Aniline-Promoted Cyclization–Replacement Cascade Reactions of 2-Hydroxycinnamaldehydes with Various Carbonic Nucleophiles through In Situ Formed N,O-Acetals

Article abstract of DOI:10.1002/chem.201601112

In this study, we report the harnessing of new reactivity of N,O-acetals in an aminocatalytic fashion for organic synthesis. Unlike widely used strategies requiring the use of acids and/or elevated temperatures, direct replacement of the amine component of the N,O-acetals by carbon-centered nucleophiles for C?C bond formation is realized under mild reaction conditions. Furthermore, without necessary preformation of the N,O-acetals, an amine-catalyzed in situ formation of N,O-acetals is developed. Coupling both reactions into a one-pot operation enables the achievement of a catalytic process. We demonstrate the employment of simple anilines as promoters for the cyclization–substitution cascade reactions of trans-2-hydroxycinnamaldehydes with various carbonic nucleophiles including indoles, pyrroles, naphthols, phenols, and silyl enol ethers. The process offers an alternative approach to structurally diverse, “privileged” 2-substituted 2H-chromenes. The synthetic power of the new process is furthermore shown by its application in a 2-step synthesis of the natural product candenatenin E and for the facile installation of 2-substituted 2H-chromene moieties into biologically active indoles.

Full text of DOI:10.1002/chem.201601112

DOI: 10.1002/chem.201601112
Full Paper
&
Organocatalysis
Aniline-Promoted Cyclization–Replacement Cascade Reactions of
2-Hydroxycinnamaldehydes with Various Carbonic Nucleophiles
through In Situ Formed N,O-Acetals
Chenguang Yu,[a] He Huang,[a] Xiangmin Li,[a, b] Yueteng Zhang,[a] Hao Li,*[b] and
Wei Wang*[a, b]
Abstract: In this study, we report the harnessing of new re-
activity of N,O-acetals in an aminocatalytic fashion for organ-
ic synthesis. Unlike widely used strategies requiring the use
of acids and/or elevated temperatures, direct replacement of
the amine component of the N,O-acetals by carbon-centered
nucleophiles for CÀC bond formation is realized under mild
reaction conditions. Furthermore, without necessary prefor-
mation of the N,O-acetals, an amine-catalyzed in situ forma-
tion of N,O-acetals is developed. Coupling both reactions
into a one-pot operation enables the achievement of a cata-
lytic process. We demonstrate the employment of simple
anilines as promoters for the cyclization–substitution cas-
cade reactions of trans-2-hydroxycinnamaldehydes with vari-
ous carbonic nucleophiles including indoles, pyrroles, naph-
thols, phenols, and silyl enol ethers. The process offers an al-
ternative approach to structurally diverse, “privileged” 2-sub-
stituted 2H-chromenes. The synthetic power of the new pro-
cess is furthermore shown by its application in a 2-step
synthesis of the natural product candenatenin E and for the
facile installation of 2-substituted 2H-chromene moieties
into biologically active indoles.
Introduction
N,O-Acetals (also called hemiaminal ethers) are useful building
blocks in organic synthesis (Scheme 1a).[1] They are widely
used for the formation of CÀC bonds by carbon-centered nu-
cleophilic-substitution reactions. It is observed that the extru-
sion of the “O” moiety in N,O-acetals is generally favored, be-
cause of the poorer leaving tendency of “N” and/or higher sta-
bility of the formed iminium ions (Scheme 1a).[2] Furthermore,
the processes generally require a Brønsted or Lewis acid and/
or elevated temperature.[2] Although cyclic N,O-acetals are also
widely used in these processes, still the extrusion of “O” moiet-
ies is often seen with “N” moieties embedded in the ring struc-
tures.[3] Furthermore, to make O-containing heterocycles, cyclic
acetals or hemiacetals are generally used.[4] These precedent
studies reflect the challenge in the replacement of “N” moieties
Scheme 1. a) Well-studied N,O-acetals in “O”-involved nucleophilic substitu-
tion reactions. b) Proposed amine-catalyzed “N”-involved cyclization–substi-
tution cascade reaction through in situ formed N,O-acetals in this study.
in N,O-acetals by a nucleophile. In addition, N,O-acetals are
often required to be preformed.
We recently challenged this dogma by developing a new
and mild approach capable of a direct substitution of the “N”
components in N,O-acetals by carbon nucleophiles. Moreover,
we proposed a method for the in situ formation of N,O-acetal
precursors (Scheme 1b). Therefore, it is expected that the
amine shall bestow a twofold function; being a leaving group
and a promoter for the formation of N,O-acetals. This cascade
process would produce an unprecedentedly powerful catalytic
approach in N,O-acetal-involved synthesis.[5]
[a] C. Yu, H. Huang, X. Li, Prof. Dr. Y. Zhang, Prof. Dr. W. Wang
Department of Chemistry & Chemical Biology
University of New Mexico
MSC03 2060, Albuquerque, NM 87131-0001 (USA)
Fax: (+1)5052772609
E-mail: wwang@unm.edu
[b] X. Li, H. Li, Prof. Dr. W. Wang
School of Pharmacy
East University of Science and Technology
130 Mei-Long Road, Shanghai 200237 (P. R. China)
E-mail: hli77@ecust.edu.cn
Our working hypothesis was inspired by our previous study
of an iminium-ion-initiated Michael–Michael cascade reaction
that serves as a one-pot protocol for the generation of chiral
chromanes.[6] The interesting N,O-acetal intermediates 8 were
Supporting information and ORCID for one of the authors for this article
can be obtained under http://dx.doi.org/10.1002/chem.201601112.
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ion. We believed that aromatic amines 10 would fulfill these
requirements. Accordingly, in an exploratory study, 2-hydroxyl-
cinnamaldehyde 5a and the indole 13a were used as the re-
spective aldehyde and nucleophile reactants in the presence
of an aromatic amine 10 (Table 1). To our delight, the reaction
of the these substrates in the presence of aniline (10a) gave
rise to the formation of 2-(3-indolyl)chromene 14a, albeit in
low yield (26%) along with its regioisomer 15a and an inter-
esting by-product 16a (entry 1). Encouraged by the results, we
surveyed other anilines that contained various electron-donat-
ing and -withdrawing substituents (entries 1–5). The results
show that, although, 4-fluoroaniline (10b) is superior to 4-me-
thoxylaniline (10c) (entries 2 and 3) as a catalyst for the
double substitution reaction, the more electron-deficient ana-
logues like 3,4-difluoroaniline (10d) and 4-nitroaniline (10e)
are less effective (entries 4 and 5). Increasing the steric bulki-
ness of the aniline compounds, as in 2-methylaniline (10 f) and
2,4-dimethylaniline (10g), leads to a deterioration of the cata-
lytic potency (entries 6 and 7). It was found that 2-hydroxylani-
line (10h) serves as an ideal catalyst for the process that gen-
erates 14a in modest yield (59%) and selectivity (entry 8,
3.5:1.3:1 for 14a:15a:16a). In contrast, 4-hydroxylaniline (10k;
entry 11, 18% yield, 2.0:0.7:1 for 14a:15a:16a) and 2-methox-
ylaniline (10l; entry 12, 30%, 1.1:0.6:1 for 14a:15a:16a) are
Scheme 2. a) Amine-catalyzed Michael–Michael cascade. b) Proposed aryla-
mine-catalyzed cyclization–substitution cascade reaction.
observed in this process by reaction of 2-hydroxy-trans-cinna-
maldehydes 5 with chiral amine 7 (Scheme 2a). Subsequent re-
action of the N,O-acetals 8 with a trans-nitroolefin led to the
formation of chromanes 6 and the concurrent regeneration of
the amine catalyst. Analysis of this observation led us to ques-
tion if the hemiaminal intermediates 8 or 12 could undergo
a direct substitution reaction with nucleophiles. The realization
of this process could offer an alternative approach to 2-substi-
tuted 2H-chromenes 11,[7] a class of “privileged” structures with
a broad range of interesting biological activities.[8] Additionally,
they have served as targets for a number of synthetic stud-
ies.[6,7,9,10]
Table 1. Optimization of the reaction conditions.[a]
Herein we wish to disclose a conceptually novel amine-cata-
lyzed formation of N,O-acetals from a,b-unsaturated aldehydes,
followed by subsequent substitution by a nucleophile in an ef-
ficient catalytic-cascade fashion. In this investigation, we un-
covered that simple aromatic amines promote cyclization–sub-
stitution cascade reactions of 2-hydroxy-trans-cinnamaldehydes
5 with various nucleophiles 9, including indoles, pyrroles,
naphthols, phenols, and silyl enol ethers (Scheme 2b). Notably,
it is found that aromatic amines 10 with balanced nucleophilic-
ity and leaving tendency are critical for the cascade processes
through in situ generated N,O-acetals 12. These processes pro-
duce structurally diverse 2-substituted 2H-chromenes 11 with
high chemo- and regioselectively. Moreover, the mild reaction
conditions enable the process to tolerate the use of a broad
range of sensitive functional groups.
Entry
Cat.
t [h]
Yield [%][b]
24 26
24 34
24 11
24 12
Ratio of 14a:15a:16a[c]
1
2
3
4
5
6
7
8
9
10a
10b
10c
10d
10e
10 f
10g
10h
10i
10j
10k
10l
10m
10h
10h
10h
10h
0.9:0.5:1.0
1.6:0.6:1.0
0.3:0.4:1.0
0.2:0.4:1.0
–
24
0
24 11
24 <5
24 59
24 24
24 28
24 18
24 30
24 49
24 63
24 56
24 70
22 86
1.2:0.5:1.0
–
3.5:1.3:1.0
0.8:0.4:1.0
1.2:0.8:1.0
2.0:0.7:1.0
1.1:0.6:1.0
2.9:0.3:1.0
17.0:1.3:1.0
11.0:1.0:1.0
12.0:1.0:0.0
10.0:1.0:0.0
Results and Discussion
10
11
Amine-catalyzed cyclization–substitution cascade reaction
of 2-hydroxylcinnamaldehydes with electron-rich arenes
12
13
14[d]
15[d,e]
16[d,f]
17[d,f,g]
Exploration and optimization of the reaction conditions
As discussed above, the extrusion of the amines from the N,O-
acetal intermediates 8 or 12 is notoriously difficult. We con-
ceived that an amine with a good leaving tendency might be
replaced by a nucleophile. Nonetheless, this property would
also need to be balanced by the requirement that the amine
serves as a good nucleophile to ensure effective addition to
the aldehyde in the route for the formation of the iminium
[a] Reaction conditions unless specified; a mixture of 5a (0.1 mmol), 13a
(0.12 mmol), and catalyst (10, 0.01 mmol) in CH2Cl2 (0.5 mL) was stirred at
rt. [b] Isolated yields. [c] Determined by using 1H NMR spectroscopy. [d] 4 Š
molecular sieves (MS) were added. [e] Ratio of 5a:13a is 1:1.5. [f] Ratio of
5a:13a is 1.2:1. [g] 20 mol% cat. 10h.
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not effective catalysts. Moreover, anilines containing other
ortho-hydrogen-bonding donor groups such as amines (e.g.,
10i) and carboxylic acids (e.g., 10j) promote only low-yielding
processes (entries 9 and 10).
Further studies were carried out accordingly to optimize the
reaction of 2-hydroxylcinnamaldehyde (5a) with the indole
13a promoted by the aniline 10h. Unexpectedly, the addition
of 4 Š molecular sieves (MS) to the reaction mixture led to
a slight increase in the yield (63%) and a dramatic increase in
regioselectivity (17:1.3:1) (entry 14). Furthermore, increasing
the ratio of 5a:13a to 1.2:1 further enhanced the efficiency
(70%) and regioselectivity (12:1:0) for the formation of the
adduct 14a (entry 16). Raising the catalyst loading to 20 mol%
further improved the yield (86%) while maintaining the regio-
selectivity (10:1.0:0) of the process (entry 17). Of the solvents
screened, CH2Cl2 was found to be optimal (Table S1 in the Sup-
porting Information). Therefore, the ideal reaction conditions
for the formation of 14a involve the use of 0.12 mmol of 5a
(1.2 equiv), 0.1 mmol of 13a (1 equiv) and 20 mol% of 10h
(0.2 equiv) in 0.5 mL of CH2Cl2 with 4 Š MS.
Reaction scope
An exploratory study was carried out to probe the scope of
the cyclization–substitution cascade reactions of the arene nu-
cleophiles and trans-2-hydroxycinnamaldehyde catalyzed by2-
hydroxyaniline (10h) (Scheme 3). We first examined potential
electronic effects in the trans-2-hydroxycinnamaldehyde reac-
tants using analogues containing electron-neutral (H, 14a),
-withdrawing (Cl, 14b) and -donating (Me, 14c) aromatic sub-
stituents. Reactions of these substrates with indole under opti-
mal conditions were found to proceed smoothly to produce
the corresponding 2H-chromenes 14a–c in high yields (69–
90% yields) and with high regioselectivities (8.3:1 to 10:1 r.r.).
A variety of electron-rich arenes were then explored as poten-
tial nucleophiles in this process. The results demonstrate that
indoles containing a wide variety of electronically different
substituents react with the aldehyde 5a under optimal condi-
tions to generate the corresponding adducts 14e–l. Further-
more, N-methyl indole also serves as a substrate for this reac-
tion, which forms the adduct 14m in high yield and with good
regioselectivity (78% yield, 5.9:1 r.r.). N-Methyl pyrrole under-
goes this reaction to exclusively generate the 2-pyrrole adduct
14n in 52% yield. In this case, as well as in others in which
less reactive nucleophiles are employed, tetrahydroquinoline
(10m) was found to be superior to 10h as a catalyst
(Scheme 3). In addition to indoles and pyrrole, naphthols and
phenols are also applicable for this protocol, as exemplified by
the observations that 1-naphthol and 2,3-dimethoxylphenol
react smoothly with 5a in the presence of aniline 10m to form
14o (50%) and 14p (51%), respectively.
Scheme 3. Substrate scope of the aniline-catalyzed cyclization–substitution
cascade reaction of 5 with electron-rich arenes 13 (unless specified, see ex-
perimental section and SI). [a] 20 mol% cat. 10m.
next. This effort was stimulated by the thought that cycliza-
tion–substitution cascade processes of this type would serve
as a new method for Csp3 –Csp3 bond formation. Unlike the case
of the electron-rich arenes shown above, we were concerned
about complications associated with the high reactivity/lability
of silyl enol ethers under the conditions employed and the po-
tential lack of regioselectivity of the processes associated with
the possible generation of competitive 1,2- and 1,4-additions
(e.g., 20 and 21) (Scheme 4). Finally, we were also concerned
Aniline-catalyzed cyclization–substitution cascade reaction
of 2-hydroxylcinnamaldehydes with silyl enol ethers
To further demonstrate the versatility of the new strategy, reac-
tions employing silyl enol ethers as nucleophiles were explored
Scheme 4. Arylamine-catalyzed cyclization–substitution cascade reactions of
trans-hydroxycinnamaldehydes 5 with silyl enol ethers 17.
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about the possible transilylation between the 2-hydroxy
moiety of the cinnamaldehyde substrates and the silyl enol
ether (e.g., 22), an occurrence that could complicate this pro-
cess.
To explore the features of the proposed silyl enol ether addi-
tion process, 2-hydroxycinnamaldehyde (5a) and the TMS (tri-
methylsilyl)-derived silyl enol ether of acetophenone 17a were
used as reactants and 2-hydroxyaniline (10h) as catalyst
(Scheme 5). We observed that the reaction of these substrates
in a respective molar ratio of 1:1.5, under the optimized condi-
tions described above, generates the expected chromene 18a
in 68% yield and a r.r. of 4.3:1 (see details of the optimization
of the reaction conditions, Supporting Information Table S2).
Except for the production of a trace amount of the conjugate
addition product and acetophenone, this process is not com-
plicated by the formation of side products. In an attempt to
improve the efficiency of the process, other arylamine catalysts
were explored. The findings showed that tetrahydroquinoline
(10m) is an ideal promoter for this reaction, which generates
18a in 82% yield and a r.r. of 4.7:1; The yield was lowered to
74% when the ratio of 5a and 17a was changed to 1.0:1.2.
Studies probing the substrate scope of the reaction showed
that some of the 2-hydroxycinnamaldehydes (e.g., 5b, 5d, 5 f
and 5v) participate in low-yielding reactions with the TMS-de-
rived silyl enol ether 17a (Scheme 5). Analysis of these reac-
tions reveals that the transfer of the TMS moiety from 17a to
the 2-hydroxy group in the trans-2-hydroxycinnamaldehydes 5
is the major reason for the diminished efficiencies of these re-
actions. To overcome this problem, the bulkier tert-butyldime-
thylsilyl (TBS) ether of acetophenone was employed as the
substrate. Indeed, in reactions with this silyl enol ether, the
silyl-transfer process is less competitive and the yields of the
respective chromene-forming reactions with 5b, 5d, 5 f and
5v increased dramatically (80% vs. 60% for 18b, 76% vs. 47%
for 18d, 86% for vs. 68% for 18 f, and 29% vs. 0% for 18v;
Scheme 5). Furthermore, the regioselectivities of all reactions
of the TBS adducts are significantly improved and the amount
of the silyl enol ether reactant can be decreased to 1.1 equiva-
lents.
An examination of the TBS-enol-ether scope of the addition
reactions of the aldehyde 5a showed that sterically demand-
ing, ortho-substituted acetophenone-derived enol ethers only
inefficiently participate in this process (e.g., 48% yield for the
formation of 18l). Nonetheless, both unhindered para- and
meta-analogues efficiently generated the corresponding ad-
ducts (e.g., 18h–k). Moreover, TBS enol ethers of polycyclic-ar-
omatic-containing methyl ketones, such as that derived from
2-acetylphenanthrene, also reacted with 5a to form the
adduct 18m in high yield and regioselectivity (e.g., 80%, 13:1
r.r.). The benzylideneacetone-derived TBS enol ether also react-
ed to form chromene 18n in 90% yield and r.r. of 5:1, in addi-
tion to those reactants arising from heteroaryl methyl ketones
like 2-acetylfuran (85%, 18o), 2-acetylthiophene (87%, 18p),
and 3-acetylindole (68%, 18q). Non-terminal TBS enol ethers
were also found to be effective substrates, each of them pro-
ducing mixtures of the diastereomeric chromenes containing
two stereogenic centers as exemplified by the conversion of
Scheme 5. Arylamine 10m catalyzed cyclization–substitution cascade reac-
tion of cinnamaldehyde derivatives 15 and silyl enol ethers 17 with isolated
yields (unless specified, see experimental section and SI). [a] 72 h. [b] 96 h.
[c] The relative stereochemistry was not assigned for this product mixture.
[d] Relative configuration is determined by comparison with known com-
pounds in reference [4f].
the (E)-TBS enol ether of butyrophenone to 18r in 62% yield
and with a d.r. of 4:1. Similarly, endocyclic TBS enol ethers of
cyclic ketones also reacted with 5a. For example, the silyl enol
ether of 1-tetralone reacted to form 18s with a high degree of
regioselecitivity, but only modest diastereoselectivity. Similar
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trends were followed in reactions of the TBS enol ethers of cy-
clohexanone and cyclopentanone. Although, we originally be-
lieved that aldehyde-derived silyl enol ethers might be more
challenging substrates for this process, we found that the TBS
enol ether of hexnal reacts with 5a to produce the desired
product 18v, albeit in low yield. It is worth noting that the
TMS enol ether of hexanal failed to generate the chromene
18v, but the TMS enol ether of isobutyraldehyde reacted with
5a to form the quaternary carbon-containing product 18w in
42% yield and with a r. r of 1:0. In contrast, the TBS analogue
of this aldehyde did not undergo this reaction.
Mechanistic study
The studies described above have produced new amine-cata-
lyzed cyclization–nucleophilic-substitution cascade reactions.
These processes, which do not require the use of acid addi-
tives or elevated temperatures to activate N,O-acetals in a cata-
lytic manner, take place under mild reaction conditions in high
yields and with high degrees of chemo- and regioselectivity.
The key to the success of these processes is the identification
of aniline derivatives as catalysts that have properly balanced
nucleophilicities and leaving abilities. The nucleophilicity is es-
sential for the effective formation of an iminium ion with the
aldehyde in the initial cyclization step. However, a good leav-
ing propensity is essential for the catalyst regeneration. For ex-
ample, we observed that the more nucleophilic Jørgensen–
Hayashi diphenylpyrrolinol TMS catalyst 7 in reaction between
the cinnamaldehyde 5a and the indole 13a is sufficiently nu-
cleophilic to promote the formation of the iminium intermedi-
ate, which then undergoes cyclization to form the N,O-acetal 8
(Scheme 2).[6] However, its poor leaving tendency prevents the
subsequent nucleophilic-substitution process even with an
acid additive (e.g., CF3CO2H).
Synthetic applications
As discussed above, chromenes and chromanes are scaffolds
widely present in a number of natural products and bioactive
compounds. The new method that we have developed can
serve as a powerful tool to construct interestingly substituted
members of these heterocyclic families. To demonstrate the
synthetic utility of the new protocol, we designed a two-step
route for the preparation of the chromene-containing natural
product candenatenin E (25), isolated from the heartwood of
the Thai medicinal plant D. candenatensis (Scheme 6).[11] (E)-4-
Hydroxy-3-(3-oxoprop-1-en-1-yl)phenyl pivalate (5h), a readily
available starting material, undergoes efficient reaction with
2,3-dimethoxyphenol (23) in the presence of 20 mol% amine
catalyst 10m at 408C to give the desired product 24 in 54%
yield and a r.r. of 6.8:1. Racemic candenatenin E (25) is then
generated in nearly quantitative yield by simple base promot-
ed saponification of the pivalate ester moiety in 24.
To understand the new aminocatalytic cyclization–substitu-
tion process, we carried out a more detailed investigation. In
this effort, we observed that treatment of the aldehyde 5a
with a stoichiometric amount of the 4-fluoroaniline 10b leads
to the generation of the N,O-acetal 28 in quantitative yield
within 1 h (Scheme 7a). The N,O-acetal is stable and can be pu-
We also used the new method to install a chromene group
at the C-3 position of 5-butyl-2-(4-methoxyphenyl)-1H-indole
(26). Specifically, reaction of 26 with the cinnamaldehyde deriv-
ative 5a, catalyzed by the aniline 10h, produces the potential-
ly bioactive indole-chromene derivative 27 in 68% yield
(Scheme 6).[12]
Scheme 7. Results of the preliminary experiments designed to gain under-
Scheme 6. Two-step synthesis of candenatenin E and functionalization of
standing of the mechanism of the cyclization–substitution cascade process.
bioactive indole-containing compounds.
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rified and characterized (see Supporting Information). More-
over, 28 was found to react with the indole 13a to form the
substitution products 14a and 15a in a combined 61% yield
and a r.r. of 3.9:1 (Scheme 7b). Furthermore, the preformed
hemiacetal 29 does not react with the indole 13a under the
standard reaction conditions in the presence of 10b, which
suggests that the route does not undergo through hemiacetal
formation (Scheme 7c). In addition, we found that trans-cinna-
maldehyde 30 does not react with the indole 13a in the pres-
ence of 10b under the standard reaction conditions. This out-
come shows that the cascade process does not take place by
a pathway involving the initial addition of indole to the imini-
um ion formed between the aldehyde and the aniline catalyst
(Scheme 7d). In a similar manner, trans-cinnamaldehyde 30
does not react with tert-butyldimethyl[(1-phenylvinyl)oxy]silane
(17a) in the presence of 10m (Scheme 7e).
Based on these experiments, a possible catalytic cycle is pro-
posed (Scheme 8). The formation of the key N,O-acetal 12
from an aniline and a trans-2-hydroxycinnamaldehyde 5 is an
essential step. It is noted that two possible pathways exist for
the substitution reaction between the N,O-acetal 12 and a nu-
cleophile; the first involving direct displacement of the amine
by the nucleophile in a concerted process and the second in-
volving the initial stepwise loss of the amine followed by the
addition of the nucleophile to the formed oxonium ion (struc-
ture not shown). At the current time, we have no evidence
that enables distinction between these two possibilities.
of 2-substituted 2H-chromene moieties in biologically active in-
doles. Importantly, the process developed in this study repre-
sents the first example of a direct germinal functionalization of
aldehydes in a catalytic fashion. Further exploration of the uti-
lization of the aminocatalytic mode in the design of new or-
ganic transformations and useful enantioselective processes is
underway in our laboratories.
Experimental Section
General procedure for the arylamine-catalyzed cyclization–
substitution cascade reaction of 2-hydroxycinnamaldehydes
with electron-rich arenes (Scheme 3)
An electron-rich arene 13 (0.1 mmol) was added to a solution of
a 2-hydroxycinnamaldehyde 5 (0.12 mmol) in anhydrous dichloro-
methane (0.5 mL) in the presence of 10h (20 mol%) and 4 Š mo-
lecular sieves (100 mg). The resulting solution was stirred for
a specified time (22–72 h) at room temperature and filtered
through a short microcolumn of celite. Concentration of the filtrate
1
gave a residue that was subjected to H NMR analysis. Isolation of
the product was conducted by subjecting the residue to silica gel
chromatography.
General procedure for the arylamine-catalyzed cyclization–
substitution cascade reaction of 2-hydroxycinnamaldehydes
with silyl enol ethers (Scheme 5)
A specified silyl enol ether 17 (0.11 mmol) was added to a solution
of hydroxycinnamaldehyde 5 (0.1 mmol) in anhydrous dichlorome-
thane (0.5 mL) in the presence of 10m (20 mol%) and 4 Š molecu-
lar sieves (100 mg). The resulting solution was stirred for 48 h at
room temperature and filtered through a short microcolumn of
celite. Concentration of the filtrate in vacuo gave a residue that
was subjected to 1H NMR analysis. Isolation of the product was
conducted by subjecting the residue to silica gel chromatography.
Acknowledgements
Financial support for this research from the the NSF (CHE-
1565085) and the National Science Foundation of China (No.
21372073) is gratefully acknowledged.
Scheme 8. Proposed catalytic cycle.
Keywords: aminocatalysis · cascade reactions · chromenes ·
iminium ions · N,O-acetals
Conclusion
In the study described above, we developed an unprecedent-
ed, arylamine-catalyzed cyclization–substitution cascade reac-
tion for the one-pot synthesis of 2-substituted 2H-chromenes.
Unlike widely used strategies, the protocol employs simple
amines as activators for the formation of N,O-acetals and sub-
sequent direct substitution by nucleophiles under mild condi-
tions without requirement of acids or elevated temperatures.
Notably, the process leads to high yields with high degrees of
chemo- and regioselectivity, and it shows a broad nucleophilic-
substrate scope including indoles, pyroles, phenols, and silyl
enol ethers. Furthermore, the synthetical value of the new
method is demonstrated by its use in a two-step synthesis of
the natural product candenatenin E and the facile installation
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Received: March 8, 2016
Published online on May 27, 2016
Chem. Eur. J. 2016, 22, 9240 – 9246
www.chemeurj.org
9246
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim