Access to oxoquinoline heterocycles by N-heterocyclic carbene catalyzed ester activation for selective reaction with an enone

Article abstract of DOI:10.1002/anie.201402620

Organocatalytic ester activation is developed for a highly selective cascade reaction between saturated esters and amino enones. The reaction involves activation of the β-carbon atom of the ester as a key step. This method allows a single-step access to multicyclic oxoquinoline-type heterocycles with high enantiomeric ratios.

Full text of DOI:10.1002/anie.201402620

Angewandte
Chemie
DOI: 10.1002/anie.201402620
Heterocycles
Hot Paper
Access to Oxoquinoline Heterocycles by N-Heterocyclic Carbene
Catalyzed Ester Activation for Selective Reaction with an Enone**
Zhenqian Fu, Ke Jiang, Tingshun Zhu, Jaume Torres, and Yonggui Robin Chi*
Abstract: Organocatalytic ester activation is developed for
a highly selective cascade reaction between saturated esters and
amino enones. The reaction involves activation of the b-carbon
atom of the ester as a key step. This method allows a single-step
access to multicyclic oxoquinoline-type heterocycles with high
enantiomeric ratios.
Nitrogen-containing heterocycles are widely used as bioac-
tive compounds and functional materials. Among these
heterocycles, the multicyclic cyclopenta[c]quinolin-4-one
(oxoquinoline-type heterocycle) is often presented as a core
structural scaffold. These oxoquinoline-type cores are found
in natural products (such as meloscine, scandine, and
epimeloscine)[1] and in synthetic molecules exhibiting anti-
tumor,[2] anti-inflammation,[3] anti-viral,[4] anti-mycobacte-
rial,[5] and anti-schizophrenia[6] activities (Figure 1a). Previ-
ous methods for this class of molecules require multiple
synthetic steps and afford only racemic products.[7] Therefore
the development of single-step, efficient, chemo- and stereo-
selective domino methods using simple starting materials and
catalysts is needed. In recent years, organocatalytic domino
reactions have emerged as an effective strategy to assemble
relatively sophisticated molecules. Studies in this direction
mainly involve primary and secondary amine catalysts
(enamine/iminium catalysis cascade).[8] Cascade reactions
using more than one type of organic catalysts (such as N-
heterocyclic carbene and amine organic catalysts) have also
been reported by the groups of Enders, Rovis, Jørgensen,
Chen, and others.[9,10]
Our laboratory is interested in organocatalytic activation
of esters.[11] Esters are stable substrates with tunable reac-
tivities. The controllable reactivities can therefore allow
highly chemoselective reactions to be developed. This feature
makes our organocatalytic ester activation strategy a poten-
tially attractive choice[12] for the development of effective
Figure 1. Rapid access to oxoquinoline-type heterocycles. a) Examples
of natural products and bioactive molecules. b) Organocatalytic access
to oxoquinoline heterocycles by activation of the inert b-sp3-carbon
atom of esters and selective reaction with enones (this work). Ts=4-
toluenesulfonyl.
[*] Dr. Z. Fu, Dr. T. Zhu, Prof. Dr. Y. R. Chi
Division of Chemistry & Biological Chemistry, School of Physical &
Mathematical Sciences, Nanyang Technological University
Singapore 637371 (Singapore)
domino reactions to quickly assemble relatively sophisticated
molecules. We recently reported N-heterocyclic carbene
(NHC) catalyzed activation of the saturated b sp3-carbon
atom of an ester as a nucleophilic center.[11j] We next set out to
selectively control the reactivities of the b, a, and carbonyl
carbon atoms of an ester (chemoselectivity issues). One
objective is to develop protocols for the synthesis of
structurally diverse products by starting from identical sub-
strates.[13] Another aim is to realize a domino cascade process
for rapid access to complex molecules. Herein we report
a highly effective domino process for the enantioselective
access to multicyclic oxoquinoline-type heterocycles (Fig-
ure 1b). The reaction involves NHC-catalyzed activaton of
E-mail: robinchi@ntu.edu.sg
Dr. K. Jiang, Prof. Dr. J. Torres
School of Biological Sciences, Nanyang Technological University
Singapore 637371 (Singapore)
[**] We thank the Singapore National Research Foundation (NRF),
Singapore Economic Development Board (EDB), GlaxoSmithKline
(GSK), and Nanyang Technological University (NTU) for generous
financial support. We thank Dr. Y. Li and Dr. R. Ganguly (X-ray
structure, NTU) for their contribution. K.J. and J.T. acknowledge the
financial support from the National Research Foundation grant
NRF-CRP4-2008-02.
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the b sp3-carbon atom of an ester as the crucial step. Key to
the success of this reaction cascade is the suppression of
several possible side reactions, including amide formation of
the NHC-bound ester intermediate I, reaction of the a-carbon
atom of the enolate intermediate II, and undesired cascade
reaction of the intermediate III. Specifically, the decreased
nucleophilicity of the tosyl-protected amine in the o-tosyla-
mino enone 2 was predicted to suppress the possible
intermolecular amide (I-a) formation between the amino
group of 2 and I. The use of a strong base (DBU) could
promote deprotonation at the b-carbon atom and suppress
reaction at the a-carbon atom (to form II-a). And the
formation of a six-membered lactam (3) is more favorable
than that of the four-membered lactone III-a.
product, and no clear side products were identified. A
benzoylamino enone gave less than 10% yield of the desired
cascade product, and the major side-product was III-a (iso-
lated from formation of cyclopentene after decarboxylation
of III-a; Figure 1). We next evaluated chiral triazolium NHC
catalysts. The aminoindanol-derived triazolium pre-catalysts
C and D, which are excellent carbene catalysts in asymmetric
reactions of aldehydes, were not effective for our ester
activation (entry 3). Lastly, the triazolium salt E, derived from
l-neopentylglycine and having a bulky tert-butyl substituent,
was found to be effective in this cascade reaction, thus
affording 3a in 80% yield, 15:1 d.r., and 96:4 e.r. (entry 4).
The use of toluene as solvent (entry 5) gave similar results
(83% yield, 10:1 d.r., 97:3 e.r.). Other common organic
solvents (e.g., CH3CN, CH2Cl2, 1,4-dioxane, and ethyl ace-
tate) also worked fine for this reaction (see the Supporting
Information).
Key results of our initial study and optimization of the
reaction conditions using 1a as a model ester substrate are
summarized in Table 1. The enone substrate 2a, bearing an
With acceptable reaction conditions in hand (Table 1,
entry 5), we next evaluated the scope with respect to the
saturated ester substrates by using 2a (Table 2, 3a–j). When
esters with a b-aryl substituent were used, both electron-rich
and electron-deficient moieties were tolerated on the aryl
group (3b–f). Esters bearing a b-naphthyl (3g) or hetero(aryl)
(3h) substituent worked effectively as well. Remarkably,
esters with a b-alkyl substituent (3i and 3j) reacted with 2a to
afford the corresponding cascade products with excellent d.r.
and e.r. values, albeit with moderate yields. The scope of the
o-tosylamino enones 2 was then studied by using 1a as
a model ester substrate (3k–v). When chalcone-type o-
tosylamino enone substrates [e.g., R’ = (hetero)aryl group in
3k–t] were used, all the reactions gave the corresponding
products with good to excellent yields, and excellent d.r. and
e.r. values (3k–t). The o-tosylamino enone substrate with R’
as an alkenyl unit was also tolerated, thus affording 3u in
93% yield, 14:1 d.r., and 96:4 e.r. In our reaction sequence,
the use of an enone with an alkyl unit (R’ as a propyl group)
afforded the desired product with 40% yield and excellent d.r.
and e.r. values (3v). In this case, the major side reaction
(accounting for about 40% consumption of the amino enone
substrate) was an intramolecular Michael addition of the
amine to the enone. The cascade products were nearly
undetectable when R or R’ = H. The cascade reactions can be
readily scaled up without obvious loss in yield and selectivity.
For example, gram-scale preparation (1.03 gram scale) of 3a
was achieved with similar yield and e.r. value as obtained
from the small-scale reaction presented in Tables 1 and 2.
The proposed pathway for the formation of the cascade
product 3 is further illustrated in Scheme 1. Addition of the
NHC to the ester 1 could give the NHC-bounded ester
intermediate I, which undergoes a-CH deprotonation to form
the ester enolate intermediate II. b-CH deprotonation of II
affords III which bears a nucleophilic b-carbon atom. A
formal Michael addition of the nucleophilic b-carbon atom of
III to 2 generates the intermediate IV. Subsequent proton
transfer followed by intramolecular aldol reaction and lactam
formation leads to VIII, which undergoes dehydration[14] to
form 3.
Table 1: Screening of reaction conditions for the reaction of 1a with 2a.[a]
Entry
NHC
Solvent
Yield [%][b]
d.r.[c]
e.r.[d]
1
2
3
4
5
A
B
THF
THF
THF
THF
0
90
trace
80
–
20:1
–
15:1
10:1
–
–
–
96:4
97:3
C or D
E
E
toluene
83
[a] Standard reaction conditions: NHC precursor (20 mol%), 1a
(2.0 equiv), 2a (0.2 mmol), DBU (1.5 equiv), solvent (0.5 mL), 4 ꢀ M.S.,
RT, 24 h. [b] Yield of products after column chromatography. [c] Diaste-
reomeric ratio of 3a, determined by 1H NMR analysis of unpurified
reaction mixtures. Absolute configuration of product was determined by
X-ray analysis of 3m (Table 2). [d] Determined by HPLC analysis using
a chiral stationary phase. DBU=1,8-diazabicyclo[5.4.0]undec-7-ene,
Mes=2,4,6-trimethylphenyl, THF=tetrahydrofuran.
arylamino moiety, was chosen as the other model reactant and
the tosyl moiety was identified as a suitable protecting group.
An imidazolium carbene pre-catalyst (A) was not effective
for this reaction (Table 1, entry 1). When the achiral triazo-
lium NHC pre-catalyst B was used with DBU as a base in
THF, the desired cascade product 3a was obtained with 90%
yield and 20:1 d.r. (entry 2). Possible side products such as
those illustrated in Figure 1b (e.g., amide formation or
reaction at the a-carbon atom) were nearly undetectable.
Notably, the protecting group on the amine moiety was
important for the success of this reaction. For example, the
free amino enone could not provide the desired cascade
Lastly, we demonstrated additional synthetic transforma-
tions of the multicyclic domino reaction products by using 3a
2
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Table 2: Scope with respect to the ester 1 and the o-tosylamino enone
2.[a]
Scheme 1. Proposed mechanism.
Scheme 2. Synthetic transformations of the cascade product 3a.
TBAF=tetra-n-butylammonium fluoride.
carbon–carbon double bond reduction of 4 was realized
stereoselectively by using magnesium in methanol to afford
the compound 5.[7c,16,17] Notably, the tricylic skeleton of 5 is
a common moiety found in natural products (such as
meloscine, scandine, and epimeloscine)[1] and biologically
active compounds[7c,d] (such as fluorinated dihydroquinolines
and dihydroquinolines with amine-containing side chains). N
to O sulfonyl migration of 3a at elevated temperature in
toluene afforded the quinoline derivative 6.[11o,18] The OTs
group is amenable to further coupling reactions based on
literature procedures.[19] Alkene dihydroxylation of 3a using
[a] Reaction conditions as in Table 1, entry 5; yields (after SiO2
chromatography purification) are based on the o-tosylamino enone 2.
[b] Reactions run with 3.0 equivalents of ester, 200 mol% DBU, and
0.25 mL toluene for 48 h at room temperature. [c] The o-tosylamino
enone was added in three portions.
as a model (Scheme 2). The Ts group of 3a could be readily
removed by TBAF at room temperature to give lactam-type
adduct 4 in 85% yield with 20:1 d.r. and 96:4 e.r.[11l,15] The
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RuCl3 and NaIO4 effectively afford the compound 7 with
65% yield and excellent diastereo- and enantioselectiv-
ity.[20,21] Oxidative carbon–carbon cleavage of the diol in 7
with HI5O6 afforded the nine-memebered lactam 8 bearing
two ketone functionalities and two stereogenic centers.[22]
Notably, in all these transformations the original stereogenic
centers were not affected and the new stereogenic centers
were formed with high selectivities.
In summary, we have developed a single-step, chemo-,
stereo-, and enantioselective domino method for synthesis of
multicyclic oxoquinoline-type heterocycles. This reaction
involves NHC-catalyzed activaton of the b sp3-carbon atom
of an ester as a crucial step. Because of the unique reactivity
patterns of carboxylic esters (e.g., in comparison with
aldehydes or ketones), we expect that previously challenging
cascade processes can be made possible through further
development of organocatalytic activation of esters.
Received: February 20, 2014
Revised: March 20, 2014
Published online: && &&, &&&&
À
Keywords: C H activation · cyclization · heterocycles ·
N-heterocyclic carbene · organocatalysis
.
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[21] The absolute configuration of 7 was determined by comparison
of the relative structure of rac-7a and the absolute configuration
of 3m. CCDC 979557 (rac-7a) contains the supplementary
crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
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the supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge
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Angew. Chem. Int. Ed. 2014, 53, 1 – 6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

.
Angewandte
Communications
Communications
Heterocycles
Z. Fu, K. Jiang, T. Zhu, J. Torres,
Y. R. Chi*
&&&& — &&&&
Access to Oxoquinoline Heterocycles by
N-Heterocyclic Carbene Catalyzed Ester
Activation for Selective Reaction with an
Enone
Under construction: A single-step enan-
tioselective access to multicyclic oxoqui-
noline-type heterocycles is disclosed. The
process takes advantage of the unique
reaction patterns of esters under N-
heterocyclic carbene (NHC) catalysis. It
involves activation of the b-carbon atom
of an ester as the key step with a subse-
quent chemoselective cascade reaction
with amino enone substrates. Ts=4-
toluenesulfonyl.
6
www.angewandte.org
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
These are not the final page numbers!