Halogen Bond-Catalyzed Friedel?Crafts Reactions of Furans Using a 2,2’-Bipyridine-Based Catalyst

Article abstract of DOI:10.1002/adsc.202001019

A halogen bond donor based on a 2,2’-bipyridine framework has been synthesized, and used to catalyze Friedel?Crafts reactions of furans. Electrophiles used successfully in these reactions included various enones, an aldehyde, and a carboxylic acid anhydride. The yields of the reactions were generally good using a moderate catalyst loading (0.025 or 0.1 equiv.) at a relatively low temperature (room temp. or 50 °C) in acetonitrile. The catalyst used was designed with a biaryl scaffold so that if it indeed proved to be an efficient halogen bond donor organocatalyst, an enantioenriched version of it could potentially serve as a stereoselective catalyst. (Figure presented.).

Full text of DOI:10.1002/adsc.202001019

Title: Halogen Bond-Catalyzed Friedel-Crafts Reactions of Furans
Using a 2,2’-Bipyridine-Based Catalyst
Authors: Huimiao Zhang and Patrick Toy
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.202001019
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10.1002/adsc.202001019
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.202
Halogen-Bond-Catalyzed Friedel–Crafts Reactions of Furans
Using a 2,2’-Bipyridine-Based Catalyst
Huimiao Zhang,a and Patrick H. Toya,*
a
Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong, P. R. of China
Tel: +852-28592167
Fax: +852-28571586
E-mail: phtoy@hku.hk
Received:
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.202######.
between a Michael acceptor and indole that was
bipyridine framework has been synthesized, and used to poorly enantioselective (22% ee).[24] More recently 6
Abstract. A halogen-bond donor based on a 2,2’-
catalyze Friedel–Crafts reactions of furans. Electrophiles
used successfully in these reactions included various
enones, an aldehyde, and a carboxylic acid anhydride. The
yields of the reactions were generally good using a
moderate catalyst loading (0.025 or 0.1 equiv) at a
relatively low temperature (room temp. or 50 °C) in
acetonitrile. The catalyst used was designed with a biaryl
scaffold so that if it indeed proved to be an efficient
halogen-bond donor organocatalyst, an enantioenriched
version of it could potentially serve as a stereoselective
catalyst.
was used to catalyze a Mukiyama aldol reaction that
was modestly enantioselective (33% ee).[25] Finally,
and perhaps most successfully, alkaloid-based
compounds such as 7 were reported as catalysts for a
range highly enantioselective Mannich reactions (3
different types of reactions, 39 total examples, 65-
98% ee).[26]
Keywords: halogen bond; organocatalysis; Friedel–Crafts
reaction; furans; enones
Non-covalent halogen bonds are interactions that can
be considered to be functionally related to hydrogen
bonds,[1] and the use of organic halides as halogen-
bond donors to catalyze organic reactions has become
an active area of research.[2] In this context organic
halides have been used experimentally to activate
quinolines,[3] imines,[4] acyl iminium ions,[5] carbon-
halogen bonds,[6] silicon-halogen bonds,[7] metal-
halogen bonds,[8] aldehydes and ketones,[9] Michael
acceptors,[10] thioamides,[11] trichloroacetimidates,[12]
hydantoins,[13] alkoxyallenes,[14] vinyl indoles,[15]
ethers,[16] and iodonium ylides[17] in various
transformations. There has even been a report of
using organic halides as templating catalysts for
macrocyclization reactions.[18] As for the organic
halide catalysts used in these reactions, the majority
of them were achiral. While some chiral catalysts
have been reported, e.g. 1-7 (Figure 1), only a few of
these were used in stereoselective reactions.[19-22] In
the first reported example of asymmetric catalysis
using an organic halide, 4 was used in Michael/Henry
reaction cascades for the synthesis of thiochromanes
that were moderately enantioselective (10 examples,
19-69% ee).[23] Later, 5, in which the chirality is in the
anion, was used to catalyze a Friedel–Crafts reaction
Figure 1 Chiral halogen-bond donor catalysts.
1
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10.1002/adsc.202001019
Advanced Synthesis & Catalysis
In the field of halogen-bond catalysis, we research, and water could inadvertently be present due
1
previously reported the use of an achiral bidentate to local environmental conditions. Gratifyingly H-
bis(benzimidazolium iodide) salt to catalyze Friedel– NMR analysis showed no evidence of any
Crafts reactions of aldehyde and ketone electrophiles hydrolysis/decomposition of 9a, even after 24 h (see
and
indole
nucleophiles
to
form Supporting Information).
bis(indolyl)methanes,[27] and Povarov reactions
between imines and electron-rich dienophiles,[28] that
were similar to reactions reported by others using
different halogen-bond-donating catalysts.[29,30] As we
considered the possibility of performing the later
reactions enantioselectively and surveyed the state of
the art, we realized that organic halide halogen-bond
donors with an axis of chirality, as in the anion of 5,
have not been examined as catalysts, even though
chiral compounds such as those based on a 1,1’-
binapthyl skeleton have been wildly successful as
catalysts and ligands in asymmetric catalysis.[31] We
were thus inspired by the report of 8 as a catalyst in
bromocarbocyclization reactions (Figure 2).[13] Since
it is well established that bidentate halogen-bond
donors are more efficient catalysts than monodentate
analogues,[6c,6f] and we previously found that
iodonium tetrafluroborate and triflate salts were both
viable catalysts,[27,28] we targeted 9a and 9b for
evaluation as halogen-bond donor catalysts, since
enantiomerically enriched versions of them could
potentially be prepared if they proved to be good
catalysts. Herein we report the synthesis of 9a and its
use as a catalyst for Friedel–Crafts reactions of furans.
Scheme 1 Synthesis of 9c and 9a.
The structures of 9a and 9c were confirmed by
single-crystal X-ray structural analysis, and they both
show evidence of halogen bonding in the solid state
(Figure 3). Notably, the pyridinium rings of both
structures are nearly perpendicular, with dihedral
angles of 86.2° and 89.7°, respectively, for 9a and 9c.
In the structure of 9a, the C-I-F bond angle is 166°, as
might be expected for a halogen bond. Additional
evidence of halogen bonding in 9a is the I to F
distance of 2.98 Å, which is shorter than the sum of
the van der Waals radii (3.45 Å).[34] The structure of
9c exhibits similar features, with a C-I-O bond angle
of 162°, and an I to O distance of 2.80 Å, compared to
the sum of the van der Waals radii of 3.50 Å.[34]
Figure 2 Pyridinium iodide halogen-bond donors.
Synthesis of our targeted catalysts started with
commercially available 10 (Scheme 1). This was
transformed into 11 via an Ullman coupling/reduction
reaction sequence.[32] Subsequent conversion of 11
into 12 was achieved using a procedure previously
reported for the synthesis of an isomer of it.[33]
Disappointingly, treatment of 12 with (Me3O)BF4 or
MeOTf failed to cleanly afford 9a or 9b, respectively,
no matter what conditions we used. Usually a mixture
of mono- and di-methylated products was obtained,
and re-subjecting the mixtures to alkylation
conditions never resulted in pure 9a or 9b. However,
we were able to successfully react 12 with Me2SO4 at
high temperature to afford 9c, which in turn could be
converted into 9a using AgBF4. At this point we
examined the stability of 9a in solution since its
decomposition could in theory lead to the formation
of acid, I2 or a radical species that could potentially
catalyze the reactions we planned to perform. For this
study we chose to use CD3CN/D2O (9:1) as the
solvent at 70 °C since MeCN proved to be a good
solvent for halogen-bond catalysis in our previous
Figure 3 X-ray structures of 9a and 9c (hydrogen atoms
omitted for clarity).
Since
halogen-bond-catalyzed
Friedel–Crafts
reactions between various Michael acceptor
electrophiles and indole,[25,27,35] N-methylpyrrole,[36]
and a variety of thiophenes[37] have previously been
reported, we chose to study reactions between
nucleophilic furans and various electrophiles in this
project.[38-40] Specifically, the reaction between 2-
methylfuran (13a) and methyl vinyl ketone (14a) to
2
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10.1002/adsc.202001019
Advanced Synthesis & Catalysis
form 15a was initially examined (Table 1). Table 1 Friedel–Crafts reactions between 13a and
Gratifyingly, when 0.025 equiv of 9a was used to 14a.[a]
catalyze the reaction at room temperature in MeCN,
very high yield of 15a was obtained after 4 h (entry 1).
When MeOH was used as the solvent, the reaction
was much more sluggish, and 24 h was required to
Entry Catalyst
(equiv)
Solvent Temp Time Yield[b]
obtain a similar yield (entry 2). When 9c was used as
the catalyst, slightly lower yield was obtained
compared to when 9a was used (entry 3), so 9a was
used for going forward. In order to assess the
scalability of the reaction catalyzed by 9a, it was
performed on a 15-fold larger scale, with good results
(entry 4). A control reaction using no catalyst resulted
in no reaction after 24 h (entry 5), as did reactions
using uncharged 12 (entry 6), and non-halogenated
analogues 16 and 17 (see Supporting Information) at
50 °C (entries 7 and 8). Thus, it is clear that the
catalyst for these reactions must be an electron-
deficient organic halide. When twice the amount of
Bu4NCl compared to the amount of 9a was added, no
reaction occurred (entry 9), providing additional
evidence of halogen bonding between 9a and 14a
being operative in this reaction. Replacing 9a with
0.10 equiv of monoiodo analogues 18 and 19 (see
Supporting Information) resulted in only very low
yield of 15a after 24 h at 50 °C (entries 10 and 11).
Thus, it seems that there is synergy between the two
iodine atoms in 9a that make it a very effective
catalyst. In order to compare halogen-bonding
catalysis to hydrogen bonding catalysis, thiourea 20
was examined in this reaction, but no reaction
occurred (entry 12).
(h)
(%)
1
2
3
9a (0.025)
9a (0.025)
9c (0.025)
9a (0.025)
Nil
MeCN rt
MeOH rt
MeCN rt
MeCN rt
MeCN rt
4
24
4
4
24
84
83
75
83
0
4[c]
5
6
7
8
9
12 (0.025)
16 (0.025)
17 (0.025)
9a (0.025),
Bu4NCl (0.05)
18 (0.10)
19 (0.10)
20 (0.025)
9a (0.025),
pyridine
MeCN 50 °C 24
MeCN 50 °C 24
MeCN 50 °C 24
0
0
0
MeCN rt
4
0
10
11
12
13
MeCN 50 °C 24
MeCN 50 °C 24
MeCN 50 °C 24
25
30
0
MeCN rt
24
68
(0.013)
14
9a (0.025), 21 MeCN rt
(0.13)
24
70
15
16
17
HBF4 (0.025) MeCN rt
I2 (0.025)
9a (0.025),
BHT (0.025)
4
4
4
12
12
85
MeCN rt
MeCN rt
In order to rule out the possibility of
adventitious/hidden acid being responsible for the
observed catalysis, a reaction was performed using 9a
together with pyridine (0.013 equiv), and good yield
of 15a could still be obtained, albeit after a longer
reaction time (entry 13). A similar result was obtained
when proton sponge 21 (0.013 equiv) was added to
the reaction instead of pyridine (entry 14).
Furthermore, when HBF4 was used as the catalyst
instead of 9a, only very low yield of 15a was
obtained under otherwise identical reaction conditions
(entry 15). This was also the case when I2 was used as
the catalyst for this reaction (entry 16), so it seems
unlikely that I2 contamination of 9a, or its generation
during the reaction is responsible for the observed
catalysis. In order to also rule out the possibility of a
radical process being involved in the reaction, a
reaction with an equal amount of BHT compared to
9a was performed, and the reaction proceeded
unchanged (entry 17). Overall the results of entries
13-17 support our observation that 9a does not
decomposed during the reactions to generate an acid,
iodine or radical species that functions as a hidden
catalyst, and provide support for the notion that 9a
does indeed act as a halogen-bond donor catalyst in
these reactions.
[a]
General reaction conditions: 13a (1.0 mmol), 14a (1.5
mmol), catalyst (0.025 mmol), in MeCN (3 mL).
[b] Isolated yield.
[c] Reaction performed using 13a (15.0 mmol), 14a (22.5
mmol), 9a (0.375 mmol) in MeCN (45 mL).
performed
a
series of reactions involving
combinations of 13a-c and 14a-k to produce 15b-l
(Table 2). Replacing 13a with 13b in the reaction
with electrophile 14a allowed for 15b to be prepared
efficiently (entry 1). When 13c was used as the
nucleophile with 14a (3.0 equiv), a double Friedel–
Crafts reaction was achieved to afford 15c in high
yield, albeit with higher catalyst loading (0.10 equiv)
and temperature (50 °C) (entry 2). When 14a was
replaced by either ester 14b or amide 14c in the
reaction with 13a, no product was formed (entries 3
and 4). When aldehyde 14d or 14e was used as the
electrophile in reactions with 13a, product 15d or 15e
was obtained, respectively, in high yield (entries 5
Next, in order to test the general utility of 9a in
catalyzing
Friedel–Crafts
reactions
between
nucleophilic furans and various electrophiles, we
3
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10.1002/adsc.202001019
Advanced Synthesis & Catalysis
Table 2 Friedel–Crafts Reactions Catalyzed by 9a[a]
Entr Fura Electro- Product 9a (equiv)/ Yield[b
y
n
phile
] (%)
Temp (°C)/
time (h)
1
2
3
4
5
6
7
8
9
10
11
12
13
0.025/rt/4
0.10/50/4
0.10/50/24
0.10/50/24
0.025/rt/4
0.025/rt/4
0.10/50/4
0.025/rt/24
0.10/50/24
0.10/50/24
0.10/50/48
0.10/50/24
0.10/50/24
80
80
nil
nil
80
82
80
86
80
82
30
80
40
13b
13c
13a
13a
13a
13a
13a
13a
13a
13b
13a
13a
13b
14a
14a
14b
14c
14d
14e
14f
14g
14h
14h
14i
15b
15c
nil
nil
15d
15e
15f
15g
15h
15i
15j
15k
15l
14j
14k
O
C
22
[a] 1H NMR signals of the ring protons of 9a.
[b] 1H NMR signal of methyl protons of 9a.
[c] 13C NMR signal of carbonyl carbon of 22.
Figure 4 NMR studies.
Finally, we found that other electrophiles besides
Michael acceptors could also be in these reactions.
For example, benzaldehyde (14j) reacted with 13a
(3.0 equiv) to afford 15k (entry 12), and acetic
anhydride (14k) afforded 15l in moderate yield when
reacted with 13b (entry 13).
[a]
General reaction conditions: 13 (1.0 mmol), 14 (1.5
mmol), 9a, in MeCN (3 mL).
[b] Isolated yield.
Additional evidence for halogen bonding being
operative in our reactions was obtained from a series
of NMR studies. For these we chose to study the
interaction between 9a and cyclohexanone (22), since
this ketone was used as a surrogate in for 14a in a
previous report (Figure 4).[10a] In the first experiments,
we examined the change in chemical shift of 4 of the
ring protons in 9a as increasing amounts of 22 were
added (Figure 4a). These measurements were
performed in the presence of 2 equiv of pyridine to
and 6). Michael acceptors with -substituents 14f and
14g were also viable electrophiles, as evidenced by
the synthesis of 15f and 15g, respectively (entries 7
and 8). However, higher catalyst loading and
temperature were required for the former reaction,
and a longer reaction time was necessary for the later
reaction. Cyclic enones 14h and 14i were used
successfully with high catalyst loading and
temperature in the synthesis of 15h-j (entries 9-11).
4
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10.1002/adsc.202001019
Advanced Synthesis & Catalysis
Crystal Structures: CCDC 2008497 (9c) and CCDC
2008498 (9a) contain 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.
ensure that no hidden acid was present. As can be
seen, this base had no noticeable effect on the
chemical shift of the protons of interest, but addition
of ever increasing amounts of 22 clearly shifted the
protons downfield, which is evidence for a halogen-
bonding interaction between 9a and 22.[10a] This
notion is supported by the observation that the
protons of the methyl groups of 9a likewise exhibited
a similar downfield shift in the presence increasing
amounts of 22 (Figure 4b).[37] It should be noted that
similar trends were observed when of mixtures of 13a
and 9a were studied (Figure SI-1), that indicate that
9a can also interact with the oxygen atom of the furan
substrates. Finally, the carbonyl carbon atom of 22
also shifted downfield in the presence of an equimolar
amount of 9a (Figure 4c).
Based on our results, we believe that 9a is able to
catalyze Friedel–Crafts reactions of between furan
nucleophiles 13 and carbonyl electrophiles 14 by
formation of complex A (Figure 5). The greater
catalytic efficiency of 9a compared to that of 18 and
19 (Table 1, entry 1 vs. entries 10 and 11) seems to
indicate that both iodine atoms of 9a are involved in
substrate activation, as in the case of other organic
halide halogen-bond donor catalysts bearing multiple
halogen atoms.[6c,6f] Reaction of the furan at the
carbonyl carbon is thus facilitated so that the reaction
can proceed to produce the observed products.
Acknowledgements
Our research was funding by the Research Grants Council of the
Hong Kong S. A. R., P. R. of China (Project GRF 17307518).
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In summary, we have designed and synthesized a
new bidentate halogen-bond donor catalyst based on a
2,2’-bipyridine skeleton that possesses an axis of
chirality, and used it to catalyze a range of Friedel–
Crafts reactions between furan nucleophiles and a
variety of electrophiles. Having established the utility
of this catalyst, we are now exploring the possibility
of preparing enantiomerically enriched versions of 9a
that can be examined as stereoselective organic
catalysts, and we will present our results in due course.
Experimental Section
General Procedure for the Friedel–Crafts Reactions: To
a solution of 9a (0.025 or 0.10 equiv) in anhydrous CH3CN
(3 mL) was added furan 13 (1 mmol) and electrophile 14
(1.5 mmol). The mixture was stirred at rt or 50 °C under an
argon atmosphere, and the progress of the reaction was
monitored by TLC or 1H NMR analysis. After it was
finished, the mixture was concentrated, and the product 15
was purified by silica gel chromatography (EtOAc:hexane).
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5
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10.1002/adsc.202001019
Advanced Synthesis & Catalysis
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7
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Advanced Synthesis & Catalysis
COMMUNICATION
Halogen-Bond-Catalyzed Friedel–Crafts Reactions
of Furans Using a 2.2’-Bipyridine-Based Catalyst
Adv. Synth. Catal. Year, Volume, Page – Page
Huimiao Zhang, and Patrick H. Toy*
8
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