Asymmetric Intramolecular Conjugate Addition Nitro-Mannich Route to cis-2-Aryl-3-nitrotetrahydroquinolines

Article abstract of DOI:10.1021/acs.orglett.5b02036

Reductive cyclization of 2-iminonitrostyrenes (from the condensation of 2-aminostyrenes with an aldehyde and subsequent nitration of the alkene) using a bifunctional thiourea catalyst and tert-butyl-Hantzsch ester leads to an intramolecular conjugate hydride addition nitro-Mannich reaction to give the corresponding cis-2-aryl-3-nitrotetrahydroquinolines as single diastereoisomers in high yields and enantioselectivities.

Full text of DOI:10.1021/acs.orglett.5b02036

Letter
pubs.acs.org/OrgLett
Asymmetric Intramolecular Conjugate Addition Nitro-Mannich Route
to cis-2-Aryl-3-nitrotetrahydroquinolines
James C. Anderson,* Joshua P. Barham, and Christopher D. Rundell
Department of Chemistry, University College London, 20 Gordon Street, London WC1H 0AJ, U.K.
S
* Supporting Information
ABSTRACT: Reductive cyclization of 2-iminonitrostyrenes (from the
condensation of 2-aminostyrenes with an aldehyde and subsequent nitration
of the alkene) using a bifunctional thiourea catalyst and tert-butyl-Hantzsch
ester leads to an intramolecular conjugate hydride addition nitro-Mannich
reaction to give the corresponding cis-2-aryl-3-nitrotetrahydroquinolines as
single diastereoisomers in high yields and enantioselectivities.
Scheme 1. Relevant Reported Work
etrahydroquinolines are present in numerous biologically
1
Tactive natural products and drug substances.
Natural
products (−)-isoschizogaline (1)2 and helquinone (2)3 display
antibiotic activity, the drug molecule viratmycin (3)4 is an
antiviral antibiotic that also possesses antifungal activity, and
drug molecule 45 is an antimalarial (Figure 1).
blocks for amino heterocycles.8 We devised a diastereoselective
intramolecular nitro-Mannich route to trans-3-nitrotetrahydro-
quinolines 5 in racemic form via in situ generation of an imine
from 2-(2-nitroethyl)phenylamine (Scheme 1, eq 1).9 This has
recently been shown to be amenable to asymmetric control
through the use of a bifunctional tertiary amine thiourea
catalyst that gave products with moderate to good enantiose-
lectivities.10 Other routes to enantiomerically pure nitro-
tetrahydroquinolines have also taken advantage of organo-
catalysis. A tandem Michael−nitro-Mannich sequence gave
Figure 1. Biologically active tetrahydroquinolines.
cis,trans-nitrotetrahydroquinolines 6 (Scheme 1, eq 2),11
a
structural motif that can also be made with the trans,trans
stereochemistry by an aza-Michael−Michael strategy using
nitroalkenes.12 The cis-diastereoisomer of 5 can also be
prepared by chiral phosphoric acid catalyzed transfer hydro-
genation of 2-aryl-3-nitroquinolines, but this is limited by the
poor yields of the multistep synthesis required to prepare the
quinolines.13 We wish to report an efficient asymmetric
synthesis of cis-2-aryl-3-nitrotetrahydroquinolines via an intra-
molecular nitro-Mannich reaction initiated by an organo-
catalyzed reduction of the parent nitrostyrene.
The efficient synthesis of functionalized tetrahydroquinolines
in enantiomerically pure form continues to be of high
importance to synthetic chemists.1 For flexible syntheses in
terms of stereochemistry and functionalization, de novo
constructions of the heterocycle are the most efficient methods.
Of those methods, the intramolecular cyclization of a
resonance-stabilized nucleophile onto an imine derived from
an aniline has proven most popular.6 In particular, the nitro-
Mannich cyclization of nitronate nucleophiles onto a pendant
aniline imine gives highly versatile stereodefined nitro-
substituted tetrahydroquinolines (Scheme 1). The nitro group
is a versatile synthetic handle and can be transformed into
amines or carbonyl groups or be denitrated.7 The nitro-
Mannich reaction is an efficient route to stereochemically pure
β-nitroamines which have been shown to be useful building
Following on from our work defining stereoselective nitro-
Mannich reactions initiated by conjugate addition to nitro-
Received: July 16, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02036
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Organic Letters
Letter
alkenes,14 we reasoned that conjugate addition of a nucleophile
to an iminonitrostyrene would trigger an intramolecular nitro-
Mannich reaction to form contiguous stereocenters with high
diastereo- and enantiocontrol (Scheme 2).
Scheme 2. Proposed Reaction
To investigate this reaction, a synthesis of the 2-
iminonitrostyrene precursors was required. The most direct
method would be from a 2-amino-β-nitrostyrene and an
aldehyde. Attempts at the chemoselective reduction of 2-nitro-
β-nitrostyrene were unsuccessful, suffering from reduction of
the nitrostyrene. This suggested to us that the reactive
nitrostyrene group should be introduced last. After some
optimization, our initial approach involved imine formation
from the intermediate Henry product between nitromethane
and 2-aminobenzaldehyde (7, Scheme 3). Selective reduction
Scheme 3. Initial Approach
of the aromatic nitro group of 7 was reliably achieved on a gram
scale using a mixture of palladium on charcoal and Pearlman’s
catalyst to give 8 in 77% yield after recrystallization.15
Formation of the imine in situ was followed by dehydration
of the nitroalcohol to form the desired 2-iminonitrostyrene.
Many dehydrating systems were investigated, and we found
that careful treatment of 8 with trifluoroacetic anhydride and
triethylamine minimized retro-Henry reaction and formation of
byproduct 9 and gave 10a in good 67% isolated yield.
Unfortunately, this sequence gave poor yields (20−30%) with
electron-rich and -poor aldehydes, presumably because with the
former the amine lone pair is not nucleophilic enough due to
the electron-withdrawing nitrostyrene group and the latter gives
mainly byproducts like 9 due to the increased electrophilicity of
the formed imine toward cyclization.
Figure 2. Synthesis of nitrostyrene substrates.
reported to be tolerant of various functional groups.17 Our
results suggest that aromatic imines are also stable to the mild
reaction conditions of AgNO2/TEMPO. For the imine derived
from pentanal, imine formation proceeded as expected, but
nitration unfortunately led to decomposition. Various 2-
iminonitrostyrenes were synthesized according to this
To circumvent this, the desired 2-iminonitrostyrenes 10a−m
from quantitative imine formation were subjected to late-stage
nitration (Figure 2).16 The stereoselective nitration of styrene
alkenes had been disclosed by Maiti et al. and had been
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procedure (Figure 1) in excellent yield. Substituents on the
styrene partner were limited due to the availability of the
starting materials. The 5-chloro substituent was tolerated
(10m), but other electron-withdrawing groups in this position
(CN, F) were unable to form the imine. This was also true of
the 4-chloro analogue and 2-amino-3-vinylpyridine. However, a
wide variety of electron-rich and -poor imines were prepared in
good yield.
Initially, cyclization of 10a was investigated using the
conditions previously described by us for the enantioselective
tandem reduction/nitro-Mannich reaction.14e When tert-butyl-
Hantzsch ester (11) was used as a transfer hydrogenation agent
in the presence of thiourea catalyst 12,14e the desired
tetrahydroquinoline 13a was isolated in quantitative yield as a
1
single diastereoisomer by H NMR in 94% ee (Table 1). No
a
Table 1. Investigation into Cyclization Conditions
b
c
d
entry temp (°C) 11 (equiv) time (h) yield (%) ee (%)
dr
1
2
3
rt
0
2
2
1
12
18
18
99
99
99
94
97
97
>95:5
>95:5
>95:5
0
a
b
Reaction scale (0.1 mmol), PhMe (1 mL). Isolated yield.
c
d
Determined by chiral HPLC (OD column). Determined by 1H
NMR analysis of crude product.
reduction of the imine was observed. Decreasing the temper-
ature from rt to 0 °C gave a small increase in ee with increased
reaction time (entry 2). Using an equimolar quantity of 11 gave
the same yield, ee, and dr.
The generality of the procedure for the synthesis of cis-2-aryl-
3-nitrotetrahydroquinolines 13 was investigated (Figure 3). All
cis-tetrahydroquinolines 13 were made in good yield, high ee,
1
and essentially as a single diastereoisomer by H NMR. The
sense of diastereoselectivity was determined by inspection of 3J
coupling constants between the vicinal protons adjacent to the
3
pendant phenyl ring and the nitro function where Jcis ∼ 4
Figure 3. Asymmetric tandem reductive intramolecular nitro-Mannich
reaction. (a) Reaction scale (0.1 mmol) in PhMe (1 mL), isolated
yield is given in all cases; ee was determined by chiral HPLC (OD
column) and diastereoselectivity by H NMR analysis. (b) Product
unstable to HPLC conditions.
Hz.18 The absolute configuration was assigned as 2R,3R by
comparison to the optical rotations reported by Zhou et
al.13,19,20 The diastereoselectivity can be attributed to the cis-
diastereoisomer being the kinetic product as treatment of cis-
tetrahydroquinoline 13a with DBU (1 equiv) in CH2Cl2 for 16
h at rt gave a 9:1 mixture in favor of the thermodynamic trans-
diastereoisomer.21 This was isolated in 72% yield and possessed
identical enantioselectivity to the starting material.22 This route
to the trans-products would deliver superior enantioselectivites
than other methods.10
The presence of groups on the meta- or para-position led to
an increase in ee but no obvious stereoelectronic preference
could be discerned. When Ar = p-NO2C6H5, the desired
product 13h was not observed; the product from conjugate
reduction of the nitrostyrene was isolated instead. This is most
probably due to the imine function not participating in the
1
nitro-Mannich reaction due to the lower reactivity of the imine
lone pair, the protonation of which is required for the nitro-
Mannich reaction to proceed.21
In summary, we have developed an expedient synthesis of
sensitive 2-iminonitrostyrenes 10 through the use of radical
alkene nitration, which exemplifies the mild nature and further
scope of this reaction. These can be cyclized by an
organocatalytic tandem reductive nitro-Mannich reaction in
high yield to give a single cis-2-aryl-3-nitrotetrahydroquinoline
13 in high yield and enantioselectivity. Further investigation is
ongoing into the utility of these nitrostyrenes for the synthesis
C
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4711. (c) Anderson, J. C.; Horsfall, L. R.; Kalogirou, A. S.; Mills, M. R.;
Stepney, G. J.; Tizzard, G. J. J. Org. Chem. 2012, 77, 6186.
(d) Anderson, J. C.; Noble, A.; Tocher, D. A. J. Org. Chem. 2012,
77, 6703. (e) Anderson, J. C.; Koovits, P. J. Chem. Sci. 2013, 4, 2897.
(f) Anderson, J. C.; Kalogirou, A. S.; Tizzard, G. J. Tetrahedron 2014,
70, 9337. (g) Anderson, J. C.; Campbell, I. B.; Campos, S.; Shannon,
J.; Tocher, D. A. Org. Biomol. Chem. 2015, 13, 170.
of densely functionalized tetrahydroquinolines of biological
interest.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b02036.
(15) Use of Pearlman’s catalyst alone gave 50% yield. Using a 1:1
mixture of 10% Pd/C and Pearlman’s catalyst, which has been
reported to give superior results for N- and O- hydrogenolysis of
benzyl groups, gave little change in yield: Li, Y.; Manickam, G.;
Ghoshal, A.; Subramaniam, P. Synth. Commun. 2006, 36, 925.
(16) The 2-aminostyrenes were prepared from the corresponding 2-
nitrophenylacetic acids by the following sequence: reduction of the
carboxylic acid to the alcohol with borane, reduction of the nitro group
to the amine with Zn, CaCl2 and H2O, and dehydration by heating
with KOH. See the Supporting Information. Other structurally diverse
substrates have been prepared in the literature by a modified Suzuki
reaction between 2-bromoanilines and potassium vinyltrifluoroborate;
see: (a) Ascic, E.; Buchwald, S. L. J. Am. Chem. Soc. 2015, 137, 4666.
(b) Li, B.; Park, Y.; Chang, S. J. Am. Chem. Soc. 2014, 135, 1125.
(17) Maity, S.; Manna, S.; Rana, S.; Naveen, T.; Mallick, A.; Maiti, D.
J. Am. Chem. Soc. 2013, 135, 3355.
Detailed experimental procedure, characterization data,
NMR spectra for new compounds, and HPLC analysis
(PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: j.c.anderson@ucl.ac.uk.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
3
(18) Compared to Jtrans ∼ 8 Hz; see ref 9.
The preliminary work was taken from the Masters research
project of J.P.B., and the main work is part of the Ph.D. work of
C.D.R. We thank the Engineering and Physical Sciences
Research Council (DTA), University College London (UCL),
and AstraZeneca for funding, Dr. V. J. Gray (UCL) for mass
spectra, and Mrs. J. Maxwell (UCL) for microanalytical data.
(19) Comparison of optical rotations gives the opposite sign and
values similar to those in ref 13. Novel tetrahydroquinolines were
assigned the same 2R,3R stereochemistry by the sign of their optical
rotation. See the Supporting Information.
(20) A transition-state model to account for the sense of
enantioselectivity would be similar to that proposed by us for the
acyclic tandem reduction/nitro-Mannich reaction of nitroalkenes (see
the Supporting Information of ref 14e).
(21) We have presented a transition-state model to account for the
kinetic cis-diastereoselectivity versus the thermodynamic trans-stereo-
chemistry previously described (ref 9).
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