Asymmetric Bronsted acid catalyzed carbonyl activation - Organocatalytic domino electrocyclization-halogenation reaction

Article abstract of DOI:10.1039/c1cc15289k

A highly efficient Bronsted acid catalyzed enantioselective Nazarov cyclization-bromination reaction has been developed. The protocol gives access to highly functionalized trans-4,5-substituted 5-bromocyclopentenone derivatives in good yields and with excellent enantioselectivities.

Full text of DOI:10.1039/c1cc15289k

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Asymmetric Brønsted acid catalyzed carbonyl activation – organocatalytic
domino electrocyclization–halogenation reactionw
Magnus Rueping* and Winai Ieawsuwan
Received 25th August 2011, Accepted 25th August 2011
DOI: 10.1039/c1cc15289k
A highly efficient Brønsted acid catalyzed enantioselective
Nazarov cyclization–bromination reaction has been developed.
The protocol gives access to highly functionalized trans-4,5-
substituted 5-bromocyclopentenone derivatives in good yields
and with excellent enantioselectivities.
an electrophile, highly diastereoselective Nazarov cyclization/
Michael addition4 and Nazarov cyclization/halogenation6,7
reactions have been developed. However, examples of enantio-
selective domino or sequential processes are scarce.5,9
Based on our experience in the field of Brønsted acid catalyzed
enantioselective reactions with carbonyl substrates,10,11 and
inspired by the enzymatic halohydration of soybean peroxidase12
we decided to investigate an asymmetric Nazarov cyclization/
halogenation domino reaction as this would provide access to
synthetically useful functionalized cyclopentenones. Recently,
we reported an efficient methodology for the Nazarov cyclization
of activated dienones which gives access to 4,5-disubstituted
cyclopent-2-enones in good yields and with excellent enantio-
selectivities.13,14
The Nazarov reaction has been established as a powerful
method for the construction of five membered rings, being
widely used for the rapid assembly of cyclopent-2-enone cores.1
In addition to its utility in the synthesis of various natural
products, the Nazarov cyclization has also found widespread
application in more complex domino, cascade and sequential
reactions. In this regard, two different approaches which take
advantage of the intermediates formed at different stages in the
classical Nazarov cyclization have been developed: (i) trapping
of the carbocation intermediate C with different carbon- or
heteroatom-based nucleophiles2,3 or (ii) trapping of enolate D
formed at a later stage with various electrophiles other than
protons (Scheme 1).4–8 The efficient integration of the Nazarov
cyclization into complex domino reactions has significantly
broadened the application scope of this transformation. Con-
siderable progress has been made in the field of interrupted
Nazarov reactions with nucleophiles. These offer access to
valuable polycyclic structures.2 Regarding the alternative way
of functionalization which implies trapping of the enolate with
However, in order to develop a generally applicable Nazarov
cyclization/halogenation protocol, different electrophiles 2a–e
and a wide range of N-triflylphosphoramides15,16 3a–h had to be
evaluated under different reaction conditions (Tables 1 and 2).
Table 1 Evaluation of different electrophilic halogenating reagents
Entrya Electrophile 2 (E+
)
Product Yieldb (%) eec,d (%)
1
2
3
4
5
Selectfluor 2a
NFSI 2b
N-Chlorosuccinimide 2c 4a
N-Bromosuccinimide 2d 5a
—
—
—
—
15
16
44
—
—
47
92
86
Scheme 1 Nazarov cyclization with subsequent electrophilic trapping.
TBCHD 2e
5a
Institute of Organic Chemistry, RWTH Aachen University,
Landoltweg 1, D-52074 Aachen, Germany.
E-mail: magnus.rueping@rwth-aachen.de;
a
Reactions were performed with dienone 1 and electrophiles 2a–e
(1.2 equiv.) in the presence of 3e (10 mol%) in CHCl3 at 0 1C to room
temperature for overnight. Yield of the isolated major diastereomer
b
Fax: +49 (0) 241-809-2665
c
(trans). Enantiomeric excess for the isolated major diastereomer
d
(trans). Determined by chiral HPLC analysis.
w Electronic supplementary information (ESI) available: Experimental
procedures and full characterization data for all new compounds are
provided. See DOI: 10.1039/c1cc15289k
c
11450 Chem. Commun., 2011, 47, 11450–11452
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Table 2 Evaluation of various Brønsted acids under different reaction
conditions
Table 3 Substrate scope for the Brønsted acid-catalyzed Nazarov
cyclization/bromination cascade reaction
Yield ee
trans-5a–l trans : cisb (%)c (%)b,d
Entrya R1 R2
1
2
3
4
Me Ph
5a
5b
5c
5d
5e
5f
5g
5h
5i
2 : 1
20 : 1
3 : 1
6.7 : 1
8 : 1
1.7 : 1
3 : 1
5.7 : 1
4.8 : 1
8 : 1
66
50
66
74
55
61
42
59
63
43
89
94
94
92
97
92
85
94
94
92
Me 4-FC6H4
Me 4-ClC6H4
Me 4-BrC6H4
Me 4-CF3C6H4
Me 4-MeC6H4
Me 4-MeOC6H4
Me 1-Naphthyl
Me 2-Naphthyl
Entrya
Catalyst
trans : cisb
Yieldc (%)
Eeb,d (%)
5
6
7e
8
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
3g
3h
3e
3e
3e
3e
1 : 1
1 : 1
1.6 : 1
2.3 : 1
2.3 : 1
4 : 1
46
48
46
35
44
5
37
40
33
54
53
66
76
58
77
87
90
88
94
93
94
92
92
89
9
10e
Me 3,4-Methylene 5j
dioxybenzene
11
12
Pr 2-Naphthyl
Pr 3-BrC6H4
5k
5l
15 : 1
3 : 1
82
51
95
92
3 : 1
2.8 : 1
2.7 : 1
2.3 : 1
2.5 : 1
2 : 1
a
9e
10f
11f,g
12g
Reactions were performed with substrates 1a–l and 2e (2.0 equiv.) in
the presence of 3e (5 mol%) in CHCl3 at 0 to 10 1C for 60 h.
Determined by chiral HPLC. Yield of the isolated major diastereo-
b
c
d
mer. Enantiomeric excess for the isolated major diastereomer
e
a
(trans). Temperature and reaction time: 0 to 5 1C for 60 h.
Reactions were performed with dienone 1, and TBCHD (2e,
b
2.0 equiv.) in the presence of 3a–h (5 mol%). Determined by chiral
c
HPLC analysis. Yield of the isolated trans diastereomer. Enantio-
d
cyclization–bromination reaction with various dienones 1a–l
(Table 3). In general, differently disubstituted dienones were
successfully converted into the corresponding a-brominated
cyclopent-2-enones. Various aryl groups are tolerated at the b
position in the dienone substrates and the desired products
were obtained in moderate to good yields and with high enantio-
selectivities (85–97% ee). Whereas the diastereoselectivity was
considerably influenced by the electronic and steric effects of
the group at the b position, the enantioselectivity was not
significantly affected.
e
meric excess for the isolated major diastereomer (trans). 1 mol%
f
catalyst. 2 mol% catalyst. Temperature and reaction time: 0 to
g
10 1C for 60 h.
The evaluation of electrophiles was performed by applying
1.2 equiv. of the halogenating reagent in the presence of
10 mol% of catalyst 3e in chloroform (Table 1).
Under these conditions the enolate did not react with electro-
philic fluoride sources such as Selectfluor and N-fluorobenzene-
sulfonimide (NFSI) (Table 1, entries 1 and 2). In the case of
N-chlorosuccinimide 2c the desired product was obtained in 15%
yield and 47% ee (Table 1, entry 3). Better enantioselectivity
(92% ee) was obtained in the case of N-bromosuccinimide 2d.
However, the yield was low (Table 1, entry 4). An improved
yield was obtained with the 2,4,4,6-tetrabromocyclohexa-2,5-
dienone 2e (TBCHD) as a bromine source (Table 1, entry 5).
Hence, TBCHD was selected as a brominating agent to further
examine the enantioselective Nazarov cyclization–bromination
reaction.
The absolute configuration of the major diastereomers was
determined by X-ray analysis. The X-ray crystal structure of
the major diastereomer trans-5a (Fig. 1) indicated that the
bromination occurred trans to the b-substituent (R = Ph) of
the Nazarov cyclization intermediate whereas the cis attack
was sterically restricted by the b-substituent.
In summary, we have developed the first asymmetric Brønsted
acid-catalyzed Nazarov cyclization–halogenation reaction.
Two chiral centers, a tertiary and a quaternary one, have been
established during this transformation. The present method
provides, for the first time, a variety of a-brominated cyclo-
pent-2-enones with a wide substrate scope and with excellent
enantioselectivities.
Our subsequent investigation focussed on the evaluation of
different chiral Brønsted acids 3a–h. Most of the investigated
catalysts afforded the trans isomer as the major product
(Table 2, entries 3–12). The highest enantioselectivities (up to
94% ee) were obtained with catalysts 3e–h, bearing large
phenanthryl groups in the 3,30-positions (Table 2, entries 5–8).
With regard to both yield and selectivity, the best results were
obtained with catalyst 3e (Table 2, entry 5). The catalyst loading
and the reaction temperature were also examined (Table 2,
entries 9–12). The best result was obtained at 0 to 10 1C in the
presence of 5 mol% of catalyst 3e (Table 2, entry 12).
With the optimized conditions in hand we explored the
scope of the Brønsted acid-catalyzed asymmetric Nazarov
Fig. 1 Crystal structure of trans-5a.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 11450–11452 11451

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The authors gratefully acknowledge DFG for financial
support.
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c
11452 Chem. Commun., 2011, 47, 11450–11452
This journal is The Royal Society of Chemistry 2011