Halogen Bond Catalyzed Bromocarbocyclization

Article abstract of DOI:10.1002/anie.201800261

A halogen bond catalyzed bromo-carbocyclization of N-cinnamyl sulfonamides and O-cinnamyl phenyl ethers has been developed. N-methyl 4-iodopyridinium triflate is used as the halogen-bonding organocatalyst and the reaction is highly chemoselective. This report represents the first proof-of-concept for halogen-bonding organocatalyst-promoted electrophilic halogenation. Mechanistic study suggests the autocatalytic nature of this reaction.

Full text of DOI:10.1002/anie.201800261

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Accepted Article
Title: Halogen-Bond Catalyzed Bromocarbocyclization
Authors: Yuk-Cheung Chan and Ying-Yeung Yeung
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Halogen-Bond Catalyzed Bromocarbocyclization
Yuk-Cheung Chan and Ying-Yeung Yeung*[a]
Dedicated to Professor Elias J. Corey on the occasion of his 90th Birthday
Abstract: A halogen-bond catalyzed bromocarbocyclization of N-
cinnamyl sulfonamides and O-cinnamyl phenyl ethers has been
developed. N-methyl 4-iodopyridinium triflate is used as the halogen-
bond organocatalyst and the reaction is highly chemoselective. This
report represents the first example of proof-of-concept of halogen-
XB catalyst could activate N-haloamide reagent to generate a soft
electrophilic halonium species for the halogenation of olefins.
Herein, we reported the first case of using halogen-bond as
organocatalyst to catalyze bromocarbocyclization of cinnamyl
substrates (Friedel-Crafts type reaction) (Scheme 1). Inexpensive
halogenating reagent was used and the reaction conditions were
mild. The resulting halogenated tetrahydroquinolines[19] and
chromanes[20] are valuable drug cores and natural products
scaffolds.
bond
organocatalyst-promoted
electrophilic
halogenation.
Mechanistic study suggests the autocatalytic nature of this reaction.
Halogen bond (XB) corresponds to a non-covalent interaction
between an electrophilic halogen substituent and a Lewis base.[1]
Key features of XB include the high directionality of the interaction
(approximately 180º),[2] polarizable halogen atoms (Cl, Br, I)[3] and
sufficiently high bond strength (10 to 180 kJ/mol),[4] making XB to
be considered as a hydrophobic and soft analogue of hydrogen
bonding.[5] Although XB has been discovered for more than 150
years, its applications are very concentrated in the fields of
supramolecular chemistry and crystal engineering.[6]
In comparison, using XB in organocatalysis remains
underexplored. In 2008, Bolm et al. reported an example on
applying perfluoroiodoalkanes as a XB catalyst in the reduction of
quinolines by Hantzsch esters.[7] Afterwards, two interesting
examples on the XB activation of carbonyl or imine functional
groups in the classical and Aza Diels-Alder type reactions were
reported by Huber et al. and Minakata et al., respectively.[8]
Another milestone was built by Huber et al. in which multidentate
XB donor assisted C-X bond activation was achieved.[9] Very
recently, Takemoto et al. reported two representative examples of
Scheme 1. Halogen-bond-Catalyzed Bromocarbocyclization
XB-catalyzed
Si-X
bond
activation/benzylic
carbon
At the outset of our investigation, bromocarbocyclization of
N-cinnamyl sulfonamide 4a was studied using 1,3-dibromo-5,5-
dimethylhydantoin (DBDMH) as the halogen source in CH2Cl2. In
the absence of catalyst, the reaction was sluggish and low
conversion was observed after 24 h (Table 1, entry 1). To our
delight, the use of 10 mol% of the iodine-containing XB
organocatalyst 1a gave good isolated yield of the desired product
5a (85%, dr > 99:1) and the reaction was found to be readily
scalable (entry 2). The structure of 5a was confirmed by an X-ray
crystallographic study.[21] In comparison, replacing the iodine
atom in catalyst 1a with bromine or chlorine atom (i.e. XB
catalysts 1b and 1c in entries 3 and 4) gradually decreased the
catalytic performance, which could be attributed to their weaker
XB strength due to the lower polarizability of the XB donor atom.[5f]
Slightly lower reaction efficiency was observed when a bulkier XB
donor iodoimidazolium triflate salt 1d was employed (entry 5). A
dramatic drop in the reaction efficiency was observed when the
cationic XB donor 1a was replaced by the neutral XB catalyst 4-
iodopyridine (1e), suggesting that the cationic character of 1a
might play a crucial role in enhancing the electron-withdrawing
property and the XB strength in the organocatalytic halogenation
process (entry 6).[5f] Pentafluoroiodobenzene or molecular iodine
was found to be inefficient in promoting the cyclization (entries 7
and 8). It was noticed that the cyclization of 4a could not be
achieved efficiently by other organocatalysts such as hydrogen-
functionalization[10] and iodonium ylide activation/cross-enolate
coupling.[11] Nevertheless, applications of XB in organocatalysis
are limited to a few types of reactions and the scope remains
sporadic when compared to that of conventional hydrogen-bond
catalysis.[12]
Halofunctionalization of olefins is a fundamental organic
transformation to furnish various kinds of building blocks. Among
halofunctionalization reactions, halo-O-cyclizations and halo-N-
cyclizations are well-documented.[13] The analogue halo-C-
cyclization, in particular the organocatalytic version, is far less
explored despite the fact that the resulting cyclized products are
valuable synthetic intermediates.[14-16] One of the challenges of
halocarbocyclization is that the C-nucleophiles might also react
with the electrophilic halogens[17] and a suitable reaction protocol
remains elusive.
susceptible toward aromatic halogenation.[18] We hypothesize the
For instance, electron-rich arenes are
[a]
Mr. Yuk-Cheung Chan, Prof. Dr. Ying-Yeung Yeung
Department of Chemistry, The Chinese University of Hong Kong
Shatin, N.T., Hong Kong (China)
E-mail: yyyeung@cuhk.edu.hk
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201800261
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Table 1. Catalyst Screening[a]
bond catalysts (thiourea 2a and squaramide 2b), Lewis bases
(thiocarbamate 2c[13e] and triphenylphosphine sulfide), Brønsted
bases (iPr2NEt, DMAP), Brønsted acids (CF3CO2H, BINOL-
derived phosphoric acid 3), and TMSOTf, which clearly
demonstrated the unique role of XB organocatalyst in
halogenation reaction (entries 9–17).
Next, the substrate scope was examined and the results are
summarized in Table 2. In general, the halocarbocyclization of N-
cinnamyl sulfonamides 4 proceeded smoothly to give the desired
tetrahydroquinolines
diastereoselectivity
5
(dr
in
>
good
99:1)
efficiency,
and regioselectivity
excellent
(endocyclization). Excellent isolated yields of 5c and 5d were
obtained, potentially due to the electron-rich nature of the methyl-
and methoxy-substituted aryl systems that favor the Friedel-
Crafts reactions. On the other hand, substrate 4b that bears an
electron-deficient chlorine substituent returned lower efficiency.
Substrate that contains silyl ether (4e) or acetal (4f) was also
found to be compatible with the XB catalytic protocol to give the
corresponding product 5e or 5f smoothly. Electron-rich aromatic
systems are susceptible to electrophilic halogenation, which is a
potential side reaction pathway in the Friedel-Crafts reaction
process. Indeed, a systematic study conducted by Jackson and
Borhan successfully predicted that highly electron-rich substrate
Entry
1
Catalyst
-
Isolated Yield [%]
4g that bears
a 3,4,5–trimethoxyphenyl group undergoes
Trace
85 (80)[b]
68
aromatic chlorination preferentially.[17] Interestingly, the
2
1a
bromocarbocyclization of 4g was the favorable pathway to give
Table 2. Scope of Bromocarbocyclization of N-Cinnamyl Sulfonamides[a]
3
1b
4
1c
55
5
1d
75
6
1e
13
7
C6F5I
Iodine
2a
Trace
30
8
9
Trace
20
10
11
12
13
14
15
16
17
2b
2c
10
Ph3P=S
iPr2NEt
DMAP
CF3CO2H
3
Trace
Trace
Trace
18
12
TMSOTf
13
[a] Reactions were carried out with 4a (0.05 mmol), catalyst (0.005 mmol) and
DBDMH (0.055 mmol) in CH2Cl2 (0.5 mL) for 24 h at 25 oC under N2 atmosphere
in the absence of light. [b] Isolated yield of 5a for the reaction at 1.0 mmol scale.
[a] Reactions were carried out with 4 (0.1 mmol), catalyst 1a (0.01 mmol),
DBDMH (0.11 mmol), CH2Cl2 (1.0 mL) for 24 h at 25 oC under N2 atmosphere
in the absence of light unless specified. [b] Reaction was carried out at for 12 h.
[c] Reaction was carried out at −20 ºC.
DBDMH
=
1,3-dibromo-5,5-dimethylhydantoin,
DMAP
=
N,N-
dimethylaminopyridine, TMSOTf = trimethylsilyl trifluoromethanesulfonate.
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5g using the XB catalytic protocol.[22] The reaction was also found
to be compatible with cinnamyl moiety that bears electron-
donating (4h) or electron-withdrawing (4i, 4j) substituent.
With the developed XB-catalyzed halocarbocyclization of N-
cinnamyl sulfonamides 4 in hand, we further investigated the
bromocarbocyclization of O-phenyl cinnamyl ethers 6 that could
give rise to valuable chromane building blocks 7 (Table 3).[20] The
reaction was expected to be more challenging in light of
chemoselectivity due to the stronger electron-donating nature of
oxygen than NTs.[23] Meanwhile, the absence of anchimeric
assistance of S=O as in NTs might also diminished the
stabilization of the putative bromocarbenium ion intermediate.[17]
Nonetheless, after a brief survey on the halogen sources and
reaction conditions (See SI), using DBDMH at 0 ºC was found to
be optimum to give the chromane products 7 (Table 3). To our
delight, the XB-catalyzed carbocyclization of O-phenyl cinnamyl
ethers 6 was applicable to substrates with electron-rich or
electron-deficient substituent at the phenol ether or the cinnamyl
chain. A relatively higher reaction temperature was applied to the
electron-deficient substrate 6b in order to drive the reaction at a
reasonable reaction rate. Similar to the bromocarbocyclization of
Scheme 2. Synthesis of Derivatives 8 and 9 (AIBN = Azobisisobutyronitrile,
DBU = 1,8-Diazabicyclo[5.4.0]undec-7-ene)
An interesting phenomenon was observed during the
mechanistic investigation; when we monitored the XB-catalyzed
bromocarbocyclization of 4a by time-dependent 1H NMR
experiment, unexpectedly, it was realized that the reaction
progress fits
a sigmodal curve, which suggests that an
autocatalytic component might exist in the reaction system
(Figure S1 in Supporting Information). Next, a more detailed
investigation was conducted aiming at identifying the species that
caused the autocatalytic behavior. Among the products/by-
products that could be generated from the reaction, it was found
that the addition of stoichiometric amount of 5,5-
dimethylhydantoin
(DMH)
or
mono-N-bromo-5,5-
N-cinnamyl
sulfonamides
4,
excellent
chemo-
and
dimethylhydantoin (MBDMH) as an additive could greatly
accelerate the bromocarbocyclization of 4a (Figure S2 in
Supporting Information).
stereoselectivity were observed in the case of O-phenyl cinnamyl
ethers 6.
Although a more detail study is needed in order to elucidate
clear mechanistic picture, we attempted to piece the
Table 3. Scope of Bromocarbocyclization of O-Cinnamyl Ethers[a]
a
experimental results together and draft a possible explanation for
the observed reaction behavior (Scheme 3). We rationalize that
the XB organocatalyst 1a might coordinate with the carbonyl
group of DBDMH to give species A,[8] which could enhance the
electrophilicity of the Br for the formation of bromiranium ion
intermediate B. The weakly coordinated XB-hydantoin anion in
intermediate B might facilitate the cyclization process to give the
arenium ionic species C.[24] Subsequent deprotonation of C could
yield the desired product 5 or 7. In addition, we speculate that
DMH or MBDMH, which would be generated after each of the
reaction cycle, might interact with the XB-hydantoin anion in
intermediate B to give the putative XB-complex D via a hydrogen-
bond/halogen-bond network.[25] We believe that the XB-complex
anion in intermediate D should be even less coordinative than the
XB-hydantoin anion in intermediate B because the negative
charge in XB-complex D is more dispersed, so that the cyclization
of the bromiranium ion intermediate in D could be accelerated. On
the basis of this plausible reaction pathway, the reaction rate
would increase at the later stage of the reaction since the
concentration of DMH and MBDMH would increase in accordance
to the reaction progress.
[a] Reactions were carried out with 6 (0.1 mmol), catalyst 1a (0.01 mmol),
DBDMH (0.11 mmol), CH2Cl2 (1.0 mL) at 0 oC under N2 atmosphere in the
absence of light unless specified. [b] Reaction was carried out at 25 ºC. [c]
Reaction was carried out for 12 h.
In summary, we have developed the first proof-of-concept
of halogen-bonding catalyzed bromocarbocyclization. The soft
Lewis acid nature of XB allows the bromocarbocyclization of N-
cinnamyl sulfonamides 4 and O-cinnamyl phenyl ethers 6 to
proceed smoothly in high chemoselectivity and regioselectivity.
Detailed mechanistic study and substrate scope expansion are
currently underway.
The cyclized products that contain a halogen handle can be
further transformed into some useful building blocks. For instance,
dehydrobromination of 5a using DBU gave the dihydroquinoline
derivative 8 in 90% yield (Scheme 2). On the other hand,
treatment of 5a with nBu3SnH and AIBN smoothly gave the
tetrahydroquinoline derivative 9.
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Scheme 3. A Plausible Mechanism
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We thank the financial support from HKSAR University Grant
Council (grant no. CUHK 14305317) and The Chinese University
of Hong Kong direct grant.
Keywords: Cyclization • Halogen Bond • Halogenation •
Heterocycle • Organocatalysis
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A mixture of brominated products was obtained when the
Crystallographic
Data
Centre
via
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This article is protected by copyright. All rights reserved.

10.1002/anie.201800261
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
Halogen-bond catalysis.
A halogen-bond catalyzed
bromocarbocyclization of
N-cinnamyl sulfonamides
and O-cinnamyl phenyl
ethers has been
Yuk-Cheung Chan and Ying-
Yeung Yeung*
Page No. – Page No.
Halogen-Bond Catalyzed
Bromocarbocyclization
developed. N-methyl 4-
iodopyridinium triflate is
used as the halogen-bond
organocatalyst and the
reaction is highly
chemoselective. This report
represents the first
example of proof-of-
concept of halogen-bond
organocatalyst-promoted
electrophilic halogenation.
Mechanistic study suggests
the autocatalytic nature of
this reaction.
This article is protected by copyright. All rights reserved.