture was stirred for 2 d at room temperature under an
atmosphere of nitrogen. The reaction mixture was evaporated
under reduced pressure and the residue purified by column
chromatography using DCM/light petroleum as eluent to yield
27 (0.128 g, 42%), mp 152–152.5 ◦C (DCM/light petroleum).
(Found: C, 52.4; H, 2.7; N, 9.8. C18H12IN3O requires C, 52.32;
=
2236 (CN), 1698 (C O), 1608, 1574, 1521, 1408, 1367, 1346,
1112, 998 and 776; dH (DMSO-d6) 7.34–7.37 (1 H, m, 6-H),
7.50–7.52 (1 H, m, 8-H), 7.59–7.61 (1 H, m, 7-H) and 7.99–8.00
(1 H, m, 5-H); dC 118.08 (CN), 123.75 (4a-C), 126.49 (5-C),
126.03 (6-C, 8-C, overlap), 132.35 (7-C), 143.62 (8a-C), 150.73
+
=
(2-C) and 171.21 (C O); m/z [CI+(NH3)] 189 [(M + NH4) ,
50%], 172 (92), 161 (30) and 147 (100); GC–MS shows one peak,
(EI) 171 (M+, 100%), 143 (50), 116 (25), 90 (25), 76 (10), 63 (30),
and 53 (25).
H, 2.93; N, 10.17%); mmax (DCM)/cm−1 2234 (CN), 1698 (C O),
=
=
1605 (C N), 1586, 1561, 1471 and 1383; dH 5.32 (2 H, s, CH2,
4-Oxo-3-[(E)-3-phenylprop-2-enyl]-3,4-dihyroquinazoline-2-
carbonitrile 28: procedure for the alkylation of 4-oxo-3,4-
dihydroquinazoline-2-carbonitrile 25
NOE enhancement from propenyl 3-H, 6%), 7.17 (1 H, s,
propenyl 3-H, NOE enhancement from CH2, 6%), 7.32–7.34
(3 H, m, phenyl 3,4,5-H), 7.52–7.49 (2 H, m, phenyl 2,6-H);
7.67–7.62 (1 H, m, 6-H), 7.81–7.85 (2 H, m, 7,8-H), 8.32–8.34
(1 H, m, 5-H); dC 56.94 (CH2), 96.14 (propenyl 2-C), 111.59 and
122.61 (CN, 4a-C), 127.36 (CH), 128.16 (CH) and 128.59 (CH)
with two overlapping CH peaks, 130.20 (CH), 131.25 (phenyl
1-C), 135.31 (7-C), 136.48 (8a-C), 139.26 (propenyl 3-C), 146.13
(2-C), and 159.51 (4-C); m/z (FAB), 414 [(M + H)+, 12%,
Found: 414.0101. C18H12IN3O + H requires 414.0105], 286
(100), 259 (41), 254 (35), 243 (45), 219 (15), 208 (25), 165 (29),
116 (70) and 105 (40); m/z (EI) 354 (6%), 286 (92), 262 (4), 146
(7), 125 (7), 115 (100), 97 (18), 83 (20), 69 (22), 63 (10), 57 (37)
and 43 (33).
NaH (93.9 mg, 2.35 mmol) was added slowly with stirring
to a solution of 4-oxo-3,4-dihydroquinazoline-2-carbonitrile 25
(0.402 g, 2.35 mmol) in anhydrous dimethyl sulfoxide (4.7 cm3)
under an atmosphere of nitrogen. Cinnamyl bromide (0.4631 g,
2.35 mmol) was added after 1 h and the solution stirred at
room temperature under nitrogen for 5 h. Water was added and
the mixture extracted with DCM. The organic fractions were
evaporated under reduced pressure and the residue purified by
column chromatography using DCM/light petroleum as eluent
to give an inseparable mixture of 4-oxo-3-[(E)-3-phenylprop-2-
enyl]-3,4-dihyroquinazoline-2-carbonitrile 28 (0.302 g, 45%) and
4-{[(E)-3-phenylprop-2-enyl]oxy}quinazoline-2-carbonitrile 29
(X = H) (59 mg, 9%). Further elution gave 4-oxo-1-[(E)-
3-phenylprop-2-enyl]-1,4-dihydroquinazoline-2-carbonitrile 31
(<1%).
11,13-Dihydroquino[2ꢀ,3ꢀ:3,4]pyrrolo[2,1-b]quinazolin-11-one
(luotonin A) 4 and 4-oxo-3-(3-phenylprop-2-enyl)-3,4-
dihydroquinazoline-2-carboxylic acid amide 38/39 (E/Z
mixture 2 : 1)
Sun lamp irradiation at 150 ◦C. A solution of 3-[(Z)-
2-iodo-3-phenylprop-2-enyl]-4-oxo-3,4-dihydroquinazoline-2-
carbonitrile 27 (107.0 mg, 0.26 mmol), hexamethylditin (1.20 g,
28: mp 147–148 ◦C (from DCM/light petroleum) (Found: C,
75.4; H, 4.4; N, 14.4. C18H13N3O requires C, 75.25; H, 4.56; N,
14.63%); mmax (Nujol)/cm−1 2207 (CN), 1693 (C O), 1590, 1558,
=
776 and 692; dH 5.02 (2 H, d, J = 6.7 Hz, CH2), 6.33 (1 H, dt,
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 4 6 0 – 1 4 6 7
1 4 6 5

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3.66 mmol, 14 equiv.) and tert-butylbenzene (6.5 cm3), in a
flat-bottomed, two-necked Pyrex flask (5 × 1 cm and 25 cm high,
wall thickness = 1 mm), was purged with nitrogen for 30 min.
The mixture was irradiated with a combined 300 W sun lamp at
150 ◦C for 46 h. The reaction was cooled to room temperature,
diluted with MeOH and evaporated under reduced pressure
to a small volume. The residue was purified using column
chromatography with light petroleum as eluent to remove the
tert-butylbenzene. Further elution with DCM/diethyl ether
gave luotonin A 4 as a white solid (15.4 mg, 21%) and 4-oxo-3-
[(E)-3-phenylprop-2-enyl]-3,4-dihydroquinazoline-2-carboxylic
acid amide 38/39 (E/Z mixture = 2.8 : 1) (22.3 mg, 30%) as
a mixture. Separation was achieved using preparative silica
gel plates and DCM as eluent. Data for 4: mp 277–279 ◦C
DCM/diethyl ether gave luotonin A 4 as a white solid (18.8 mg,
30%) and 38/39 (E/Z mixture 3.5 : 1) (10 mg, 16%) as a
mixture. All data agreed with authentic materials.
The reaction was repeated except that a higher dilution
was used [tert-butylbenzene (15 cm3)]. The reaction gave only
luotonin A 4 as a white solid (13.8 mg, 22%).
4-Oxo-3-[(E)-3-phenylprop-2-enyl]-3,4-dihydroquinazoline-2-
carboxylic acid ethyl ester 47
To a pre-dried flask was added 4-oxo-3,4-dihydroquinazoline-
2-carboxylic acid ester (1.00 g, 4.61 mmol), anhydrous DMF
(30 cm3) and sodium hydride (60% mineral oil suspension,
0.28 g, 6.92 mmol) and the reaction stirred for 10 min. Cinnamyl
bromide (0.61 g, 3.09 mmol) was added and the mixture stirred
for 1.5 h. The DMF was removed under reduced pressure and
the residue washed with saturated brine and extracted into
ethyl acetate. The product was purified by flash silica column
chromatography to yield 47 as a pale yellow semi-solid (0.52 g,
50%) (Found M+ 334.1319. C20H18N2O3 requires: 334.1317); mmax
(thin film)/cm−1 2359, 1734, 1683, 1596, 1464, 1301, 1262, 1153
and 1033; dH (400 MHz) 1.03 (3 H, t, J = 7.1 Hz, CH3), 4.14
(2 H, q, J 7.1, CH2O), 4.75 (2 H, dd, J 6.4, 1.4, CH2N), 5.97
(1 H, dt, J 15.9, 6.4, propenyl-2-H), 6.35 (1 H, dd, J 15.9, 1.4,
propenyl-3-H), 6.91–7.08 (5 H, m, phenyl-H), 7.23–7.30 (1 H, m,
8-H), 7.48–7.50 (2 H, m, 6-H and 7-H) and 8.04 (1 H, ddd, J 1.2,
1.2, 8.1, 5-H); dC (100 MHz) 161.6 (qC), 160.8 (qC), 146.7 (qC),
146.2 (qC), 135.8 (qC), 134.7 (CH), 134.6 (CH), 128.6 (CH),
128.4 (CH), 128.1 (CH), 128.0 (CH), 127.0 (CH), 126.5 (CH),
122.9 (CH), 121.9 (qC), 63.3 (CH2), 45.9 (CH2) and 13.8 (CH3);
m/z (EI) 334 (M+, 8%), 261 (100), 145 (5), 115 (30) and 91(16).
◦
(DCM/light petroleum ether) (lit.,10 281–283 C) (Found M+,
285.0904. C18H11N3O requires 285.0902); mmax (DCM)/cm−1
1674, 1628, 1605, 1465, 1352, 1320, 1234, 1189, 1134, 1026, 768
and 686; dH 5.36 (2 H, s, 13-H), 7.57–7.61 (1 H, dd, J = 8.0,
8.0 Hz, 9-H), 7.69–7.73 (1 H, ddd, J 0.8, 8.0, 8.0, 2-H), 7.86
and 7.87 (2 H, dd and dd, J 8.0, 8.0, 3-H and 8-H, overlap),
7.97 (1 H, d, J 7.6, 1-H), 8.13 (1 H, d, J 8.0, 7-H), 8.44 (1 H,
dd, J 0.8, 8.0, 4-H H-4), 8.47 (1 H, s, 14-H) and 8.49 (1 H,
d, J 8.0, 4-H), values were assigned using NOESY and COSY
correlation spectra; dC 47.33 (13-C), 121.38 (10a-C), 126.49
(10-C), 127.49 (9-C), 128.00 (1-C), 128.59 (2-C), 128.79 (7-C),
128.85 (14a-C), 129.45 (13a-C), 130.71 and 130.75 (3-C and
4-C), 131.56 (14-C), 134.60 (8-C), 149.40 and 149.47 (6a-C,
4a-C), 151.22 (5a-C), 152.58 (5b-C) and 160.68 (11-C);
m/z(FAB) 286 [(M + H)+, 100%, Found 286.0984. C18H11N3O +
H requires 286.0980], 249 (45), 190 (30), 167 (12), 127 (14), 115
(45) and 105 (25); m/z (EI) 285 (M+, 100%), 257 (10), 229 (8),
189 (3), 149 (8), 128 (5), 115 (11), 84 (28), 77 (9), 71 (18), 57 (29)
and 43 (14).
Data for 38/39 [(mixture of E/Z-isomers (2.8 : 1)]: [Found
(M − CONH2)+ 261.1027. C18H13N3O − CONH2 requires
261.1027]; mmax (DCM)/cm−1 1682, 1587, 1265 and 727; dH
(400 MHz) 5.40 (2 H, dd, J = 1.2, 6.6 Hz, CH2, E-isomer),
5.50 (2 H, dd, J 2.0, 6.0, CH2, Z-isomer), 5.67 (1 H, dt, J 6.0,
11.8, propenyl 2-H, Z), 5.77 (1 H, brs, NH, E), 6.39 (1 H, dt, J
6.6, 15.8, propenyl 2-H, E), 6.61 (1 H, dd, J 2.0, 11.8, propenyl
3-H, Z; NOE with Z-propenyl 2-H of 8.4% but none with the
methylene indicating Z-stereochemistry), 6.73 [1 H, br d, J 1.2,
15.8, propenyl 3-H, E; NOE with Z-propenyl 2-H (1.7%) and
the methylene (3.8%) indicating E-stereochemistry], 7.21 (1 H,
ddd, J 8.0, 1.6, 1.6, phenyl o-H, Z), 7.22 (1 H, ddd, J 8.0, 8.0, 1.6,
phenyl p-H, E), 7.25–7.31 (2 H each, m, phenyl-H, E,Z overlap),
7.35–7.37 (2 H each, m, phenyl-H, E,Z overlap), 7.47 (1 H, brs,
NH), 7.56 (1 H, ddd, J 1.3, 7.9, 7.9, 6-H, Z), 7.58 (1 H, ddd, J
1.3. 7.9, 7.9, 6-H, E), 7.69 (1 H, ddd, J 0.6, 1.3, 7.9, 8-H, Z),
7.70 (1 H, ddd, J 0.6, 1.3, 7.9, 8-H, E), 7.75 and 7.77 (1 H each,
ddd, J 1.3, 7.9, 7.9, 7-H, E,Z overlap), 8.30 (1 H, ddd, J 0.6,
1.3, 7.9, aryl 5-H, Z) and 8.34 (1 H, ddd, J 0.6, 1.3, 7.9, 5-H, E);
values were assigned using COSY correlation; m/z (GC–MS,
EI) GC–MS showed two peaks with similar retention times and
mass spectra; major isomer: 287 (25%), 279 (5), 258 (2), 196
(50), 167 (10), 117 (100), 91 (34), 76 (13), 63 (12) and 51 (8). The
structure of 38 was confirmed by unambiguous synthesis (TLC,
IR and 1H NMR spectra).
4-Oxo-3-[(E)-3-phenylprop-2-enyl]-3,4-dihydroquinazoline-2-
carboxylic acid amide 38
4-Oxo-3-[(E)-3-phenylprop-2-enyl]-3,4-dihydroquinazoline-2-
carboxylic acid ethyl ester 47 (0.50 g, 1.5 mmol) was dissolved
in a absolute ethanol (10 cm3) to which was added concentrated
aqueous ammonia (100 cm3). The reaction was stirred for
30 min and the resultant precipitate filtered off. The precipitate
was washed with water and dried to yield the title compound 38
as a white solid (0.315 g, 69%) (Found 306.1237. C18H15N3O2 +
H requires 306.1237); mmax (thin film)/cm−1 1675, 1653, 1585,
1559, 1457 and 1436; dH (400 MHz, d6-DMSO) 4.93 (1 H, J =
6.8 Hz, CH2N), 6.36 (1 H, J 6.8, 16.1, propenyl-2-H), 6.55 (1 H,
J 16.1, propenyl-3-H), 7.23 (1 H, t, J 7.6, Ph p-H), 7.31 (2 H,
t, J 7.6, 7.6, Ph m-H), 7.40 (2 H, t, J 7.6, 7.6, Ph o-H), 7.62
(1 H, ddd, J 1.2, 7.9, 7.9, 6-H), 7.74 (1 H, ddd, J 0.5, 1.2, 7.9,
8-H), 7.90 (1 H, ddd, J 1.2, 7.9. 7.9, 7-H), 8.19 (1 H, ddd,
J 0.5, 1.2, 7.9, 5-H), 8.15 (1 H, brs, NH) and 8.45 (1 H, brs,
NH); dC (100 MHz, d6-DMSO) 50.8 (CH2), 126.3 (qC), 129.3
(propenyl-2-C), 131.5 (Ph o-C), 131.6 (5-C), 132.6 (8-C), 133.0
(6-C), 133.1 (Ph p-C), 133.8 (Ph m-C), 137.8 (propenyl-3-C),
140.0 (7-C), 141.2 (qC), 151.5 (qC), 155.5 (qC), 165.5 (qC),
and 168.8 (qC). The assignments were confirmed with COSY,
HMQC and NOESY techniques; m/z (EI) no M+; (CI) 306
([M + H]+, 90%), 263, (100) and 190 (28). The 1H NMR spectra
in CDCl3 and TLC were identical to those in the mixture from
the radical reaction to synthesise luotonin A. All peaks in the
IR spectrum taken in DCM were identified in the IR spectrum
of the mixture.
With di-tert-butyl peroxide.
A solution of 3-[(Z)-2-
iodo-3-phenylprop-2-enyl]-4-oxo-3,4-dihydroquinazoline-2-
carbonitrile 27 (90.6 mg, 0.219 mmol), hexamethylditin
(274.2 mg, 0.837 mmol, 3.8 equiv.) and di-tert-butyl peroxide
(98%, 64.9 mg, 0.423 mmol, 2.0 equiv.) in tert-butylbenzene
(3.5 cm3) in a Schlenk tube was subjected to the freeze–thaw
method (six times). The sealed tube was immersed in an oil bath
at 120 ◦C for 24 h surrounded by a safety shield in a fumehood.
The reaction mixture was cooled to room temperature and
placed directly on a silica gel column. Elution with light
petroleum removed the tert-butylbenzene. Further elution with
Acknowledgements
We thank the EPSRC for postdoctoral Research Associate
grants (M. O. C and A. J. F) and a DTA grant (T. S.) and the
EPSRC Mass Spectrometry Unit, Swansea University, Wales for
mass spectra.
1 4 6 6
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 4 6 0 – 1 4 6 7

View Article Online
17 Reviews: A. G. Fallis and I. M. Brinza, Tetrahedron, 1997, 53, 17543;
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