Bifunctional primary amine-squaramide catalyzed enantioselective intramolecular Michael addition of keto-enones: A convenient process to the stereocontrolled construction of trans-dihydrobenzofuran skeletons

Article abstract of DOI:10.1002/ejoc.201300331

A highly diasterero- and enantioselective intramolecular Michael addition of keto-enones has been realized. By using the (R,R)-1,2-diphenylethane-1,2- diamine-based bifunctional primary amine-squaramide catalyst, the reaction proceeded smoothly to generate the corresponding trans-2,3-disubstituted dihydrobenzofuran derivatives in excellent yields with good to excellent diastereo- and enantioselectivities (up to 97:3 dr, up to >99 % ee). Copyright

Full text of DOI:10.1002/ejoc.201300331

FULL PAPER
DOI: 10.1002/ejoc.201300331
Bifunctional Primary Amine-Squaramide Catalyzed Enantioselective
Intramolecular Michael Addition of Keto-enones: A Convenient Process to the
Stereocontrolled Construction of trans-Dihydrobenzofuran Skeletons
Yunting Liu,[a] Aidang Lu,[b] Keling Hu,[a] Youming Wang,*[a] Haibin Song,[a]
Zhenghong Zhou,*[a] and Chuchi Tang[a]
Keywords: Synthetic methods / Oxygen heterocycles / Asymmetric catalysis / Michael addition / Enantioselectivity /
Diastereoselectivity
A highly diasterero- and enantioselective intramolecular
Michael addition of keto-enones has been realized. By using
the (R,R)-1,2-diphenylethane-1,2-diamine-based bifunc-
tional primary amine-squaramide catalyst, the reaction pro-
ceeded smoothly to generate the corresponding trans-2,3-di-
substituted dihydrobenzofuran derivatives in excellent yields
with good to excellent diastereo- and enantioselectivities (up
to 97:3 dr, up to Ͼ99%ee).
aldehydes with quinones to generate DHB derivatives with
excellent enantioselectivities.[8] The enantioselective con-
struction of the DHB core skeleton of (–)-variabilin and (–)-
glycinol was realized by Calter through a cinchona alkaloid
catalyzed enantioselective interrupted Feist–Bénary reac-
tion as the key step.[9] Jørgensen reported an anodic oxi-
dation/organocatalytic protocol for the α-arylation of alde-
hydes with N-tosyl-4-aminophenol to generate DHBs in
good yields with excellent enantiomeric excesses.[10] An-
other elegant organocatalytic approach to optically active
DHBs, also developed by Jørgensen and co-authors, is the
l-prolinol silyl ether catalyzed one-pot reaction cascade.[11]
A highly enantio- and diastereoselective approach to cis-
2,3-dihydrobenzofurans was achieved by Smith et al.
through an isothiourea-promoted intramolecular Michael
addition of aryloxyacetic acids that contain an enone moi-
ety on the aromatic tether.[12] Our group has also developed
an efficient method for the synthesis of optically active
trans-DHBs through a primary amine-thiourea catalyzed
intramolecular Michael addition of a ketone to a nitro-
olefin.[13] Most recently, Alemán presented the asymmetric
synthesis of trans-dihydroarylfurans through a Friedel–
Crafts/substitution domino reaction under squaramide ca-
talysis.[14] Because of their inherent importance and the
scarcity of organocatalytic methods reported for these
structures, new organocatalytic strategies to prepare these
substrates are highly desirable. In this context, we realized
that although there are a number of reports of elegant cata-
lytic enantioselective intermolecular Michael additions to
chalcones, intramolecular catalytic asymmetric Michael ad-
ditions of ketones to chalcones are unexplored.[15] Herein,
we report the efficient asymmetric aminocatalysis of intra-
molecular Michael reactions of keto-enones.
Introduction
The 2,3-dihydrobenzofuran (DHB) skeleton is wide-
spread in many natural products and biologically active
molecules.[1] The biological activities of these systems are
well recognized,[2] and these diverse and intriguing proper-
ties, combined with their broad occurrence in nature, have
motivated chemists to develop various approaches to con-
struct DHBs.[3] However, methods for their preparation in
a catalytic asymmetric fashion are limited and rely mainly
on the application of transition-metal catalysis.[4]
In contrast to the great progress made in asymmetric or-
ganocatalysis during the past three decades,[5,6] with regard
to the organocatalyzed asymmetric synthesis of DHBs with
high enantioselectivity, only limited examples of the stereo-
selective construction of the DHB ring have emerged in the
past several years. In 2006, Enders developed the first exam-
ple of an organocatalyzed enantioselective construction of
a DHB ring system through an l-proline-catalyzed intra-
molecular aldol reaction.[7] A second example involves a di-
rect organocatalytic enantioselective α-arylation by treating
[a] State Key Laboratory of Elemento-Organic Chemistry, Institute
of Elemento-Organic Chemistry, Nankai University,
Tianjin 300071, P. R. China
Fax: +86-22-23503627
E-mail: z.h.zhou@nankai.edu.cn
Homepage: http://skleoc.nankai.edu.cn/professors/zhouzh/
index.html
[b] Engineering Research Center of Seawater Utilization
Technology, Ministry of Education, Hebei University of
Technology,
Tianjin 300130, P. R. China
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300331.
4836
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 4836–4843

Stereocontrolled Construction of trans-Dihydrobenzofurans
was observed for bifunctional squaramide catalyst 3, it
demonstrated a great advantage over the previous two types
of catalysts with respect to the stereocontrol of the reaction.
For example, in comparison to thiourea 1a, the use of
squaramide catalyst 3a, which contained the same diamine
scaffold, resulted in a dramatically increased enantio-
selectivity, but at the expense of the reaction time (see
Table 1, Entry 4 vs. 1). Although squaramide 3b, which con-
tained a cyclohexane-1,2-diamine skeleton, was not suffi-
ciently active to ensure the full conversion of 4a over a
week, the cyclization product was also obtained with a high
level of stereocontrol (see Table 1, Entry 5, 87%ee).
With this promising catalyst 3a in hand, other factors
that may influence the reaction, such as solvent, acidic co-
catalyst, catalyst loading, and reaction temperature, were
thoroughly investigated by employing the intramolecular
Michael addition of (E)-3-[2-(2-oxopropoxy)phenyl]-1-
phenylprop-2-en-1-one (4a) as a model. The results are
listed in Table 2.
Results and Discussion
We initially investigated the intramolecular Michael ad-
dition of (E)-3-[2-(2-oxopropoxy)phenyl]-1-phenylprop-2-
en-1-one (4a) by employing bifunctional primary amine-
thiourea 1,[16] primary amine-thiophosphonamide 2,[17] and
primary amine-squaramide 3[18] as the catalyst candidates
(see Figure 1). The results are summarized in Table 1.
Table 2. Optimization of reaction conditions.[a]
.
Figure 1. Catalyst candidates.
Table 1. Catalyst evaluation.[a]
Entry Solvent
Cocatalyst
Time [h] % Yield[b] trans/cis[c] % ee[d]
1
2
3
4
5
CH2Cl2 4-NO2BzOH
CHCl3 4-NO2BzOH
THF[e] 4-NO2BzOH
PhCH3 4-NO2BzOH
CH3OH 4-NO2BzOH
20
26
49
96
Ͼ7 d
30
Ͼ7 d
10
80
12
24
98
96
76
84
80
88
62
96
80
95
90
94:6
93:7
96:4
94:6
87:13
94:6
99:1
95:5
98:2
95:5
95:5
95
93
95
93
91
96
97
97
97
97
97
Entry Catalyst
Time [h]
% Yield[b] trans/cis[c]
% ee[d]
1
2
3
4
5
1a
1b
2
3a
3b
2
1.5
2.5
20
Ͼ7 d
88
Ͼ99
Ͼ99
98
95:5
89:11
83:17
94:6
9
84
61
94
87
6
7
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
PhCO2H
PhOH
AcOH
AcOH
AcOH
AcOH
8
53
89:11
9[f]
10[g] CH2Cl2
11[h] CH2Cl2
[a] Reagents and conditions: keto-enone 4a (0.3 mmol) in CH2Cl2
(1 mL) at 20 °C in the presence of catalyst (20 mol-%) and 4-nitro-
benzoic acid (4-NO2BzOH, 10 mol-%). [b] Yield of isolated prod-
uct after chromatography on silica gel. [c] Determined by 1H NMR
analysis. [d] Determined by chiral HPLC analysis.
[a] Reagents and conditions: keto-enone 4a (0.3 mmol) in solvent
(1 mL) in the presence of catalyst 3a and acidic cocatalyst (10 mol-
%). [b] Yield of isolated product after chromatography on silica
gel. [c] Determined by H NMR analysis. [d] Determined by chiral
HPLC analysis. [e] THF = tetrahydrofuran. [f] Reaction was car-
1
As shown in Table 1, bifunctional primary amine-thio-
urea 1 demonstrated high catalytic efficacy in the model
ried out at 0 °C. [g] Catalyst 3a (15 mol-%) was employed. [h] Cata-
reaction to generate the corresponding cyclization product lyst 3a (10 mol-%) was loaded.
5a in high yield within 2 h. However, the enantioselectivity
was significantly influenced by the backbone of the thio-
Although the reaction proceeded smoothly in several
urea, and 1,2-diphenylethane-1,2-diamine-based thiourea conventional solvents (see Table 2) to afford the corre-
1a, which previously provided a high degree of enantio- sponding trans-dihydrobenzofuran 5a with almost the same
selectivity in the intramolecular Michael addition of keto- high ee values, performing the asymmetric intramolecular
nitro olefins,[12] appeared to be ineffective in this transfor- Michael addition in CH2Cl2 resulted in a slightly higher
mation. The corresponding cyclization product 5a was ob- reaction efficiency and enantioselectivity (see Table 2, En-
tained almost in racemic form (see Table 1, Entry 1, 9%ee). tries 1–5). Moreover, an acidic cocatalyst was determined as
The use of cyclohexane-1,2-diamine-derived thiourea 1b re- essential to both the efficiency and enantioselectivity of the
sulted in a sharp increase of the ee value of product 5a (see reaction. Acetic acid gave superior results with respect to
Table 1, Entry 2, 84%ee). Primary amine-thiophosphon- reaction rate and enantioselectivity (see Table 2, Entry 8).
amide 2 also worked well and gave trans-dihydrobenzofuran Decreasing the reaction temperature from 20 to 0 °C led to
5a with an enantioselectivity of 61%ee (see Table 1, En- a sluggish reaction with an unaltered enantioselectivity (see
try 3). Although an obvious decrease in catalytic activity Table 2, Entry 9). Adjusting the catalyst loading had almost
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Y. Liu, A. Lu, K. Hu, Y. Wang, H. Song, Z. Zhou, C. Tang
FULL PAPER
no influence on the outcome of the enantioselectivity. The Entries 15 and 16). Keto-enone 4m, which is 2,4-dichlo-
catalyst loading was successfully reduced to 15 mol-% with- rophenyl-substituted, is an exception, as the bulky nature
out any detrimental effect to the reaction (see Table 2, En- of this substrate resulted in an obvious decrease in the dia-
try 10 vs. 8). The reaction also proceeded well with a cata- stereo- and enantioselectivity (see Table 3, Entry 14). More-
lyst loading of 10 mol-% without any erosion of the ob- over, 2-acetofuran-based keto-enone 4p also work well to
served ee value, but at the expense of the reaction time (see generate the corresponding dihydrobenzofuran 5p in quan-
Table 2, Entry 11).
titative yield with an excellent stereochemical outcome (see
With a set of optimized reaction conditions in hand Table 3, Entry 17; trans/cis, 95:5; Ͼ99%ee). In addition, the
(15 mol-% of bifunctional squaramide 3a in combination reaction was carried out on a gram scale to give the isolated
with 10 mol-% of acetic acid as the catalyst at 20 °C in product in excellent yield with an almost unaltered stereo-
dichloromethane), we then explored the scope of the intra- chemical outcome, which demonstrates the potential appli-
molecular Michael addition reaction with various keto-en- cation of this method for preparative purposes (see Table 3,
ones. The results are collected in Table 3.
Entry 1 vs. 2). The absolute configuration of product 5a was
unequivocally established as (S,S) by X-ray crystal structure
analysis (see Figure 2), and the remaining configurations
were assumed by analogy.[19]
Table 3. Substrate scope of 3a-catalyzed asymmetric intramolecular
Michael addition of keto-enones 4.[a]
Entry
5 (R, Ar)
Time [h] % Yield[b]
trans/cis[c,d]
% ee[d]
1
2[e,f]
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
5a (H, Ph)
5a (H, Ph)
5b (5-F, Ph)
5c (5-Cl, Ph)
5d (5-Br, Ph)
5e (5,7-Cl2, Ph)
5f (5-Me, Ph)
5g (6-Me, Ph)
5h (5-tBu, Ph)
5i (H, 3-FC6H4)
5j (H, 4-FC6H4)
5k (H, 4-ClC6H4)
5l (H, 4-BrC6H4)
5m (H, 2,4-Cl2C6H3)
5n (H, 4-MeOC6H4)
5o (H, 4-MeC6H4)
5p (H, 2-furyl)
12
15
15
17
17
30
7
6
10
8
9
8.5
8
6
12
6
95
90 (85)
94
99
99
95
99
99
90
90
98
94
90
66
99
99
98
95:5
97
94:6 (Ͼ99:1) 96 (Ͼ99)
96:4
95:5
95:5
96:4
97:3
93:7
94:6
97:3
96:4
95:5
97:3
76:24
90:10
90:10
95:5
97
98
95
97
97
98
96
98
97
97
98
88:94
95
95
Figure 2. X-ray crystal structure of the major diastereomer of com-
pound 5a. Most of hydrogen atoms have been omitted for clarity.
Conclusions
In summary, we have developed a highly diastereo- and
enantioselective organocatalytic asymmetric intramolecular
Michael addition of a keto-enone to give trans-dihydro-
benzofurans with two contiguous stereocenters in high
5
Ͼ99
[a] Reagents and conditions: keto-enone (0.3 mmol) in CH2Cl2
(1 mL) at 20 °C in the presence of catalyst (15 mol-%) and AcOH
(10 mol-%). [b] Yield of isolated product after chromatography on
1
silica gel. [c] Determined by H NMR analysis. [d] Determined by yields with up to 97:3 dr and up to Ͼ99%ee. Hence, this
chiral HPLC analysis. [e] Performed on 10 mmol scale. [f] Data in
parenthesis was obtained after a single recrystallization.
reaction provides a convenient and scalable process for the
syntheses of pharmaceutically valuable trans-dihydrobenzo-
furans.
As shown in Table 3, this transformation has a broad
substrate scope. Keto-enones that were derived from both
electron-rich and electron-deficient salicylaldehydes with
various substitution patterns participated in the intramolec-
Experimental Section
General Methods: All reagents and solvents were commercial grade
and purified prior to use when necessary. The NMR spectroscopic
data were recorded with a Varian 400 MHz instrument. Chemical
shifts are recorded relative to the solvent peaks as an internal stan-
dard set to δ = 7.26 and 77.0 ppm (CHCl3, CDCl3, respectively).
Specific rotations were measured with a Perkin–Elmer 341MC po-
larimeter. Enantiomeric excesses (ee) were determined by using an
HP-1100 instrument (chiral column; mobile phase: hexane/iPrOH).
HRMS was performed with a Varian QFT-ESI instrument. Melt-
ing points were determined with a Taike X-4 melting point appara-
ular Michael addition to give trans-DHBs in excellent yields
with excellent diasteroselectivities (trans/cis, 93:7–97:3) and
enantioselectivities (from 95 to Ͼ98%ee; see Table 3, En-
tries 1–9). With respect to keto-enones prepared from sub-
stituted acetophenone and salicylaldehyde, substrates with
an electron-withdrawing group substituent generally gave
cyclization products with high diastereo- and enantio-
selectivities (see Table 3, Entries 10–13), whereas introduc-
ing an electron-donating group to the benzene ring led to a
slightly decreased trans/cis ratio and ee value (see Table 3, tus.
4838
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Eur. J. Org. Chem. 2013, 4836–4843

Stereocontrolled Construction of trans-Dihydrobenzofurans
Synthesis of Squaramide Catalyst 3a {3-[(1R,2R)-2-Amino-1,2-di- 13C NMR (100.6 MHz, CDCl3): δ = 26.7, 73.4, 113.3, 124.4, 125.9,
phenylethylamino]-4-[3,5-bis(trifluoromethyl)phenylamino]-cyclobut-
3-ene-1,2-dione}: To a solution of dimethyl squarate (284 mg,
2.00 mmol) in CH2Cl2 (8 mL) was added 3,5-bis(trifluoromethyl)
benzenamine (2.0 mmol). The resulting mixture was stirred at room
temperature until the amine was completely consumed (monitored
by TLC). Then, the reaction mixture was filtered, and the filtrate
was washed with HCl (1 m aqueous solution). The organic layer
was dried with anhydrous MgSO4, filtered, and concentrated to
afford the monosquaramide intermediate. To a solution of the
(1R,2R)-1,2-diphenylethane-1,2-diamine (1.00 mmol) in MeOH
(4 mL) was added the monosquaramide (1.00 mmol). The reaction
mixture was stirred at room temperature until the raw material was
completely consumed (monitored by TLC). After removal of the
solvent, the residue was purified through column chromatography
on silica gel (200–300 mesh; petroleum ether/ethyl acetate, 5:1) to
give the desired squaramide catalyst (343 mg, 66% yield) as a white
solid; m.p. 215–218 °C. [α]2D0 = +13.6 [c = 1.5, DMSO (dimethyl
sulfoxide)]. 1H NMR (400 MHz, [D6]DMSO): δ = 3.41 (br. s, 4 H),
4.47 (d, J = 4.8 Hz, 1 H), 5.37 (d, J = 4.4 Hz, 1 H), 7.18–7.29 (m,
4 H, Ar), 7.37–7.44 (m, 6 H, Ar), 7.66 (s, 1 H, Ar), 8.07 (s, 2 H,
Ar) ppm. 13C NMR (100.6 MHz, [D6]DMSO): δ = 59.4, 63.4,
114.6, 117.9, 121.8, 124.5, 126.5, 127.0, 127.4, 128.0, 128.5, 131.2,
131.5, 140.3, 141.1, 142.4, 162.5, 169.6, 180.5, 184.1 ppm. HRMS
(ESI): calcd. for C26H19F6N3NaO2 [M + Na]+ 542.1274; found
542.1278.
127.0, 128.6, 129.0, 131.0, 132.9, 138.0, 155.2, 190.4, 203.7 ppm.
HRMS (ESI): calcd. for C18H15ClO3Na [M + Na]+ 337.0602;
found 337.0609.
(E)-3-[2-(2-Oxopropoxy)-5-bromophenyl]-1-phenylprop-2-en-1-one
(4d): White solid (75 % yield); m.p. 147–149 °C. 1H NMR
(400 MHz, CDCl3): δ = 2.31 (s, 3 H), 4.64 (s, 2 H), 6.66 (d, J =
8.8 Hz, 1 H, Ar), 7.44 (dd, J = 2.4, 8.8 Hz, 1 H, Ar), 7.51–7.62 (m,
3 H, Ar), 7.75 (d, J = 15.6 Hz), 7.78 (d, J = 2.4 Hz, 1 H, Ar), 8.05
(d, J = 15.6 Hz, 1 H), 8.09 (d, J = 6.8 Hz, 2 H, Ar) ppm. 13C NMR
(100.6 MHz, CDCl3): δ = 26.7, 73.3, 113.7, 114.3, 124.5, 126.4,
128.6, 128.7, 131.9, 132.9, 133.9, 137.9, 138.0, 155.7, 190.4,
203.7 ppm. HRMS (ESI): calcd. for C18H15BrO3Na [M + Na]+
381.0097; found 381.0101.
(E)-3-[2-(2-Oxopropoxy)-3,5-dichlorophenyl]-1-phenylprop-2-en-1-
one (4e): White solid (74 % yield); m.p. 113–115 °C. 1H NMR
(400 MHz, CDCl3): δ = 2.36 (s, 3 H), 4.53 (s, 2 H), 7.44 (d, J =
2.4 Hz, 1 H, Ar), 7.50–7.61 (m, 3 H, Ar), 7.58 (d, J = 2.4 Hz, 1 H,
Ar), 7.62 (d, J = 16.0 Hz, 1 H), 7.96 (d, J = 16.0 Hz, 1 H), 8.03 (d,
J = 7.2 Hz, 2 H, Ar) ppm. 13C NMR (100.6 MHz, CDCl3): δ =
26.7, 77.6, 125.8, 126.5, 128.6, 128.8, 129.2, 130.6, 131.6, 133.3,
136.7, 137.5, 152.0, 189.7, 203.4 ppm. HRMS (ESI): calcd. for
C18H14Cl2O3Na [M + Na]+ 371.0212; found 371.0208.
(E)-3-[2-(2-Oxopropoxy)-5-methylphenyl]-1-phenylprop-2-en-1-one
(4f): White solid (66 % yield); m.p. 117–118 °C. 1H NMR
(400 MHz, CDCl3): δ = 2.31 (s, 3 H), 2.34 (s, 3 H), 4.62 (s, 2 H),
6.68 (d, J = 8.4 Hz, 1 H, Ar), 7.16 (d, J = 8.4 Hz, 1 H, Ar), 7.49–
7.59 (m, 4 H, Ar), 7.76 (d, J = 16.0 Hz, 1 H), 8.09 (d, J = 7.2 Hz,
2 H, Ar), 8.14 (d, J = 16.0 Hz, 1 H) ppm. 13C NMR (100.6 MHz,
CDCl3): δ = 20.4, 26.7, 73.4, 111.9, 123.3, 124.0, 128.5, 128.6,
130.0, 131.2, 132.2, 132.6, 138.4, 139.8, 154.8, 191.0, 204.9 ppm.
HRMS (ESI): calcd. for C19H18O3Na [M + Na]+ 317.1148; found
317.1145.
General Procedure for the Preparation of Keto-enone 4: To a suspen-
sion of K2CO3 (1.38 g, 10 mmol) and the 2-hydroxyl-substituted
chalcones (5 mmol) in acetone (60 mL) was added 1-bromopropan-
2-one (1.03 g, 7.5 mmol) at 0 °C. The resulting mixture was
warmed to room temperature and stirred until the starting material
was completely consumed (observed by TLC). After removal of
solvent under reduced pressure, the crude product was purified by
column chromatography to furnish the corresponding keto-enone
4 as a white solid.
(E)-3-[2-(2-Oxopropoxy)-4-methylphenyl]-1-phenylprop-2-en-1-one
1
(4g): White solid (68% yield); m.p. 95–98 °C. H NMR (400 MHz,
(E)-3-[2-(2-Oxopropoxy)phenyl]-1-phenylprop-2-en-1-one (4a):
White solid (62 % yield); m.p. 97–98 °C. 1H NMR (400 MHz,
CDCl3): δ = 2.32 (s, 3 H), 4.66 (s, 2 H), 6.79 (d, J = 8.0 Hz, 1 H,
Ar), 7.06 (t, J = 8.0 Hz, 1 H, Ar), 7.06 (t, J = 8.0 Hz), 7.36 (dd, J
= 1.2, 8.0 Hz, 1 H, Ar), 7.50–7.61 (m, 3 H, Ar), 7.69 (dd, J = 1.2,
8.0 Hz, 1 H, Ar), 7.79 (d, J = 16.0 Hz, 1 H), 8.09 (d, J = 7.2 Hz,
2 H, Ar), 8.16 (d, J = 16.0 Hz, 1 H) ppm. 13C NMR (100.6 MHz,
CDCl3): δ = 26.8, 73.2, 111.9, 121.9, 123.6, 124.3, 128.5, 128.6,
129.8, 131.7, 132.7, 138.3, 139.7, 156.7, 191.0, 204.5 ppm. HRMS
(ESI): calcd. for C18H16O3Na [M + Na]+ 303.0992; found 303.0985.
CDCl3): δ = 2.32 (s, 3 H), 2.37 (s, 3 H), 4.64 (s, 2 H), 6.59 (s, 1 H,
Ar), 6.87 (d, J = 8.0 Hz, 1 H, Ar), 7.49–7.60 (m, 4 H, Ar), 7.76 (d,
J = 16.0 Hz, 1 H), 8.09 (d, J = 7.6 Hz, 2 H, Ar), 8.13 (d, J =
16.0 Hz, 1 H) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 21.9, 26.7,
73.1, 112.7, 121.5, 122.5, 122.7, 128.5, 129.7, 132.5, 138.4, 139.8,
142.7, 156.7, 191.1, 204.6 ppm. HRMS (ESI): calcd. for
C19H18O3Na [M + Na]+ 317.1148; found 317.1151.
(E)-3-[2-(2-Oxopropoxy)-5-tert-butylphenyl]-1-phenylprop-2-en-1-
one (4h): White solid (72 % yield); m.p. 95–97 °C. 1H NMR
(400 MHz, CDCl3): δ = 1.34 (s, 9 H), 2.31 (s, 3 H), 4.64 (s, 2 H),
6.72 (d, J = 8.4 Hz, 1 H, Ar), 7.38 (dd, J = 2.4, 8.4 Hz, 1 H, Ar),
7.50–7.61 (m, 3 H, Ar), 7.66 (d, J = 2.4 Hz, 1 H, Ar), 7.80 (d, J =
16.0 Hz, 1 H), 8.09 (d, J = 6.4 Hz, 2 H, Ar), 8.12 (d, J = 16.0 Hz,
1 H) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 26.7, 31.4, 34.2,
73.3, 111.6, 123.6, 127.1, 128.5, 128.6, 128.7, 132.6, 138.4, 140.6,
144.6, 154.7, 191.3, 204.7 ppm. HRMS (ESI): calcd. for
C22H24O3Na [M + Na]+ 359.1618; found 359.1617.
(E)-3-[2-(2-Oxopropoxy)-5-fluorophenyl]-1-phenylprop-2-en-1-one
1
(4b): White solid (65% yield); m.p. 96–98 °C. H NMR (400 MHz,
CDCl3): δ = 2.31 (s, 3 H), 4.63 (s, 2 H), 6.73 (d, J = 4.4, 9.2 Hz, 1
H, Ar), 7.03–7.08 (m, 1 H, Ar), 7.38 (dd, J = 3.2, 8.8 Hz, 1 H, Ar),
7.51 (t, J = 8.0 Hz, 2 H, Ar), 7.60 (t, J = 7.2 Hz, 1 H, Ar), 7.73 (d,
J = 16.0 Hz, 1 H), 8.08 (d, J = 8.4 Hz, 1 H, Ar), 80.9 (d, J =
16.0 Hz, 1 H) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 26.6, 37.3,
113.3 (d, J = 8.1 Hz), 115.4 (d, J = 23.5 Hz), 117.8 (d, J = 23.6 Hz),
124.4, 125.7 (d, J = 7.3 Hz), 128.5, 128.6, 132.9, 138.0, 138.3, 152.9,
157.4 (d, J = 240.7 Hz), 190.5, 204.1 ppm. HRMS (ESI): calcd. for
C18H15FO3Na [M + Na]+ 321.0897; found 321.0902.
(E)-3-[2-(2-Oxopropoxy)phenyl]-1-(3-fluorophenyl)prop-2-en-1-one
(4i): White solid (64 % yield); m.p. 129–131 °C. 1H NMR
(400 MHz, CDCl3): δ = 2.32 (s, 3 H), 4.68 (s, 2 H), 6.79 (d, J =
8.4 Hz, 1 H, Ar), 7.07 (t, J = 7.6 Hz, 1 H, Ar), 7.29 (dd, J = 1.6,
8.0 Hz, 1 H, Ar), 7.38 (dt, J = 1.6, 8.4 Hz, 1 H, Ar), 7.48–7.53 (m,
1 H, Ar), 7.67 (dd, J = 1.6, 7.6 Hz, 1 H, Ar), 7.77–7.81 (m, 1 H,
Ar), 7.81 (d, J = 15.6 Hz, 1 H), 7.91 (d, J = 7.6 Hz, 1 H, Ar), 8.15
(E)-3-[2-(2-Oxopropoxy)-5-chlorophenyl]-1-phenylprop-2-en-1-one
(4c): White solid (72 % yield); m.p. 129–131 °C. 1H NMR
(400 MHz, CDCl3): δ = 2.32 (s, 3 H), 4.65 (s, 2 H), 6.72 (d, J =
8.8 Hz, 1 H, Ar), 7.30 (dd, J = 2.4, 8.8 Hz, 1 H, Ar), 7.51–7.62 (m,
3 H, Ar), 7.64 (d, J = 2.4 Hz, 1 H, Ar), 7.76 (d, J = 16.0 Hz, 1 H), (d, J = 15.6 Hz, 1 H) ppm. 13C NMR (100.6 MHz, CDCl3): δ =
8.08 (d, J = 16.0 Hz, 1 H), 8.09 (dd, J = 1.6, 6.8 Hz, 2 H, Ar) ppm.
26.7, 73.1, 112.0, 115.4 (d, J = 22.3 Hz), 119.7 (d, J = 21.3 Hz),
Eur. J. Org. Chem. 2013, 4836–4843
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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4839

Y. Liu, A. Lu, K. Hu, Y. Wang, H. Song, Z. Zhou, C. Tang
FULL PAPER
121.9, 123.2, 124.1, 124.3, 130.2, 131.9, 140.6, 156.9, 162.9 (d, J =
Ar), 7.78 (d, J = 16.0 Hz, 1 H), 8.01 (d, J = 8.4 Hz, 2 H, Ar), 8.15
247.8 Hz), 189. 7, 204.0 ppm. HRMS (ESI): calcd. for (d, J = 16.0 Hz, 1 H) ppm. 13C NMR (100.6 MHz, CDCl3): δ =
C18H15FO3Na [M + Na]+ 321.0897; found 321.0903.
21.7, 26.7, 73.2, 111.9, 121.9, 123.6, 124.5, 128.7, 129.3, 129.7,
131.5, 135.7, 139.2, 143.5, 156.7, 190.4, 204.6 ppm. HRMS (ESI):
calcd. for C19H18O3Na [M + Na]+ 317.1148; found 317.1155.
(E)-3-[2-(2-Oxopropoxy)phenyl]-1-(4-fluorophenyl)prop-2-en-1-one
(4j): White solid (69 % yield); m.p. 143–145 °C. 1H NMR
(400 MHz, CDCl3): δ = 2.33 (s, 3 H), 4.69 (s, 2 H), 6.80 (d, J =
8.4 Hz, 1 H, Ar), 7.07 (t, J = 7.6 Hz, 1 H, Ar), 7.19 (t, J = 8.4 Hz,
2 H, Ar), 7.37 (dt, J = 1.6, 8.4 Hz, 1 H, Ar), 7.67 (dd, J = 1.2,
7.6 Hz, 1 H, Ar), 7.87 (d, J = 15.6 Hz, 1 H), 8.13 (d, J = 15.6 Hz,
1 H), 8.15–8.19 (m, 2 H, Ar) ppm. 13C NMR (100.6 MHz, CDCl3):
δ = 26.6, 73.2, 111.9, 115.5 (d, J = 21.7 Hz), 121.9, 123.4, 124.3,
130.3, 131.2, 131.3, 131.7, 140.6, 156.8, 165.6 (d, J = 254.0 Hz),
189.3, 203.9 ppm. HRMS (ESI): calcd. for C18H15FO3Na [M +
Na]+ 321.0897; found 321.0897.
(E)-3-[2-(2-Oxopropoxy)phenyl]-1-(furan-2-yl)prop-2-en-1-one (4p):
White solid (58% yield); m.p. 147–149 °C. 1H NMR (400 MHz,
CDCl3): δ = 2.35 (s, 3 H), 4.68 (s, 2 H), 6.61 (dd, J = 1.6, 7.6 Hz,
1 H, Ar), 7.05 (d, J = 7.6 Hz, 1 H, Ar), 7.35 (d, J = 8.0 Hz, 1 H,
Ar), 7.51 (t, J = 3.6 Hz, 1 H, Ar), 7.65–7.67 (m, 2 H, Ar), 7.79 (d,
J = 16.0 Hz, 1 H), 8.16 (d, J = 16.0 Hz, 1 H) ppm. 13C NMR
(100.6 MHz, CDCl3): δ = 26.7, 73.1, 111.9, 112.5, 117.9, 121.9,
123.1, 124.2, 130.6, 131.7, 139.0, 146.6, 153.9, 156.9, 178.5,
204.2 ppm. HRMS (ESI): calcd. for C16H14O4Na [M + Na]+
293.0784; found 293.0778.
(E)-3-[2-(2-Oxopropoxy)phenyl]-1-(4-chlorophenyl)prop-2-en-1-one
(4k): White solid (66 % yield); m.p. 123–127 °C. 1H NMR
(400 MHz, CDCl3): δ = 2.31 (s, 3 H), 4.69 (s, 2 H), 6.79 (d, J =
8.4 Hz, 1 H, Ar), 7.06 (t, J = 7.6 Hz, 1 H, Ar), 7.37 (dt, J = 1.6,
8.4 Hz, 1 H, Ar), 7.49 (d, J = 8.4 Hz, 2 H, Ar), 7.66 (d, J = 8.0 Hz,
1 H, Ar), 7.86 (d, J = 16.0 Hz, 1 H), 8.08 (d, J = 8.4 Hz, 2 H, Ar),
8.12 (d, J = 16.0 Hz, 1 H) ppm. 13C NMR (100.6 MHz, CDCl3): δ
= 26.6, 73.1, 111.9, 121.9, 123.3, 124.2, 128.9, 129.6, 130.1, 130.4,
131.8, 136.6, 139.1, 140.4, 156.9, 189.7, 203.8 ppm. HRMS (ESI):
calcd. for C18H15ClO3Na [M + Na]+ 337.0602; found 337.0596.
General Procedure for the Primary Amine-Squaramide 3a Catalyzed
Asymmetric Intramolecular Michael Addition of Keto-enone 4:
Keto-enone 4 (0.3 mmol), glacial acetic acid (0.03 mmol), and pri-
mary amine-squaramide catalyst 3a (0.045 mmol) were dissolved in
dichloromethane (1 mL). The resulting solution was stirred at
20 °C until the keto-enone was completely consumed (monitored
by TLC). After completion of the reaction, the mixture was directly
purified by column chromatography on silica gel [100–200 mesh;
petroleum ether (PE)/EtOAc, 15:1] to afford the desired product 5.
The enantiomeric excess of the pure product was determined by
chiral HPLC analysis.
(E)-3-[2-(2-Oxopropoxy)phenyl]-1-(4-bromophenyl)prop-2-en-1-one
(4l): White solid (72 % yield); m.p. 143–145 °C. 1H NMR
(400 MHz, CDCl3): δ = 2.32 (s, 3 H), 4.68 (s, 2 H), 6.79 (d, J =
8.4 Hz, 1 H, Ar), 7.06 (t, J = 7.6 Hz, 1 H, Ar), 7.37 (dt, J = 1.6,
8.0 Hz, 1 H, Ar), 7.64–7.67 (m, 3 H, Ar), 7.85 (d, J = 15.6 Hz, 1
H), 8.00 (d, J = 8.8 Hz, 2 H, Ar), 8.12 (d, J = 15.6 Hz, 1 H) ppm.
13C NMR (100.6 MHz, CDCl3): δ = 26.6, 73.1, 111.9, 121.9, 123.2,
124.1, 127.8, 129.7, 130.2, 131.8, 131.9, 137.1, 140.4, 156.9, 189.9,
203.8 ppm. HRMS (ESI): calcd. for C18H15BrO3Na [M + Na]+
381.0097; found 381.0103.
(2S,3S)-2-Acetyl-3-(1-oxo-1-phenylethyl)-2,3-dihydrobenzofuran
(5a): White solid (95% yield; trans/cis, 95:5; 97%ee for trans iso-
mer); m.p. 74–78 °C. [α]2D0 = +84.4 (c = 1.0, ethyl acetate). 1H NMR
(400 MHz, CDCl3): δ = 2.30 (s, 0.15 H, cis isomer), 2.36 (s, 2.85
H, trans isomer), 3.45 (dd, J = 6.8, 11.2 Hz, 2 H), 4.18 (dd, J =
6.4, 12.8 Hz, 0.95 H, trans isomer), 4.45 (dd, J = 6.4, 16.0 Hz, 0.05
H, cis isomer), 4.78 (d, J = 5.6 Hz, 0.95 H, trans isomer), 5.21 (d,
J = 10.0 Hz, 0.05 H, cis isomer), 6.88–6.92 (m, 2 H, Ar), 7.17–7.21
(m, 2 H, Ar), 7.47 (t, J = 8.0 Hz, 2 H, Ar), 7.59 (t, J = 7.6 Hz, 1
H, Ar), 7.97 (d, J = 7.6 Hz, 1.90 H, Ar, trans isomer), 7.90 (d, J =
7.2 Hz, 0.10 H, Ar, cis isomer) ppm. 13C NMR (100.6 MHz,
CDCl3): δ = 26.1, 40.7, 44.4, 90.6, 109.9, 121.5, 124.9, 128.1, 128.5,
128.7, 129.0, 133.5, 136.4, 158.8, 197.5, 207.1 ppm. HRMS (ESI):
calcd. for C18H16O3Na [M + Na]+ 303.0992; found 303.0990.
HPLC analysis (Chiralpak AD column; hexane/2-propanol, 98:2;
flow rate: 1.0 mL/min; wavelength: 220 nm): Rt (retention time) =
33.65 (minor, trans isomer) and 36.84 min (major, trans isomer).
(E)-3-[2-(2-Oxopropoxy)phenyl]-1-(2,4-dichlorophenyl)prop-2-en-1-
one (4m): White solid (74 % yield); m.p. 113–115 °C. 1H NMR
(400 MHz, CDCl3): δ = 2.22 (s, 3 H), 4.58 (s, 2 H), 6.75 (d, J =
8.4 Hz, 1 H, Ar), 7.05 (t, J = 7.6 Hz, 1 H, Ar), 7.23 (d, J = 16.4 Hz,
1 H), 7.35–7.40 (m, 2 H, Ar), 7.46 (d, J = 8.4 Hz, 1 H, Ar), 7.48
(d, J = 2.0 Hz, 1 H, Ar), 7.64 (dd, J = 1.6, 7.6 Hz, 1 H, Ar), 7.87
(d, J = 16.4 Hz, 1 H) ppm. 13C NMR (100.6 MHz, CDCl3): δ =
26.6, 73.1, 112.0, 122.0, 123.6, 126.8, 127.2, 129.1, 130.1, 130.4,
132.3, 132.4, 136.7, 137.6, 141.5, 156.6, 193.1, 204.6 ppm. HRMS
(ESI): calcd. for C18H14Cl2O3Na [M + Na]+ 371.0212; found
371.0214.
(2S,3S)-2-Acetyl-5-fluoro-3-(1-oxo-1-phenylethyl)-2,3-dihydrobenzo-
furan (5b): White solid (94% yield; trans/cis, 96:4; 97%ee for trans
isomer); m.p. 84–87 °C. [α]2D0 = +88.0 (c = 1.0, ethyl acetate). 1H
NMR (400 MHz, CDCl3): δ = 2.31 (s, 0.12 H, cis isomer), 2.36 (s,
2.88 H, trans isomer), 3.45 (dd, J = 1.2 and 6.8 Hz, 2 H), 4.17 (dd,
J = 6.4, 12.8 Hz, 2 H), 4.80 (d, J = 6.0 Hz, 0.95 H, trans isomer),
5.22 (d, J = 9.6 Hz, 0.05 H, cis isomer), 6.80–6.93 (m, 3 H, Ar),
7.48 (t, J = 7.6 Hz, 2 H, Ar), 7.60 (t, J = 7.6 Hz, 1 H, Ar), 7.96–
7.98 (m, 2 H, Ar) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 26.1,
40.7, 44.0, 91.0, 110.0 (d, J = 8.5 Hz), 112.2 (d, J = 25.2 Hz), 128.0,
128.7, 129.9 (d, J = 8.8 Hz), 133.6, 136.1, 154.6, 157.8 (d, J =
238.4 Hz), 197.2, 206.8 ppm. HRMS (ESI): calcd. for
C18H15FO3Na [M + Na]+ 321.0897; found 321.0900. HPLC analy-
sis (Chiralpak AD column; hexane/2-propanol, 98:2; flow rate:
1.0 mL/min; wavelength: 220 nm): Rt = 31.31 (minor, trans isomer)
and 38.01 min (major, trans isomer).
(E)-3-[2-(2-Oxopropoxy)phenyl]-1-(4-methoxyphenyl)prop-2-en-1-
one (4n): White solid (62 % yield); m.p. 131–134 °C. 1H NMR
(400 MHz, CDCl3): δ = 2.33 (s, 3 H), 3.89 (s, 3 H), 4.66 (s, 2 H),
6.78 (d, J = 8.4 Hz, 1 H, Ar), 6.99 (d, J = 8.8 Hz, 2 H, Ar), 7.05
(t, J = 7.6 Hz, 1 H, Ar), 7.35 (dt, J = 1.6, 8.4 Hz, 1 H, Ar), 7.67
(dd, J = 1.6, 7.6 Hz, 1 H, Ar), 7.84 (d, J = 16.0 Hz, 1 H), 8.12 (d,
J = 8.8 Hz, 2 H, Ar), 8.13 (d, J = 16.0 Hz, 1 H) ppm. 13C NMR
(100.6 MHz, CDCl3): δ = 26.7, 55.5, 73.2, 111.9, 113.8, 121.8,
123.5, 124.5, 129.9, 130.9, 131.2, 131.4, 138.9, 156.7, 163.3, 189.1,
204.5 ppm. HRMS (ESI): calcd. for C19H18O4Na [M + Na]+
333.1097; found 333.1102.
(E)-3-[2-(2-Oxopropoxy)phenyl]-1-p-tolylprop-2-en-1-one (4o):
White solid (70% yield); m.p. 115–119 °C. 1H NMR (400 MHz,
CDCl3): δ = 2.33 (s, 3 H), 2.45 (s, 3 H), 4.65 (s, 2 H), 6.78 (d, J = (2S,3S)-2-Acetyl-5-chloro-3-(1-oxo-1-phenylethyl)-2,3-dihydrobenzo-
8.4 Hz, 1 H, Ar), 7.06 (t, J = 7.6 Hz, 1 H, Ar), 7.32 (d, J = 8.4 Hz,
2 H, Ar), 7.36 (t, J = 7.2 Hz, 1 H, Ar), 7.67 (d, J = 7.6 Hz, 1 H,
furan (5c): White solid (99% yield, trans/cis, 95:5; 98%ee for trans
isomer); m.p. 93–95 °C. [α]2D0 = +31.8 (c = 1.0, ethyl acetate). 1H
4840
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Eur. J. Org. Chem. 2013, 4836–4843

Stereocontrolled Construction of trans-Dihydrobenzofurans
NMR (400 MHz, CDCl3): δ = 2.29 (s, 0.15 H, cis isomer), 2.36 (s,
2.85 H, trans isomer), 3.45 (dd, J = 4.0 and 6.8 Hz, 2 H), 4.16 (dd,
J = 6.4, 12.8 Hz, 1 H), 4.81 (d, J = 5.6 Hz, 0.96 H, trans isomer),
5.23 (d, J = 10.0 Hz, 0.04 H, cis isomer), 6.83 (d, J = 8.4 Hz, 1 H,
Ar), 7.13–7.17 (m, 2 H, Ar), 7.48 (t, J = 8.0 Hz, 2 H, Ar), 7.60 (t,
(2S,3S)-2-Acetyl-6-methyl-3-(1-oxo-1-phenylethyl)-2,3-dihydro-
benzofuran (5g): Pale yellow oil (99% yield; trans/cis, 93:7; 98%ee
1
for trans isomer). [α]2D0 = +53.3 (c = 2.5, ethyl acetate). H NMR
(400 MHz, CDCl3): δ = 2.29 (s, 0.21 H, cis isomer), 2.32 (s, 3 H),
2.35 (s, 2.79 H, trans isomer), 3.42 (dd, J = 6.8, 8.8 Hz, 2 H), 4.12
J = 7.2 Hz, 1 H, Ar), 7.91 (d, J = 7.2 Hz, 0.10 H, Ar, cis isomer), (dd, J = 6.8, 12.8 Hz, 1 H), 4.77 (d, J = 5.2 Hz, 0.93 H, trans
7.97 (d, J = 7.2 Hz, 1.90 H, Ar, trans isomer) ppm. 13C NMR isomer), 5.20 (d, J = 9.6 Hz, 0.07 H, cis isomer), 6.71 (d, J = 7.6 Hz,
(100.6 MHz, CDCl3): δ = 26.2, 40.6, 44.1, 91.0, 110.8, 125.2, 126.3, 1 H, Ar), 6.74 (s, 1 H, Ar), 7.47 (t, J = 7.6 Hz, 2 H, Ar), 7.58 (t, J
128.1, 128.8, 128.9, 130.5, 133.7, 136.2, 157.5, 197.2, 206.5 ppm.
= 7.6 Hz, 1 H, Ar), 7.90 (d, J = 7.2 Hz, 0.14 H, Ar, cis isomer), 7.96
HRMS (ESI): calcd. for C18H15ClO3Na [M + Na]+ 337.0602; (d, J = 7.2 Hz, 1.86 H, Ar, cis isomer) ppm. 13C NMR (100.6 MHz,
found 337.0598. HPLC analysis (Chiralpak AD column; hexane/2-
propanol, 98:2; flow rate: 1.0 mL/min; wavelength: 220 nm): Rt =
31.11 (minor, trans isomer) and 35.94 min (major, trans isomer).
CDCl3): δ = 21.5, 26.1, 40.6, 44.5, 90.9, 110.6, 122.2, 124.5, 125.5,
128.1, 133.5, 136.4, 139.3, 159.1, 197.6, 207.3 ppm. HRMS (ESI):
calcd. for C19H18O3Na [M + Na]+ 317.1148; found 317.1141.
HPLC analysis (Chiralpak AD column; hexane/2-propanol, 98:2;
flow rate: 1.0 mL/min; wavelength: 220 nm): Rt = 31.14 (minor,
trans isomer) and 36.70 min (major, trans isomer).
(2S,3S)-2-Acetyl-5-bromo-3-(1-oxo-1-phenylethyl)-2,3-dihydro-
benzofuran (5d): White solid (99% yield; trans/cis, 95:5; 95%ee for
trans isomer); m.p. 96–98 °C. [α]2D0 = +12.2 (c = 1.0, ethyl acetate).
1H NMR (400 MHz, CDCl3): δ = 2.29 (s, 0.15 H, cis isomer), 2.36
(s, 2.85 H, trans isomer), 3.45 (dd, J = 4.4 and 6.4 Hz, 2 H), 4.16
(dd, J = 6.4, 12.8 Hz, 1 H), 4.81 (d, J = 5.6 Hz, 0.95 H, trans
isomer), 5.22 (d, J = 9.6 Hz, 0.05 H, cis isomer), 6.79 (d, J = 8.4 Hz,
1 H, Ar), 7.27–7.31 (m, 2 H, Ar), 7.48 (t, J = 8.0 Hz, 2 H, Ar),
7.60 (t, J = 7.2 Hz, 1 H, Ar), 7.91 (d, J = 7.2 Hz, 0.10 H, Ar, cis
isomer), 7.97 (d, J = 7.2 Hz, 1.90 H, Ar, trans isomer) ppm. 13C
NMR (100.6 MHz, CDCl3): δ = 26.2, 40.5, 44.1, 90.9, 111.4, 113.4,
128.0, 128.1, 128.8, 131.0, 131.8, 133.7, 136.2, 158.0, 197.2,
204.1 ppm. HRMS (ESI): calcd. for C18H15BrO3Na [M + Na]+
381.0097; found 381.0098. HPLC analysis (Chiralpak AD column;
hexane/2-propanol, 98:2; flow rate: 1.0 mL/min; wavelength:
220 nm): Rt = 32.73 (minor, trans isomer) and 38.19 min (major,
trans isomer).
(2S,3S)-2-Acetyl-5-tert-butyl-3-(1-oxo-1-phenylethyl)-2,3-dihydro-
benzofuran (5h): Pale yellow oil (90% yield; trans/cis, 94:6; 96%ee
1
for trans isomer). [α]2D0 = +14.8 (c = 7.1, ethyl acetate). H NMR
(400 MHz, CDCl3): δ = 1.23 (s, 0.54 H, cis isomer), 1.26 (s, 8.46
H, trans isomer), 2.30 (s, 0.18 H, cis isomer), 2.35 (s, 2.82 H, trans
isomer), 3.45 (dd, J = 6.4, 12.4 Hz, 2 H), 4.16 (dd, J = 6.8, 12.8 Hz,
1 H), 4.77 (d, J = 5.2 Hz, 0.94 H, trans isomer), 5.21 (d, J = 9.6 Hz,
0.06 H, cis isomer), 6.83 (d, J = 8.4 Hz, 1 H, Ar), 7.18–7.22 (m, 2
H, Ar), 7.47 (t, J = 7.6 Hz, 2 H, Ar), 7.59 (t, J = 7.6 Hz, 1 H, Ar),
7.89 (d, J = 7.2 Hz, 0.12 H, Ar, cis isomer), 7.97 (d, J = 7.2 Hz,
1.88 H, Ar, cis isomer) ppm. 13C NMR (100.6 MHz, CDCl3): δ =
26.2, 31.6, 34.4, 41.0, 44.4, 90.9, 109.1, 121.7, 125.9, 128.0, 128.1,
128.7, 133.5, 136.6, 144.6, 156.5, 197.8, 207.3 ppm. HRMS (ESI):
calcd. for C22H24O3Na [M + Na]+ 359.1618; found 359.1616.
HPLC analysis (Chiralpak AD column; hexane/2-propanol, 98:2;
flow rate: 1.0 mL/min; wavelength: 220 nm): Rt = 13.57 (minor,
trans isomer) and 14.82 min (major, trans isomer).
(2S,3S)-2-Acetyl-5,7-dichloro-3-(1-oxo-1-phenylethyl)-2,3-dihydro-
benzofuran (5e): White solid (95% yield; trans/cis, 96:4; 97%ee for
trans isomer); m.p. 127–130 °C. [α]2D0 = +38.8 (c = 1.0, ethyl acet-
ate). 1H NMR (400 MHz, CDCl3): δ = 2.33 (s, 0.12 H, cis isomer),
2.39 (s, 2.88 H, trans isomer), 3.46 (dd, J = 2.0, 6.8 Hz, 2 H), 4.24
(dd, J = 6.4, 12.8 Hz, 1 H), 4.89 (d, J = 6.0 Hz, 0.96 H, trans
isomer), 5.20 (d, J = 10.0 Hz, 0.04 H, cis isomer), 7.09 (s, 1 H, Ar),
7.20 (d, J = 1.6 Hz, 1 H, Ar), 7.49 (t, J = 7.6 Hz, 2 H, Ar), 7.61
(t, J = 7.6 Hz, 1 H, Ar), 7.90 (d, J = 7.2 Hz, 0.08 H, Ar, cis isomer),
7.96 (d, J = 7.2 Hz, 1.92 H, Ar, cis isomer) ppm. 13C NMR
(100.6 MHz, CDCl3): δ = 26.4, 41.2, 43.9, 91.2, 115.9, 123.8, 126.7,
128.1, 128.8, 128.9, 131.7, 133.8, 136.0, 153.6, 196.8, 205.7 ppm.
HRMS (ESI): calcd. for C18H14Cl2O3Na [M + Na]+ 371.0212;
found 371.0208. HPLC analysis (Chiralpak AD column; hexane/2-
propanol, 98:2; flow rate: 1.0 mL/min; wavelength: 220 nm): Rt =
24.12 (minor, trans isomer) and 31.07 min (major, trans isomer).
(2S,3S)-2-Acetyl-3-[1-oxo-1-(3-fluorophenyl)ethyl]-2,3-dihydro-
benzofuran (5i): Pale yellow oil (90% yield; trans/cis, 97:3; 98%ee
1
for trans isomer). [α]2D0 = +71.8 (c = 2.2, ethyl acetate). H NMR
(400 MHz, CDCl3): δ = 2.29 (s, 0.09 H, cis isomer), 2.35 (s, 2.91
H, trans isomer), 3.41 (dd, J = 6.8 and 9.2 Hz, 2 H), 4.16 (dd, J =
6.4, 12.8 Hz, 1 H), 4.76 (d, J = 5.6 Hz, 1 H), 6.88–6.92 (m, 2 H,
Ar), 7.16–7.21 (m, 2 H, Ar), 7.62 (d, J = 8.8 Hz, 2 H, Ar), 7.83 (d,
J = 8.8 Hz, 2 H, Ar) ppm. 13C NMR (100.6 MHz, CDCl3): δ =
26.1, 40.5, 44.4, 90.5, 109.9, 114.8 (d, J = 22.3 Hz), 120.5 (d, J =
21.4 Hz), 121.5, 123.8, 124.8, 128.3, 129.0, 130.4 (d, J = 7.6 Hz),
138.4 (d, J = 6.2 Hz), 158.7, 162.8 (d, J = 248.4 Hz), 196.3,
207.1 ppm. HRMS (ESI): calcd. for C18H15FO3Na [M + Na]+
321.0897; found 321.0892. HPLC analysis (Chiralpak AD column;
hexane/2-propanol, 98:2; flow rate: 1.0 mL/min; wavelength:
220 nm): Rt = 28.42 (minor, trans isomer) and 29.95 min (major,
trans isomer).
(2S,3S)-2-Acetyl-5-methyl-3-(1-oxo-1-phenylethyl)-2,3-dihydro-
benzofuran (5f): Pale yellow oil (99% yield; trans/cis, 97:3; 97%ee
1
for trans isomer). [α]2D0 = +25.8 (c = 2.7, ethyl acetate). H NMR
(400 MHz, CDCl3): δ = 2.25 (s, 3 H), 2.28 (s, 0.09 H, cis isomer),
2.34 (s, 2.91 H, trans isomer), 3.44 (dd, J = 6.8 and 12.0 Hz, 2 H),
4.13 (dd, J = 6.4, 12.4 Hz, 1 H), 4.75 (d, J = 5.6 Hz, 0.97 H, trans
isomer), 5.19 (d, J = 9.6 Hz, 0.03 H, cis isomer), 6.79 (d, J = 8.8 Hz,
1 H, Ar), 6.95–6.99 (m, 2 H, Ar), 7.48 (t, J = 7.6 Hz, 2 H, Ar),
(2S,3S)-2-Acetyl-3-[1-oxo-1-(4-fluorophenyl)ethyl]-2,3-dihydro-
benzofuran (5j): Pale yellow oil (98% yield; trans/cis, 96:4; 97%ee
1
for trans isomer). [α]2D0 = +68.3 (c = 2.3, ethyl acetate). H NMR
(400 MHz, CDCl3): δ = 2.30 (s, 0.12 H, cis isomer), 2.35 (s, 2.88
7.59 (t, J = 7.6 Hz, 1 H, Ar), 7.91 (d, J = 7.2 Hz, 0.06 H, Ar, cis H, trans isomer), 3.42 (dd, J = 6.4 and 9.6 Hz, 2 H), 4.17 (dd, J =
isomer), 7.97 (d, J = 7.6 Hz, 1.94 H, Ar, trans isomer) ppm. 13C 6.4, 12.8 Hz, 1 H), 4.77 (d, J = 5.6 Hz, 0.96 H, trans isomer), 45.21
NMR (100.6 MHz, CDCl3): δ = 20.8, 26.1, 40.8, 44.4, 90.8, 109.4,
125.4, 128.1, 128.5, 128.7, 129.4, 130.9, 133.5, 136.4, 156.7, 197.6,
207.4 ppm. HRMS (ESI): calcd. for C19H18O3Na [M + Na]+
(d, J = 9.6 Hz, 0.04 H, cis isomer), 6.88–6.92 (m, 2 H, Ar), 7.12–
7.21 (m, 4 H, Ar), 7.98–8.01 (m, 2 H, Ar) ppm. 13C NMR
(100.6 MHz, CDCl3): δ = 26.1, 40.6, 44.1, 90.5, 109.8, 115.8 (d, J
317.1148; found 317.1149. HPLC analysis (Chiralpak AD column; = 21.8 Hz), 121.4, 124.8, 128.3, 128.9, 130.6, 130.7, 132.7, 132.8,
hexane/2-propanol, 98:2; flow rate: 1.0 mL/min; wavelength:
220 nm): Rt = 28.87 (minor, trans isomer) and 30.77 min (major,
trans isomer).
158.7, 165.8 (d, J = 255.5 Hz), 4.3, 121.3, 124.0, 128.0, 129.3, 129.6,
129.9, 131.8, 156.8, 206.2 ppm. HRMS (ESI): calcd. for
C18H15FO3Na [M + Na]+ 321.0897; found 321.0902. HPLC analy-
Eur. J. Org. Chem. 2013, 4836–4843
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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4841

Y. Liu, A. Lu, K. Hu, Y. Wang, H. Song, Z. Zhou, C. Tang
FULL PAPER
sis (Chiralpak AD column; hexane/2-propanol, 98:2; flow rate:
1
for trans isomer). [α]2D0 = +44.4 (c = 4.8, ethyl acetate). H NMR
1.0 mL/min; wavelength: 220 nm): Rt = 45.49 (minor, trans isomer) (400 MHz, CDCl3): δ = 2.28 (s, 0.30 H, cis isomer), 2.35 (s, 2.70
and 48.61 min (major, trans isomer).
H, trans isomer), 3.39 (dd, J = 6.8, 8.8 Hz, 2 H), 3.85 (s, 0.30 H,
cis isomer), 3.86 (s, 2.70 H, trans isomer), 4.15 (dd, J = 6.4, 12.8 Hz,
0.90 H, trans isomer), 4.44 (d, J = 6.8, 16.0 Hz, 0.10 H, cis isomer),
4.78 (d, J = 5.6 Hz, 0.90 H, trans isomer), 5.21 (d, J = 9.6 Hz, 0.10
H, cis isomer), 6.87–6.94 (m, 4 H, Ar), 7.15–7.19 (m, 2 H, Ar), 7.88
(d, J = 8.8 Hz, 0.20 H, Ar, cis isomer), 7.94 (d, J = 8.8 Hz, 1.80 H,
Ar, trans isomer) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 26.1,
40.8, 44.0, 55.4, 90.6, 109.8, 113.8, 121.4, 124.9, 128.6, 128.9, 129.5,
130.3, 158.8, 163.7, 196.0, 207.0 ppm. HRMS (ESI): calcd. for
C19H18O4Na [M + Na]+ 333.1097; found 333.1091. HPLC analysis
(Chiralpak AD column; hexane/2-propanol, 98:2; flow rate:
1.0 mL/min; wavelength: 220 nm): Rt = 51.81 (minor, trans isomer)
and 55.34 min (major, trans isomer).
(2S,3S)-2-Acetyl-3-[1-oxo-1-(4-chlorophenyl)ethyl]-2,3-dihydro-
benzofuran (5k): Pale yellow oil (94% yield; trans/cis, 95:5; 97%ee
1
for trans isomer). [α]2D0 = +45.2 (c = 2.1, ethyl acetate). H NMR
(400 MHz, CDCl3): δ = 2.29 (s, 0.15 H, cis isomer), 2.35 (s, 2.85
H, trans isomer), 3.41 (dd, J = 6.8, 9.6 Hz, 2 H), 4.16 (dd, J = 6.4,
12.8 Hz, 1 H), 4.76 (d, J = 5.6 Hz, 0.95 H, trans isomer), 5.20 (d,
J = 9.6 Hz, 0.05 H, cis isomer), 6.88–6.92 (m, 2 H, Ar), 7.16–7.21
(m, 2 H, Ar), 7.45 (d, J = 8.4 Hz, 2 H, Ar), 7.90 (d, J = 8.4 Hz, 2
H, Ar) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 26.2, 40.7, 44.3,
90.6, 109.9, 121.6, 124.9, 128.3, 129.1, 129.5, 134.7, 140.1, 158.8,
196.3, 207.2 ppm. HRMS (ESI): calcd. for C18H15ClO3Na [M +
Na]+ 337.0602; found 337.0596. HPLC analysis (Chiralpak AD
column; hexane/2-propanol, 98:2; flow rate: 1.0 mL/min; wave-
length: 220 nm): Rt = 48.67 (minor, trans isomer) and 54.36 min
(major, trans isomer).
(2S,3S)-2-Acetyl-3-[1-oxo-1-(4-methylphenyl)ethyl]-2,3-dihydro-
benzofuran (5o): Pale yellow oil (99% yield; trans/cis, 90:10; 95%ee
1
for trans isomer). [α]2D0 = +73.7 (c = 2.7, ethyl acetate). H NMR
(400 MHz, CDCl3): δ = 2.29 (s, 0.30 H, cis isomer), 2.36 (s, 2.70
H, trans isomer), 2.42 (s, 3 H), 3.42 (dd, J = 6.8, 11.6 Hz, 2 H),
4.17 (dd, J = 6.4, 12.8 Hz, 0.90 H, trans isomer), 4.45 (dd, J = 6.4,
16.4 Hz, 0.10 H, cis isomer), 4.78 (d, J = 5.6 Hz, 0.90 H, trans
isomer), 5.21 (d, J = 9.6 Hz, 0.10 H, cis isomer), 6.86–6.92 (m, 2
H, Ar), 7.17–7.20 (m, 2 H, Ar), 7.27 (d, J = 8.0 Hz, 2 H, Ar), 7.80
(d, J = 8.0 Hz, 0.20 H, Ar, cis isomer), 7.87 (d, J = 8.0 Hz, 1.80 H,
Ar, trans isomer) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 21.6,
26.1, 40.7, 44.2, 90.6, 109.8, 121.4, 124.9, 128.2, 128.5, 128.9, 129.4,
133.9, 144.4, 158.8, 197.1, 207.0 ppm. HRMS (ESI): calcd. for
C19H18O3Na [M + Na]+ 317.1148; found 317.1148. HPLC analysis
(Chiralpak AD column, hexane/2-propanol, 98:2; flow rate:
1.0 mL/min; wavelength: 220 nm): Rt = 47.23 (minor, trans isomer)
and 51.29 min (major, trans isomer).
(2S,3S)-2-Acetyl-3-[1-oxo-1-(4-bromophenyl)ethyl]-2,3-dihydro-
benzofuran (5l): Pale yellow oil (90% yield; trans/cis, 97:3; 98%ee
for trans isomer). [α]2D0 = +59.6 (c = 3.1, ethyl acetate). H NMR
1
(400 MHz, CDCl3): δ = 2.30 (s, 0.09 H, cis isomer), 2.36 (s, 2.91
H, trans isomer), 3.43 (dd, J = 6.8, 8.8 Hz, 2 H), 4.17 (dd, J = 6.4,
12.8 Hz, 1 H), 4.77 (d, J = 6.0 Hz, 0.97 H), 5.20 (d, J = 9.6 Hz,
0.03 H), 6.88–6.93 (m, 2 H, Ar), 7.17–7.22 (m, 2 H, Ar), 7.27–7.31
(m, 1 H, Ar), 7.43–7.48 (m, 1 H, Ar), 7.64–7.67 (m, 1 H, Ar), 7.74
(d, J = 8.0 Hz, 1 H, Ar) ppm. 13C NMR (100.6 MHz, CDCl3): δ =
26.2, 40.6, 44.2, 90.5, 109.9, 121.5, 124.9, 128.3, 128.8, 129.0, 129.6,
132.0, 136.1, 158.7, 196.5, 207.1 ppm. HRMS (ESI): calcd. for
C18H15BrO3Na [M + Na]+ 381.0097; found 381.0095. HPLC analy-
sis (Chiralpak AD column; hexane/2-propanol, 98:2; flow rate:
1.0 mL/min; wavelength: 220 nm): Rt = 59.88 (minor, trans isomer)
and 63.78 min (major, trans isomer).
(2S,3S)-2-Acetyl-3-[1-oxo-1-(furan-2-yl)ethyl]-2,3-dihydrobenzo-
furan (5p): Pale yellow oil (98% yield; trans/cis, 95:5; Ͼ99%ee for
trans isomer). [α]2D0 = +73.1 (c = 2.8, ethyl acetate). 1H NMR
(400 MHz, CDCl3): δ = 2.30 (s, 0.15 H, cis isomer), 2.32 (s, 2.85
H, trans isomer), 3.29 (dd, J = 6.8, 18.4 Hz, 2 H), 4.13 (dd, J =
6.8, 12.8 Hz, 1 H), 4.78 (d, J = 5.6 Hz, 0.95 H, trans isomer), 5.16
(d, J = 9.6 Hz, 0.05 H, cis isomer), 6.54 (dd, J = 1.6, 3.6 Hz, 1 H,
Ar), 6.86–6.90 (m, 2 H, Ar), 7.15–7.19 (m, 2 H, Ar), 7.22 (d, J =
3.2 Hz, 1 H, Ar), 7.54 (d, J = 0.80 Hz, 0.05 H, Ar, cis isomer), 7.58
(d, J = 0.8 Hz, 0.95 H, Ar, trans isomer) ppm. 13C NMR
(100.6 MHz, CDCl3): δ = 26.1, 40.5, 43.9, 90.4, 109.8, 112.4, 117.5,
121.5, 124.9, 128.2, 129.0, 146.7, 152.4, 158.7, 186.6, 207.0 ppm.
HRMS (ESI): calcd. for C16H14O4Na [M + Na]+ 293.0784; found
293.0782. HPLC analysis (Chiralpak OD column; hexane/2-prop-
(2S,3S)-2-Acetyl-3-[1-oxo-1-(2,4-dichlorophenyl)ethyl]-2,3-dihydro-
benzofuran (5m): Pale yellow oil (66% yield; trans/cis, 76:24; 88%ee
for trans isomer, 94%ee for cis isomer). [α]2D0 = +23.4 (c = 2.6, ethyl
1
acetate). H NMR (400 MHz, CDCl3): δ = 2.28 (s, 0.72 H, cis iso-
mer), 2.33 (s, 2.28 H, trans isomer), 3.26, (dd, J = 6.8, 10.4 Hz,
0.48 H, cis isomer), 3.42 (dd, J = 6.8, 8.8 Hz, 1.52 H, trans isomer),
4.15 (dd, J = 6.8, 12.8 Hz, 0.76 H, trans isomer), 4.42 (dd, J = 7.2,
16.4 Hz, 0.24 H, cis isomer), 4.76 (d, J = 5.6 Hz, 0.76 H, trans
isomer), 5.16 (d, J = 9.6 Hz, 0.24 H, cis isomer), 6.86–6.92 (m, 2
H, Ar), 7.15–7.21 (m, 2 H, Ar), 7.29–7.33 (m, 1 H, Ar), 7.42–7.52
(m, 2 H, Ar) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 26.2 (trans
isomer), 28.6 (cis isomer), 40.1 (cis isomer), 40.9 (trans isomer),
43.4 (cis isomer), 48.3 (trans isomer), 87.6 (cis isomer), 90.3 (trans
isomer), 109.9 (trans isomer), 110.0 (cis isomer), 121.5 (cis isomer),
121.6 (trans isomer), 124.3 (cis isomer), 124.8 (trans isomer), 127.4
(cis isomer), 127.5 (trans isomer), 128.0 (trans isomer), 128.5 (cis
isomer), 129.0 (cis isomer), 129.1 (trans isomer), 130.4 (cis isomer),
130.5 (trans isomer), 130.6 (trans isomer), 130.9 (cis isomer), 132.0
(cis isomer), 132.3 (trans isomer), 136.6 (trans isomer), 136.8 (cis
isomer), 137.7 (cis isomer), 138.0 (trans isomer), 158.6 (cis isomer),
158.7 (trans isomer), 199.0 (cis isomer), 199.2 (trans isomer), 207.4
(trans isomer), 209.1 (cis isomer) ppm. HRMS (ESI): calcd. for
C18H14Cl2O3Na [M + Na]+ 371.0212; found 371.0214. HPLC
analysis (Chiralpak AD column; hexane/2-propanol, 98:2; flow
rate: 1.0 mL/min; wavelength: 220 nm): Rt = 16.58 (major, cis iso-
mer), 20.61 (minor, cis isomer), 29.76 (minor, trans isomer), and
32.87 min (major, trans isomer).
anol, 70:30; flow rate: 1.0 mL/min; wavelength: 220 nm): Rt
8.28 min (major, trans isomer).
=
Supporting Information (see footnote on the first page of this arti-
cle): Copies of NMR and HRMS spectra as well as the chiral
HPLC spectra of the prepared optically active trans-dihydrobenzo-
furans.
Acknowledgments
The authors are grateful to the National Natural Science Founda-
tion of China (NSFC) (grant numbers 20972070 and 21121002),
the National Basic Research Program of China (973 Program,
grant number 2010CB833300), the Program for New Century Ex-
cellent Talents in University (grant number NCET-11-0265), and
the Key Laboratory of Elemento-Organic Chemistry for their gen-
erous financial support of our programs.
(2S,3S)-2-Acetyl-3-[1-oxo-1-(4-methoxyphenyl)ethyl]-2,3-dihydro-
benzofuran (5n): Pale yellow oil (99% yield; trans/cis, 90:10; 95%ee
4842
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 4836–4843

Stereocontrolled Construction of trans-Dihydrobenzofurans
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[19] CCDC-931250 (for 5a) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
Received: March 6, 2013
Published Online: June 17, 2013
Eur. J. Org. Chem. 2013, 4836–4843
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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