Halogen Bond-Catalyzed Povarov Reactions

Article abstract of DOI:10.1002/adsc.202000665

The use of a bidentate halogen bond donor to catalyse Povarov reactions of imines derived from aryl adehydes and anilines is reported. Dienophiles used in these reactions included 2,3-dihydrofuran, N-vinyl-2-pyrrolidone and N-Cbz-protected 2,3-dihydropyrr

Full text of DOI:10.1002/adsc.202000665

Title: Halogen Bond-Catalyzed Povarov Reactions
Authors: Xuelei Liu and Patrick Toy
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10.1002/adsc.202000665
Advanced Synthesis & Catalysis
UPDATE
DOI: 10.1002/adsc.201
Halogen Bond-Catalyzed Povarov Reactions
Xuelei Liu,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.201######.
Povarov reactions[19,20] of imines derived from
Abstract. The use of a bidentate halogen bond donor to
catalyse Povarov reactions of imines derived from aryl arylaldehydes and anilines with a range of dienophiles
adehydes and anilines is reported. Dienophiles used in these
reactions included 2,3-dihydrofuran, N-vinyl-2-pyrrolidone
and N-Cbz-protected 2,3-dihydropyrrole. Very high isolated
yields of the desired 1,2,3,4-tetrahydroquinoline products
were obtained with low catalyst loadings (0.01 equivalents)
and short reaction times (minutes to hours) at ambient
temperature. Notably, the bis(benzimidazolium iodide)-
based catalyst used in these reactions proved to be more
efficient than analogous bromine and chlorine functionalized
to form 1,2,3,4-tetrahydroquinolines in high isolated
yields using mild reaction conditions and low catalyst
loadings (Figure 2b).[21]
compounds, as well as
a
related monodentate
benzimidizolium iodide. These observations are similar to
what has been reported by others regarding halogen bond
organocatalysis, and may prove useful in guiding catalyst
design as the field moves forward.
Keywords: halogen bond; organocatalysis; Povarov
reaction; cycloaddition; tetrahydroquinolines
Halogen bonds are non-covalent interactions that can
be considered to be functionally analogous to
hydrogen bonds,[1] and the use of organic halides as
halogen bond donors to catalyse organic reactions has
been examined recently.[2] In this context organic
halides have been used to activate quinolines,[3]
imines,[4] carbon-halogen bonds,[5] silicon-halogen
bonds,[6] aldehydes and ketones,[7] Michael
acceptors,[8] thioamides,[9] trichloroacetimidates,[10]
hydantoins,[11]
nitroalkenes,[12] alkoxyallenes,[13]
ethers,[14] and iodonium ylides[15] in various
transformations. With regards to the reactions studied,
one area of focus has been cycloaddition reactions, and
numerous variations of Diels-Alder reactions have
been reported to be catalyzed by organic halide
halogen bond donors (Figure 1).[16]
In the context of halogen bond catalysis, we
previously reported the use of bidentate
bis(benzimidazolium iodide) salt 1 to catalyse Friedel-
Crafts reactions between aldehyde and ketone
electrophiles and indole nucleophiles to form
bis(indolyl)methanes (Figure 2a).[17,18] Now we wish
to report that 1 is also efficient as a catalyst for
Figure 1. Halogen bond-catalyzed Diels-Alder reactions.
1
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10.1002/adsc.202000665
Advanced Synthesis & Catalysis
same as what was observed in the halogen bond-
catalyzed aza-Diels-Alder reaction reported by Kanger
and co-workers (Figure 2b).[16c] Furthermore, addition
of 0.1 equivalents of Bu4NI to the reaction mixture
completely shut down the formation of 4a, as might be
expected (entry 12). While the addition of the bases
pyridine, iPr2EtN or K2CO3 did not dramatically affect
the outcome of the reaction in terms of yield (entries
13-15), diastereoselectivity did seem to
Table 1. Povarov reactions between 2a and 3.[a]
entry catalyst additive yield[b] endo:exo[c]
1
2
3
4
5
nil
nil
nil
nil
nil
90
0
55
23
0
60:40
-
56:44
59:41
-
1
nil
5
6
7
Figure 2. Halogen bond-catalyzed Friedel-Crafts and
Povarov reactions.
6
7
8
9
10
11
12
13
14
15
16
17[f]
nil
nil
nil
nil
nil
nil
0
0
0
82
65
0
-
-
-
8
9
As the starting point for this project we chose to
study the reaction between imine 2a and 2,3-
dihydrofuran (3) (Table 1), and since the use of 1
mol% of 1 in acetonitrile worked well in the
aforementioned Friedel-Crafts reactions, we applied
these conditions to this reaction as well. Gratifyingly
a separable mixture of endo and exo isomers of 4a was
formed in very high isolated yield after only 0.5 hour
at room temperature (entry 1). The endo:exo ratio was
determined by 1H NMR analysis of the crude reaction
mixture, before the isomers were separated by
chromatography for characterization, and was found to
be typical for this reaction.[22] When 1 was omitted
from the reaction mixture, no reaction was observed
(entry 2). Replacement of 1 by monodentate analogue
5 resulted in a lower yield of 4a (entry 3), as was the
case in our Friedel-Crafts reactions, in which case even
using 2 mol% of 5 did not provide the catalytic
efficiency of 1 mol% of 1.[17] When the triflate anions
of 1 were replaced with tetrafluoroborate anions in 6,
the yield of 4a was even lower (entry 4). The reason
for the lower yield in this reaction is unclear at this
point, but it has previously been noted that counter ion
effects in halogen bond catalysis of such reactions is
complicated and rather unpredictable.[16c] Neutral
analogue 7 was unable to catalyse the reaction, as were
simple hydrogen bond donor CBr4 (8), hydrogen bond
donor thiourea 9, and organic cation malachite green
(10) (entries 5-8).
10
11
12
13
1
1
1
1
1
58:42
60:40
-
Bu4NI[d]
pyridine
iPr2EtN
K2CO3
BHT[e]
nil
0
-
85
83
78
89
91
73:27
75:25
76:24
65:35
63:37
1
A series of control reactions was then performed in
order to provide evidence that halogen bonding was
indeed operative in the reaction between 2a and 3 in
the presence of 1. Replacing the iodine atoms of 1 with
bromine atoms in catalyst 11 afforded 4a in slightly
lower yield (entry 9), and with chlorine atoms in
catalyst 12 the yield of 4a was lower still (entry 10).
Omitting the halogen atoms altogether in 13 resulted
in no desired product being formed in its presence
(entry 11). This reactivity trend of I > Br > Cl is the
[a] General reaction conditions: 2a (1.0 mmol), 3 (4.0 mmol),
catalyst (0.01 mmol), additive (0.001 mmol) in MeCN (2
mL), rt, 0.5 h.
[b]
Combined isolated yield of endo and exo isomers of 4a.
[c]
Determined by 1H NMR analysis of crude 4a.
[d]
Reaction was performed using 0.1 mmol Bu4NI.
Reaction was performed using 0.02 mmol of BHT.
[e]
[f] Reaction performed using 2a (10.0 mmol), 3 (40.0 mmol),
and 1 (0.1 mmol) in MeCN (20 mL) at rt for 0.5 h.
2
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10.1002/adsc.202000665
Advanced Synthesis & Catalysis
improve slightly for reasons that we cannot explain at
this point. These results indicate that the presence of
adventitious acid was likely not responsible for the
observed catalysis. Furthermore, the addition of BHT
to the reaction mixture also did not significantly alter
the outcome of the reaction (entry 16), indicating that
a radical mechanism was unlikely. Finally, to examine
the scalability of the reaction we performed on a 10-
fold larger gram-scale and obtained similar results in
terms of yield and selectivity (entry 17).
Having established that 1 can indeed act as an
efficient catalyst for Povarov reactions, we next
examined the range of imines that can be used in such
transformations. Imines 2b-j, bearing either an
electron-donating or electron-withdrawing substituent
on one or both of the aromatic rings, were all
successfully used, and we were able to prepare 1,2,3,4-
tetrahydroquinolines 4b-j in good to very high isolated
yields in generally short reaction times using the
optimized reaction conditions (0.01 equivalents of 1 in
MeCN at room temperature) (Figure 3). Only the
reaction involving chlorine-substituted imine 2c was a
bit of an outlier, and afforded relatively low yield
(62%) of 4c, with some recovered starting material,
after a longer reaction time (24 h), compared to all of
the other reactions performed (80-93% yield, 1-2 h).
and 17a-c, respectively (0.01 equivalents of 1 in
MeCN at room temperature) (Figure 4). The reactions
with 14 were generally a bit more sluggish than the
reactions with 3, while the reactions with 15 were very
efficient. Even when chlorine-substituted 2c was the
imine reaction partner for 15, product 17b could be
isolated in 92% yield after only 1 hour. It should be
noted that for products 16a-g, the cis:trans ratios could
only be estimated in some cases due to the very high
diastereoselectivity observed that is consistent to what
has previously been reported.[23]
Figure 4. Povarov reaction products using 14 and 15.
Figure 3. Povarov reaction products using 3.
[a] 1H NMR signal of N=CH of 2a.
[b] 13C NMR signal of N=CH of 2a.
[c] 13C NMR signal of C-I of 1.
We next looked at what other dienophiles could be
used in our Povarov reactions, and found that both N-
vinyl-2-pyrrolidone (14)[23] and N-Cbz-protected 2,3-
dihydropyrrole (15)[24] were suitable, and allowed for
the production of 1,2,3,4-tetrahydroquinolines 16a-g
Figure 5. NMR studies.
3
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10.1002/adsc.202000665
Advanced Synthesis & Catalysis
Our research was funding by the Research Grants Council of the
Hong Kong S. A. R., P. R. of China (Project GRF 17307518).
Additional evidence for halogen bonding between 1
and the imine substrate 2 being responsible for the
observed catalysis in our reactions was obtained from
a series of NMR experiments (Figure 5). The imine
proton of 2a clearly shifted downfield slightly when in
the presence of 1 equivalent of 1 (Figure 5a), as did the
imine carbon atom of 2a (Figure 5b). Furthermore, the
same was true for the iodine functionalized carbon
atoms of 1 when 1 equivalent of 2a was added (Figure
5c).[7d]
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5
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10.1002/adsc.202000665
Advanced Synthesis & Catalysis
UPDATE
Halogen Bond-Catalyzed Povarov Reactions
Adv. Synth. Catal. Year, Volume, Page – Page
Xuelei Liu, and Patrick H. Toy*
6
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