Microwave-assisted syntheses of N-heterocycles using alkenone-, alkynone- and aryl-carbonyl O-phenyl oximes: Formal synthesis of neocryptolepine

Article abstract of DOI:10.1021/jo800847h

(Chemical Equation Presented) This research aimed to provide a new and "clean" synthetic method that would enable both known and novel N-heterocycles to be prepared efficiently. O-Phenyl oximes were found to be excellent precursors for iminyl radicals with a variety of acceptor side chains. Dihyropyrroles were made in good yields from O-phenyl oximes containing pent-4-ene acceptors. The analogous process with a hex-5-enyl acceptor did not yield a dihydropyridine, probably because the 6-exo-trig ring closure of the iminyl radical was too slow to compete with H-atom abstraction. The iminyl radical from a precursor with a pent-4-yne type side chain underwent ring closure followed by rearrangement to afford a pyrrole derivative. Suitably substituted iminyl radicals ring closed readily onto aromatic acceptors, thus enabling several polycyclic systems to be accessed. Quinolines were made from 3-phenylpropanones via their O-phenyl oximes. Syntheses of phenanthridines starting from 2-formylbiphenyls were particularly efficient, and this approach enabled the natural product trisphaeridine to be made. Starting from 2-phenylnicotinaldehyde derivatives, ring closures of the derived iminyl radicals onto the phenyl rings yielded benzo[h][1,6]naphthyridines. Similarly, ring closure onto a phenyl ring from a benzothiophene-based iminyl yielded a benzo[b-]thieno[2,3-c]quinoline. By way of contrast, iminyl radical ring closure onto pyridine rings was not observed. However, iminyl radicals did cyclize onto indoles, enabling indolopyridines to be prepared. The latter route was exploited in a short formal synthesis of neocryptolepine starting from 2-((1H-indol-3-yl)methyl)cyclohexanone.

Full text of DOI:10.1021/jo800847h

Microwave-Assisted Syntheses of N-Heterocycles Using Alkenone-,
Alkynone- and Aryl-carbonyl O-Phenyl Oximes: Formal Synthesis of
Neocryptolepine
Fernando Portela-Cubillo,† Jackie S. Scott,§ and John C. Walton*,†
School of Chemistry, EaStChem, UniVersity of St. Andrews, St. Andrews, Fife KY16 9ST, U.K., and
GlaxoSmithKline, New Frontiers Science Park, Third AVenue, Harlow, Essex CM19 5AW, U.K.
jcw@st-and.ac.uk
ReceiVed April 21, 2008
This research aimed to provide a new and “clean” synthetic method that would enable both known and
novel N-heterocycles to be prepared efficiently. O-Phenyl oximes were found to be excellent precursors
for iminyl radicals with a variety of acceptor side chains. Dihyropyrroles were made in good yields from
O-phenyl oximes containing pent-4-ene acceptors. The analogous process with a hex-5-enyl acceptor
did not yield a dihydropyridine, probably because the 6-exo-trig ring closure of the iminyl radical was
too slow to compete with H-atom abstraction. The iminyl radical from a precursor with a pent-4-yne
type side chain underwent ring closure followed by rearrangement to afford a pyrrole derivative. Suitably
substituted iminyl radicals ring closed readily onto aromatic acceptors, thus enabling several polycyclic
systems to be accessed. Quinolines were made from 3-phenylpropanones via their O-phenyl oximes.
Syntheses of phenanthridines starting from 2-formylbiphenyls were particularly efficient, and this approach
enabled the natural product trisphaeridine to be made. Starting from 2-phenylnicotinaldehyde derivatives,
ring closures of the derived iminyl radicals onto the phenyl rings yielded benzo[h][1,6]naphthyridines.
Similarly, ring closure onto a phenyl ring from a benzothiophene-based iminyl yielded a benzo[b-
]thieno[2,3-c]quinoline. By way of contrast, iminyl radical ring closure onto pyridine rings was not
observed. However, iminyl radicals did cyclize onto indoles, enabling indolopyridines to be prepared.
The latter route was exploited in a short formal synthesis of neocryptolepine starting from
2-((1H-indol-3-yl)methyl)cyclohexanone.
Introduction
because the products are convenient for further functional group
manipulations. The literature on iminyl radical cyclizations is
not extensive, but the most studied process is the 5-exo-trig
closure of pent-4-enyl-iminyl types yielding 3,4-dihydro-2H-
pyrroles.2 It can be inferred from available kinetic data that the
rate constant for this iminyl cyclization is only about a factor
of 20 less than that of the archetype hex-5-enyl radical3 and
therefore the reaction is fast enough for incorporation into a
variety of preparative sequences.1a,2 An important objective has
been to find ways of generating iminyls that are “clean”, flexible,
Radical-mediated methods of preparing heterocycles are
steadily entering mainstream organic synthesis because their
experimental conditions are usually mild and neutral and because
novel derivatives can be accessed in this way.1 Ring closures
of iminyl radicals (R2CdN•) appear particularly promising
† University of St. Andrews.
§ GSK Harlow.
(1) For reviews, see: (a) Bowman, W. R.; Bridge, C. F.; Brookes, P. J. Chem.
Soc. Perkin Trans. 1 2000, 1–14. (b) Stella, L. In Radicals in Organic Synthesis;
Renaud, P., Sibi, M. P., Eds; Wiley-VCH: Weinheim, 2001; Vol. 1, p 317. (c)
Walton, J. C. Top. Curr. Chem. 2006, 264, 163–200. (d) McCarroll, A. J.; Walton,
J. C. Angew. Chem., Int. Ed. 2001, 40, 2224–2248. (e) Baguley, P. A.; Walton,
J. C. Angew. Chem., Int. Ed. 1998, 37, 3072–3082.
(2) Fallis, A. G.; Brinza, I. M. Tetrahedron 1997, 53, 17543–17594.
(3) Le Tadic-Biadatti, M.-H.; Callier-Dublanchlet, A.-C.; Horner, J. H.;
Quiclet-Sire, B.; Zard, S. Z.; Newcomb, M. J. Org. Chem. 1997, 62, 559–563.
5558 J. Org. Chem. 2008, 73, 5558–5565
10.1021/jo800847h CCC: $40.75 2008 American Chemical Society
Published on Web 06/13/2008

Syntheses of N-Heterocycles using O-Phenyl Oximes
SCHEME 1. Products from Thermal Reaction of Phenyl
N-Phenoxybenzimidate 1
and simple. Iminyl radical precursors used with tin hydrides or
transition metals, e.g., N-alkenyl-S-arylthiohydroxylamines,4
N-benzotriazolylimines,5 and oxime esters,4,6 are not ideal
because of the toxicity of the metals. Direct or sensitized
photolyses of oxime esters of N-hydroxypyridine-2-thione,7 of
ketoxime xanthates,8 of acyloximes,9,10 and of O-(4-cyanophe-
nyl)oximes11 also yield iminyl radicals. However, for preparative
work, thermal treatment of an appropriate precursor is usually
a more desirable tactic because it is simpler and experimentally
convenient and because it readily lends itself to scale-up.
Scarcely any precursors suitable for thermal release of iminyls
are known, except for special cases such as the formation of
quinoline derivatives by heating suitably functionalized O-2,4-
dinitrophenyloximes with sodium hydride12 and preparations of
several types of heterocycles in cascade processes involving
iminyl formation from ring closure of imidoyl radicals onto
cyanoalkyl groups.13,14
SCHEME 2. Microwave-Assisted Preparation of a
Dihydropyrrole
Quite recently it was discovered that O-phenyl oxime ethers
(RR′CdN-OPh) are a new class of nonazo and nonperoxide
free-radical initiators that release iminyl and phenoxyl radicals
at relatively low temperatures.15 From detailed studies of the
thermal dissociation of a representative set of these compounds
the N-O bond dissociation energies were determined to be only
ca. 35 kcal mol-1 for R,R′ ) Me and Ph. Thus the N-O bonds
of these compounds are actually weaker than the O-O bonds
of dialkyl peroxides.15 O-Phenyl oxime ethers are easily
prepared from aldehydes or ketones simply by condensing them
with the commercially available O-phenylhydroxylamine hy-
drochloride in anhydrous pyridine at room temperature. We
anticipated, therefore, that it would be possible to devise
convenient thermal procedures for preparing dihydropyrroles
and other heterocycles from conversion of unsaturated ketones
to the corresponding O-phenyl oxime ethers. Thermal release
of the unsaturated iminyl radicals would be followed by their
ring closure. In practice, however, difficulties were encountered
in preparative work. In conventional, sealed tube type ther-
molyses of O-phenyl oxime ethers derived from hexenone and
related ketones, reaction times had to be long, products were
not cleanly formed at higher temperatures, and yields were
disappointingly low. Similarly, thermal decomposition of phenyl
N-phenoxybenzimidate 1 in a sealed tube was still incomplete
after 26 h at 90 °C and the ring-closed oxazole 2 (∼9%) was
accompanied by significant amounts of phenyl benzimidate and
benzonitrile (Scheme 1).15
It occurred to us that thermolyses of O-phenyl oxime ethers
might give cleaner product mixtures and that the reaction times
would be considerably shortened if microwave irradiation were
to be employed. We therefore investigated iminyl radical
generation and cyclization using microwave irradiation of a
representative range of functionalized O-phenyl oxime ethers.
We found that under appropriate microwave conditions good
to excellent yields of heterocycles could indeed be obtained. In
this paper we report that dihydropyrroles can be prepared from
alkenone O-phenyl oximes and that phenanthridine, benzonaph-
thiridine, and indolopyridine derivatives can be made by iminyl
ring closures onto aromatic radical acceptors. Part of this
research has previously been published as a preliminary
communication.16
Results and Discussion
Discovery and Optimization. The O-phenyl oxime ether 4
was prepared in 75% yield as a mixture of E and Z isomers by
stirring methyl 4-oxooct-7-enoate 3 with O-phenylhydroxy-
lamine hydrochloride in pyridine at room temperature. The fact
that two isomers were present did not matter because both
released the same iminyl radical 5 on scission of their N-O
bonds (Scheme 2). Solutions of 4 in toluene were irradiated in
a Biotage Initiator microwave reactor (nominally 300 MHz) at
various temperatures and for various times. The loss factor of
toluene is low (tan δ ) 0.04), so the ionic liquid 1-ethyl-3-
methyl-1H-imidazol-3-ium hexafluorophosphate (emimPF6, IL)
was included to increase the microwave absorbance level of
the medium. Encouragingly, this process cleanly gave the 3,4-
dihydropyrrole 7 (1:1 mixture of enantiomers) and phenol as
the only detectable products. The ionic liquid should be
recoverable, but we made no attempt to recycle it.
(4) Zard, S. Z. Synlett 1996, 1148–1154.
(5) Kaim, L. E.; Meyer, C. J. Org. Chem. 1996, 61, 1556–1557.
(6) Takai, K.; Katsura, N.; Kunisada, Y. Chem. Commun. 2001, 1724–1725.
(7) Boivin, J.; Fouquet, E.; Zard, S. Z. Tetrahedron Lett. 1991, 32, 4299–
4302.
(8) Boivin, J.; Schiano, A.-M.; Zard, S. Z. Tetrahedron Lett. 1992, 33, 7849–
7852.
(9) Kitamura, M.; Mori, Y.; Narasaka, K. Tetrahedron Lett. 2005, 46, 2373–
2376. (b) Yoshida, M.; Kitamura, M.; Narasaka, K. Bull. Chem. Soc. Jpn. 2003,
76, 2003–2008.
(10) (a) Alonso, R.; Campos, P. J.; Garcia, B.; Rodriguez, M. A. Org. Lett.
2006, 8, 3521–3523. (b) Alonso, R.; Campos, P. J.; Rodrıguez, M. A.; Sampedro,
D. J. Org. Chem. 2008, 73, 2234–2239.
(11) Mikami, T.; Narasaka, K. Chem. Lett. 2000, 338–339.
(12) Narasaka, K.; Uchiyama, K.; Ono, A.; Hyashi, Y. Bull. Chem. Soc. Jpn.
1998, 71, 2945–2955.
The effect of different temperatures and reaction times on
the yield of 7 was monitored by NMR spectroscopy, and the
results are shown in Table 1. Entries 1-4 show that a
temperature of 160 °C was necessary to achieve complete
(13) Nanni, D.; Pareschi, P.; Rizzoli, C.; Sgarabotto, P.; Tundo, A. Tetra-
hedron 1995, 51, 9045–9062.
(14) Leardini, R.; McNab, H.; Minozzi, M.; Nanni, D. J. Chem. Soc., Perkin
Trans. 1 2001, 1072–1078.
(15) (a) Blake, J. A.; Pratt, D. A.; Lin, S.; Walton, J. C.; Mulder, P.; Ingold,
K. U. J. Org. Chem. 2004, 69, 3112–3120. (b) Portela-Cubillo, F.; Scott, J. S.;
Walton, J. C. Chem. Commun. 2008, in press. DOI: 10.1039/b803630f.
(16) Portela-Cubillo, F.; Scott, J. S.; Walton, J. C. Chem. Commun. 2007,
4041–4043.
J. Org. Chem. Vol. 73, No. 14, 2008 5559

Portela-Cubillo et al.
TABLE 1. Optimization of Dihydropyrrole Yield from Microwave
Irradiations of 4a
SCHEME 3. Potential Route to a Pyrrolizidine Derivative
entry phenyl oxime 4 (mmol) T (°C) time (min) yield of 7 (mol %)b
1
2
3
4
5
6
7
8
9
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.3
0.4
0.5
120
140
160
180
160
160
160
160
160
160
10
10
10
10
5
15
20
15
15
15
25
55
75
72c
66
99
96
78
67
59
10
a Reactions in PhMe (1.5 mL) containing emimPF6 (0.05 g) with
CH2Br2 as internal standard. b Yields in mol % determined by 1H NMR.
c Amount of emimPF6 was 0.075 g.
of 4-methoxy-4-oxobutanoic acid and 5-methoxy-5-oxopen-
tanoic acid, respectively, with but-3-enylmagnesium bromide.
The aryl-butenyl ketones 8d,e were made by treatment of
4-methoxyacetophenone, and the 2,4-dimethoxy analogue, with
KH and allyl bromide.
TABLE 2. Preparation of 3,4-Dihydropyrroles from Alkenone
O-Phenyl Oximes
The conversions of the ketones to the corresponding oxime
ethers 9a-e by treatment with O-phenylhydroxylamine hydro-
chloride were straightforward, and yields of 70-75% were
normally obtained (Table 2). The optimum conditions for
microwave irradiations established before, i.e., 160 °C for 15
min, proved to be very effective. Entry 1 shows that the method
was tolerant of a side chain containing an additional double
bond. Entries 2 and 3 indicate good tolerance of ester groups.
The final two entries (4 and 5) show that butenyl ketones with
aromatic substituents also worked well, affording 5-aryldihy-
dropyrroles in good yields.
We investigated methods for converting ester-containing
dihydropyrrole 10b into a pyrrolizidine derivative by means of
an intramolecular nucleophilic substitution. Initially we hoped
to achieve selective reduction of the imine bond in the
dihydropyrrole ring to yield pyrrolidinyl ester 11a. In practice,
reactions with NaBH4, NaBH3CN, and NaBH(OAc)3 all gave
mixtures of 11a and alcohol 11b from reductions of both the
ester and imine groups. Complete reduction of the imine and
ester to cleanly give 11b was therefore carried out with LiAlH4.
Ring closure was first attempted via the mesylate. However,
it was found that treatment of 11b with MeSO2Cl led to a
dimesylate from conversion of both the alcohol and amine
groups. An alternative Appel type method, which has worked
for other pyrrolizidine derivatives,18 was therefore tried. Surpris-
ingly, however, when amine 11b was treated with PPh3, CCl4,
and Et3N in DCM, the main product (26%) was found to be
2-(but-3-enyl)pyrrolidine 14. A mechanistic rationale of this
result is shown in Scheme 3. The alcohol side chain is likely to
react with the phosphonium chloride to yield alkoxy-triph-
enylphosphonium intermediate 12.19 Intramolecular nucleophilic
displacement of the phosphonium group will generate pyrroliz-
idinyl-ammonium ion 13. This intermediate will be susceptible
to Hofmann type eliminations, promoted by the triethylamine
base. In keeping with the Hofmann rule, one of the methyl
H-atoms will be selectively removed by the base, rather than
any of the secondary ring ꢀ-H atoms, to yield the least stable
alkene 14.
entry
ketone
yield of 9 (mol %)a
yield of 10 (mol %)a
1
2
3
4
5
8a
8b
8c
8d
8e
71
75
78
73
70
70
78
82
68
77
a Yields of isolated products.
conversion and high yields but that at higher temperatures side
reactions/degradative process set in. Entries 3 and 5-7 show
that at 160 °C best yields were obtained with an irradiation time
of 15 min. However, for larger amounts of precursor 4 (entries
8-10), yields fell off in 15 min reactions.
The NMR spectrum of the total reaction mixture from entry
6 showed essentially quantitative formation of dihydropyrrole
7 together with an equal quantity of phenol. This supported the
mechanism shown in Scheme 2 and indicated that microwave
irradiation could be applied in an efficient method for use with
O-phenyl oximes.
Application to Dihydropyrrole Preparations. Numerous
biologically active alkaloids contain dihydropyrrole or related
rings.17 Our thermal methodology appeared capable of convert-
ing ketones with but-3-enyl type substituents into dihydropyr-
roles in two steps. The scope of this pathway was probed by
preparing the set of precursor oxime ethers shown in Table 2.
Ketone 8a was commercially available. The ester-containing
ketones 8b,c were prepared by treatment of the acid chlorides
In principle, tetrahydropyridines might be obtained from 6-exo
ring closures of hexenyl-iminyls. The O-phenyl oxime of
1-phenylhex-5-en-1-one [i.e., PhO-NdC(Ph)(CH2)3CHdCH2]
(18) Vargas-Sanchez, M.; Couty, F.; Evano, G.; Prim, D.; Marrot, J. Org.
Lett. 2005, 7, 5861–5864.
(19) (a) Appel, R.; Kleinstueck, R.; Ziehn, K. Angew. Chem., Int. Ed. 1971,
10, 132–132. (b) Slagle, J. D.; Huang, T. T.-S.; Franzus, B. J. Org. Chem. 1981,
46, 3526–3530.
(17) (a) Bellina, F.; Rossi, R. Tetrahedron 2006, 62, 7213–7256. (b)
Constantino, L.; Barlocco, D. Curr. Med. Chem. 2006, 13, 65–85.
5560 J. Org. Chem. Vol. 73, No. 14, 2008

Syntheses of N-Heterocycles using O-Phenyl Oximes
SCHEME 4. Pyrrole Formation from Iminyl Cyclization
onto an Alkyne Acceptor
SCHEME 5. Preparation of Quinolines
was examined as a model compound for this process. Microwave
irradiation of this precursor in toluene, followed by the usual
workup, gave phenol and 1-phenylhex-5-en-1-one, together with
several minor components. The 1-phenylhex-5-en-1-one was
almost certainly produced from in situ hydrolysis of the
corresponding imine. The main reaction was therefore simply
H-atom abstraction by the iminyl radical from the solvent and
6-exo-cyclization was too slow to compete.
Cyclization onto an Alkyne Acceptor; Preparation of a
Pyrrole Derivative. The O-phenyl oxime of cyclohexylhex-5-
yn-2-one 15 was chosen as a precursor to probe the effectiveness
of the alkyne group as an acceptor for iminyl radical cycliza-
tions. Compound 15 was prepared by ruthenium catalyzed
conjugate addition of ethynyl cyclohexane to methyl vinyl
ketone using the method of Kim and co-workers,20 followed
by the standard O-phenyl oxime conversion. Microwave ir-
radiation of 15 in toluene at 160 °C for 15 min gave pyrrole 18
in 72% yield (Scheme 4). Vinyl radical 16 was expected to
rapidly abstract an H-atom from the solvent to produce 17.
However, under the microwave conditions, it appears that two
1,3-proton migrations converted 17 to pyrrole 18, the aromaticity
of this product ensuring this was a rapid and complete
rearrangement.
O-Phenyl oxime ether 19, with an alkynylaryl skeleton, was
also prepared by Pd-catalyzed coupling of 2-bromobenzaldehyde
with ethynylcyclohexane followed by condensation with O-
phenylhydroxylamine hydrochloride. Microwave irradiation of
19 in toluene led to a complex mixture of products including
the imine 20a, its hydrolysis product 20b, and trace amounts
of the corresponding nitrile. In this case neither 5-exo nor 6-endo
ring closure was fast enough to compete successfully with
H-atom abstraction from solvent, and other side reactions.
Cyclization onto Phenyl Rings: Preparation of Quino-
line, Phenanthridine, and Benzonaphthiridine Derivatives.
With aromatic rings acting as iminyl radical acceptors, cyclo-
hexadienyl-type radicals will be produced. In principle, cyclo-
hexadienes, formed in a final H-atom transfer from solvent,
could be expected, but in practice, removal of an H-atom and
restoration of aromaticity to the ring has usually been
observed.1,10,16 Non-H-atom donor solvents were therefore
required to facilitate this oxidative process. We originally tried
some 5-exo-type cyclizations, but apart from the microwave-
assisted reaction of 2-oxo-2-phenylacetaldehyde oxime giving
3H-indol-3-one,16 intractable mixtures were obtained. However,
the methodology proved much more successful in preparations
of six-membered ring azaaromatics from 6-endo ring closures
of appropriate precursors. 3-Phenyl oxime ethers 22a,b were
easily prepared from the corresponding ketones (Scheme 5).
When subjected to microwave irradiation in tert-butylbenzene
as non-H-atom donor solvent and including emimPF6, 22a gave
a 46% yield of quinoline (26a) and similarly 22b afforded
tetrahydroacridine (26b) in 51% yield. For these and subsequent
cyclizations onto aromatic acceptors an irradiation time of 30
min was adopted to ensure complete reaction. 6-Endo cycliza-
tions of the initial iminyl radicals 23a,b will produce cyclo-
hexadienyl radicals 24a,b. Loss of an H-atom will restore
aromaticity to the benzo rings with production of dihydroquino-
lines 25a,b.21 However, in both cases, a further in situ
dehydrogenation took place such that only the fully aromatic
quinolines 26a,b could be isolated after the microwave irradiation.
In another application we used an aromatic ring, rather than
a chain, to support a second aromatic acceptor next to the oxime
ether group, i.e., situated ortho to each other. In these systems
the derived iminyl radicals are ideally placed for intramolecular
addition to the ring of the adjacent acceptor. An iminyl radical
mediated route to derivatives of phenanthridine is shown in
Scheme 6. These azaaromatics are biologically active and have
numerous other uses.22 2-Formylbiphenyls 27 were prepared
by Pd-catalyzed coupling of 2-bromobenzaldehyde with various
aromatic boronic acids23 in yields ranging from 62% to 71%
(Scheme 6). They were converted to the corresponding O-phenyl
oximes 28a-d by treatment with PhONH2 ·HCl. Individual
precursors in t-BuPh with emimPF6 as ionic liquid were then
irradiated with microwaves for 30 min. Using this methodology
gave the parent phenanthridine 29a which was isolated in 76%
yield along with phenol. The reaction was equally successful
(21) The cyclohexadienyl H-atoms could be abstracted by phenoxyl radicals
or other radicals in the system, or possibly by electron transfer from 24 yielding
the corresponding cyclohexadienyl cations which then lose a proton. The latter
route seems unlikely in t-BuPh solvent and in the absence of a good electron-
acceptor molecule. Air oxidation of 25a,b during workup is another possibility.
(22) Keller, P. A. Sci. Synth. 2005, 15, 1065–1088.
(23) Khanapure, S. P.; Garvey, D. S.; Young, D. V.; Ezawa, M.; Earl, R. A.;
Gaston, R. D.; Fang, X.; Murty, M.; Martino, A.; Shumway, M.; Trocha, M.;
Marek, P.; Tam, S. W.; Janero, D. R.; Letts, L. G. J. Med. Chem. 2003, 46,
5484–5504.
(20) Chang, S.; Na, Y.; Choi, E.; Kim, S. Org. Lett. 2001, 3, 2089–2091.
J. Org. Chem. Vol. 73, No. 14, 2008 5561

Portela-Cubillo et al.
SCHEME 6. Preparations of Phenanthridines
In a similar vein, the natural product trisphaeridine 35 was
prepared in three steps starting from commercial 6-bromopip-
eronal, via the corresponding formyl 32a and oxime ether 33a
derivatives. A 70% yield of 35 was obtained from microwave
irradiation of 33a in t-BuPh. Previous syntheses have been
accomplished via tributyltin hydride induced cyclization of N-(2-
bromobenzyl)aniline,27 via the internal Pd-catalyzed aryl-aryl
coupling reaction of MOM protected halo amides, followed by
reduction with LiAlH4 and treatment with hydrochloric acid,28
and by Pd[0]-mediated Ullmann cross-coupling of 1-bromo-2-
nitrobenzene with 6-bromopiperonal.29
A simple extension of this method appeared to offer a route
to benzo[c][1,7]naphthiridine derivatives. The sequence started
with Pd-catalyzed coupling of 6-bromopiperonal with pyridin-
4-ylboronic acid to give formyl derivative 32b, which was then
transformed to the O-phenyl oxime ether 33b in good yield.
However, when the latter was subjected to microwave irradia-
tion, none of the desired benzonaphthiridine was formed.
Instead, a mixture of imine 36 and its hydrolysis product 32b
was obtained. This result suggested that ring closure of
intermediate iminyl radical 34b onto the pyridine ring was
slower than cyclization onto the phenyl ring and unable to
compete with H-atom abstraction from other reaction compo-
nents. Reports of ring closures of C-centered radicals onto
pyridine rings are comparatively rare,30 and the reaction is
usually low-yielding in comparison with ring closure onto
pyridinium salts.31–33 Iminyl radicals are expected to be elec-
trophilic in comparison with C-centered radicals, and therefore
their even slower cyclization onto pyridine, due to an unfavor-
able polar effect with the ring N-atom, makes reasonable sense.
SCHEME 7. Preparation of Trisphaeridine 35
The methodology was, however, readily adapted for prepara-
tions of benzo[h][1,6]naphthyridines by using pyridine as the
basal support for the aromatic acceptor and iminyl radical.
2-Bromonicotinaldehyde 37 underwent Pd-catalyzed couplings
with phenylboronic acids to afford 2-aryl-3-formyl-pyridine
derivatives 38a-c, which were smoothly converted to the
corresponding oxime ethers 39a-c (Scheme 8). On irradiation
of 39a with microwaves in the usual way a very satisfactory
yield of benzo[h][1,6]naphthyridine 40a was obtained. The
results from the precursors with CN and Br substituents showed
that benzo[h][1,6]naphthyridines containing useful functionality
at the 8-position 40b,c could easily be accessed. A few
benzo[h][1,6]naphthiridine derivatives have been reported in the
literature,34 but none appear to be commercially available. We
also examined the use of benzothiophene as the support for the
iminyl radical and acceptor. Thus, precursor 43 was prepared
from 3-bromobenzothiophene-2-carbaldehyde 41 using an analo-
gous sequence (Scheme 8). On irradiation with microwaves we
were able to isolate benzo[b]thieno[2,3-c]quinoline 44 in a 53%
yield.35
for precursors containing electron-withdrawing substituents (Br,
CN), which yielded 29b,c, and for a precursor containing an
electron-releasing substituent (OMe), which gave the 3-methoxy
derivative 29d. The 3-bromo and 3-cyano-phenanthridines are
convenient for further functional group transformations.
The interesting analog benzo[k]phenanthridine (31) appeared
to be accessible via an analogous route. It had previously been
made by cyclization of aryl formamides,24 photocyclization of
4-phenyl-3-vinylquinolines,25 and an anionic/aryne cyclization
and in situ oxidation sequence starting from 2-bromonaphthyl-
2-fluorophenylamine.26 Our three-step preparative method is
based on the naphthalene-containing precursor 30, which was
made by a Suzuki coupling route similar to that shown for 27
but starting from 2-bromonaphthaldehyde and phenylboronic
acid. Microwave irradiation of 30 under the standard conditions
in t-BuPh enabled 31 to be isolated in 64% yield.
(27) Rosa, A. M.; Prabhakar, S.; Lobo, A. M. Tetrahedron Lett. 1990, 31,
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(28) Harayama, T.; Akamatsu, H.; Okamura, K.; Miyagoe, T.; Akiyama, T.;
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(29) Banwell, M. G.; Lupton, D. W.; Ma, X.; Renner, J.; Sydnes, M. O.
Org. Lett. 2004, 6, 2741–2744.
(30) Cyclizations onto 6-chloropyridines appear to be an exception; see:
Bacque, E.; Qacemi, M. El.; Zard, S. Z. Org. Lett. 2004, 6, 3671–3674.
(31) Barton, D. H. R.; Garcia, B.; Togo, H.; Zard, S. Z. Tetrahedron Lett.
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(32) Minisci, F.; Vismara, E.; Fontana, F. Heterocycles 1989, 28, 489–519.
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W. Pol. J. Chem. 1981, 55, 2199–2204. (c) Godard, A.; Queguiner, G.
J. Heterocycl. Chem. 1982, 19, 1289–1296.
(24) Boyer, J. H.; Patel, J. R. Synthesis 1978, 205–205.
(25) Veeramani, K.; Shanmugam, P. Indian J. Chem. 1987, 26B, 116–121.
(26) Sanz, R.; Fernandez, Y.; Castroviejo, M. P.; Perez, A.; Fananas, F. J.
Eur. J. Org. Chem. 2007, 62–69.
5562 J. Org. Chem. Vol. 73, No. 14, 2008

Syntheses of N-Heterocycles using O-Phenyl Oximes
SCHEME 8. Preparation of Benzo[h][1,6]naphthyridines
and Benzothiophenoquinolines
SCHEME 9. Preparation of Indolopyridine and
Indoloquinoline Derivatives
resonance stabilized benzyl type radical, unlike the alternative
5-exo mode which would involve formation of a strained spiro-
C-atom.
An analogous sequence was designed for the preparation of
the natural product neocryptolepine 50 (Scheme 9). The indolo-
ketone 47 was obtained in 78% yield from reaction of gramine
with 1-cyclohexenylpyrrolidine.39 Conversion to the correspond-
ing O-phenyl oxime ether 48 was accomplished in 70% yield.
Microwave irradiation of 48 in t-BuPh afforded tetrahydroin-
dolo[2,3-b]quinoline 49 in 69% yield. As with several previous
products of these microwave-mediated reactions, a second in
situ dehydrogenation step rendered the newly formed pyridine
ring aromatic. Tetrahydroindolo[2,3-b]quinoline 49 is a known
compound and has previously been converted to neocryptolepine
50 in two steps by dehydrogenation/aromatization with DDQ
followed by methylation with methyl sulfate.37a Thus, overall,
the sequence represents a formal synthesis of neocryptolepine
50 in five steps from gramine.
It is evident that iminyl ring closure onto the phenyl ring
occurs readily, although the lower yield may indicate it is
slightly more difficult with this architecture because of the larger
bond angles of the adjacent iminyl and phenyl groups on the
5-membered ring as compared with a six-membered ring.
Cyclization onto Indole: Syntheses of Functionalized
Indolopyridines. Compounds related to indolopyridines and
indoloquinolines are known to be cytotoxic and to have
anticancer activity. For example, neocryptolepine derivatives
(e.g., 50) showed potent in vitro antimalarial activity.36 Related
heterocycles37 including 5-aza-ellipticine analogues38 are also
biologically active. The ZrCl4-catalyzed reaction of indole with
methyl vinyl ketone yielded 4-(1H-indol-3-yl)butan-2-one from
which O-phenyl oxime ether 45 was obtained. Interestingly,
microwave irradiation of 45 in tert-butanol afforded indolopy-
ridine derivative 46 in which both the acceptor ring and the
pyridyl ring had become aromatic. 6-Endo cyclization was
probably favored in this example because it generated a
Conclusions
We have shown that O-phenyl oximes are excellent precursors
for a variety of iminyl radicals. The oximes are easily made in
one step from carbonyl compounds and can be stored indefi-
nitely. Their microwave-assisted reactions have several advan-
tages over existing methods for N-heterocycle preparations.
Reactions are rapid (e30 min), require no acids, bases, or toxic
metals, and are comparatively mild and high-yielding. Unlike
many other radical-mediated synthetic methods, no initiator is
needed and hence no byproducts from initiator fragments
contaminate the system. Comparatively few microwave-assisted
synthetic methods, based around radical intermediates, are
known.40 The feature most such reactions have in common with
(35) For previous syntheses, see: (a) Deprets, S.; Kirsch, G. ARKIVOC 2002,
40–48. (b) Luo, J. K.; Castle, S. L.; Castle, R. N. J. Heterocycl. Chem 1990, 27,
2047–2052. (c) Luo, J. K.; Kudo, H.; Federspiel, R. F.; Castle, R. N.
J. Heterocycl. Chem 1995, 32, 317–322. (d) McKenney, J. D., Jr.; Castle, R. N.
J. Heterocycl. Chem. 1987, 24, 1525–1529.
(36) Jonckers, T. H. M.; van Miert, S.; Cimanga, K.; Bailly, C.; Colson, P.;
De Pauw-Gillet, M.-C.; van den Heuvel, H.; Claeys, M.; Lemie`re, F.; Esmans,
E. L.; Rozenski, J.; Quirijnen, L.; Maes, L.; Dommisse, R.; Lemie`re, G. L. F.;
Vlietinck, A.; Pieters, L. J. Med. Chem. 2002, 45, 3497–3508.
(37) (a) Sundaram, G. S. M.; Venkatesh, C.; Syam Kumar, U. K.; Ila, H.;
Junjappa, H. J. Org. Chem. 2004, 69, 5760–5762. (b) Chen, Y.-L.; Hung, H.-
M.; Lu, C.-M.; Li, K.-C.; Tzeng, C.-C. Bioorg. Med. Chem. 2004, 12, 6539–
6546.
(38) (a) Moody, D. L.; Dyba, M.; Kosakowska-Cholody, T.; Tarasova, N. I.;
Michejda, C. J. Bioorg. Med. Chem. Lett. 2007, 17, 2380–2384. (b) Zhang, Q.;
Shi, C.; Zhang, H.-R.; Wang, K. K. J. Org. Chem. 2000, 65, 7977–7983.
(39) Strandtmann, von, M.; Cohen, M. P.; Shavel, J., Jr. J. Org. Chem. 1965,
30, 3240–3242.
(40) (a) Kappe, C. O. Angew. Chem., Int. Ed. 2004, 43, 6250–6284. (b)
Kappe, C. O.; Stadler, A. MicrowaVes in Organic and Medicinal Chemistry;
Wiley-VCH: Weinheim, 2005; pp 213-215.
J. Org. Chem. Vol. 73, No. 14, 2008 5563

Portela-Cubillo et al.
General Procedure for Suzuki Coupling.41 The bromo-
compound (3 mmol) and the boronic acid (3 mmol) were dissolved
in toluene (40 mL), and sodium carbonate (6 mmol, 2M) was added.
To this reaction mixture was added ethanol (2 mL) followed by
tetrakis(triphenylphosphine)-palladium (2%). The reaction mixture
was refluxed overnight under N2 and then diluted with water, the
organic layer was separated, and the aqueous layer was extracted
with EtOAc (2 × 30 mL). The combined organic extracts were
washed with water (3 × 30 mL) and brine (1 × 30 mL) dried over
MgSO4 and filtered. The filtrate was evaporated under reduced
pressure and the residue was purified by column chromatography
on silica gel (hexane/EtOAc).
4-(3-Formylpyridin-2-yl)benzonitrile (38b). White solid, 63%;
138-140 °C; 1H NMR (400 MHz, CDCl3) δ 7.46 (1H, t, J ) 8.0,
CH), 7.65 (2H, d, J ) 8.5 Hz, CH), 7.76 (2H, d, J ) 8.5 Hz, CH),
8.27 (1H, dd, J ) 7.9, 1.8 Hz, CH), 8.84 (1H, dd, J ) 4.7, 1.7 Hz,
CH), 9.97 (1H, s, CH); 13C NMR δ 113.5, 118.3 (C), 123.6 (CH),
129.8 (C), 131.0 (CH × 2), 132.4 (CH × 2), 136.4 (CH), 141.5
(C), 153.8 (CH), 160.0 (C), 190.8 (CH); IR 3020, 2233, 1699, 1581
cm-1; HRMS (CI+) calcd for C13H9N2O 209.0715; found 209.0712.
General Procedure for Microwave-Induced Reactions of
O-Phenyl Oximes. The O-phenyl oxime (∼100 mg) and emimPF4
(1 equiv) were dissolved in toluene (sufficient to make the solution
0.15 M) in a microwave vessel (2-5 mL). For ring closures onto
aromatic acceptors, tert-butylbenzene was used as solvent. The
vessel was sealed and subjected to microwave irradiation for 15
min at 160 °C (30 min for aromatic acceptors) in a Biotage Initiator
system. The temperature was measured by an infrared temperature
probe that determined the temperature on the surface of the vial.
After cooling the ionic liquid was filtered off and the solvent was
removed under reduced pressure. The residue was purified by flash
column chromatography (25% EtOAc/hexane).
our methodology is that the starting radicals are generated by
direct homolysis of a weak bond in the relevant precursor,
brought about by microwave heating, rather than by radical-
induced dissociations brought about by peroxide- or azo-
initiators.
Dihydropyrroles can be made in good yields from O-phenyl
oximes containing pent-4-ene acceptors. However, the analogous
process with a hex-5-enyl acceptor did not yield a dihydropy-
ridine; probably because the 6-exo-trig iminyl radical ring
closure was too slow to compete with H-atom abstraction.
Reduction of dihydropyrrole 10b gave 2-(5-methylpyrrolidin-
2-yl)ethanol 11b, which seemed suitable for conversion to a
pyrrolizidine. In practice, treatment of 11b under Appel type
conditions yielded only 2-(but-3-enyl)pyrrolidine 14. It is
probable that this results from base attack on the 5-methyl group
of a pyrrolizidinyl-ammonium ion intermediate in a Hofmann
elimination. If this explanation is correct, similar eliminations
can be expected for other 5-alkyl-substituted analogs.
Suitably substituted iminyl radicals ring closed readily onto
aromatic acceptors, thus enabling several N-heterocyclic systems
to be accessed. The favored mode of cyclization was 6-endo in
this case because this generated resonance-stabilized cyclo-
hexadienyl (or analogous) radicals. Quinoline was made from
3-phenylpropanone via the O-phenyl oxime; a process with
obvious further scope. Syntheses of phenanthridines starting
from 2-formylbiphenyls were particularly efficient and this
approach enabled the natural product trisphaeridine to be made.
Starting from 2-phenylnicotinaldehyde, and derivatives, ring
closures of the derived iminyl radicals onto the phenyl rings
yielded benzo[h][1,6]naphthyridines. Similarly, ring closure onto
a phenyl ring from benzothiophene-based iminyl yielded ben-
zo[b]thieno[2,3-c]quinoline. It was found that the analogous
iminyl ring closure onto pyridine rings did not compete with
other reactions of the iminyl radical. However, iminyl radical
closure onto indole enabled indolopyridines to be prepared. This
latter route was exploited in a short formal synthesis of
neocryptolepine starting from 2-((1H-indol-3-yl)methyl)cyclo-
hexanone. It is clear that microwave-assisted reactions of
O-phenyl oximes are promising as “clean” and flexible routes
to many biologically active compounds.
5-Methyl-2-(6-methylhept-5-en-2-yl)-3,4-dihydro-2H-pyr-
role (10a). Yellow oil, 70%; 1H NMR (400 MHz, CDCl3) δ 0.71/
0.89 (3H, d, J ) 6.8 Hz, CH3), 1.09 (1H, m, CH2), 1.32-1.54 (2H,
m, CH2), 1.53 (3H, s, CH3), 1.60 (3H, s, CH3), 1.78-1.92 (2H, m,
CH2), 1.95 (3H, s, CH3), 2.05 (2H, m, CH2), 2.36 (2H, m, CH2),
3.80 (1H, m, CH), 5.04 (1H, m, CH); 13C NMR δ 14.6/16.3, 17.7,
19.7 (CH3), 24.5 (CH2), 25.7 (CH3), 25.8/26.2, 32.9/34.3 (CH2),
37.1/37.8 (CH), 39.1/39.2 (CH2), 77.3/77.9, 124.8/124.9 (CH),
131.4, 174.0 (C); IR 2964, 1652 cm-1; HRMS (CI+) calcd for
C13H24N 194.1909; found 194.1909.
2-(Cyclohexylmethyl)-5-methyl-1H-pyrrole (18). Orange oil,
1
72%; H NMR (400 MHz, CDCl3) δ 0.75-1.71 (11H, m, CH2,
CH), 2.16 (3H, s, CH3), 2.33 (2H, d, J ) 7.1 Hz, CH2), 5.70 (2H,
m, CH), 7.45 (1H, s, NH); 13C NMR δ 12.0 (CH3), 25.3 (CH2 ×
2), 25.4, (CH2), 32.2 (CH2 × 2), 34.9 (CH2), 37.8, 104.6, 104.8
(CH), 124.6, 129.0 (C); IR 3370, 2921, 1595, 1448 cm-1. HRMS
(CI+) calcd for C12H20N 178.1596; found 178.1601.
Experimental Section
General Procedure for Preparation of O-Phenyl Oximes.
O-Phenylhydroxylamine hydrochloride (200 mg, 1.5 mmol) was
dissolved in anhydrous pyridine (4.0 mL) under N2 at room
temperature, and the carbonyl compound (1.5 mmol) was added in
one portion. The resulting solution was stirred at room temperature
overnight, and the progress of the reaction was monitored by TLC
(EtOAc/hexane, 1:2). Upon completion, the reaction mixture was
poured into water (4.0 mL) and extracted with EtOAc (3 × 10
mL), and the combined organic phases were washed several times
with saturated, aqueous CuSO4 solution to remove any traces of
pyridine. The solution was then dried over MgSO4 and concentrated
under reduced pressure. The residue was purified by column
chromatography (5% EtOAc/hexane).
Phenanthridine-3-carbonitrile (29c). Yellow solid, 66%; mp
1
117-119 °C; H NMR (400 MHz, CDCl3) δ 7.75-7.83 (2H, m,
CH), 7.90 (1H, t, J ) 7.8 Hz, CH), 8.06 (1H, d, J ) 7.7 Hz, CH),
8.46 (1H, d, J ) 1.6 Hz, 1H), 8.58 (2H, d, J ) 8.9 Hz, 2H), 9.31
(1H, s, CH); 13C NMR δ 112.0, 118.6 (C), 122.5, 123.7 (CH), 127.0,
127.4 (C), 128.7, 129.2, 129.4 (CH), 131.5 (C), 132.0, 135.1 (CH),
143.7 (C), 155.5 (CH); IR 3020, 2232, 1593, 1480 cm-1. HRMS
(ES+) calcd for C14H9N2 205.0766; found 205.0764.
Benzo[k]phenanthridine (31).42 Brown solid, 64%; mp 108-110
1
°C; H NMR (400 MHz, CDCl3) δ 7.66-7.77 (4H, m, CH), 7.89
(1H, d, J ) 8.4 Hz, CH), 7.96 (1H, d, J ) 8.4 Hz, CH), 8.02 (1H,
d, J ) 7.0 Hz, CH), 8.26 (1H, d, J ) 8.1, 1.6 Hz, CH), 9.05 (1H,
d, J ) 8.5 Hz, CH), 9.15 (1H, d, J ) 8.0 Hz, CH), 9.29 (1H, s,
CH); 13C NMR δ 119.0, 124.1 (CH), 124.2 (C), 125.8, 125.9, 126.0
(5E)-6,10-Dimethylundeca-5,9-dien-2-one O-Phenyl Oxime
(9a). Red oil, 71%; two isomers; H NMR (400 MHz, CDCl3) δ
1
1.50-1.78 (12H, m, CH3), 2.08 (4H, m, CH2), 2.32 (4H, m, CH2),
5.12 (1H, m, CH), 5.19 (1H, m, CH), 6.98 (1H, J ) 7.3 Hz, CH),
7.21 (2H, m, CH), 7.31 (2H, m, CH); 13C NMR δ 11.3/14.1, 20.4,
23.1 (CH3), 24.2/24.3 (CH2), 25.3 (CH3), 26.7, 30.0/30.2, 40.0
(CH2), 115.0 (CH × 2), 122.0, 123.1, 124.3, 129.8 (CH × 2), 131.3,
136.5, 159.8, 161.5/161.8 (C); IR 2965, 1590, 1488 cm-1; HRMS
(CI+) calcd for C19H28NO 286.2171; found 286.2177.
(41) Khanapure, S. P.; Garvey, D. S.; Young, D. V.; Ezawa, M.; Earl, R. A.;
Gaston, R. D.; Fang, X.; Murty, M.; Martino, A.; Shumway, M.; Trocha, M.;
Marek, P.; Tam, S. W.; Janero, D. R.; Letts, L. G. J. Med. Chem. 2003, 46,
5484–5504.
(42) Sanz, R.; Fernandez, Y.; Castroviejo, M. P.; Perez, A.; Fananas, F. J.
Eur. J. Org. Chem. 2007, 62–69.
5564 J. Org. Chem. Vol. 73, No. 14, 2008

Syntheses of N-Heterocycles using O-Phenyl Oximes
(CH), 126.5 (C), 127.1, 127.2 (CH), 127.4 (C), 127.8, 128.0, (CH),
128.0, (C), 129.2 (CH), 134.2, 145.7 (C), 151.6 (CH); IR 2923,
2-Methyl-9H-pyrido[2,3-b]indole (46).45 Brown solid, 59%; mp
219-220 °C; H NMR (400 MHz, CDCl3) δ 2.67 (3H, s, CH3),
7.00 (1H, d, J ) 7.8 Hz, CH), 7.18 (1H, m, CH), 7.43 (2H, m,
CH), 7.95 (1H, d, J ) 7.7 Hz, CH), 8.17 (1H, d, J ) 7.8 Hz, CH),
9.42 (1H, s, NH); 13C NMR δ 24.2 (CH3), 111.3, 115.3 (CH), 115.5
(C), 120.4, 120.7 (CH), 120.8 (C), 126.6, 129.4 (CH), 139.5, 143.8,
146.3 (C); IR 1602, 1456, 1417 cm-1. HRMS (CI+) calcd for
C12H11N2 183.0922; found 183.0928.
1
1579, 1451, 1381 cm-1
.
[1,3]Dioxolo[4,5-j]phenanthridine (Trisphaeridine, 35).43
Brown solid, 70%; mp 144-146 °C; 1H NMR (400 MHz, CDCl3)
δ 6.00 (2H, s, CH2), 7.33 (1H, s, CH), 7.62 (1H, td, J ) 7.5, 1.5,
CH), 7.62 (1H, td, J ) 7.5, 1.2 Hz, CH), 7.91 (1H, s, CH), 8.13
(1H, dd, J ) 7.4, 1.2 Hz, CH), 8.37 (1H, dd, J ) 8.4, 1.2 Hz, CH),
9.08 (1H, s, CH); 13C NMR δ 99.9 (CH), 101.9 (CH2), 105.5, 122.0
(CH), 123.0, 124.3 (C), 126.7, 128.0, 130.0 (CH), 130.3, 144.0,
148.2, 151.5 (C), 151.7 (CH); IR 2904, 1620, 1580, 1498, 1464
cm-1; HRMS (CI+) calcd for C14H10NO2 224.0712; found, 224.0712.
Benzo[h][1,6]naphthyridine (40a).44 Brown solid, 66%; mp
6H-1,2,3,4-Tetrahydroindolo[2,3-b]quinoline (49).37a Brown
solid, 69%; mp 220-221 °C; 1H NMR (400 MHz, CDCl3) δ
1.79-1.98 (4H, m, CH2), 2.90 (2H, t, J ) 6.11 Hz, CH2), 3.10
(2H, t, J ) 6.5 Hz, CH2), 7.16 (1H, t, J ) 7.4 Hz, CH), 7.36 (1H,
t, J ) 7.5 Hz, CH), 7.43 (1H, d, J ) 8.1 Hz, CH), 7.91 (1H, d, J
) 7.7 Hz, CH), 7.96 (1H, s, CH), 10.20 (1H, s, NH); 13C NMR δ
22.2, 22.2, 28.0, 31.7 (CH2), 110.2 (CH), 113.9 (C), 118.8, 119.6
(CH), 120.1, 122.8 (C), 125.4, 128.5 (CH), 137.9. 149.4, 152.5
(C); IR 3128, 2931, 1609, 1458 cm-1. HRMS (CI+) calcd for
C15H15N2 223.1235; found 223.1231.
1
95-97 °C; H NMR (400 MHz, CDCl3) δ 7.60 (1H, dd, J ) 8.0,
4.4 Hz, CH), 7.72 (1H, t, J ) 7.6 Hz, 7.81 (1H, t, J ) 7.6 Hz,
CH), 8.20 (1H, d, J ) 8.3 Hz, CH), 8.31 (1H, dd, J ) 8.0, 1.8 Hz,
CH), 9.10 (1H, d, J ) 8.0 Hz, CH), 9.14 (1H, dd, J ) 4.4, 1.8 Hz,
CH), 9.27 (1H, s, CH); 13C NMR δ 120.3 (C), 120.7 (CH), 125.1
(C), 127.6, 127.8, 129.2, 129.4, 140.8 (CH), 146.2, 147.4 (C), 151.6,
152.4 (CH); IR 1589, 1440 cm-1. HRMS (CI+) calcd for C12H9N2
181.0766; found 181.0761.
Acknowledgment. We thank GSK and EaStChem for
financial support and Dr. M. C. Clarke and Prof. R. Morris for
the loan of microwave reactors.
[1]Benzothieno[2,3-c]quinoline (44). Brown solid, 53%; mp
1
129-131 °C, H NMR (400 MHz, CDCl3) δ 7.59 (2H, m, CH),
Supporting Information Available: Preparation and char-
acterization of O-phenyl oxime ethers, aromatic carbonyl
compounds and N-heterocycles. NMR spectra for new com-
pounds. This material is available free of charge via the Internet
at http://pubs.acs.org.
7.71 (2H, m, CH), 8.01 (1H, m, CH), 8.26 (1H, m, CH), 8.84 (2H,
m, CH), 9.30 (1H, s, CH); 13C NMR δ 121.9, 122.8, 124.4 (CH),
124.5 (C), 125.1 (CH), 126.6 (CH × 2), 126.9, 129.7 (CH), 131.6,
132.3, 134.2, 140.5, 141.5 (C), 145.2 (CH); IR 3018, 1502 cm-1
HRMS (CI+) calcd for C15H10NS 236.0534; found 236.0538.
.
JO800847H
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Org. Lett. 2004, 6, 2741–2744.
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2006, 8, 415–418.
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J. Org. Chem. Vol. 73, No. 14, 2008 5565