Remarkable Differences in Reactivity between Cyanide and N-Heterocyclic Carbenes in Ring-Closing Reactions of 4-(2-Formylphenoxy)but-2-Enoate Derivatives

Full text of DOI:10.1002/bkcs.12146

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DOI: 10.1002/bkcs.12146
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E. Park et al.
KOREAN CHEMICAL SOCIETY
Remarkable Differences in Reactivity between Cyanide and
N-Heterocyclic Carbenes in Ring-Closing Reactions of
4
-(2-Formylphenoxy)but-2-Enoate Derivatives
†
†
*
Eunjoon Park, Jina Park, and Cheol-Hong Cheon
Department of Chemistry, Korea University, Seoul 02841, Korea. *E-mail: cheon@korea.ac.kr
Received October 6, 2020, Accepted October 30, 2020
Cyanide and N-heterocyclic carbenes (NHCs) have been
known to display similar reactivity as versatile
organocatalysts in organic transformations. Particularly,
influence on the efficiency of this transformation and the
desired benzofurans 3 were obtained in high yields regard-
less of the electronic nature of a substituent (entries 1–4).
In addition, the position of a substituent on the phenyl ring
was also found to exert little effect on the formation of the
desired products 3 (entries 4–6). The steric bulk of the ester
moiety was further investigated and found that the effi-
ciency of this transformation was little affected by the size
of alkoxy group in the ester moiety (entries 1 and 7). Fur-
thermore, this protocol could be applicable to the prepara-
tion of benzofuran derivative bearing a simple ester moiety
at the 2-position although this substrate displayed lower
reactivity than its vinylogous analogues (entry 8)
1
they can serve as nucleophilic catalysts toward the aldehyde
to generate umpolung of the aldehyde, i.e., conversion of
an electrophilic reactivity of the aldehyde to a nucleophilic
2
reactivity, and a number of useful organic transformations
including benzoin and Stetter reactions have been devel1-
oped based on the umpolung reactivity of the aldehyde.
Despite the general acceptance of the similar reactivity of
cyanide and NHCs in the generation of umpolung of the
aldehyde, there have been few actual studies on the differ-
3
,4
ence in reactivity between them. Herein, we describe the
significant reactivity difference between cyanide and NHCs
in the ring-closing reaction of 4-(2-formylphenoxy)but-
(Scheme 2).
With these rather unexpected results in hand, we per-
2
-enoate derivatives; NHCs afford dihydrochromones
derivatives via the intramolecular Stetter reaction, while
cyanide acts as base catalyst to provide
-vinylbenzofurans through aldol condensation reaction.
formed several control experiments to understand the reac-
tion mechanism for this transformation. When 1a was
treated with 10 mol% of cyanide, 1a was completely con-
a
2
8
sumed in 10 min and a mixture of aldol product A were
Since the intramolecular Stetter reaction of
obtained in a quantitative yield (Eq. (1)). Then, the dehy-
dration of the resulting mixture of the aldol adduct A was
investigated. It was found that both cyanide and reaction
temperature played a critical role in the dehydration leading
to the desired benzofuran 3a. When the resulting mixture
from Eq. (1) was directly subjected to the dehydration reac-
tion at room temperature, only trace amount of 3a was
4-(2-formylphenoxy)but-2-enoate derivatives 1 leading to
dihydrochromones 2 is one of the most well-developed
reactions utilizing the umpolung reactivity of the aldehyde
5
with a NHC catalyst, we compared the reactivity between
NHCs and cyanide in the Stetter reaction using methyl
4-(2-formylphenoxy)but-2-enoate (1a) as a model com-
pound (Scheme 1).
obtained. However, the dehydration reaction occurred at
As expected, when 1a was treated with a catalytic
amount of NHC catalyst derived from thiazolium salt in the
presence of base, the corresponding dihydrochromone
ꢀ
8
0 C to provide benzofuran 3a in quantitative yield in 2 h
(Eq. (2)). In addition, when the isolated aldol product
A was subjected to the thermal dehydration conditions at
2
was obtained in a quantitative yield in 22 h through the
6
intramolecular Stetter reaction. On the other hand, the
treatment of 1a with a catalytic amount of cyanide provided
no Stetter product 2 even though 1a was completely con-
sumed in 10 min at room temperature. In addition, the
ꢀ
resulting mixture was warmed to 80 C to afford the
7
2-vinylbenzofuran 3a with 85% yield in 2 h.
With this rather unexpected result in hand, we explored
the generality of 4-(2-formylphenoxy)but-2-enoates 1 with
a catalytic amount of cyanide (Table 1). The electronic
nature of the substituents on the phenyl ring had little
Scheme 1. Reactivity difference between NHCs and cyanide with
ring-closing reaction of 1a.
†These authors equally contribute to this work.
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Table 1. Substrate scope
.
Entry Product (3)
1
Time 1 Time 2 Yield (%)
10 min
1 h
85
2
3
4
60 min
3 h
78
10 min
10 min
2 h
3 h
81
76
Scheme 2. Control experiments.
5
6
20 min
10 min
3 h
3 h
85
80
α-position, undergoes addition to the aldehyde giving aldol
adduct A. Subsequent cyanide-catalyzed thermal dehydra-
tion affords benzofuran 3 (Scheme 3).
10
Although cyanide and NHCs have been known to display
similar reactivity in organic transformations as versatile
1
7
10 min
2 h
2 h
75
organocatalysts, this result strongly suggested that there
should be considerable difference in the reactivity between
cyanide and NHCs. Particularly, since the cyanide is more
basic than the NHC catalyst, they would display a consider-
able different reactivity toward the substrates carrying an acidic
proton, such as compound 1. These results would be in consis-
tence with the fact that the cyanide-catalyzed benzoin conden-
11
a
8
22 h
80
a
1
00 mol% of NaCN was used.
12
sation has been limited to the aromatic aldehydes, which
could possibly imply that cyanide could act as a base to
deprotonate the α-proton of carbonyl group in the aliphatic
ꢀ
8
0 C in the absence of cyanide, the formation of 3a was
not observed even after 24 h (Eq. (3)). However, upon
addition of a catalytic amount of cyanide to the reaction
mixture, the elimination reaction again proceeded to pro-
vide 3a in a similar efficiency (Eq. (4)). Since cyanide acts
as the active catalyst in cyclization and dehydration, 1a
ꢀ
could be directly converted to 3a at 80 C in a much shorter
reaction time without any loss of efficiency (Eq. (5)).
Based on this result, we rationalized the reactivity differ-
ence between cyanide and NHCs toward the cyclization of
compound 1. NHCs acts as a nucleophilic catalyst to the9
aldehyde in 1 to generate the Breslow intermediate I,
which subsequently undergoes the Michael reaction leading
to intermediate II. Hydrolysis of II would afford
dihydrochromone 2 and NHC is regenerated as the catalyst.
On the other hand, cyanide acts as a base catalyst rather
than a nucleophilic catalyst. Thus, carbanion intermediate
III, generated from 1 by a deprotonation at the vinylogous
Scheme 3. Reactivity difference between NHC and cyanide in the
cyclization of 1.
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aldehydes, although the importance of cyanide as the base cat-
alyst has not been fully recognized.
In conclusion, we described a significant difference in
reactivity between NHCs and cyanide toward
Kim, C.-H. Cheon, Org. Lett. 2014, 16, 2514. (b) Y.-J. Kim,
C.-H. Cheon, Bull. Kor. Chem. Soc. 2015, 36, 2055.
. For selected recent examples of the intramolecular Stetter
reaction of 1 leading to dihydrochromones 2, see:(a)T. Ema,
Y. Nanjo, S. Shiratori, Y. Terao, R. Kimura, Org. Lett. 2016,
5
4-(2-formylphenoxy)but-2-enoates. NHCs act as a nucleo-
1
8, 5764. (b) S. Wei, X.-G. Wei, X. Su, J. You, Y. Ren,
philic catalyst toward the aldehyde group to promote the
expected intramolecular Stetter reaction, while cyanide
could act as a base to generate the corresponding
vinylogous enolate, which undergoes condensation with the
aldehyde group. Particularly, the cyanide is more basic than
the NHC catalyst, it displays a considerable different reac-
tivity toward the substrates carrying acidic protons, such as
compound 1. Further applications of the base reactivity of
cyanide are currently underway in our laboratory and will
be reported in due course.
Chem. Eur. J. 2011, 17, 5965. (c) Z.-Q. Rong, Y. Li, G.-Q.
Yang, S.-L. You, Synlett 2011, 22, 1033. (d) A. Aupoix, G.
Vo-Thanh, Synlett 2009, 1915. (e) K. Zeitlera, I. Magera,
Adv. Synth. Catal. 2007, 349, 1851. (f) J. R. de Alaniz, T.
Rovis, J. Am. Chem. Soc. 2005, 127, 6284.
6. For the seminal report on the NHC-catalyzed synthesis of
2, see:E. Ciganek, Synthesis 1995, 1995, 1311.
7
. For the formation of 2-vinyl benzofurans via the base-
promoted aldol condensation of 1, see:(a)S. C. Schlitzer, D.
Arunprasath, K. G. Stevens, I. Sharma, Org. Chem. Front.
2
020, 7, 913. (b) B. Harish, M. Subbireddy, O. Obulesu, S.
Acknowledgments. This work was supported by National
Research Foundation of Korea (NRF) grants funded by the
Korean Government (NRF-2018R1D1A1A02086110).
Suresh, Org. Lett. 2019, 21, 1823. (c) R. Liu, L. Han, J. Liu,
B. Fan, R. Li, Y. Qiao, R. Zhou, Synth. Commun. 2018, 48,
3
079. (d) S. Reddy, S. Thadkapally, M. Mamidyala, J. B.
Nanubolu, R. S. Menon, RSC Adv. 2015, 5, 8199. (e) Y.
Zhao, W. Liu, X. Sun, G. Lin, Chin. J. Org. Chem. 2012,
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Supporting Information. Additional supporting informa-
tion is available in the online version of this article.
8
9
. In the reaction mixture were observed cis- and trans-isomers
of aldol adduct A along with its β,γ-unsaturated isomer. For
details, see Supporting Information.
. (a) R. Breslow, J. Am. Chem. Soc. 1957, 79, 1762. (b) R.
Breslow, J. Am. Chem. Soc. 1958, 80, 3719.
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2
3
4
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Bull. Korean Chem. Soc. 2020
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