Regioselective carbolithiation of o-amino-(E)-stilbenes: Cascade route to the quinoline scaffold

Article abstract of DOI:10.1021/ol061348n

The regioselective carbolithiation of substituted ortho-amino-(E)-stilbenes can be exploited to initiate cascade reaction sequences that can be utilized as new routes to substituted 3,4-dihydro-1H-quinolin-2-ones, 1,2,3,4- tetrahydroquinolines, 1,4-dihydr

Full text of DOI:10.1021/ol061348n

ORGANIC
LETTERS
2006
Vol. 8, No. 17
3769-3772
Regioselective Carbolithiation of
o-Amino-(E)-Stilbenes: Cascade Route
to the Quinoline Scaffold
Anne-Marie L. Hogan and Donal F. O’Shea*
Centre for Synthesis and Chemical Biology, School of Chemistry and Chemical
Biology, UniVersity College Dublin, Belfield, Dublin 4, Ireland
donal.f.oshea@ucd.ie
Received June 2, 2006
ABSTRACT
The regioselective carbolithiation of substituted ortho-amino-(E)-stilbenes can be exploited to initiate cascade reaction sequences that can be
utilized as new routes to substituted 3,4-dihydro-1H-quinolin-2-ones, 1,2,3,4-tetrahydroquinolines, 1,4-dihydroquinolines, and quinolines.
Carbolithiation of alkenes offers a unique means of creating
a carbon-carbon bond and a new organolithium species in
a single step. The carbolithiation of unactivated alkenes such
as ethene, styrene, â-methylstyrene, and stilbene has been
described.1 Carbolithiation of styrene and â-methylstyrene
is regiospecific, exclusively generating the more stabilized
benzylic lithiated compounds in both cases (Scheme 1, eq
1). In contrast, the relatively unstudied carbolithiation of
unsymmetrical stilbenes poses a considerable selectivity
challenge, as two possible benzylic lithiated regioisomers
could be generated from the reaction (Scheme 1, eq 2). For
the specific case of o-amino-stilbenes, it was anticipated that
Scheme 1. Regioselectivity of Alkene Carbolithiation
if reaction conditions could be identified in which one
regioisomer was favored, then the resulting benzylic lithiated
species would be a very synthetically versatile intermediate
that could be applied to further in situ transformations. We
have recently advanced the carbolithiation of o-amino-
styrenes as an effective methodology for initiating a cascade
reaction sequence to generate the functionalized indole and
7-azaindole ring systems.2 The cascade methodology involves
a regiospecific alkyllithium addition to the alkene, subsequent
trapping of the intermediate organolithium with a suitable
(1) (a) Bartlett, P. D.; Friedman, S.; Stiles M. J. Am. Chem. Soc. 1953,
75, 1771. (b) Bartlett, P. D.; Tauber, S. J.; Weber, W. P. J. Am. Chem. Soc.
1969, 91, 6362. (c) Wei, X.; Taylor, R. J. K. Chem. Commun. 1996, 187.
(d) Wei, X.; Johnson, P.; Taylor, R. J. K. J. Chem. Soc., Perkin Trans 1
2000, 1109. (e) Klein, S.; Marek, I.; Poisson, J. F.; Normant, J. F. J. Am.
Chem. Soc. 1995, 117, 8853. (f) Norsikian, S.; Marek, I.; Normant, J. F.
Tetrahedron Lett. 1997, 38, 7523. (g) Norsikian, S.; Marek, I.; Klein, S.;
Poisson, J. F.; Normant, J. F. Chem.sEur. J. 1999, 5, 2055. (h) Clayden,
J. Organolithiums: SelectiVity for Synthesis; Pergamon Press: Oxford, U.K.,
2002; pp 273-335.
10.1021/ol061348n CCC: $33.50
© 2006 American Chemical Society
Published on Web 07/18/2006

electrophile, followed by an in situ ring closure and dehydra-
tion to provide fused ring systems (Scheme 2).
Table 1. Carbolithiation of o-Amino Stilbenes 1a and 1b
Scheme 2. Indole and 7-Azaindole Synthesis
entry
sm
R1
product
R2
yielda (%)
1
2
3
4
5
6
1a
1a
1a
1b
1b
1b
Boc
Boc
Boc
Bn
Bn
Bn
3a
3b
3c
3d
3e
3f
t-Bu
n-Bub
Etb
t-Bu
n-Bub
s-Bu
87
62c
76d
79
61e
81
In this report, we outline our initial results to develop
regioselective carbolithiations of o-amino-substituted stil-
benes and the exploitation of this transformation for initiating
cascade reaction sequences from which complex structural
architectures can be generated in an efficient manner. The
starting substrates t-butoxycarbonyl and benzyl N-substituted
o-amino-(E)-stilbenes 1a and 1b were synthesized stereo-
selectively by Suzuki-Miyaura cross-coupling of the cor-
responding functionalized o-bromo-anilines with commer-
cially available trans-2-phenylvinylboronic acid (Scheme 3).
a Isolated purified yield. b PMDTA added. c Compound 5b was also
isolated in 10% yield (see Table 3). d Compound 5c was also isolated in
7% yield (see Table 3). e Starting material recovered in 29% yield.
2, in which the lithiated carbon is R to the aniline ring. The
subtlety of this selectivity achievement was highlighted by
the fact that mixtures of both possible regioisomers were
obtained when reactions were carried out using diethyl ether
as solvent. For example, the reaction of 1a and 1b with
t-BuLi provided a mixture of 3a/4a and 3d/4d in a 9:1 and
6:4 ratio, respectively (Table 2). The regioisomer assignments
Scheme 3. Synthesis of N-Substituted o-Amino-(E)-stilbenes
Table 2. Regioisomer Ratios for Carbolithiation in Diethyl
Ether
An extensive study of the carbolithiation reaction condi-
tions of 1a and 1b was undertaken to identify an optimal
regio outcome for a series of alkyllithiums (t-Bu-, n-Bu-,
s-Bu-, and EtLi). The carbolithiation selectivity was deter-
mined by reacting the lithiated intermediates with methanol,
and the crude reaction products were analyzed by NMR and
HPLC. Encouragingly, it was found that when THF was
employed as the reaction solvent at -25 °C, a single
regioisomer 3a-f was formed in high yields from the
reaction of the four different alkyllithiums with the substrates
1a and 1b (Table 1). For n-Bu and EtLi, the inclusion of the
additive N,N,N′,N′′,N′′-pentamethyldiethylenetriamine (PM-
DTA) was found to give improved conversions to 2 with
good isolated yields of 3b, 3c, and 3e obtained following
protonation with methanol (entries 2, 3, and 5). Significantly,
in all cases, the regioisomer formed had the alkyl group
exclusively on the carbon R to the aniline ring, which would
be consistent with the formation of the benzylic intermediates
2a-f in the carbolithiation step (Table 1).
entry
substrate
products
ratio 3:4a
yieldb (%)
1
2
1a
1b
3a, 4a
3d, 4d
9:1
6:4
72
30c
a Ratios determined by HPLC and H NMR. b Combined yield of both
isomers. c Starting material recovered in 41% yield.
1
were confirmed by independently synthesizing compounds
4a and 4d (Supporting Information). During the course of
this work, we became aware of a similar finding in which
carbolithiation of o-methoxy-stilbene with n-BuLi in cumene
and (-)-sparteine gave a 94:6 ratio of regioisomers, with
the major isomer having the butyl group substituted at the
carbon R to the o-methoxy functionalized benzene ring.3
Having established conditions for a regioselective alkyl-
lithium addition, our next aim was to demonstrate the utility
of lithiated compounds 2a-f in cascade reaction sequences,
to provide a new entry to the quinoline scaffold at a range
of oxidation levels. Polysubstituted quinolinones, dihydro-
quinolines, tetrahydroquinolines, and quinolines are common
This is the opposite carbolithiation pattern from our
previously reported styrene examples, as shown in Scheme
(2) (a) Coleman, C. M.; O’Shea, D. F. J. Am. Chem. Soc. 2003, 125,
4054. (b) Kessler, A.; Coleman, C. M.; Charoenying, P.; O’Shea, D. F. J.
Org. Chem. 2004, 69, 7836. (c) Cottineau, B.; O’Shea, D. F. Tetrahedron
Lett. 2005, 46, 1935.
(3) (a) Norsikian, S. Ph.D. Thesis, Universite´ Pierre et Marie Curie, Paris,
France, 1999. (b) Prof. I. Marek, Department of Chemistry, Technion-Israel
Institute of Technology, Israel, private communication.
3770
Org. Lett., Vol. 8, No. 17, 2006

motifs found in important natural products and pharmaceuti-
cal agents.4 As such, a common cascade route to each class
would be of significant synthetic value.
(J ) 5.3 and 5.4 Hz, respectively). During purification on
silica gel chromatography, the isomer mixture of 5b and 5c
converted to a 9:1 and 8:2 ratio, respectively, in favor of
the thermodynamic trans isomer. The relative stereochem-
istry of the major trans isomer of 5b was confirmed by X-ray
crystallography (Figure 1, Supporting Information). The
It was envisioned that the lithiated intermediates 2a-c
could provide access to 3,4-dihydro-1H-quinolin-2-ones by
intramolecular nucleophilic substitution of the benzylic
lithium center at the Boc group.5 The susceptibility of the
Boc group to intermolecular nucleophilic attack by alkyl-
lithiums has previously been reported.6 The intramolecular
cyclization was readily achieved following the carbolithiation
of 1a in THF at -25 °C by raising the reaction temperature
to either 0 °C or room temperature for 1 to 6 h, thereby
providing direct access to the 3,4-dihydro-1H-quinolin-2-
ones 5a-c (Table 3). It was found that cyclization proceeded
Table 3. Synthesis of 3,4-Dihydro-1H-quinolin-2-ones
Figure 1. X-ray crystal structure of the major 3,4-trans-diastere-
oisomer of 5b.
source of the cis isomers could be attributed to the strongly
basic reaction conditions, as resubjecting the purified trans
isomer of 5b to the reaction conditions resulted in the
isolation of product in a trans/cis isomer ratio of 3:7. It was
observed that cyclization of the tert-butyl-substituted 2a into
5a required a higher temperature, with the product isolated
in lower yield, possibily due to geometrical restrictions
imposed by the t-Bu group on the conformation necessary
for cyclization (Table 3, entry 1). As a result of the higher
temperature required for cyclization, significant quantities
of 3a were also isolated due to competing deprotonation of
the THF solvent by 2a (entry 1). However, it was possible
to achieve an improved 68% yield of 5a (as the trans isomer)
by the reaction of 2a with CO2, followed by acidification
with aqueous 12 M HCl (Supporting Information).
entry
temp (°C)
time (h)
R1
product
yielda (%)
1
2
3
rt
0
0
6
1
2
t-Bu
n-Bu
Et
5a
5b
5c
22b
90
84
a Isolated purified yield. b Compound 3a also isolated in 51% yield.
more efficiently in the absence of PMDTA additive and, as
such, it was omitted from the reaction for the formation of
quinolin-2-ones 5b and 5c.
Compound 5a was isolated as a single diastereoisomer,
which was assigned a relative stereochemistry of 3,4-trans,
as both the C-3 and C-4 proton signals appeared as two
1
singlets in the H NMR spectrum. Compounds 5b and 5c
To further extend the synthetic utility of the lithiated
intermediates 2a-c, treatment with DMF as electrophile,
followed by acidification with aqueous acid, provided a
versatile synthesis of the 1,2,3,4-tetrasubstituted tetrahyd-
roquinolines 6a-c in good isolated yields (Table 4).
were isolated crude as a 6:4 ratio mixture of two isomers
with the predominant being the 3,4-trans (J ) 1.2 and 1.8
Hz, respectively) and the minor isomer assigned as 3,4-cis
(4) For examples, see quinolin-2-ones: (a) Carling, R. W.; Leeson, P.
D.; Moore, K. W.; Smith, J. D.; Moyes, C. R.; Mawer, I. M.; Thomas, S.;
Chan, T.; Baker, R.; Foster, A. C.; Grimwood, S.; Kemp, I. M.; Marshall,
G. R.; Tricklebank, M. D.; Saywell, K. L. J. Med. Chem. 1993, 36, 3397.
(b) Rowley, M.; Kulagowski, J. J.; Watt, A. P.; Rathbone, D.; Stevenson,
G. I.; Carling, R. W.; Baker, R.; Marshell, G. R.; Kemp, J. A.; Foster, A.
C.; Grimwood, S.; Hargreaves, R.; Hurley, C.; Saywell, K. L.; Tricklebank,
M. D.; Leeson, P. D. J. Med. Chem. 1997, 40, 4053. (c) Foucaud, B.; Laube,
B.; Schemm, R.; Kreimeyer, A.; Goeldner, M.; Betz, H. J. Biol. Chem.
2003, 278, 24011. Tetrahydroquinolines: (d) Katritzky, A.; Rachwal, S.;
Rachwal, B. Tetrahedron, 1996, 52, 15031. Dihydroquinolines: (e) Michne,
W. F.; Guiles, J. W.; Treasurywala, A. D.; Castonguay, L. A.; Weigelt, C.
A.; Oconnor, B.; Volberg, W. A.; Grant, A. M.; Chadwick, C. C.; Krafte,
D. S.; Hill, R. J. J. Med. Chem. 1995, 38, 1877. (f) Gaillard, S.; Papamicael,
C.; Marsais, F.; Dupas, G.; Levacher, V. Synlett 2005, 441. (g) van Straten,
N. C. R.; van Berkel, T. H. J.; Demont, D. R.; Karstens, W.-J. F.; Merkx,
R.; Oosterom, J.; Schulz, J.; van Someren, R. G.; Timmers, C. M.; van
Zandvoort, P. M. J. Med. Chem. 2005, 48, 1697. Quinolines: (h) Michael,
J. P. Nat. Prod. Rep. 2003, 20, 476.
Two diastereomeric products were observed in each case,
and for 6a, separation by column chromatography was
achieved and the relative stereochemistry determined by
NMR and X-ray crystallography (Figure 2, Supporting
Information). Both diastereoisomers gave the tert-butyl and
the phenyl group trans to each other (J ) 4.0 Hz for both
diastereoisomers), differing in the relative stereochemistry
of the phenyl and alcohol groups. The n-butyl- and ethyl-
substituted tetrahydroquinolines 6b and 6c were also suc-
essfully isolated in good yields from the cascade reaction
sequence. In each case, it was possible to readily convert
6a-c into the fully aromatic 3- and 3,4-substituted quinolines
7a-c by treatment with aqueous hydrochloric acid (Table
4). Compounds 6b and 6c dehydrated and in situ air-oxidized
as expected to yield the 2,3-disubstituted quinolines, 7b and
7c, respectively. Interestingly, the tert-butyl-substituted
(5) For a review of the synthetic exploitation of the Boc protecting group,
see: Agami, C.; Couty, F. Tetrahedron 2002, 58, 2701.
(6) (a) Stanetty, P.; Koller, H.; Mohovilovic, M. J. Org. Chem. 1992,
57, 6833.
Org. Lett., Vol. 8, No. 17, 2006
3771

In additon, synthetic access to the 1,4-dihydroquinoline
class was achieved by the treatment of the N-benzyl-
substituted dilithiated intermediates 2d-f with DMF, fol-
lowed by aqueous acidic workup, to effect a dehydration.
This provided a new route to the medicinally important
1-benzyl-4-alkyl-3-phenyl-1,4-dihydro-quinolines 8a-c in
good yields (Table 5).
Table 4. Synthesis of 3,4-Disubstituted and 3-Substituted
Quinolines and 1,2,3,4-Tetrasubstituted tetrahydroquinolines
Table 5. Synthesis of 1,3,4-Trisubstituted
1,4-Dihydroquinolines
entry product
R1
yielda 6 product
R2
yielda 7
1
2
3
6a
6b
6c
t-Bu
n-Bub
Etb
76%
63%
71%
7a
7b
7c
H
n-Bu
Et
78%
78%
61%
entry
product
R1
yielda (%)
1
2
3
8a
8b
8c
t-Bu
n-Bu
s-Bu
82%
51%
84%
a Isolated purified yield. b PMDTA added.
a Isolated purified yield.
In summary, a regioselective carbolithiation of o-amino-
substituted stilbenes can be utilized to provide lithiated
intermediates of high synthetic potential from which new
synthetic routes to substituted dihydroquinolin-2-ones, tet-
rahydroquinolines, 1,4-dihydroquinolines, and aromatic quin-
olines are possible. The synthetic scope of this methodology
and the mechanism of carbolithiation regioselectivity is
currently being investigated in terms of substituent diversity
and routes to other fused-ring systems.
Acknowledgment. A.-M.L.H. thanks the Irish Research
Council for Science, Engineering and Technology for stu-
dentship. Funding support from the Program for Research
in Third-Level Institutions administered by the HEA. Thanks
to Dr. D. Rai of the CSCB Mass Spectrometry Centre and
Dr. H. Mueller-Bunz of the UCD Crystallographic Centre
for analysis.
Figure 2. X-ray crystal structure of the minor 2,3-trans-3,4-trans
diastereoisomer of 6a (see Supporting Information for major
diastereoisomer).
analogue 6a yielded only the monosubstituted 3-phenyl-
quinoline 7a, indicating that the aromatic ring was generated
by an elimination of the tert-butyl group. The elimination
of a tert-butyl group from dihydroquinolines has been
observed.7
Supporting Information Available: Synthetic proce-
dures, analytical data, and NMR spectra for all new
compounds. X-ray crystallographic data of 5b and 6a as CIF
files. This material is available free of charge via the Internet
at http://pubs.acs.org.
(7) Anne, A.; Fraoua, S.; Moiroux, J.; Save´ant, J.-M. J. Am. Chem. Soc.
1996, 118, 3938.
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