Carbocation Organocatalysis in Interrupted Povarov Reactions to cis-Fused Pyrano- and Furanobenzodihydropyrans

Article abstract of DOI:10.1002/ejoc.201700634

Tritylium cation-catalyzed interrupted Povarov reactions afforded cis-4-aminobenzodihydropyrans in excellent yields (90 %) within 10 min by low catalyst loadings (1 mol-%). A mechanism involving Lewis acidic catalysis by a carbocation was proposed and val

Full text of DOI:10.1002/ejoc.201700634

A Journal of
Accepted Article
Title: Carbocation organocatalysis in interrupted Povarov reactions to
cis-fused pyrano- and furanobenzodihydropyrans
Authors: Jingjing Liu, Jiaxi Xu, Zhenjiang Li, Yu Huang, Haixin Wang,
Yu Gao, Tianfo Guo, Pingkai Ouyang, and Kai Guo
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201700634
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10.1002/ejoc.201700634
European Journal of Organic Chemistry
Title: Carbocation organocatalysis in interrupted Povarov reactions to cis-fused
pyrano- and furanobenzodihydropyrans
Authors: Jingjing Liu, Jiaxi Xu, Zhenjiang Li, Yu Huang, Haixin Wang, Yu Gao,
Tianfo Guo, Pingkai Ouyang and Kai Guo*
State Key Laboratory of Materials-Oriented Chemical Engineering, College of
Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, 30
Puzhu Road South, Nanjing 211816, China.
Corresponding Author
Kai Guo; E-mail: guok@njtech.edu.cn. Tel +86 25 5813 9926; Fax +86 25 5813
9935.
Abstract
Tritylium cation catalyzed interrupted Povarov reactions afforded cis-4-
aminobenzodihydropyrans in excellent yields (90%) within 10 min by low catalyst
loading (1 mol %). Lewis acidic catalysis mechanism by carbocation was proposed
and validated. Switching a one-pot batch version of the reaction into a two-stage
convergent continuous flow procedures received 10-fold time reduction to 1 min
with 88% yield.
Keywords: Tritylium ion; Lewis acid; Organocatalyst; Povarov reaction; 4-
Aminobenzodihydropyran
Graphic Abstract
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10.1002/ejoc.201700634
European Journal of Organic Chemistry
Introduction
Benzodihydropyran (BDHP) skeletons1-6 (A, Scheme 1) are recognized as
privileged substructures7-9 pivotal in bioactive molecules10-12 and drug
discovery13-15. Compounds containing BDHP core featured natural product like
scaffold16-19 and allowed high potential in effective drug-like molecular entities in
both biological20-22 and synthetic7, 23-27 explorations. Constructions of the BDHP
core by formal [4 + 2] cycloadditions showed step economy routes via reactions
of dienophiles with ortho-quinone methide28-34 (Scheme 1 a), or with
oxocarbenium35-37 (Scheme 1 b). Our interest in carbocation catalyzed Povarov
reactions38 promoted us to probe a version of interrupted Povarov reactions
(Scheme 1 c) of electron-rich alkenes with salicylaldehyde imine (salicylaldimine)
to afford 4-aminobenzodihydropyrans (Scheme 2 a).
Scheme 1. Synthetic routes to benzodihydropyran skeletons
4-Aminobenzodihydropyran derivatives (Scheme 2 a) are valuable motifs in
ATP-sensitive potassium channel openers with a broad spectrum of potential
therapeutic applications10, 12, 39, 40. Cromakalim (Scheme 2 b) was the first agent
1, 14, 41
of BDHP type which showed antihypertensive activities.
The reference
cardioselective agent BMS-180448 (Scheme 2 c) functioned as anti-ischemic42,
43to control heart and blood pressure.44
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10.1002/ejoc.201700634
European Journal of Organic Chemistry
Scheme 2. a. 4-Aminobenzodihydropyrans derivatives; b. Structure of cromakalim c. Structure of
BMS-180448; d. Reaction between salicylaldimines and electron-rich alkenes
In the manifold variants of Povarov reactions45, 46, an interrupted Povarov
version towards 4-aminobenzodihydropyrans (Scheme 2 d) proved an attractive
one. Activations of the imine moiety by Lewis acids, such as Sc(OTf)347 and its N-
49
50
51
oxide complex48, LiBF4 , InCl3 , I2 , or by phosphoric acids,52, 53 were reported.
Despite their significances, most of the catalysts suffered from disadvantages of
expensiveness, high loading, long reaction time, or metal residue. Therefore, we
suppose carbocation will work as green and efficient Lewis acidic organocatalyst
in these important transformations.
Albeit carbocation was discovered early in 1901.54 Stable carbocations have
been pursued as conceptually attractive highly powerful and tunable organic
Lewis acid catalysts in the last couple of years.54-59 Herein, we report
triphenylmethylium (tritylium) tetrafluoroborate (TrBF4) as an organocatalyst in
synthesis of cis-4-aminobenzodihydropyrans with excellent yields (>90%) within
10 min by a remarkably low catalyst loading (1 mol %). Lewis acidic catalysis
mechanism by carbocation was proposed and validated. Finally, the interrupted
Povarov reaction was developed into a practical continuous flow60, 61 procedure
by 10 times reducing of the reaction time (1 min) with 88% yield.
Result and discussion
At the onset of the experiment, salicylaldimine 1a (Table 1) was chosen as
the model substrate to react with 2,3-dihydrofuran (DHF) 2 in the presence of
TrBF4 (0.5 mol %) and THF. After stirring at room temperature for 30 min, the
reaction was finished and gave the corresponding furanobenzodihydropyrans 3
in 60% isolated yield as a mixture of cis- and trans-isomers, which could be
readily separated and purified by column chromatography on silica gel.
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European Journal of Organic Chemistry
Table 1. Reactions of salicylaldimine (1a) with 2,3-dihydrofuran (DHF) 2 under
different conditions.
Entry
Solvent
Catalyst
loading
Time
Product ratio
Overall
(min)
Yield (%)b
（cis/trans)a
1
2
3
4
5
6
7
8
THF
THF
0.5 mol %
1 mol %
2 mol %
1 mol %
1 mol %
1 mol %
1 mol %
1 mol %
30
10
8
85:15
95:5
60
90
91
75
85
78
56
70
THF
93:7
Toluene
CH3CN
Dioxane
ether
DCM
30
12
20
60
50
80:20
90:10
78:22
70:30
83:17
a The ratio is based on isolation by chromatography
b Isolated yield
In order to establish an optimized reaction conditions, an array of trial
reactions was carried out, and the results were summarized in Table 1. We were
pleased to see that both the diastereoselectivities and the yields were significantly
increased as the amount of catalyst was increased to 1 mol %, along with the
reaction time decreased from 30 min to 10 min (Table 1, entries 1-2). However,
further increase in TrBF4 loading from 1 to 2 mol % resulted in a similar yield and
selectivity, even though the reaction was slightly accelerated (Table 1, entry 3).
Screening of solvents showed THF was better than ether, dioxane, DCM,
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10.1002/ejoc.201700634
European Journal of Organic Chemistry
acetonitrile, and toluene (Table 1, entries 4-8). Furanobenzodihydropyran 3a
was obtained in 90% isolated yield and with a dr of 95:5 in favour of the cis-
product under the optimized conditions.
Table 2. Scope of the substratesa
a All reaction were conducted at room temperature using 1mol% TrBF4 in THF.
b
The ratio is based on isolation by chromatography. (cis: trans)
c Isolated yield
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European Journal of Organic Chemistry
With the optimum conditions in hand, the scope of the reaction was evaluated
on a set of salicylaldimines/alkenes combinations. A range of salicylaldimines with
different substituents, which derived from substituted salicylaldehydes and
anilines, readily reacted with 2,3-dihydrofuran to produce the corresponding
products in good to excellent yields (Table 2). In all of the tested cases, cis-
fused pyranobenzodihydropyran was the major product. The reaction was
workable with regard to both electron-withdrawing and electron-donating
substituents on either side of the imine C=N moitey. Besides that, the scope of
the TrBF4-catalyzed interrupted Povarov
reaction to cis-4-
aminobenzodihydropyran derivatives was explored by changing the alkenes.
Acyclic and cyclic enol ethers and enamides, such as ethyl vinyl ether and 1-
vinylpyrrolidin-2-one also promptly underwent the title reaction to provide
benzodihydropyrans in good yields; conjugated dienes, viz. cyclopentadiene and
indene, were essentially unreactive under the established reaction conditions,
wherein only traces of the target products were observed. Due to their poor
nucleophilicity, alkenes display poor reactivity.5, 6, 45
Based on the above experimental facts and prior work by others58, 62, a
plausible mechanism of an interrupted Povarov reaction was proposed (Scheme
3). Initially, salicylaldimine (1) was activated by complexation with Lewis acidic
tritylium ion into intermediate I; next, complex I was attacked nucleophilically
by electron-rich alkene 2,3-dihydrofuran 2 to form the corresponding
intermediate II; then an intramolecular nucleophilic attack within II launched
from hydroxyl oxygen to the oxocarbenium carbon produced the intermediate
III; finally, proton transfer of intermediate III released the final product 3, and
the tritylium (Tr+) was regenerated.
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10.1002/ejoc.201700634
European Journal of Organic Chemistry
Scheme 3. Proposed mechanism for the tritylium ion (Tr+) catalyzed interrupted
Povarov reactions between salicylaldimine (1) and 2,3-dihydrofuran (2).
1
To confirm the catalytic interactions of tritylium with salicylaldimine 1, H-
NMR experiments were carried out by varying the catalyst loading with respect
to the salicylaldimine 1a. The 1H-NMR spectra of salicylaldimine 1a were run on
its own in CD3CN on a Bruker AV-400 spectrometer and compared to samples
with ratios of 5, 20, 50 and 100 mol % of TrBF4 (Figure 1). With increasing the
ratio of TrBF4 to 1a, the obvious effect was the deshielding on the CH proton of
the imine moiety, whose chemical shift down fielded from δ 8.78 to δ 9.07, this
evidenced a strong binding complexation between tritylium and the imine
nitrogen.
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10.1002/ejoc.201700634
European Journal of Organic Chemistry
Figure 1. 1H NMR chemical shifts of the imine =CH proton with increasing ratios
of TrBF4 to salicylaldimines.
Phenol hydroxyl proton resonanced at δ 13.26 as a sharp singlet in a pure
salicylaldimine sample (0% TrBF4), which meant strong intramolecular H-bonding
deshielding the proton, and prohibited fast proton exchange. With addition of the
Lewis acidic TrBF4, the singlet disappeared abruptly. This clued tritylium may
break the intramolecular hydrogen bond, which resulted in a rapid exchange, and
the singlet flattened into indiscernible.
Scheme 4. The reaction of salicylaldimine with 2,3-dihydrofuran in the presence
of TrBF4 and 2,6-di-tert-butylpyridine (DBPy).
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European Journal of Organic Chemistry
Considering the difficulties encountered with imines in general such as their
instability at higher temperatures, the difficulty in purifying them by distillation
and column chromatography as well as poor yields, studies were extended to
examine the possibility of a one-pot synthesis. The reaction of o-
hydroxybenzaldehyde, substituted aromatic amines and 2,3-dihydrofuran in THF
at ambient temperature catalyzed by TrBF4 in the presence of anhydrous Na2SO4
under mild conditions resulted in the expected furanobenzopyrans product. The
yields and the diastereoselectivity were always somewhat lower, however, which
may be attributed to the decomposition or deactivation of the carbenium by water
formed during salicylaldimine formation.
In some Lewis acid catalyzed reactions, “hidden proton” formed from
hydrolysis of the Lewis acid with trace of water,intentionally or inadvertently, may
worked as the actual catalysts63-66. In order to exclude potential Brønsted acidic
catalysis, we performed the model reaction in the presence of sterically hindered
base 2,6-di-tert-butylpyridine (DBPy) as a proton scavenger. When the reaction
between salicylaldimine 1a and 2,3-dihydrofuran 2 was conducted in the
presence of TrBF4 (1 mol %) and DBPy (2 mol %), the yields of
pyranobenzodihydropyrans were essentially not changed (87% yield) (Scheme
4). These results obviated the possibility of Brønsted acid catalysis via proton
transfer. Taken together, the findings offered strong support to an active
carbocation being responsible for the catalysis in Lewis acidic nature.
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10.1002/ejoc.201700634
European Journal of Organic Chemistry
Scheme 5. Switching of a batch mode and a continuous flow mode of the TrBF4-
catalyzed interrupted Povarov reactions in (a) one-pot; and in (b) two-stage
procedures.
In parallel with the above investigated reactions based on preformed
salicylaldimine (Table 1), a one-pot, three-component synthesis of the
benzodihydropyrans from salicylaldehyde, anilines, and 2,3-dihydrofuran under
the catalysis of TrBF4 (1 mol %) was probed. The reaction was carried out in THF
by stirring for 10 min at room temperature, the expected products were obtained,
respectively (Scheme 5, a). The yields and the selectivity were somewhat lower,
however, which may be attributed to the decomposition or deactivation of the
carbocation by water formed during salicylaldimine formation.
In order to circumvent this obstacle, we designed a two-stage, three-
component reactions through a continuous flow arrangement (Scheme 5, b).
The preparation composed of the following steps: firstly a salicylaldehyde solution
and an aniline solution were pumped into a microreactor I, then the resulting
salicylaldimine solution passed through a water absorption tube; in parallel 2,3-
dihydrofuran solution containing tritylium tetrafluoroborate was pumped into a T-
shape mixer with the de-watered salicylaldimine solution before further reaction
in a microreactor II. Satisfactorily, the benzodihydropyran was obtained at a
residence time of 1 min and a total flow rate of 5 mL/min with 88% yield.
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10.1002/ejoc.201700634
European Journal of Organic Chemistry
Switching from batch to flow process received comparable yields but it avoided
preparation and separation steps to preformed salicylaldimines. This exemplified
the first efficient and scalable preparation of cis-4-aminobenzodihydropyran
derivatives in continuous flow.
Conclusions
We described a novel method for the diastereoselective synthesis3 of cis-4-
aminobenzodihydropyran derivatives using tritylium as a mild and efficient
organocatalyst with low loading (1 mol %). Carbocation working in Lewis acidic
catalysis
mechanism
was
proposed
and
validated.
A
series
of
pyranobenzodihydropyrans and furanobenzodihydropyrans were obtained by
exploiting the interrupted Povarov reactions between salicylaldimines and alkenes
in good to excellent yields. One pot, three-component condensations of
salicylaldehydes, aniline, and 2,3-dihydrofuran catalyzed by carbocation was also
investigated, and revealed appreciable deactivation of the catalyst. A two-stage,
three-component reaction in continuous flow apparatus was designed to facilitate
a streamlined preparation of the benzodihydropyrans in a practical and scalable
manner with high yield (88%) in short residence time (1 min).
Experimental
General Remarks
All reactions were carried out under argon atmosphere in oven dried
glassware with magnetic stirring. Reagents were obtained from commercial
supplier and used without further purification unless otherwise noted. All solvents
used in the reactions were distilled from appropriate drying agents prior to use.
Routine monitoring of reaction was performed by TLC using pre-coated Haiyang
GF254 silica gel TLC plates. All the column chromatography separations were
done by silica gel (200-300 mesh) at increased pressure. The crude products
were purified by column chromatography with petroleum ether/ethyl acetate as
eluent.
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European Journal of Organic Chemistry
1H NMR and 13C NMR spectra were taken on a Bruker AV 300 or AV 400 MHz
and 75 or 100 MHz spectrometer in CDCl3., chemical shift are given in part per
million (ppm) relative to TMS as an internal standard. Mass spectra and high
resolution mass spectra were performed on Agilent Q TOF 6520 mass
spectrometer with electron spray ionization (ESI) as the ion mode. Optical
rotations were recorded using a sodium lamp with a Rudolph Autopol I Automatic
Polarimeter with 1 dm tube.
General Procedure A for the Synthesis of N - aryl imine667
A round-bottom flask was charged with aryl amine (10 mmol), substituted
salicylaldehyde (10 mmol) and 30 ml of absolute ethanol. The reaction mixture
was heated to reflux. The reaction was complete detected by TLC. The reaction
mixture was concentrated and recrystallized from methanol to give a series of
salicylaldimine compounds. The product was confirmed by HRMS.
General
Procedure
B
for
the
Synthesis
of
Cis-4-
Aminobenzodihydropyran Derivatives by Tritylium Cation and Their
Structural spectra
A dry round-bottomed flask, taken from the oven was filled with argon. Then
different substituted salicylaldimine 1 (2 mmol) and TrBF4 (1 mol%) were
transferred into the flask along with magnetic pellet. Freshly distilled anhydrous
Solvent (5 ml) and electron rich alkene 2 (4 mmol) were added by syringe and
the reaction mixture was stirred at room temperature. After full conversion of the
imines 1 (determined by TLC), the reaction mixture was passed through a short
plug of SiO2 and the solvent removed under vacuum. The residue was purified
by column chromatography on silica gel with petroleum ether and ethyl acetate
as eluent to give the product 3a-3m. The product was characterized by 1H-NMR,
13C-NMR and HRMS.
N-phenyl-2,3,3a,9a-tetrahydro-4H-furo[2,3-b]chromen-4-amine(cis) (3aa)
White solid. 1H NMR (300 MHz, CDCl3) δ 7.35 (d, J = 7.5 Hz, 1H), 7.24-7.17
(m, 3H), 6.97-6.91 (m, 2H), 6.80-6.71 (m, 3H), 5.87 (d, J = 5.7 Hz, 1H), 4.99-
4.94 (m, 1H), 3.93-3.87 (m, 1H), 3.87-3.79 (m, 2H), 3.14-3.04 (m, 1H), 1.95-
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10.1002/ejoc.201700634
European Journal of Organic Chemistry
1.85 (m, 1H), 1.67-1.58 (m, 1H). 13C NMR (75 MHz, CDCl3) δ 152.9, 147.0, 129.5,
128.8, 126.1, 124.6, 121.8, 118.3, 117.2, 113.4, 102.3, 67.9, 48.8, 43.3, 23.9.
HRMS (ESI+) calcd for [C17H17NO2+H]+ 268.1338, found: 268.1343.
N-phenyl-2,3,3a,9a-tetrahydro-4H-furo[2,3-b]chromen-4-amine(trans)
(3ab)
1
White solid. H NMR (300 MHz, CDCl3) δ 7.29-7.22 (m, 4H), 6.96-6.92 (m,
2H), 6.76 (t, J = 7.2 Hz, 1H), 6.65 (d, J = 8.1 Hz, 2H), 5.68 (d, J = 4.8 Hz, 1H),
4.54 (s, 1H), 4.10-4.03 (m, 1H), 4.00-3.90 (m, 2H), 2.98-2.89 (m, 1H), 2.22-
2.11 (m, 1H), 1.75-1.62 (m, 1H). 13C NMR (75 MHz, CDCl3) δ 152.5, 146.4, 129.8,
129.5, 121.7, 118.1, 117.6, 113.0, 100.0, 67.7, 50.5, 43.3, 26.9. HRMS (ESI+)
calcd for [C17H17NO2+H]+ 268.1338, found: 268.1349.
N-(4-chlorophenyl)-2,3,3a,9a-tetrahydro-4H-furo[2,3-b]chromen-4-amine
(cis) (3ba)
White solid. 1H NMR (300 MHz, CDCl3) δ 7.30 (d, J = 7.5 Hz, 1H), 7.25-7.16
(m, 3H), 6.99-6.93 (m, 2H), 6.66 (d, J = 8.7 Hz, 2H), 5.89 (d, J = 5.7 Hz, 1H),
4.94-4.90 (m, 1H), 3.96-3.90 (m, 1H), 3.89-3.83 (m, 2H), 3.15-3.05 (m, 1H),
1.97-1.86 (m, 1H), 1.68-1.56 (m, 1H). 13C NMR (75 MHz, CDCl3) δ 152.9, 145.6,
129.4, 128.9, 125.9, 124.2, 122.9, 121.8, 117.3, 114.5, 114.4, 102.2, 67.9, 49.0,
43.3, 23.9. HRMS (ESI+) calcd for [C17H16ClNO2+H]+ 302.0948, found: 302.0911.
N-(4-chlorophenyl)-2,3,3a,9a-tetrahydro-4H-furo[2,3-b]chromen-4-amine
(trans)(3bb)
White solid. 1H NMR (300 MHz, CDCl3) δ 7.24-7.20 (m, 2H), 7.15 (d, J = 8.4
Hz, 2H), 6.96-6.92 (m, 2H), 6.56 (d, J = 8.7 Hz, 2H), 5.66 (d, J = 4.8 Hz, 1H),
4.46 (s, 1H), 4.07-4.00 (m, 1H), 3.96-3.91 (m, 2H), 2.92-2.85 (m, 1H), 2.21-
2.10 (m, 1H), 1.73-1.60 (m, 1H). 13C NMR (75 MHz, CDCl3) δ 152.5, 144.9, 129.9,
129.6, 129.3, 122.7, 121.7, 121.5, 117.7, 114.1, 99.9, 67.7, 50.8, 43.3, 27.0.
HRMS (ESI+) calcd for [C17H16ClNO2+H]+ 302.0948, found: 302.0919.
N-(p-tolyl)-2,3,3a,9a-tetrahydro-4H-furo[2,3-b]chromen-4-amine (cis)(3ca)
White solid. 1H NMR (300 MHz, CDCl3) δ 7.40 (d, J = 7.5 Hz, 1H), 7.23 (t, J
= 7.8 Hz, 1H), 7.06 (d, J = 8.4 Hz, 2H), 7.00-6.94 (m, 2H), 6.69 (d, J = 8.1 Hz,
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10.1002/ejoc.201700634
European Journal of Organic Chemistry
2H), 5.90 (d, J = 5.4 Hz, 1H), 4.96 (d, J = 4.8 Hz, 1H), 3.98-3.82 (m, 2H), 3.57
(brs, 1H), 3.17-3.07 (m, 1H), 2.30 (s, 3H), 1.96-1.87 (m, 1H), 1.69-1.56 (m,
1H). 13C NMR (75 MHz, CDCl3) δ 153.0, 144.7, 130.1, 128.8, 127.7, 126.2, 124.9,
121.8, 117.2, 113.7, 102.4, 68.0, 49.1, 43.3, 23.9, 20.4. HRMS (ESI+) calcd for
[C18H19NO2+H]+ 282.1494, found: 282.1501.
N-(p-tolyl)-2,3,3a,9a-tetrahydro-4H-furo[2,3-b]chromen-4-amine
(3cb)
(trans)
White solid. 1H NMR (300 MHz, CDCl3) δ 7.25-7.23 (m, 2H), 7.03 (d, J = 8.1
Hz, 2H), 6.95-6.92 (m, 2H), 6.58 (d, J = 8.1 Hz, 2H), 5.67 (d, J = 4.5 Hz, 1H),
4.49 (s, 1H), 4.09-3.91 (m, 2H), 3.78 (s, 1H), 2.96-2.89 (m, 1H), 2.26 (s, 3H),
2.19-2.10 (m, 1H), 1.74-1.61 (m, 1H). 13C NMR (75 MHz, CDCl3) δ 152.5, 144.1,
130.0, 129.8, 129.7, 127.4, 121.9, 121.6, 117.6, 113.3, 100.0, 67.7, 50.9, 43.4,
27.0, 20.4. HRMS (ESI+) calcd for [C18H19NO2+H]+ 282.1494, found: 282.1498.
N-(4-methoxyphenyl)-2,3,3a,9a-tetrahydro-4H-furo[2,3-b]chromen-4-
amine (cis)(3da)
White solid. 1H NMR (300 MHz, CDCl3) δ 7.40 (d, J = 7.5 Hz, 1H), 7.21 (t, J
= 8.1 Hz, 1H), 6.99-6.92 (m, 2H), 6.85-6.81 (m, 2H), 6.73-6.70 (m, 2H), 5.88
(d, J = 5.7 Hz, 1H), 4.89 (d, J = 4.8 Hz, 1H), 3.96-3.83 (m, 2H), 3.77 (s, 3H),
13
3.57 (brs, 1H), 3.14-3.02 (m, 1H), 1.94-1.86 (m, 1H), 1.65-1.53 (m, 1H). C
NMR (75 MHz, CDCl3) δ 152.9, 152.7, 141.0, 128.7, 126.1, 125.0, 121.8, 117.1,
115.1, 115.0, 102.4, 67.9, 55.7, 49.7, 43.3, 23.8. HRMS (ESI+) calcd for
[C18H19NO3+H]+ 298.1443, found: 298.1453.
N-(4-methoxyphenyl)-2,3,3a,9a-tetrahydro-4H-furo[2,3-b]chromen-4-
amine (trans)(3db)
1
White solid. H NMR (300 MHz, CDCl3) δ 7.28-7.24 (m, 2H), 6.98-6.93 (m,
2H), 6.86-6.83 (m, 2H), 6.67-6.64 (m, 2H), 5.71 (d, J = 4.8 Hz, 1H), 4.47 (s,
1H), 4.11-3.96 (m, 2H), 3.79 (s, 3H), 3.55 (brs, 1H), 3.00-2.91 (m, 1H), 2.22-
2.11 (m, 1H), 1.74-1.60 (m, 1H). 13C NMR (75 MHz, CDCl3) δ 152.8, 152.6, 140.6,
129.8, 129.7, 121.7, 117.6, 115.2, 114.9, 100.1, 67.8, 55.9, 51.8, 43.4, 27.1.
HRMS (ESI+) calcd for [C18H19NO3+H]+ 298.1443, found: 298.1449.
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10.1002/ejoc.201700634
European Journal of Organic Chemistry
6-chloro-N-phenyl-2,3,3a,9a-tetrahydro-4H-furo[2,3-b]chromen-4-amine
(cis)(3ea)
1
White solid. H NMR (300 MHz, CDCl3) δ 7.36-7.35 (m, 1H), 7.25-7.20 (m,
2H), 7.15 (dd, J = 8.1, 2.4 Hz, 1H), 6.87-6.77 (m, 2H), 6.72 (d, J = 7.8 Hz, 2H),
5.86 (d, J = 5.7 Hz, 1H), 4.94-4.89 (m, 1H), 3.92-3.82 (m, 2H), 3.79-3.74 (m,
1H), 3.14-3.04 (m, 1H), 1.96-1.86 (m, 1H), 1.64-1.51 (m, 1H). 13C NMR (75 MHz,
CDCl3) δ 151.6, 146.6, 129.6, 128.8, 126.9, 126.6, 126.1, 118.7, 118.6, 114.5,
113.5, 102.5, 67.9, 48.9, 43.1, 23.8.HRMS (ESI+) calcd for [C17H16ClNO2+H]+
302.0948, found: 302.0953.
6-chloro-N-phenyl-2,3,3a,9a-tetrahydro-4H-furo[2,3-b]chromen-4-amine
(trans)(3eb)
White solid. 1H NMR (300 MHz, CDCl3) δ 7.25-7.17 (m, 4H), 6.88 (d, J = 8.7
Hz, 1H), 6.78 (t, J = 7.2 Hz, 1H), 6.65 (d, J = 8.1 Hz, 2H), 5.65 (d, J = 4.8 Hz,
1H), 4.49 (s, 1H), 4.10-3.92 (m, 2H), 3.87 (s, 1H), 2.95-2.87 (m, 1H), 2.22-2.12
13
(m, 1H), 1.74-1.61 (m, 1H). C NMR (75 MHz, CDCl3) δ 151.1, 146.0, 129.8,
129.6, 129.3, 126.4, 123.4, 119.1, 118.4, 113.1, 100.2, 67.8, 50.4, 43.4, 26.9.
HRMS (ESI+) calcd for [C17H16ClNO2+H]+ 302.0948, found: 302.0951.
6-methyl-N-phenyl-2,3,3a,9a-tetrahydro-4H-furo[2,3-b]chromen-4-amine
(cis)(3fa)
1
White solid. H NMR (300 MHz, CDCl3) δ 7.29-7.24 (m, 2H), 7.21 (s, 1H),
7.04 (d, J = 8.1 Hz, 1H), 6.88-6.82 (m, 2H), 6.78 (d, J = 8.1 Hz, 2H), 5.89 (d, J
= 5.4 Hz, 1H), 5.00-4.96 (m, 1H), 3.99-3.90 (m, 1H), 3.87-3.82 (m, 2H), 3.18-
3.08 (m, 1H), 2.30 (s, 3H), 1.98-1.88 (m, 1H), 1.72-1.59 (m, 1H). 13C NMR (75
MHz, CDCl3) δ 150.2, 146.6, 130.7, 129.0, 128.8, 125.9, 123.9, 117.8, 116.5,
114.1, 112.9, 101.8, 67.4, 48.4, 42.8, 23.5, 20.3. HRMS (ESI+) calcd for
[C18H19NO2+H]+ 282.1494, found: 282.1498.
6-methyl-N-phenyl-2,3,3a,9a-tetrahydro-4H-furo[2,3-b]chromen-4-amine
(trans)(3fb)
White solid. 1H NMR (300 MHz, CDCl3) δ 7.24 (t, J = 7.5 Hz, 2H), 7.07-7.05
(m, 2H), 6.86 (d, J = 8.7 Hz, 1H), 6.78 (t, J = 7.5 Hz, 1H), 6.66 (d, J = 8.1 Hz,
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European Journal of Organic Chemistry
2H), 5.76 (d, J = 4.8 Hz, 1H), 4.50 (s, 1H), 4.10-4.06 (m, 1H), 4.03-3.92 (m,
2H), 2.98-2.89 (m, 1H), 2.28 (s, 3H), 2.20-2.12 (m, 1H), 1.76-1.60 (m, 1H). 13C
NMR (75 MHz, CDCl3) δ 149.8, 145.7, 130.5, 129.9, 129.5, 128.9, 120.9, 117.5,
116.9, 114.1, 112.4, 99.4, 67.2, 50.1, 42.9, 26.5, 20.0. HRMS (ESI+) calcd for
[C18H19NO2+H]+ 282.1494, found: 282.1493.
6-methoxy-N-phenyl-2,3,3a,9a-tetrahydro-4H-furo[2,3-b]chromen-4-amine
(cis)(3ga)
1
White solid. H NMR (300 MHz, CDCl3) δ 7.26-7.21 (m, 2H), 6.95-6.88 (m,
2H), 6.82-6.74 (m, 4H), 5.86 (d, J = 5.7 Hz, 1H), 4.93 (d, J = 4.8 Hz, 1H), 3.92-
3.85 (m, 1H), 3.83-3.77 (m, 2H), 3.73 (s, 3H), 3.17-3.07 (m, 1H), 1.95-1.85 (m,
1H), 1.67-1.54 (m, 1H). 13C NMR (75 MHz, CDCl3) δ 154.8, 146.9, 146.6, 129.5,
126.5, 118.5, 118.0, 113.6, 113.5, 111.7, 102.5, 67.9, 55.6, 49.3, 43.5, 24.2.
HRMS (ESI+) calcd for [C18H19NO3+H]+ 298.1443, found: 298.1429.
6-methoxy-N-phenyl-2,3,3a,9a-tetrahydro-4H-furo[2,3-b]chromen-4-amine
(trans)(3gb)
White solid. 1H NMR (300 MHz, CDCl3) δ 7.26-7.21 (m, 2H), 6.90 (d, J = 9.0
Hz, 1H), 6.84-6.75 (m, 3H), 6.67 (d, J = 8.1 Hz, 2H), 5.65 (d, J = 5.1 Hz, 1H),
4.50 (s, 1H), 4.08-4.01 (m, 1H), 3.99-3.91 (m, 2H), 3.74 (s, 3H), 2.97-2.88 (m,
1H), 2.23-2.12 (m, 1H), 1.78-1.65 (m, 1H). 13C NMR (75 MHz, CDCl3) δ 153.9,
145.9, 145.8, 129.0, 122.7, 118.0, 117.6, 115.3, 113.3, 112.6, 99.8, 67.2, 55.2,
50.6, 43.1, 26.9. HRMS (ESI+) calcd for [C18H19NO3+H]+ 298.1443, found:
298.1430.
6-chloro-N-(4-chlorophenyl)-2,3,3a,9a-tetrahydro-4H-furo[2,3-b]chromen-
4-amine (cis) (3ha)
1
White solid. H NMR (300 MHz, CDCl3) δ 7.29 (s, 1H), 7.19-7.16 (m, 3H),
6.87 (d, J = 5.1 Hz, 1H), 6.65 (d, J = 5.4 Hz, 2H), 5.88 (d, J = 3.3 Hz, 1H), 4.88-
4.86 (m, 1H), 3.94-3.84 (m, 2H), 3.79 (d, J = 5.4 Hz, 1H), 3.12-3.06 (m, 1H),
1.96-1.88 (m, 1H), 1.62-1.54 (m, 1H). 13C NMR (75 MHz, CDCl3) δ 151.6, 145.2,
129.5, 128.9, 127.0, 126.2, 126.0, 123.4, 118.8, 114.6, 102.5, 68.0, 49.2, 43.1,
23.9. HRMS (ESI+) calcd for [C17H15Cl2NO2+H]+ 336.0558, found: 336.0552.
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6-chloro-N-(4-chlorophenyl)-2,3,3a,9a-tetrahydro-4H-furo[2,3-b]chromen-
4-amine (trans)(3hb)
White solid. 1H NMR (300 MHz, CDCl3) δ 7.23-7.17 (m, 4H), 6.89 (d, J = 5.1
Hz, 1H), 6.57 (d, J = 5.1 Hz, 2H), 5.66 (d, J = 3.0 Hz, 1H), 4.44 (s, 1H), 4.08-
4.04 (m, 1H), 4.00-3.95 (m, 1H), 3.89 (s, 1H), 2.90-2.85 (m, 1H), 2.21-2.15 (m,
1H), 1.71-1.63 (m, 1H). 13C NMR (75 MHz, CDCl3) δ 151.1, 144.6, 130.0, 129.4,
129.2, 126.5, 123.2, 123.1, 119.2, 114.2, 100.2, 67.7, 50.7, 43.3, 27.0. HRMS
(ESI+) calcd for [C17H15Cl2NO2+H]+ 336.0558, found: 336.0553.
6-chloro-N-(p-tolyl)-2,3,3a,9a-tetrahydro-4H-furo[2,3-b]chromen-4-amine
(cis)(3ia)
White solid. 1H NMR (300 MHz, CDCl3) δ 7.39 (s, 1H), 7.17 (dd, J = 8.7, 2.1
Hz, 1H), 7.06 (d, J = 8.1 Hz, 2H), 6.87 (d, J = 8.7 Hz, 1H), 6.66 (d, J = 8.1 Hz,
2H), 5.87 (d, J = 5.4 Hz, 1H), 4.90 (s, 1H), 3.95-3.81 (m, 2H), 3.65 (s, 1H),
3.15-3.01 (m, 1H), 2.29 (s, 3H), 1.98-1.87 (m, 1H), 1.65-1.52 (m, 1H). 13C NMR
(75 MHz, CDCl3) δ 151.6, 144.3, 130.1, 128.8, 128.1, 126.9, 126.8, 126.2, 118.6,
113.8, 102.6, 68.0, 49.3, 43.1, 23.9, 20.4. HRMS (ESI+) calcd for
[C18H18ClNO2+H]+ 316.1104, found: 316.1112.
6-chloro-N-(p-tolyl)-2,3,3a,9a-tetrahydro-4H-furo[2,3-b]chromen-4-amine
(trans)(3ib)
White solid. 1H NMR (300 MHz, CDCl3) δ 7.24-7.18 (m, 2H), 7.04 (d, J = 7.8
Hz, 2H), 6.88 (d, J = 8.7 Hz, 1H), 6.58 (d, J = 8.1 Hz, 2H), 5.66 (d, J = 4.8 Hz,
1H), 4.46 (s, 1H), 4.10-3.93 (m, 2H), 3.73 (s, 1H), 2.94-2.89 (m, 1H), 2.27 (s,
3H), 2.21-2.12 (m, 1H), 1.74-1.61 (m, 1H). 13C NMR (75 MHz, CDCl3) δ 151.1,
143.8, 130.1, 129.7, 129.3, 127.8, 126.4, 123.7, 119.1, 113.4, 100.3, 67.8, 50.8,
43.4, 27.0, 20.4. HRMS (ESI+) calcd for [C18H18ClNO2+H]+ 316.1104, found:
316.1109.
N-(4-chlorophenyl)-6-methoxy-2,3,3a,9a-tetrahydro-4H-furo[2,3-
b]chromen-4-amine (cis)(3ja)
White solid. 1H NMR (300 MHz, CDCl3) δ 7.16 (d, J = 5.1 Hz, 2H), 6.89-6.86
(m, 2H), 6.76-6.74 (m, 1H), 6.65 (d, J = 5.1 Hz, 2H), 5.86 (d, J = 3.6 Hz, 1H),
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European Journal of Organic Chemistry
4.85-4.83 (m, 1H), 3.88-3.82 (m, 2H), 3.80-3.79 (m, 1H), 3.72 (s, 3H), 3.12-
3.06 (m, 1H), 1.92-1.86 (m, 1H), 1.65-1.54 (m, 1H). 13C NMR (75 MHz, CDCl3)
δ 154.8, 146.6, 145.5, 129.4, 126.2, 123.0, 118.2, 114.6, 113.6, 111.7, 102.5,
67.9, 55.6, 49.5, 43.5, 24.2. HRMS (ESI+) calcd for [C18H18ClNO3+H]+ 332.1053,
found: 332.1061.
N-(4-chlorophenyl)-6-methoxy-2,3,3a,9a-tetrahydro-4H-furo[2,3-
b]chromen-4-amine (trans)(3jb)
White solid. 1H NMR (300 MHz, CDCl3) δ 7.17 (d, J = 4.5 Hz, 2H), 6.91-6.81
(m, 2H), 6.77 (s, 1H), 6.58 (d, J = 4.5 Hz, 2H), 5.64 (s, 1H), 4.43 (s, 1H), 4.04-
3.99 (m, 1H), 3.96-3.92 (m, 2H), 3.74 (s, 3H), 2.92-2.84 (m, 1H), 2.19-2.12 (m,
1H), 1.69-1.67 (m, 1H). 13C NMR (75 MHz, CDCl3) δ 154.5, 146.2, 144.9, 129.3,
123.1, 122.7, 118.6, 115.7, 114.2, 113.8, 100.4, 67.6, 55.7, 51.4, 43.6, 27.5.
HRMS (ESI+) calcd for [C18H18ClNO3+H]+ 332.1053, found: 332.1056.
6-methoxy-N-(p-tolyl)-2,3,3a,9a-tetrahydro-4H-furo[2,3-b]chromen-4-
amine (cis)(3ka)
White solid. 1H NMR (300 MHz, CDCl3) δ 7.04 (d, J = 7.8 Hz, 2H), 6.97-6.96
(m, 1H), 6.88 (d, J = 8.7 Hz, 1H), 6.77-6.73 (m, 1H), 6.67 (d, J = 8.1 Hz, 2H),
5.85 (d, J = 5.7 Hz, 1H), 4.89 (s, 1H), 3.91-3.79 (m, 2H), 3.73 (s, 3H), 3.69 (brs,
1H), 3.16-3.06 (m, 1H), 2.28 (s, 3H), 1.94-1.83 (m, 1H), 1.65-1.52 (m, 1H). 13C
NMR (75 MHz, CDCl3) δ 154.8, 146.7, 144.6, 130.1, 127.8, 126.7, 118.0, 113.9,
113.7, 111.7, 102.6, 67.9, 55.7, 49.6, 43.4, 24.2, 20.4. HRMS (ESI+) calcd for
[C19H21NO3+H]+ 312.1600, found: 312.1597.
6-methoxy-N-(p-tolyl)-2,3,3a,9a-tetrahydro-4H-furo[2,3-b]chromen-4-
amine (trans)(3kb)
White solid. 1H NMR (300 MHz, CDCl3) δ 7.04 (d, J = 8.1 Hz, 2H), 6.91-6.80
(m, 3H), 6.59 (d, J = 7.8 Hz, 2H), 5.64 (d, J = 4.8 Hz, 1H), 4.46 (s, 1H), 4.04-
3.89 (m, 2H), 3.81 (s, 1H), 3.74 (s, 3H), 2.92-2.90 (m, 1H), 2.67 (s, 3H), 2.21-
2.15 (m, 1H), 1.76-1.63 (m, 1H). 13C NMR (75 MHz, CDCl3) δ 154.4, 146.3, 144.1,
130.0, 127.5, 123.5, 118.5, 115.7, 113.8, 113.4, 100.4, 67.7, 55.7, 51.5, 43.7,
27.4, 20.4. [C19H21NO3+H]+ 312.1600, found: 312.1599.
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European Journal of Organic Chemistry
1-(4-(phenylamino)chroman-2-yl)pyrrolidin-2-one (cis)(3la)
White solid. 1H NMR (300 MHz, CDCl3) δ 7.47 (d, J = 7.5 Hz, 1H), 7.23-7.15
(m, 3H), 6.94-6.82 (m, 2H), 6.78-6.67 (m, 3H), 6.07 (d, J = 11.4 Hz, 1H), 5.04-
4.99 (m, 1H), 3.77 (brs, 1H), 3.65-3.58 (m, 1H), 3.44-3.36 (m, 1H), 2.49-2.44
13
(m, 3H), 2.12-1.89 (m, 3H). C NMR (75 MHz, CDCl3) δ 175.5, 154.0, 146.9,
129.6, 129.0, 126.8, 124.0, 121.3, 118.2, 116.9, 113.3, 77.33, 48.9, 42.0, 32.9,
31.3, 18.0. HRMS (ESI+) calcd for [C19H20N2O2+H]+ 309.1603, found: 309.1609.
1-(4-(phenylamino)chroman-2-yl)pyrrolidin-2-one (cis)(3lb)
1
White solid. H NMR (300 MHz, CDCl3) δ 7.25-7.19 (m, 4H), 6.96-6.87 (m,
2H), 6.77-6.73 (m, 1H), 6.66 (d, J = 7.8 Hz, 2H), 5.98 (d, J = 10.5 Hz, 1H), 4.73
(s, 1H), 4.04 (brs, 1H), 3.67-3.59 (m, 1H), 3.49-3.41 (m, 1H), 2.52-2.43 (m,
2H), 2.30-2.22 (m, 1H), 2.17-2.04 (m, 3H). 13C NMR (75 MHz, CDCl3) δ 175.7,
154.3, 145.8, 130.2, 129.5, 129.4, 121.4, 121.2, 117.9, 117.4, 112.7, 74.7, 47.8,
42.6, 31.3, 30.6, 18.0. HRMS (ESI+) calcd for [C19H20N2O2+H]+ 309.1603, found:
309.1610.
2-ethoxy-N-phenylchroman-4-amine (cis)(3ma)
White solid. 1H NMR (300 MHz, CDCl3) δ 7.44 (d, J = 7.8 Hz, 1H), 7.26-7.19
(m, 3H), 6.96-6.87 (m, 2H), 6.78-6.72 (m, 3H), 5.30-5.28 (m, 1H), 4.95-4.91
(m, 1H), 4.00-3.90 (m, 1H), 3.72-3.62 (m, 1H), 3.44 (brs, 1H), 2.42-2.34 (m,
13
1H), 2.05-1.95 (m, 1H), 1.24 (t, J = 6.9 Hz, 3H). C NMR (75 MHz, CDCl3) δ
152.2, 147.1, 129.4, 128.8, 127.6, 124.9, 121.0, 117.8, 117.0, 113.1, 97.5, 64.2,
45.2, 33.5, 15.1. HRMS (ESI+) calcd for [C17H19NO2+H]+ 270.1494, found:
270.1502.
2-ethoxy-N-phenylchroman-4-amine (trans) (3mb)
White solid. 1H NMR (300 MHz, CDCl3) δ 7.38 (d, J = 7.8 Hz, 1H), 7.25-7.19
(m, 3H), 6.97-6.89 (m, 2H), 6.79-6.72 (m, 3H), 5.37-5.36 (m, 1H), 4.69-4.68
(m, 1H), 4.13 (brs, 1H), 3.95-3.84 (m, 1H), 3.63-3.53 (m, 1H), 2.41-2.35 (m,
13
1H), 2.22-2.15 (m, 1H), 1.21 (t, J = 6.9 Hz, 3H). C NMR (75 MHz, CDCl3) δ
151.2, 147.3, 130.1, 129.3, 128.9, 124.1, 121.3, 117.9, 117.4, 114.2, 97.2, 64.2,
45.6, 31.6, 15.1. HRMS (ESI+) calcd for [C17H19NO2+H]+ 270.1494, found:
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10.1002/ejoc.201700634
European Journal of Organic Chemistry
270.1502.
General Procedure C for one-pot formation of furanobenzopyrans
Batch mode
A dry round-bottomed flask, taken from the oven was filled with argon. Then
salicylaldehyde (2 mmol), aryl amine (2 mmol), TrBF4 (1 mol%) and 4 Å
molecular sieves (5 beads) were transferred into the flask in a glovebox. Freshly
distilled anhydrous THF (5 ml) and electron rich alkene 2 (4 mmol) were added
by syringe and the reaction mixture was stirred at room temperature. After 10
min, the reaction mixture was passed through a short plug of SiO2 and the solvent
removed under vacuum. The residue was purified by column chromatography on
silica gel with petroleum ether and ethyl acetate as eluent to give the product.
Micro-flow mode
Solution A (1.104 M of salicylaldehyde in THF) and Solution B (1.104 M of
aniline in THF) were pumped into the flow reactor via two pumps (the pumps are
part of the Vapourtec Microreactor), then they were mixed in a Y-shaped mixer.
The combined mixture went through a 10 mL reactor at 60 °C。After a residence
time of 4min, the resulting imine solution was combined with Solution C (1 mol%
of tritylium tetrafluoroborate, and 1.104 M of 2,3-dihydrofuran in THF) in a second
mixer, before the solution went through a 10 mL reactor at 25℃。After a residence
time of 1 min，the reaction mixture was passed through a short plug of SiO2 and
the solvent removed under vacuum. The residue was purified by column
chromatography on silica gel with petroleum ether and ethyl acetate as eluent to
give the product.
Associated content
Supporting Information
Materials and apparatus, general experimental procedure and respective scanned
spectra (1H- and 13C NMR) of all the synthesized compounds.
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10.1002/ejoc.201700634
European Journal of Organic Chemistry
This Supporting Information is available free of charge on the ACS Publications
website at DOI:
Acknowledgements
The authors thank the National Natural Science Foundation of China (U1463201,
21522604), Natural Science Foundation of Jiangsu Province, China (BK20150031),
Jiangsu National Synergetic Innovation Center for Advanced Materials (SICAM),
and the Project Funded by the Priority Academic Program Development of Jiangsu
Higher Education Institutions (PAPD) for financial supports.
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