Halogen Bond-Catalyzed Friedel-Crafts Reactions of Aldehydes and Ketones Using a Bidentate Halogen Bond Donor Catalyst: Synthesis of Symmetrical Bis(indolyl)methanes

Article abstract of DOI:10.1021/acs.orglett.9b03578

The use of a halogen bond donor to catalyze Friedel-Crafts reactions of indoles with a range of aldehydes and ketones to directly produce bis(indolyl)methanes, including the natural products arsindoline A, arundine, trisindoline, and vibrindole A, is reported. The bidentate catalyst used in these reactions proved to be more effective than a monondentate analogue, a thiourea commonly used as an organocatalyst, and even a trityl cation that has been used previously in the synthesis of bis(indolyl)methanes.

Full text of DOI:10.1021/acs.orglett.9b03578

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Halogen Bond-Catalyzed Friedel−Crafts Reactions of Aldehydes and
Ketones Using a Bidentate Halogen Bond Donor Catalyst: Synthesis
of Symmetrical Bis(indolyl)methanes
†
Xuelei Liu, Shuang Ma, and Patrick H. Toy*
Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong, P. R. of China
*
S Supporting Information
ABSTRACT: The use of a halogen bond donor to catalyze
Friedel−Crafts reactions of indoles with a range of aldehydes
and ketones to directly produce bis(indolyl)methanes,
including the natural products arsindoline A, arundine,
trisindoline, and vibrindole A, is reported. The bidentate
catalyst used in these reactions proved to be more effective
than a monondentate analogue, a thiourea commonly used as
an organocatalyst, and even a trityl cation that has been used previously in the synthesis of bis(indolyl)methanes.
1
hile halogen bonds, which in some ways can be
considered to be functionally akin to hydrogen bonds,
similar reactions. Given the enduring interest in the synthesis
39,40
W
of symmetrical bis(indolyl)methanes 1 (Figure 1),
many of
have been known and studied in a variety of contexts for quite
some time, the use of organic halides as halogen bond donors
2
to catalyze organic transformations is a relatively unexplored
3
aspect of organocatalysis. Early studies of such applications of
halogen bonds focused on the activation of carbon−nitrogen
4
,5
6,7
double bonds for reduction, Mannich reactions, Diels−
6
−8
Alder reactions,
and carbon/silicon-halogen bonds in
and conceptually related reactions involving
9
−11
Ritter-type
cationic intermediates.
12−17
Only more recently has halogen
bond-catalyzed reactions of carbonyl groups been examined.
For example, halogen bond catalysis of the Diels−Alder
reaction between cyclopentadiene and methyl vinyl ketone has
1
8,19
Figure 1. Structures of bis(indolyl)methanes (1) and bidentate
halogen bond donors (2−4).
been studied,
as have tandem Michael/Henry reactions of
20
α,β-unsaturated aldehydes, nucleophilic addition reactions to
aldehydes for chalcone synthesis, Michael addition reactions
21
22−25
to α,β-unsaturated ketones,
and Mukiyama aldol reac-
2
6
which are naturally occurring and have interesting biological
tions. Other recent examples of halogen bond catalysis
4
1
27
activities, and their conversion to more complicated natural
include thioamide activation, iodonium ylide activation for
42
2
8
and unnatural structures, we focused our efforts on the
catalytic synthesis of such compounds.
cross-enolate couplings,
N-glycofunctionalization of
2
9
30
amides, α-C-H amination of ethers, bromocarbocyclization
3
1
32
A survey of the literature makes it clear that bidentate
reactions, cyclopropyl ketone ring-openings, a Nazarov
13
22
33
halogen bond donors such as 2 and 3 are generally more
efficient catalysts than monodentate compounds, and there-
fore, based on available materials, we targeted 4 (Figure 1) as
the catalyst for our studies. Catalyst 4 was synthesized as
outlined in Scheme 1. Specifically, intermediate 5 was prepared
according to the literature method from 1,3-dibromobenzene
cyclization reaction, carbon nucleophile additions to N-
34
acylimminium ions, and [4 + 2] cycloaddition reactions of 2-
3
5
vinylindoles. Importantly, a water-soluble amino acid-based
halogen bond donor catalyst has been described for use in
36
aqueous reactions, and the first highly enantioselective
example of halogen bond catalysis in any context has been
43
3
7
and benzimidazole, and this was subsequently deprotonated
and iodinated to generate 6, which was then methylated to
afford 4 using procedures similar to those used for the
reported. It is against this backdrop that we report what is to
our knowledge the first application of an organic halide
1
7
halogen bond donor as a catalyst in Friedel−Crafts reactions
13,16
synthesis of 2 (Scheme 1).
of aldehyde and ketone electrophiles and indole nucleophiles.
We previously studied the use of a chiral phosphoric acid as
a catalyst in Friedel−Crafts reactions of indoles and were
interested in studying the potential of halogen bond catalysis of
38
Received: October 10, 2019
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03578
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Synthesis of 4
Table 1. Friedel-Crafts Reactions between Indole (7a) and
Benzaldehyde (8a) to Synthesize 1a
a
With catalyst 4 prepared, we then studied its use as a
halogen bond donor in the catalytic synthesis of 1a, the
44
reduced form of triaryl cation antibiotic turbomycin B, from
indole (7a) and benzaldehyde (8a) (Table 1). Gratifyingly, 1a
was synthesized in very high yield from a 4:1 ratio of 7a:8a
using 0.1 equiv of 4 as catalyst in MeCN at room temperature
in our very first unoptimized reaction (entry 1). Changing the
solvent to THF did not improve the situation (entry 2), and
lowering the catalyst loading increased the time required for
complete reaction (entries 3 and 4). However, heating the
reaction to 70 °C in MeCN using 0.01 equiv of 4 afforded
excellent yield of 1a in a short period of time (entry 5), even
on a 10 mmol scale (entry 6). Therefore, these conditions were
used for further studies. When no catalyst was used, 1a was not
formed (entry 7), as was the case when unalkylated 6 was used
(
entry 8), indicating the importance of the charged nature of 4.
Furthermore, to confirm the requirement of the iodine atoms
45
in 4 for catalysis, 9 (prepared by alkylation of 5) was used in
place of 4, and no 1a was formed even using a higher loading
and a longer reaction time (entry 9). Evidence for halogen
bonding being responsible for catalysis rather than the
presence of a hidden acid was provided by the observation
that the addition of increasing amounts of Bu NI to the
4
standard reaction conditions resulted in increasing inhibition
of the formation of 1a (entries 10 and 11), while the addition
of pyridine or iPr EtN did not produce such a dramatic effect
2
(
entries 12 and 13). Furthermore, the addition of BHT did not
affect the reaction (entry 14), nor did changing the
counterions from triflate groups to tetrafluoroborate groups
(
45
entry 15). Monoiodide 10 was also examined as a catalyst,
but when 0.01 equiv of it was used, a much longer reaction
time was required for a high yield of 1a compared to when 4
was used (entry 16). Even doubling the loading of 10 to 0.02
equiv did not produce 1a with the efficiency of 0.01 equiv of 4
(
entry 17). Finally, we examined commonly used hydrogen
bond donor thiourea 11, malachite green (12), which was
previously used to catalyze such reactions,
40i
and carbon
tetrabromide (13), which was previously used to activate
21
aldehydes in aldol reactions. Thiourea 11 was unable to
catalyze the formation of 1a (entry 18), and 12 and 13 proved
to be much less efficient catalysts compared to 4 (entries 19
and 20).
Having identified reaction conditions [4 (0.01 mmol), 7 (4
mmol), 8 (1 mmol), MeCN (2 mL), 70 °C] that afforded 1a
efficiently from 7a and 8a in excellent yield using catalyst 4 at a
low loading level, we next studied their general applicability by
reacting various indoles with a range of aldehydes and ketones
a
Conditions: 7a (4.0 mmol), 8a (1.0 mmol), catalyst, solvent (2.0
b
c
mL). Isolated yield. Reaction performed using 40 mmol 7a and 10.0
mmol 8a in MeCN (20 mL).
(
see Figure SI-1 for structures) to produce a wide range of
45
bis(indolyl)methanes 1 (Figure 2). For example, methyl-
substituted benzaldehydes 8b−d afforded excellent yields of
the corresponding products 1b−d regardless of the position of
the substituent, but ortho-substituted 1d did require a
significantly longer time for the reaction to complete.
Furthermore, 2,6-dimethylbenzldehyde (8e) only reacted to
a very limited extent to form 1e, even after heating for 72 h.
B
DOI: 10.1021/acs.orglett.9b03578
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
rt. Thus, all things considered, it seems that 4 is indeed a good
catalyst for the synthesis of a wide range of bis(indoyl)-
methanes 1 from simple indole and carbonyl compound
starting materials.
With regard to the mechanism of these reactions, based on
the results summarized in Table 1, and the steric effects
observed in the synthesis of 1b−e, it seems plausible that 4 can
enhance the electrophilicity of the aldehyde or ketone starting
material 8 through a pair of halogen bonds as in complex A
(
Scheme 2), thereby facilitating nucleophilic addition of 7 to
Scheme 2. Proposed Reaction Mechanism
afford complex B. This in turn can lose an equivalent of water
40g,i
to generate azafulvene intermediate C,
which can react with
another equivalent of 7 to afford final product 1. The notion of
electrophile activation by halogen bonding was supported by
1
3
C NMR analysis of a 1:1 mixture of 8a:4 showed a 0.2 ppm
downfield shift of the aldehyde carbon signal of 8a (Figure SI-
A), and a similar upfield shift for the signal corresponding to
the iodine-bearing carbon atoms of 4 (Figure SI-2B), results
2
25,32
similar to what has been reported by others.
Additionally,
1
Figure 2. Bis(indolyl)methanes 1a−ab synthesized.
H NMR analysis of 4 indicated that heating it at 70 °C in
MeCN for 72 h did not lead to any noticeable decomposition
(
Figure SI-2C), providing further evidence against hidden acid
Significantly, no such steric effects were observed when either
or I catalysis being operative in these reactions. Finally, it
2
TFA or I was used to catalyze the synthesis of 1b−d. Also,
should be noted that attempts to isolate C (from 7a and 8a)
failed, and only 1a was obtained in every instance. Thus, it
seems that the conversion of C to 1 is facile and does not
require catalysis using our reaction conditions.
2
both of these catalysts led to high yield of 1e after 72 h at rt.
Other substituted benzaldehydes such as 8f−m, including ones
with potentially reducible or acid labile groups, afforded 1f−m
cleanly and efficiently. Basic heteroaromatic aldehyde 8n also
In summary, we demonstrated that the concept of halogen
bond catalysis can be extended to the use of a bidentate
halogen bond donor to the catalysis of Friedel−Crafts
reactions of aldehyde and ketone electrophilic starting
materials with indole nucleophiles to afford a broad range of
symmetrical bis(indolyl)methanes, including some natural
products with interesting biological activities. We are now
examining the synthesis and use of chiral analogues of 4 with
the hope that they will be able to serve as efficient and highly
enantioselective catalysts in the types of asymmetric Friedel−
Crafts reactions that we previously reported with only
moderate stereoselectivity using a chiral phosphoric acid
46
reacted to afford arsindoline A (1n) in good yield. Even alkyl
aldehydes 8o and p reacted using our conditions to afford 1o
and p, while electron-withdrawing group activated aldehyde 8q
reacted to afford 1q even more efficiently. Ethyl pyruvate (8r)
reacted to produce 1r in good yield. Istatins 1s and t reacted
47
efficiently to afford trisindoline (1s) and 1t, respectively, as
did cyclohexanone (8u) to afford 1u. Even substituted indoles
7
b−f reacted with 8a using our conditions to produce 1v−z in
excellent yields. Finally, we reacted volatile aldehydes form-
aldehyde (8v) and acetaldehyde (8w) with 7a, but used them
in a 4-fold excess rather than as the limiting reagent, to
4
8
49
38
produce arundine (1aa)
and vibrindole A (1ab),
catalyst. Not only do we hope to increase the enantiose-
respectively, in good yields after extended reaction times at
lectivity of such reactions, but we also expect that the neutral
C
DOI: 10.1021/acs.orglett.9b03578
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
nature of catalysts such as 4 will allow for a broader substrate
scope than is possible when using a strongly acidic catalyst.
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ASSOCIATED CONTENT
Supporting Information
■
(
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S
F.; Huber, S. M. Chem. Commun. 2014, 50, 6281.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
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Detailed experimental procedures, compound character-
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AUTHOR INFORMATION
Corresponding Author
■
*
2
(
E-mail: phtoy@hku.hk.
ORCID
(
Patrick H. Toy: 0000-0001-6322-0121
Present Address
†S.M.: School of Environmental Science & Engineering,
Southern University of Science and Technology, Shenzhen
18055, P. R. of China.
(
2
(27) Matsuzawa, A.; Takeuchi, S.; Sugita, K. Chem. - Asian J. 2016,
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The authors declare no competing financial interest.
(
1
(
3
ACKNOWLEDGMENTS
Our research was funded by the Research Grants Council of
the Hong Kong S. A. R., P.R. China (Project GRF 17307518).
■
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