Asymmetric organocatalytic quadruple cascade reaction of 2-hydroxychalcone with cinnamaldehyde for the construction of tetrahydro-6H-benzo[c]chromene containing five stereocenters

Article abstract of DOI:10.1002/ejoc.201402159

An asymmetric organocatalytic quadruple cascade reaction was developed for the stable and sterically hindered 2-hydroxychalcones and substituted cinnamaldehydes. This process proceeded through an oxa-Michael-Michael-Michael- aldol condensation to afford h

Full text of DOI:10.1002/ejoc.201402159

FULL PAPER
DOI: 10.1002/ejoc.201402159
Asymmetric Organocatalytic Quadruple Cascade Reaction of
2-Hydroxychalcone with Cinnamaldehyde for the Construction of Tetrahydro-
6H-benzo[c]chromene Containing Five Stereocenters
Lingyan Liu,*[a] Yunna Zhu,[a] Kaimeng Huang,[a] Bing Wang,[a] Weixing Chang,[a] and
Jing Li*[a]
Keywords: Asymmetric synthesis / Organocatalysis / Domino reactions / Oxygen heterocycles / Enantioselectivity
An asymmetric organocatalytic quadruple cascade reaction
was developed for the stable and sterically hindered 2-hy-
droxychalcones and substituted cinnamaldehydes. This pro-
cess proceeded through an oxa-Michael–Michael–Michael–
aldol condensation to afford highly functionalized tetra-
hydro-6H-benzo[c]chromene derivatives with high dia-
stereoselectivity and enantioselectivity (Ͼ99 %ee). The
structure of adduct 4g with five stereocenters was unambigu-
ously confirmed by single-crystal X-ray diffraction, and valu-
able mass spectrometry data provided direct support for the
proposed reaction mechanism.
activated cinammaldehydes, α,β-unsaturated esters, nitro-
alkenes, and o-hydroxy- or o-thio-substituted aromatic alde-
hydes (see Figure 2).[4] Moreover, these reactions usually af-
ford a chromane or thiochromane as a binary fused hetero-
cycle with less than three chiral centers, which is formed
through an oxa- or sulfa-Michael–Michael or -Michael–
aldol cascade reaction. A higher order cascade reaction has
hardly been reported in which more than a ternary fused
Introduction
Chalcone is an α,β-unsaturated carbonyl compound with
an aromatic ring at each end, and these aromatic rings, the
double bond, and the carbonyl unit can be converted into
other functional groups to provide enriched structures and
diverse compounds. Hence, chalcone is an important build-
ing block in organic synthesis and has a wide potential of
applications.[1] Despite this, little research has been done
on chalcones because of their low activity and high steric
hindrance. Most reports of the last few decades mainly fo-
cus on the simple asymmetric Michael reaction of chalc-
ones.[2] To date, higher order asymmetric cascade reactions
of the stable chalcone substrate still remain virtually unex-
plored.
Optically active chiral oxygen- and sulfur-containing
compounds, especially chromanes and thiochromanes (see
Figure 1), have important applications in many areas of
chemistry and biology.[3] Therefore, the exploration of new
and facile synthetic strategies to access such heterocycles
has attracted intense attention. Vast efforts have been de-
voted to enantioselective cascade reactions to construct
these heterocyclic compounds as a result of the exploration
and proliferation of organocatalyzed reactions. However,
the scope of the substrates for these reactions is limited to
Figure 1. Examples of oxygen-containing natural products.
[a] State Key Laboratory of Elemento-Organic Chemistry,
The College of Chemistry, Nankai University, Collaborative
Innovation Center of Chemical Science and Engineering
(Tianjin)
Weijin Road 94#, Nankai District, Tianjin 300071, P. R. China
E-mail: lijing@nankai.edu.cn
liulingyan@mail.nankai.edu.cn
http://skleoc.nankai.edu.cn/professors/Lij/index.html
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402159.
Figure 2. Previously reported substrate types.
4342
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Asymmetric Organocatalytic Quadruple Cascade Reaction
Scheme 1. Organocatalytic enantioselective oxa-Michael–Michael–Michael–aldol cascade reaction.
heterocycle ring is formed with more than three consecutive in similar asymmetric cascade reactions that have been pre-
chiral stereocenters. To the best of our knowledge, there is viously reported, whereas product such as 4a is difficult to
only one report of a ternary fused cyclic compound that is generate.[4] In the presence of (S)-2-[(diphenylphosphoryl)-
derived from an activated 2-[(E)-2-nitrovinyl]phenol.[5]
methyl]pyrrolidine (A), which displays excellent catalytic ac-
In view of that, it is of considerable interest and a great tivity in the asymmetric Michael addition of a cycloketone
challenge to develop new and simple synthetic methodology and chalcone,[6b] product 3a was mainly obtained but with
for chalcone derivatives in the construction of multiply a low enantioselectivity (28 %ee; see Table 1, Entry 1).
fused oxygen-containing heterocycles. As a continuation of When the privileged chiral organocatalyst (R)-2-[di-
our ongoing work to explore new cascade reactions that are phenyl(trimethylsilyloxy)methyl]pyrrolidine[7] was used, the
catalyzed by organocatalysts,[6] we herein report the enan- enantiomeric excess value of 3a drastically improved to
tioselective synthesis of a tetrahydro-6H-benzo[c]chromene 93 %ee, but the yield was unsatisfactory (see Table 1, En-
with five contiguous stereocenters. This approach uses try 2). Surprisingly, when the absolute configuration of the
chalcone as the starting material and proceeds through a privileged catalyst was changed from the (R) to the (S) iso-
domino oxa-Michael–Michael–Michael–aldol condensation mer, no reaction occurred under the same reaction condi-
reaction (see Scheme 1).
tions (see Table 1, Entry 3). Nevertheless, when the Lewis
base Et3N was used as an additive, the reaction smoothly
proceeded again in the presence of the (S)-isomer of the
chiral catalyst to result in the good conversion of 3a and 4a
Results and Discussion
In our initial study, various organocatalysts were exam- (33 and 33 %, respectively) with an excellent enantiomeric
ined in the reaction of the simple 2-hydroxychalcone and excess value (97 %ee) for product 3a (see Table 1, Entry 4).
cinnamaldehyde under the standard reaction conditions An explanation for this phenomenon remains unclear.
(room temperature, toluene, 20 mol-% of organocatalyst, However, (S)-2-[diphenyl(trimethylsilyloxy)methyl]pyrrol-
and 20 mol-% of additive). As shown in Table 1, this reac- idine was considered as the optimum chiral catalyst.
tion generally afforded a complex mixture of products 3a
Next, the experimental parameters, which included the
and 4a. Noteworthy, product such as 3a is usually obtained solvent and additive, were carefully investigated (see
Table 1. The screening of organocatalysts in the reaction of chalcone and cinnamaldehyde.[a]
Entry
Catalyst
Additive
Conv. 3a [%][b]
Conv. 4a [%][b]
% ee 3a[c]
1
2
3
4
A
B
C
C
PhCOOH
PhCOOH
PhCOOH
Et3N
36
20
trace
33
14
13
trace
33
28
93
–
97
[a] Into a Schlenk tube were added toluene (0.5 mL), cinnamaldehyde (26.4 mg, 0.2 mmol), and the organocatalyst (0.04 mmol, 0.2 equiv.),
and the mixture was stirred at room temperature for 10 min. 2-Hydroxychalcone (67.2 mg, 0.3 mmol) and the additive (0.04 mmol,
1
0.2 equiv.) were then added. The reaction was monitored by thin layer chromatography. [b] The conversion was calculated by H NMR
analysis. [c] The enantiomeric excess value was determined by chiral HPLC analysis.
Eur. J. Org. Chem. 2014, 4342–4350
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L. Liu, Y. Zhu, K. Huang, B. Wang, W. Chang, J. Li
FULL PAPER
Table 2). As a result, this reaction preferentially afforded substrate was used in an excess amount relative to the 2-
product 3a in 57 % conversion with 97 %ee by using CHCl3 hydroxychalcone. As expected, there was more product 4a
instead of toluene (see Table 2, Entry 1 vs. Table 1, Entry 4). than 3a after 72 h (see Table 3, Entry 3). To our delight,
When a stronger Lewis base such as 4-(dimethylamino)pyr- only product 4a was obtained by using the highly active
idine (DMAP) was employed, the conversion rate of both 2-hydroxy-4Ј-(trifluoromethyl)chalcone as the substrate (see
3a and 4a slightly increased with a reduced reaction time Table 3, Entry 4).
(see Table 2, entry 2). When the amount of the organocata-
Encouraged by the above results, we then selected 2-hy-
lyst was decreased, the reaction proceeded poorly with low droxy-4Ј-(trifluoromethyl)chalcone as the model substrate.
conversion even after a prolonged reaction time (see Because of the effect of solvation on the regio- and enantio-
Table 2, Entry 3). In the absence of an additive, the reaction selectivity, the solvent of this cascade reaction was again
yield decreased (see Table 2, Entry 4). Therefore, the opti- examined (see Table 4). The reaction afforded the ternary
mal reaction conditions involved 20 mol-% of (S)-2-[di- fused oxygen-containing heterocyclic compounds in moder-
phenyl(trimethylsilyloxy)methyl]pyrrolidine and 20 mol-% ate yields with excellent enantiomeric excess values
of DMAP in CHCl3 (0.4 m).
(Ͼ99 %ee) by using weakly polar or nonpolar solvents such
Because a complex mixture of 3a and 4a was always ob- as CHCl3, toluene, and CH2Cl2 (see Table 4, Entries 1–3).
tained, even with an excess amount of 2-hydroxychalcone, However, the reaction could hardly proceed in the strongly
we attempted to adjust the ratio between 2-hydroxychalc- polar solvents of CH3OH, CH3CN, and N,N-dimethylform-
one (1a) and cinnamaldehyde (2a) to achieve a single prod- amide (DMF; see Table 4, Entries 4–6). Therefore, both tol-
uct. Theoretically, product 4a is generated from compound uene and CHCl3 were two suitable solvents for this reac-
3a and cinnamaldehyde. Thus, the reaction time was first tion. Toluene was the better solvent in the presence of
prolonged from 36 to 72 h. Part of 3a was indeed further DMAP as the additive, whereas CHCl3 was preferable when
transformed into 4a (see Table 3, Entries 1 and 2), as there Et3N was used as the additive. Thus, the combination of
were nearly equal amounts of 3a and 4a. Inspired by this, CHCl3 with Et3N was identified to be optimal combination.
we changed the raw ratio of 2-hydroxychalcone and cinna-
The effect of the additive on the reaction was then fine-
maldehyde from 1.5:1 to 1:3. Namely, the cinnamaldehyde tuned. As shown in Table 5, when the secondary amine
Table 2. The effects of the solvent and additive on the reaction of 2-hydroxychalcone and cinnamaldehyde.
Entry
Solvent
Additive
Time [h]
Conv. 3a [%][a]
Conv. 4a [%][a]
% ee 3a[b]
1
CHCl3
CHCl3
CHCl3
CHCl3
Et3N
DMAP
DMAP
–
48
36
72
36
57
59
30
44
15
18
22
7
97
96
97
97
2
3[c]
4
[a] The conversion rate was calculated by the 1H NMR analysis. [b] The enantiomeric excess value was determined by chiral HPLC
analysis. [c] The loading of organocatalyst was 15 mol-%.
Table 3. Screening for the ratio of substrates in the reaction of 2-hydroxychalcone and cinnamaldehyde.
Entry
1/2
Time [h]
3a/4a[a]
1
2
1.5:1
1.5:1
1:3
36
72
72
72
3a Ͼ 4a
3a = 4a
3a Ͻ 4a
4b
3
4[b]
1:3
1
[a] The ratio was determined by H NMR analysis. [b] The substrate was 2-hydroxy-4Ј-(trifluoromethyl)chalcone.
4344 Eur. J. Org. Chem. 2014, 4342–4350
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Asymmetric Organocatalytic Quadruple Cascade Reaction
Table 4. The effect of solvent on the asymmetric cascade reaction of 2-hydroxy-4Ј-(trifluoromethyl)chalcone and cinnamaldehyde.[a]
Entry
Solvent
% Yield[b]
% ee 4b[c]
1
2
3
4
CHCl3
toluene
CH2Cl2
CH3OH
CH3CN
DMF
47
65
54
trace
trace
trace
61
Ͼ99
Ͼ99
Ͼ99
–
–
–
5
6
7[d]
8[d]
toluene
CHCl3
Ͼ99
Ͼ99
67
[a] Into a Schlenk tube were added solvent (0.5 mL), cinnamaldehyde (79 mg, 0.6 mmol), and (S)-2-[diphenyl(trimethylsilyloxy)methyl]-
pyrrolidine (0.04 mmol, 0.2 equiv.), and the mixture was stirred at room temperature for 10 min. 2-Hydroxy-4Ј-(trifluoromethyl)chalcone
(58.5 mg, 0.2 mmol) and DMAP (0.04 mmol, 0.2 equiv.) were then added. The reaction was monitored by TLC. Upon completion, the
mixture was purified by chromatography on a silica gel column (n-hexane/ethyl acetate) to afford the product. [b] Isolated yield. [c] The
ee value was determined by chiral HPLC analysis (Chiralpak AS-H and AD-H columns). [d] The additive was Et3N.
Et2NH was employed, the ee value remained excellent, but mal reaction conditions with a variety of α,β-unsaturated
the yield of product decreased slightly (see Table 5, En- aldehydes and 2-hydroxychalcone derivatives. As shown in
try 2). In the presence of iPr2NEt, no obvious improvement Table 6, all reactions proceeded in 72 h to give products in
was observed (see Table 5, Entry 3). The reaction proceeded moderate to good yields (15–74 %) with excellent levels of
poorly without a Lewis base, although the enantio- enantioselectivity (Ͼ99 %). The process appeared to have a
selectivity of the product was still excellent (see Table 5, En- certain scope of substrates, and the reaction efficiencies var-
try 4). On the other hand, when the reaction temperature ied with the electronic and steric features of the 2-hydroxy-
was increased to 35 °C, the product was obtained in a lower chalcone derivatives 1 and α,β-unsaturated aldehydes 2. The
yield (see Table 5, Entry 5). Hence, the optimal reaction 2-hydroxychalcones 1 with different electron-withdrawing
conditions employed CHCl3 as the solvent, a chalcone 1 to groups at the same position, such as 4Ј-trifluoromethyl, 4Ј-
cinnamaldehyde 2 ratio of 1:3, 20 mol-% of Et3N, and fluro, and 4Ј-nitro group (R2 = 4-CF3, 4-F, 4-NO2), gave
20 mol-% of (S)-2-[diphenyl(trimethylsilyloxy)methyl]pyr- entirely different reaction results. For example, when R2 was
rolidine at room temperature.
4Ј-CF3, the reaction proceeded satisfactorily to give ternary
The scope of the tandem oxa-Michael–Michael– fused oxygen-containing heterocyclic compound 4b in good
Michael–aldol process was next examined under the opti- yield with an excellent ee value (see Table 6, Entry 1). With
Table 5. The screening of additives in the asymmetric cascade reaction.
Entry
Additive
% Yield[a]
% ee 4b[b]
1
2
3
Et3N
Et2NH
(iPr)2NEt
–
67
60
66
18
57
Ͼ99
Ͼ99
Ͼ99
Ͼ99
Ͼ99
4
5[c]
Et3N
[a] Isolated yield. [b] The ee value was determined by chiral HPLC analysis. [c] The reaction temperature was 35 °C.
Eur. J. Org. Chem. 2014, 4342–4350
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L. Liu, Y. Zhu, K. Huang, B. Wang, W. Chang, J. Li
Table 6. The asymmetric cascade reactions of various substituted chalcones and cinnamaldehydes.[a]
FULL PAPER
Entry
Substrate
Product
% Yield[b]
% ee 4[c]
1
R1 = H, R2 = 4-CF3, R3 = H
R1 = H, R2 = 4-F, R3 = H
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
67
15
Ͼ99
Ͼ99
–
2[d]
3
R1 = H, R2 = 4-NO2, R3 = H
R1 = H, R2 = 3-CF3, R3 = H
R1 = H, R2 = 4-CF3, R3 = 4-Br
R1 = H, R2 = 4-CF3, R3 = 4-Cl
R1 = H, R2 = 4-CF3, R3 = 3-CH3
R1 = H, R2 = 4-CF3, R3 = 4-N(CH3)2
R1 = 5-F, R2 = 4-CF3, R3 = H
R1 = 5-F, R2 = 4-CF3, R3 = 4-Br
R1 = 5-F, R2 = 4-CF3, R3 = 3-CH3
R1 = 3-F, R2 = 4-CF3, R3 = 4-Br
R1 = 3-F, R2 = 4-CF3, R3 = H
n.r.[e]
trace
54
4
5
6
7
8
9
10
11
12
13
–
Ͼ99
Ͼ99
Ͼ99
–
Ͼ99
Ͼ99
Ͼ99
–
49
44
n.r
74
66
70
n.r.
n.r.
–
[a] Into a Schlenk tube were added CHCl3 (0.5 mL), cinnamaldehyde (0.6 mmol), (S)-2-[diphenyl(trimethylsilyloxy)methyl]pyrrolidine
(0.04 mmol, 0.2 equiv.), and the mixture was stirred at room temperature for 10 min. The 2-hydroxychalcone (0.2 mmol) and Et3N
(0.04 mmol, 0.2 equiv.) were then added. The reaction was monitored by TLC. Upon completion, the mixture was purified by chromatog-
raphy on a silica gel column (n-hexane/ethyl acetate) to afford the product. [b] Isolated yield. [c] The ee value was determined by chiral
1
HPLC analysis. [d] The reaction conversion was determined by H NMR spectroscopic analysis. [e] n.r.: no reaction.
the relatively weak electron-withdrawing fluoro group (R2
= 4Ј-F), the reaction provided a complex mixture of prod-
ucts 3c and 4c (conversion 15 %), although the enantio-
selectivity remained excellent (see Table 6, Entry 2). For the
4Ј-nitro-2-hydroxychalcone substrate, with the strong elec-
tron-withdrawing group, the reaction could hardly proceed
(see Table 6, Entry 3). This demonstrated that fine-tuning
the electronic nature of the chalcone substrate would have
a large influence on this reaction. Changing the R2 substitu-
tion position from the 4Ј-CF3 to 3Ј-CF3 led to a trace
amount of the target compound (see Table 6, Entry 4). The
reactions with chalcone substrate 1b (R1 = H, R2 = 4Ј-CF3)
and various substituted cinnamaldehydes proceeded
smoothly (see Table 6, Entries 5–7). Having electron-with-
drawing (R3 = 4-Br, 4-Cl) and electron-donating (R3 = 3-
CH3) substituents on the cinnamaldehyde and changing
their position of substitution on the aryl ring gave products
Figure 4. The HRMS spectra of the intermediates I (top) and II
Figure 3. ORTEP plot for X-ray crystal structure of 4g.
4346
(bottom).
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Asymmetric Organocatalytic Quadruple Cascade Reaction
in moderate to good yields with nearly quantitative enantio- is (6R,6aS,9S,10S,10aS)-6,9-bis(4-chlorophenyl)-10[4-(tri-
meric excess values. However, when R3 was 4-N(CH3)2, no fluoromethyl)benzoyl]-6a,9,10,10a-tetrahydro-6H-benzo[c]-
reaction occurred (see Table 6, Entry 8). As chalcone has chromene-8-carbaldehyde (see Figure 3).[8]
two aryl rings, we attempted to change the other aryl ring,
With regard to the mechanism of this tandem oxa-
next to the double bond, by introducing a fluoro group at Michael–Michael–Michael–aldol quadruple reaction, we
the 5-position. It was encouraging that the reactions be- failed to monitor for intermediates I and II by NMR spec-
tween the 5-fluoro-2-hydroxy-4Ј-(trifluoromethyl)chalcone troscopy. By HRMS analysis, we observed the rapid forma-
and various substituted cinnamaldehydes gave improved tion of iminium ion intermediate I and the subsequent oxa-
yields up to 74 % (see Table 6, Entries 9–11). When the Michael–Michael adduct with the activation of iminium ion
fluoro position was changed from 5- to 3-F, that is, 3- II (see Figure 4). On the basis of this, we proposed the
fluoro-2-hydroxy-4Ј-(trifluoromethyl)chalcone, no reaction probable reaction mechanism (see Scheme 2). First, the
was observed (see Table 6, Entries 12 and 13). It was further cinnamaldehyde is activated by the chiral catalyst (S)-2-[di-
inferred that the position of the substitutent on the aryl phenyl(trimethylsilyloxy)methyl]pyrrolidine to form imin-
ring of chalcone was also a key factor. The above results ium ion intermediate
I
[HRMS (found): 518.1509
indicate that both the electronic and steric qualities of the (518.1502); see Figure 4 (top)]. The hydroxy group of 2-hy-
substitutents of 2-hydroxy-α,β-unsaturated ketones 1 dra- droxychalcone 1 then attacks the α-carbon atom on the re
matically affected the reaction yields, whereas the substitu- face of intermediate I through an oxa-Michael reaction that
ents of α,β-unsaturated aldehydes 2 had a small effect on is accompanied by a Michael addition between the β-car-
the reaction.
bon atom of the cinnamaldehyde moiety and the α-carbon
To determine the absolute configuration of the cascade atom of the chalcone moiety to give intermediate II [HRMS
reaction products, single-crystal structure analysis was car- (found): 828.2126 (828.2118); see Figure 4 (bottom)]. The
ried out by X-ray diffraction. For example, the absolute carbon anion of intermediate II then undergoes a reaction
configurations of the five stereocenters of product 4g were with a second activated iminium ion I through a Michael
determined to be (R) for C-7, (S) for C-8, (S) for C-11, (S) addition and subsequent intramolecular aldol condensation
for C-12, and (S) for C-13, and the name of this compound to obtain intermediate III, whereupon the catalyst is re-
Scheme 2. Proposed mechanism for the cascade reaction.
Eur. J. Org. Chem. 2014, 4342–4350
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4347

L. Liu, Y. Zhu, K. Huang, B. Wang, W. Chang, J. Li
FULL PAPER
The mass spectrometry was performed with a Thermo-Finnigan
LCQ-Advantage instrument.
leased for the next cycle along with the formation of com-
pound 4. For this cascade reaction, it is essential to use a
slight excess amount of 2 (e.g., 1/2, 1:3).
Standard Procedure for the Cascade Reactions of Cinnamaldehydes
and 2-Hydroxy-4Ј-(trifluoromethyl)chalcones: To a Schlenk tube
were sequentially added chloroform (0.5 mL), the cinnamaldehyde
2 (0.6 mmol, 3.0 equiv.), and (S)-2-[diphenyl(trimethylsilyloxy)-
methyl]pyrrolidine (0.04 mmol, 0.2 equiv.), and the mixture was
stirred for 10 min. The 2-hydroxy-4Ј-(trifluoromethyl)chalcones
(0.2 mmol, 1.0 equiv.) and the base additive Et3N (0.04 mmol,
0.2 equiv.) were then added. The reaction was monitored by TLC.
Upon completion, the reaction mixture was purified by chromatog-
raphy on a silica gel column to afford the desired cascade reaction
products. The enantiomeric excess value was determined by the
HPLC analysis. The procedure for racemic samples was similar to
the above reaction conditions, with the exception of using racemic
2-[diphenyl(trimethylsilyloxy)methyl]pyrrolidine instead.
From the above experimental data, we could draw some
conclusions. First, the scope of substrates for this quadruple
cascade reaction is relatively limited. Second, the Michael
reaction in the third step is the key process to construct the
ternary fused ring compound. Specifically, the carbon
anion of intermediate II must be sufficiently nucleophilic to
attack the second molecule of intermediate I, that is, the
cinnamaldehyde that was activated by the organocatalyst.
Thus, fine-tuning the substituents on the chalcone by their
electronic nature and position would dramatically influence
this cascade reaction, and thus explains the limited sub-
strate scope. Finally, the 2-hydroxychalcone with R2 = 4-
CF3 was the only substrate for which this cascade reaction
could occur and afford a sole ternary fused ring product. It
is surmised that the electron-withdrawing –CF3 substituent
on the chalcone could indirectly stabilize the carbon anion
of intermediate II to proceed with the third step of the reac-
tion mechanism.
Characterization Data of the Cascade Reaction Products
4-(2-Oxo-2-phenylethyl)-2-phenylchroman-3-carbaldehyde (3a): Yel-
1
low oil (conversion 57 %). H NMR (300 MHz, CDCl3): δ = 9.54
(d, J = 1.6 Hz, 1 H), 7.69 (d, J = 7.8 Hz, 2 H), 7.48–7.43 (m, 2 H),
7.37–7.22 (m, 6 H), 7.13–7.04 (m, 2 H), 6.95–6.84 (m, 2 H), 5.32
(d, J = 7.2 Hz, 1 H), 4.12 (dd, J = 12.3, 6.9 Hz, 1 H), 4.12 (dd, J
= 12.3, 6.9 Hz, 1 H), 3.27 (dd, J = 6.9, 5.4 Hz, 1 H), 3.13 (dd, J =
17.9, 6.3 Hz, 2 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 200.79,
198.42, 154.35, 139.03, 136.59, 133.52, 129.09, 128.69, 128.57,
128.52, 128.22, 128.05, 126.45, 124.05, 121.82, 117.54, 76.42, 56.32,
44.31, 30.29 ppm. MS (ESI): calcd. for C24H20O3 [M – H]– 355.133;
found 355.098. The enantiomeric excess value of Ͼ97 % was deter-
mined by HPLC analysis. HPLC (Daicel Chiralpak AD; iPrOH/
Conclusions
In summary, we have developed a highly diastereoselec-
tive and enantioselective organocatalytic process that pro-
ceeds through an oxa-Michael–Michael–Michael–aldol
quadruple cascade reaction to construct a ternary fused
ring compound. The stable and largely sterically hindered
substituted 2-hydroxychalcones were easily prepared and
employed as a challenging starting material. Four new
bonds and five stereocenters were constructed in the one-
pot reaction, which provided expedited access to highly en-
antiomerically enriched tetrahydro-6H-benzo[c]chromenes
with a substantial diversity of substituents in moderate to
good yields with excellent enantiomeric excess values
(Ͼ99 %ee). The structure of adduct 4g was confirmed by
hexane, 5:95; wavelength: 254 nm; flow rate: 1.0 mLmin–1): tR
=
24.56 min (major), tR = 28.08 min (minor). (Because of the diffi-
cultly isolating 3a from the complex of 3a and 4a, the characteriza-
tion of 3a was determined by comparing the corresponding 1H
NMR of the racemic product with the 1H NMR of the complex
of 3a and 4a. The conversion of 3a was calculated by 1H NMR
spectroscopic analysis. For 4a, we failed to obtain its racemic sam-
ple. Thus, the characterization of 4a cannot be reported at the pres-
ent time.).
(6R,6aS,9S,10S,10aS)-6,9-Diphenyl-10-[4-(trifluoromethyl)benzoyl]-
6a,9,10,10a-tetrahydro-6H-benzo[c]chromene-8-carbaldehyde (4b):
X-ray diffraction analysis. Furthermore, a probable reaction White solid (72 mg, 67 % yield); m.p. 190–191 °C. [α]2D0 = –162 (c
= 0.77, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 9.21 (s, 1 H),
mechanism was proposed on the basis of evidence from
HRMS data. Further applications of this approach for the
total syntheses of natural products and pharmaceutical
agents are currently under active investigation.
8.10 (d, J = 8.1 Hz, 2 H), 7.79 (d, J = 8.2 Hz, 2 H), 7.55 (d, J =
7.2 Hz, 2 H), 7.50–7.41 (m, 3 H), 7.35 (t, J = 7.5 Hz, 2 H), 7.30–
7.14 (m, 3 H), 7.01 (t, J = 7.6 Hz, 1 H), 6.83 (d, J = 8.1 Hz, 1 H),
6.70 (d, J = 7.6 Hz, 1 H), 6.64–6.53 (m, 2 H), 5.09 (d, J = 10.6 Hz,
1 H), 4.46 (d, J = 3.7 Hz, 1 H), 4.13 (s, 1 H), 3.96 (t, J = 10.8 Hz,
1 H), 3.54 (dd, J = 11.1, 3.5 Hz, 1 H) ppm. 13C NMR (101 MHz,
CDCl3): δ = 199.18, 192.47, 155.06, 149.28, 142.11, 140.53, 139.55,
138.66, 135.24, 129.44, 129.22, 128.75, 128.39, 127.86, 127.56,
Experimental Section
1
General Methods: The H and 13C NMR spectroscopic data were
126.45, 126.42, 123.90, 123.09, 121.95, 120.54, 117.10, 83.63, 46.85,
recorded with a Bruker AV 300 or Varian mercury Plus 400. CDCl3
41.52, 40.42, 34.92 ppm. MS (ESI): calcd. for C34H25F3O3
was used as the solvent, and TMS was used as the internal stan-
[M – H]– 537.168; found 537.159. The enantiomeric excess value of
dard, unless otherwise noted. Chemical shifts are reported in ppm,
Ͼ99 % was determined by HPLC analysis. HPLC (Daicel Chi-
and coupling constants (J) are reported in Hz. The enantiomeric
excess values were determined by HPLC analysis by using Chi-
ralpak AS-H and AD-H columns (Daicel Chemical Ind., Ltd.) and
with n-hexane and isopropanol as eluents. All other solvents and
ralpak AD; iPrOH/hexane, 5:95; wavelength: 254 nm; flow rate:
1.0 mLmin–1): tR = 17.44 min (minor), tR = 21.22 min (major).
C34H22F3O3: calcd. C 75.83, H 4.68; found C 76.07, H 4.56.
commercially available reagents were used as received without fur-
ther purification, unless otherwise stated. Analytical thin layer
chromatography was performed using Merck 60 F254 precoated sil-
ica gel plates. After elution, the plates were visualized by UV radia-
tion (254 nm) with a Spectroline Model ENF-24061/F (254 nm).
(6R,6aS,9S,10S,10aS)-10-(4-Fluorobenzoyl)-6,9-diphenyl-6a,9,
10,10a-tetrahydro-6H-benzo[c]chromene-8-carbaldehyde (4c): White
solid (conversion 15 %). H NMR (400 MHz, CDCl3): δ = 9.21 (s,
1 H), 8.04 (dd, J = 8.7, 5.3 Hz, 2 H), 7.54 (d, J = 7.0 Hz, 2 H),
7.50–7.40 (m, 3 H), 7.34 (t, J = 7.5 Hz, 2 H), 7.30–7.15 (m, 7 H),
1
4348
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 4342–4350

Asymmetric Organocatalytic Quadruple Cascade Reaction
7.00 (t, J = 8.3 Hz, 1 H), 6.82 (d, J = 8.1 Hz, 1 H), 6.71 (d, J =
7.7 Hz, 1 H), 6.64–6.50 (m, 2 H), 5.09 (d, J = 10.6 Hz, 1 H), 4.41
6.89 (t, J = 12.6 Hz, 1 H), 6.79 (d, J = 7.6 Hz, 1 H), 6.72–6.62 (m,
2 H), 5.13 (d, J = 10.6 Hz, 1 H), 4.53 (d, J = 3.6 Hz, 1 H), 4.18 (s,
(d, J = 3.8 Hz, 1 H), 4.13 (s, 1 H), 4.00 (t, J = 10.9 Hz, 1 H), 3.51 1 H), 4.05 (t, J = 10.8 Hz, 1 H), 3.62 (dd, J = 11.1, 3.5 Hz, 1 H),
(dd, J = 11.1, 3.7 Hz, 1 H) ppm. 13C NMR (101 MHz, CDCl3): δ
2.49 (s, 3 H), 2.42 (s, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ
= 198.51, 192.63, 155.05, 149.43, 142.34, 140.67, 138.75, 131.17,
= 199.32, 192.59, 155.06, 149.34, 142.07, 140.50, 139.58, 139.10,
131.07, 129.38, 129.19, 128.30, 127.88, 127.74, 127.57, 126.44, 138.51, 135.18, 134.86, 130.25, 129.22, 129.02, 128.75, 128.64,
123.98, 123.33, 120.49, 117.01, 116.60, 116.38, 83.72, 46.27, 41.59, 128.35, 128.33, 128.27, 126.40, 125.12, 124.62, 123.94, 123.11,
40.62, 34.95 ppm. MS (ESI): calcd. for C33H25FO3 [M – H]–
488.179; found 487.057. The enantiomeric excess value of Ͼ99 %
122.29, 120.46, 117.07, 83.68, 46.86, 41.30, 40.34, 34.94, 21.84,
21.70 ppm. MS (ESI): calcd. for C36H29F3O3 [M – H]– 565.158;
was determined by HPLC analysis. HPLC (Daicel Chiralpak AD; found 565.141. The enantiomeric excess value of Ͼ99 % was deter-
iPrOH/hexane, 5:95; wavelength: 254 nm; flow rate: 1.0 mLmin–1):
tR = 17.24 min (minor), tR = 47.81 min (major). C33H25FO3: calcd.
C 81.13, H 5.16; found C 80.95, H 5.35. (In this case, we obtained
a complex of 3c and 4c, and they were difficult to separate by
column chromatography. Thus, the conversion was determined by
1H NMR analysis.)
mined by HPLC analysis. HPLC (Daicel Chiralpak AD; iPrOH/
hexane, 3:97; wavelength: 254 nm; flow rate: 1.0 mLmin–1): tR
=
10.02 min (minor), tR = 15.86 min (major). C36H29F3O3: calcd. C
76.31, H 5.16; found C 76.45, H 5.31.
(6R,6aS,9S,10S,10aS)-2-Fluoro-6,9-diphenyl-10-[4-(trifluorometh-
yl)benzoyl]-6a,9,10,10a-tetrahydro-6H-benzo[c]chromene-8-carb-
aldehyde (4j): White solid (83 mg, 74 % yield); m.p. 217–218 °C.
(6R,6aS,9S,10S,10aS)-6,9-Bis(4-bromophenyl)-10-[4-(trifluoro-
methyl)benzoyl]-6a,9,10,10a-tetrahydro-6H-benzo[c]chromene-8-
carbaldehyde (4f): White solid (75 mg, 54 % yield); m.p. 203–
204 °C. [α]2D0 = –112 (c = 1.46, CHCl3). 1H NMR (400 MHz,
1
[α]2D0 = –157 (c = 2.10, CHCl3). H NMR (400 MHz, CDCl3): δ =
9.28 (s, 1 H), 8.19 (d, J = 8.1 Hz, 2 H), 7.88 (d, J = 8.2 Hz, 2 H),
7.63 (d, J = 7.1 Hz, 2 H), 7.59–7.50 (m, 3 H), 7.44 (t, J = 7.4 Hz,
CDCl3): δ = 9.29 (s, 1 H), 8.13 (d, J = 7.6 Hz, 2 H), 7.86 (d, J = 2 H), 7.39–7.27 (m, 3 H), 6.85 (dd, J = 8.9, 4.9 Hz, 1 H), 6.77 (td,
7.7 Hz, 2 H), 7.69 (d, J = 7.7 Hz, 2 H), 7.52 (dd, J = 17.3, 7.8 Hz, J = 8.6, 2.5 Hz, 1 H), 6.65 (s, 1 H), 6.54–6.46 (m, 1 H), 5.15 (d, J
4 H), 7.22–7.02 (m, 3 H), 6.89 (d, J = 7.9 Hz, 1 H), 6.77 (d, J = = 10.5 Hz, 1 H), 4.45 (d, J = 3.2 Hz, 1 H), 4.25 (s, 1 H), 4.07 (t, J
7.1 Hz, 1 H), 6.70–6.64 (m, 2 H), 5.11 (d, J = 10.4 Hz, 1 H), 4.48
= 10.8 Hz, 1 H), 3.59 (dd, J = 11.1, 3.0 Hz, 1 H) ppm. 13C NMR
(s, 1 H), 4.13 (s, 1 H), 4.00 (t, J = 10.6 Hz, 1 H), 3.53 (d, J = (101 MHz, CDCl3): δ = 198.93, 192.30, 158.02, 155.64, 150.98,
9.8 Hz, 1 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 198.86, 148.80, 141.89, 140.44, 139.32, 138.36, 135.28, 134.95, 129.44,
192.19, 154.72, 148.94, 141.08, 140.42, 139.34, 137.51, 135.33, 129.20, 128.69, 127.89, 127.78, 127.48, 126.48, 124.94, 124.37,
135.01, 132.54, 132.40, 129.52, 129.17, 128.65, 128.54, 126.50, 124.30, 122.23, 117.98, 117.89, 114.89, 114.66, 110.77, 110.53,
126.46, 124.91, 123.92, 123.46, 122.53, 122.20, 121.84, 120.80, 83.44, 47.13, 41.17, 40.39, 34.87 ppm. MS (ESI): calcd. for
117.10, 82.68, 46.48, 41.23, 39.87, 34.81 ppm. MS (ESI): calcd. for
C
C34H24F4O3 [M – H]– 555.158; found 555.197. The enantiomeric
excess value of Ͼ99 % was determined by HPLC analysis. HPLC
(Daicel Chiralpak AD; iPrOH/hexane, 3:97; wavelength: 254 nm;
flow rate: 1.0 mLmin–1): tR = 26.08 min (minor), tR = 29.57 min
(major). C34H24F4O3: calcd. C 73.37, H 4.35; found C 73.13, H
4.22.
34H23Br2F3O3 [M – H]– 694.987; found 695.129. The enantio-
meric excess value of Ͼ99 % was determined by HPLC analysis.
HPLC (Daicel Chiralpak AD; iPrOH/hexane, 5:95; wavelength:
254 nm; flow rate: 1.0 mLmin–1): tR = 26.51 min (minor), tR
=
39.87 min (major). C34H23Br2F3O3: calcd. C 58.64, H 3.33; found
C 58.60, H 3.50.
(6R,6aS,9S,10S,10aS)-6,9-Bis(4-bromophenyl)-2-fluoro-10-[4-(tri-
fluoromethyl)benzoyl]-6a,9,10,10a-tetrahydro-6H-benzo[c]chromene-
8-carbaldehyde (4k): White solid (94 mg, 66 % yield); m.p. 177–
178 °C. [α]2D0 = –130 (c = 0.83, CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 9.28 (s, 1 H), 8.12 (d, J = 8.1 Hz, 2 H), 7.87 (d, J =
(6R,6aS,9S,10S,10aS)-6,9-Bis(4-chlorophenyl)-10-[4-(trifluoro-
methyl)benzoyl]-6a,9,10,10a-tetrahydro-6H-benzo[c]chromene-8-
carbaldehyde (4g): White solid (60 mg, 49 % yield); m.p. 171–
172 °C. [α]2D0 = –138 (c = 1.23, CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 9.29 (s, 1 H), 8.14 (d, J = 8.1 Hz, 2 H), 7.86 (d, J = 8.1 Hz, 2 H), 7.69 (d, J = 8.2 Hz, 2 H), 7.51 (dd, J = 21.0, 8.2 Hz,
8.2 Hz, 2 H), 7.55 (q, J = 8.6 Hz, 4 H), 7.39 (d, J = 8.3 Hz, 2 H),
7.21 (d, J = 8.3 Hz, 2 H), 7.09 (t, J = 7.6 Hz, 1 H), 6.89 (d, J =
8.1 Hz, 1 H), 6.78 (d, J = 7.6 Hz, 1 H), 6.69 (t, J = 7.4 Hz, 1 H),
6.64 (s, 1 H), 5.12 (d, J = 10.6 Hz, 1 H), 4.49 (d, J = 3.6 Hz, 1 H),
4.16 (s, 1 H), 4.00 (t, J = 10.8 Hz, 1 H), 3.54 (dd, J = 11.1, 3.4 Hz, 1
H) ppm. 13C NMR (101 MHz, CDCl3): δ = 198.90, 192.17, 154.77,
4 H), 7.13 (d, J = 8.2 Hz, 2 H), 6.89–6.72 (m, 2 H), 6.61 (s, 1 H),
6.48 (d, J = 7.0 Hz, 1 H), 5.08 (d, J = 10.5 Hz, 1 H), 4.37 (d, J =
3.4 Hz, 1 H), 4.15 (s, 1 H), 4.00 (t, J = 10.8 Hz, 1 H), 3.49 (d, J =
7.5 Hz, 1 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 198.62,
192.02, 158.15, 155.77, 150.73, 148.48, 140.88, 140.41, 139.18,
137.25, 135.48, 135.15, 132.60, 132.44, 129.48, 129.11, 128.63,
148.90, 140.57, 140.51, 139.41, 137.03, 135.33, 135.30, 135.01, 126.57, 124.87, 123.85, 123.78, 123.56, 121.94, 118.12, 118.04,
133.79, 129.59, 129.45, 129.22, 128.83, 128.65, 128.53, 126.49, 115.17, 114.94, 110.82, 110.59, 82.60, 46.83, 40.96, 39.91,
124.93, 123.94, 122.59, 122.22, 120.79, 117.11, 82.66, 46.62, 41.31, 34.84 ppm. MS (ESI): calcd. for C34H22Br2F4O3 [M – H]– 712.977;
39.82, 34.86 ppm. MS (ESI): calcd. for C34H23Cl2F3O3 [M – H]–
found 713.401. The enantiomeric excess value of Ͼ99 % was deter-
mined by HPLC analysis. HPLC (Daicel Chiralpak AD; iPrOH/
605.090; found 605.074. The enantiomeric excess value of Ͼ99 %
was determined by HPLC analysis. HPLC (Daicel Chiralpak AD; hexane, 5:95; wavelength: 254 nm; flow rate: 1.0 mLmin–1): tR
=
iPrOH/hexane, 5:95; wavelength: 254 nm; flow rate: 1.0 mLmin–1): 27.80 min (minor), tR = 33.52 min (major). C34H22Br2F4O3: calcd.
tR = 25.77 min (minor), tR = 33.25 min (major). C34H23Cl2F3O3:
C 57.17, H 3.10; found C 56.96, H 2.98.
calcd. C 67.23, H 4.35; found C 66.62, H 3.82.
(6R,6aS,9S,10S,10aS)-2-Fluoro-6,9-di-m-tolyl-10-[4-(trifluoro-
methyl)benzoyl]-6a,9,10,10a-tetrahydro-6H-benzo[c]chromene-8-
carbaldehyde (4l): White solid (982 mg, 70 % yield); m.p. 212–
213 °C. [α]2D0 = –130 (c = 1.43, CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 9.18 (s, 1 H), 8.08 (d, J = 8.1 Hz, 2 H), 7.77 (d, J =
8.2 Hz, 2 H), 7.41–7.25 (m, 3 H), 7.26–7.12 (m, 2 H), 7.05 (d, J =
7.5 Hz, 1 H), 7.01–6.91 (m, 2 H), 6.80–6.60 (m, 2 H), 6.53 (s, 1 H),
(6R,6aS,9S,10S,10aS)-6,9-Di-m-tolyl-10-[4-(trifluoromethyl)-
benzoyl]-6a,9,10,10a-tetrahydro-6H-benzo[c]chromene-8-carb-
aldehyde (4h): White solid (50 mg, 44 % yield); m.p. 179–180 °C.
[α]2D0 = –155 (c = 0.6, CHCl3). 1H NMR (400 MHz, CDCl3): δ =
9.30 (s, 1 H), 8.19 (d, J = 8.1 Hz, 2 H), 7.87 (d, J = 8.2 Hz, 2 H),
7.49–7.37 (m, 3 H), 7.31 (t, J = 7.7 Hz, 2 H), 7.19–7.04 (m, 4 H),
Eur. J. Org. Chem. 2014, 4342–4350
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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4349

L. Liu, Y. Zhu, K. Huang, B. Wang, W. Chang, J. Li
FULL PAPER
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6.39 (dd, J = 8.9, 2.3 Hz, 1 H), 4.99 (d, J = 10.5 Hz, 1 H), 4.32 (d,
J = 3.6 Hz, 1 H), 4.09 (s, 1 H), 3.95 (t, J = 10.8 Hz, 1 H), 3.48 (dd,
J = 11.1, 3.2 Hz, 1 H), 2.39 (s, 3 H), 2.32 (s, 3 H) ppm. 13C NMR
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148.87, 141.88, 140.47, 139.39, 139.16, 138.26, 135.31, 134.98,
130.33, 129.26, 129.05, 128.73, 128.29, 128.24, 126.43, 125.07,
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83.56, 77.48, 41.02, 40.36, 34.95, 21.82, 21.68 ppm. MS (ESI):
calcd. for C36H28F4O3 [M – H]– 583.190; found 583.208. The enan-
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Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures and characterization data of chalc-
ones as well as 1H and 13C NMR spectra, HPLC, XRD, and crystal
data of the corresponding ternary fused cyclic products.
Acknowledgments
The authors are grateful for the financial support from the
National Natural Science Foundation of China (NSFC) (grant
numbers 21202084 and 21142009) and the Tianjin Natural Science
Foundation of China (12JCQNJC03500 me) for this work.
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[8] Crystal data for product 4g: C34H23Cl2F3O3, formula mass:
607.42 gmol–1, rhombohedral,
a = 27.5799(11) Å, b =
27.5799(11) Å, c = 10.2741(8) Å, α = 90°, β = 90°, γ = 120°,
unit cell volume = 6768.0(7) Å3, T = 113(2) K, space group =
R3, Z = 9, no. of reflections measured = 22373, no. of indepen-
dent reflections = 7068, Rint = 0.0484, final R1 values [I Ͼ
2σ(I)] = 0.0580, final wR(F2) values [I Ͼ 2σ(I)] = 0.1525, final
R1 values (all data) = 0.0676, final wR(F2) values (all data)
= 0.1586. CCDC-976415 (for 4g) contains the supplementary
crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data
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