Asymmetric Michael addition reactions of 3-substituted benzofuran-2(3H)- ones to nitroolefins catalyzed by a bifunctional tertiary-amine thiourea

Article abstract of DOI:10.1039/c1ob06518a

The current work reports an organocatalytic strategy for the asymmetric catalysis of chiral benzofuran-2(3H)-ones bearing 3-position all-carbon quaternary stereocenters. Accordingly, highly enantioselective Michael addition reactions of 3-substituted benz

Full text of DOI:10.1039/c1ob06518a

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PAPER
Asymmetric Michael addition reactions of 3-substituted
benzofuran-2(3H)-ones to nitroolefins catalyzed by a bifunctional
tertiary-amine thiourea†
Xin Li,*a Xiao-Song Xue,‡a Cong Liu,‡a Bin Wang,b Bo-Xuan Tan,a Jia-Lu Jin,a Yue-Yan Zhang,a Nan Donga
and Jin-Pei Cheng*a
Received 4th September 2011, Accepted 29th September 2011
DOI: 10.1039/c1ob06518a
The current work reports an organocatalytic strategy for the asymmetric catalysis of chiral
benzofuran-2(3H)-ones bearing 3-position all-carbon quaternary stereocenters. Accordingly, highly
enantioselective Michael addition reactions of 3-substituted benzofuran-2(3H)-ones to nitroolefins
have been developed by utilizing a bifunctional tertiary-amine thiourea catalyst. The reactions
accommodate a number of nitroolefins and 3-substituted benzofuran-2(3H)-ones to give the desired
chiral benzofuran-2(3H)-one products with moderate to excellent yields (up to 98%) and moderate to
very good selectivities (up to 19 : 1 dr and up to 91% ee). Theoretical calculations using the DFT
method on the origin of the stereoselectivity were conducted. The effect of the nitroolefin substituent
position on the stereoselectivity of the Michael addition reaction was also theoretically rationalized.
as amines, nitrile oxides and ketones. In this context, a number of
Introduction
influential bifunctional tertiary-amine thiourea catalyzed Michael
The development of novel and highly enantioselective transfor-
additions, in which nitroolefins are used as electrophiles, have left
a deep impression.5
mations is one of the most exciting goals for organic chemists
involved in the competitive and stimulating field of asymmetric
organocatalysis.1 In this area, asymmetric hydrogen-bonding
catalysis, especially using a bifunctional chiral thiourea/urea,
which has a combination of thiourea/urea and tertiary-amine
group, has been recognized as an impactful strategy to realize a
number of important asymmetric C–C bond-forming reactions.2,3
Among the multitudinous realized asymmetric reactions pro-
moted by bifunctional tertiary-amine thiourea/ureas, the Michael
addition reaction takes up the considerably dominant status.4
Several impressive Michael acceptors, which can be activated
through the double hydrogen-bonding interaction of the N–H of
thiourea/urea to realize a specific role in efficient enantiocontrol,
have been successfully applied. Among them, nitroolefins have
attracted special attention by virtue of their high activity and di-
versiform synthetic application, in which the resulting nitroalkanes
can readily be transformed into many useful building blocks, such
3,3¢-Disubstituted benzofuran-2(3H)-ones and their derivatives
have received extensive attention, since the structural motif of this
type of compound, which has in its construction a quaternary
chiral center, is a prominent feature in a number of biologically
and pharmaceutically active natural products.6 In this context,
great efforts have been focused toward the total synthesis of
corresponding benzofuran-2(3H)-one type compounds in recent
years.7 However, direct and valuable strategies for the asymmetric
synthesis of the 3,3¢-disubstituted benzofuran-2(3H)-one frame-
work have been less studied and only a few examples based
on organocatalytic protocols have been investigated to date.5h,5l,8
Therefore, the development of new and efficient organocatalytic
methodologies to obtain chiral 3,3¢-disubstituted benzofuran-
2(3H)-ones is still of remarked importance, and is strongly desired.
Continuing our recent research program towards a new strategy
for synthesis of chiral 3,3¢-disubstituted benzofuran-2(3H)-ones
by asymmetric organocatalysis5h,5l,8c and based on our experience
using bifunctional tertiary-amine thiourea catalysts,5h–5l herein, we
report a highly enantioselective Michael addition reaction of 3-
substituted benzofuran-2(3H)-ones to nitroolefins promoted by a
bifunctional tertiary-amine thiourea catalyst (Fig. 1). A number of
nitroolefins and 3-substituted benzofuran-2(3H)-ones are favored
in this synthetic strategy for chiral 3,3¢-substituted benzofuran-
2(3H)-one type compounds. In addition, we have sought to explain
the stereoselectivity results using a DFT theoretical study. And the
results are presented in the following.
aState Key Laboratory of Elemento-organic Chemistry and Department of
Chemistry, Nankai University, Tianjin, 300071, China. E-mail: xin_li@
nankai.edu.cn; Fax: (+86)-22-23499147; Tel: (+86)-22-23499174
bTianjin Key Laboratory of Structure and Performance for Functional
Molecule, College of Chemistry, Tianjin Normal University, Tianjin, 300387,
China
† Electronic supplementary information (ESI) available: NMR and HPLC
spectra for all the new compounds, details of theoretical calculations.
CCDC reference number 810503 (3h). For ESI and crystallographic data
in CIF or other electronic format see DOI: 10.1039/c1ob06518a
‡ These authors contributed equally to this work.
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Fig.
1 Strategy for bifunctional tertiary-amine thiourea catalyzed
Michael reactions of benzofuran-2(3H)-ones to nitroolefins.
Results and discussion
Bifunctional tertiary-amine thiourea catalyzed Michael addition
reaction of 3-alkyl substituted benzofuran-2(3H)-ones to
nitroolefins
The Michael addition reaction of 3-methylbenzofuran-2(3H)-
one 1a to nitrostyrene was first selected as our initial testing
reaction. The Michael addition reaction cannot progress when
no catalyst is added. Although a simple alkali 4a can completely
promote the Michael addition (entry 2 in Table 1), the obtained
product is racemic. Then six widely used bifunctional tertiary-
amine thiourea/urea catalysts 4b–4g5 (Fig. 2) with different chiral
scaffolds were screened in the current model reaction at 20 ◦C. To
our delight, all of the chiral bifunctional hydrogen-bonding cata-
lysts 4b–4gexhibitedhighcatalyticactivity. As aresult, theMichael
addition products were cleanly isolated with quantitative yields
and moderate selectivities (entries 3–8 in Table 1). It is obvious that
the activation effect of the double hydrogen-bonding of thiourea
or urea on benzofuran-2(3H)-one is of significant importance for
the inducement of enantioselectivity. In comparison, catalyst 4g,
was found to give the optimal enantioselectivity (98% yield, 3 : 1
dr and 53% ee, entry 8 in Table 1). In order to further improve the
catalytic results, we then examined the catalysts 4h–4j, which are
chiral scaffolds based on the predominate structure of (1S,2S)-
(-)-1,2-diphenyl-1,2-ethanediamine. To our disappointment, the
obtained three enantioselectivities catalyzed by 4h–4j are all lower
than the corresponding result catalyzed by 4g.
Fig. 2 Examined catalysts.
With thiourea 4g as the optimal catalyst, the reaction was
further optimized by screening different solvents (Table 2). Highly
polar solvents such as DMSO and DMF were not applicable
solvents leading to totally depleted activity (entries 1 and 2 in
Table 2). The reactions generally proceeded smoothly in less polar
solvent such as CH2Cl2, CHCl3, ClCH2CH2Cl, THF, C6H6 and
PhCH3. Among a number of solvents examined, PhCH3 was the
optimal one, furnishing the best enantioselectivity (entry 10 in
Table 2, 96% yield, 3.5 : 1 dr and 57% ee). Further improvement
could be achieved by lowering the reaction temperature (entries
˚
10–12 in Table 2). Addition of 4 A molecular sieves to the
reaction mixture slightly increased both the diastereoselectivity
Table 2 Screening of solventa
Table 1 Catalyst screeninga
Entry
Solvent
Time (h)
Yieldb (%)
drc
eed (%)
1
2
3
4
5
6
7
8
DMSO
DMF
Et2O
CH3CN
CH2Cl2
CHCl3
ClCH2CH2Cl
THF
4
4
4
4
4
4
4
4
4
4
12
48
48
trace
trace
30
85
98
97
91
90
95
96
85
90
95
nd
nd
nd
nd
35
30
53
44
47
57
52
57
62
64
66
Entry
Catalyst
Time (h)
Yieldb (%)
drc
eed (%)
2 : 1
2 : 1
3 : 1
2 : 1
3 : 1
3 : 1
3 : 1
3.5 : 1
3.5 : 1
4 : 1
4 : 1
1
2
3
4
5
6
7
8
No catalyst
72
24
4
4
4
4
4
4
4
No reaction
nde
nde
rac
33
28
40
39
31
53
50
51
48
4a
4b
4c
4d
4e
4f
80
91
95
93
99
90
98
83
87
94
1 : 1
2 : 1
2 : 1
3 : 1
3 : 1
2 : 1
3 : 1
3 : 1
3 : 1
3 : 1
9
C6H6
10
11e
12f
13g
PhCH3
PhCH3
PhCH3
PhCH3
4g
4h
4i
9
10
11
4
4
4j
a The reaction was carried out on a 0.1 mmol scale in 400 uL of solvent at
20 ◦C, and the molar ratio of 1a/nitrostyrene is 1/1.5. b Isolated yield.
c Determined by 1H NMR of crude product. d Determined by HPLC.
e Conducted at -20 ◦C. f Conducted at -60 ◦C. g Conducted at -60 ◦C
a The reaction was carried out on a 0.1 mmol scale in 400 uL CH2Cl2
at 20 ◦C, and the molar ratio of 1a/nitrostyrene is 1/1.5. b Isolated yield.
c Determined by 1H NMR of crude product. d Determined by HPLC. e Not
determined.
˚
with 40 mg 4 A molecular sieves.
414 | Org. Biomol. Chem., 2012, 10, 413–420
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Table 3 Asymmetric Michael addition reaction of 3-methylbenzofuran-
2(3H)-one to different substituted nitrostyrenesa
entry
G =
Time
Yieldb (%)
d.r.c
eed (%)
1
2
3
4
5
6
7
8
H
4-MeO
4-F
4-Ph
4-Cl
3,4-2Cl
3-NO2
2-Cl
2-Br
2-F-6-Cl
2,6-2Cl
48
72
48
60
48
48
72
48
48
72
72
3a: 96
3b: 92
3c: 90
3d: 90
3e: 87
3f: 87
3g: 91
3h:: 95
3i: 98
3j: 85
3k: 87
4 : 1
3 : 1
3 : 1
3 : 1
2 : 1
3 : 1
1 : 1
19 : 1
19 : 1
4 : 1
11 : 1
66
65
64
58
52
Fig. 3 Investigation of other substrates.
fde
75/15
86
We obtained the X-ray crystal structure of product 3h (Fig. 4),9
which proved the absolution configuration for 3h. The absolute
configurations of other products can therefore be determined by
analogy.
9
10
11
80
82
91
a The re◦action was carried out on a 0.1 mmol scale in 400 uL PhCH3
˚
at -60 C with 40 mg 4 A molecular sieves, and the molar ratio of
1a/nitroolefin is 1/1.5. b Isolated yield. c Determined by 1H NMR of
crude products. d Determined by HPLC. e fd = Failed to determine the
ee because the two enantiomers could not be separated on the Daicel
chiralpak columns.
and enantioselectivity (entry 13 in Table 2). Collectively, the best
results with respect to yield and stereoselectivity were obtained by
◦
˚
performing the reaction at -60 C in PhCH3 in the presence of 4 A
molecular sieves. Under this condition, the reaction provided the
desired product with 95% yield in 4 : 1 dr and 66% ee.
With the optimal conditions in hand, the substrate scopes
were next explored. Firstly, eleven substituted nitrostyrenes were
examined. As shown in Table 3, the reactions worked well with
nitrostyrenes bearing either electronic withdrawing or electronic
donating groups to give the desired products with high yield (85–
96%), moderate to very good diastereoselectivities (3 : 1–19 : 1 dr)
and moderate to very good enantioselectivities (52–91% ee). It
is obviously found that the stereoselectivity of the reaction is
sensitive to the substitution position of the nitrostyrene. Slightly
lower selectivities were obtained, when p-substituted nitrostyrenes
2a–2e were used as Michael acceptors (entries 1–5 in Table
3). As a result, the corresponding conjugate addition products
3a–3e were obtained with 4 : 1–3 : 1 dr and 52–66% ee. On the
other hand, higher selectivities were obtained, when o-substituted
nitrostyrenes 2h–2k were selected as Michael acceptors (entries
8–11 in Table 3, up to 19 : 1 dr and 80–91% ee).
Fig. 4 X-ray crystal structure of 3h.
Bifunctional tertiary-amine thiourea catalyzed Michael addition
reaction of 3-aryl substituted benzofuran-2(3H)-ones to nitroolefins
3-Aryl substituted benzofuran-2(3H)-ones, were next attempted
in the current Michael strategy with the hope of further expand-
ing the substrate scope. Indeed, various 3-aromatic substituted
benzofuran-2(3H)-ones worked very well with nitrostyrene to give
the desired products 3p–3t in high yields with good stereoselectiv-
ities (Fig. 5).
In order to expand the substrate scope, other types of ni-
troolefins, such as naphthyl and alkyl substituted nitroolefins
were investigated in this study. From the results in Fig. 3 (3l–
3n), we found that not only the naphthyl nitroolefin, but also
the two alkyl type nitroolefins put up very good activities (85–
90% yield), moderate to excellent diastereoselectivities (2 : 1–19 : 1
dr) and good enantioselectivities (77–85% ee) in the current bi-
functional tertiary-amine thiourea catalytic system. Furthermore,
we also explored the influence of Michael donor. As a result, 3-
benzylbenzofuran-2(3H)-one was reacted with nitrostyrene 2a un-
der the optimized conditions, in which the desired Michael product
3o was obtained with high yield (91%), bad diastereoselectivity
(1 : 1 dr) and good enantioselectivities (84%/65% ee).
Fig. 5 Results of 3-aryl substituted benzofuran-2(3H)-ones as Michael
donors.
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˚
Theoretical study of the bifunctional tertiary-amine thiourea
catalyzed Michael addition reactions of 3-substituted
benzofuran-2(3H)-ones to nitroolefins
of 2a (1.84 A) contributed to the electrostatic stabilization of the
TS2. Furthermore, the potential p–p interaction between the two
aromatic rings of 1a and 2a in TS2 would also help drop the
energy. This computed result means that the TS2’s corresponding
compound was the main product of our asymmetric catalytic
reaction, which is consistent with the experimental results.
In order to understand the effects of the substitution’s
position on nitrostyrene on stereoselectivities in the current
studied Michael strategy, transition states of the reaction of
3-methylbenzofuran-2(3H)-one (1a) and 2-chloro substituted ni-
trostyrene (2h) were also investigated. As shown in Fig. 7, the
enantioselectivity’s energy gap of the reaction between 1a and 2h
is 2.0 kcal mol-1 (TS5 and TS6 in Fig. 7), which is 1.4 kcal mol-1
higher than the corresponding reaction between 1a and 2a (0.6 kcal
mol-1, TS2 and TS4 in Fig. 6). Based on the calculated results, it is
obvious that the enantioselectivity of 3h should be higher than 3a,
which is in good qualitative agreement with experimental results
(86% ee for 3h and 66% ee for 3a, Table 3). It is worth noting
that the observed possible lone pair–p interaction between the Cl
atom and the aromatic ring of nitrostyrene may contribute to the
stabilization of the TS5.12
The activation of nitroolefins by tertiary-amine thioureas has
been demonstrated earlier in many other mechanism studies and
indicated the bifunctional character of this structure in Michael
reactions.5c,10 On the basis of the catalytic results, we assumed
that the enantioselectivity of the reaction is controlled during the
C–C bond formation between the activated nitroolefin and the
nucleophile.
Since nitro compounds are known to form hydrogen bonds with
urea and thiourea,11 nitroolefins have been assumed to interact
with the thiourea moiety via multiple H-bonds, enhancing the
electrophilic character of the reacting carbon center. On the other
hand, the enolic forms of benzofuran-2(3H)-ones are assumed
to interact with the tertiary amine group, and a subsequent
deprotonation results in a highly nucleophilic enolate species.
According to the above described model, a mechanism based upon
catalyst 4g is proposed to account for the observed diastereo-
and enantioselectivity. As shown in Fig. 6, we have studied the
approach of 3-methylbenzofuran-2(3H)-one (1a) and nitrostyrene
(2a), which have been employed as the model reagents, to both
Re and Si faces of the nitroalkene. For each enantiotopic face,
the attack can also arise from two possible orientations of the
3-methylbenzofuran-2(3H)-one, leading to four transition states
(Fig. 6).
Fig. 7 Transition state geometries for the reaction of 3-methylbenzo-
furan-2(3H)-one (1a) and 2-chloro substituted nitrostyrene (2h) (units:
kcal mol-1).
Using the same transition state model, we also investigated the
transition states of the reaction between 1a and 2a catalyzed by
the Takemoto catalyst (See Fig. S2 in ESI†). From the results, we
can see that only a 0.2 kcal mol-1 energy gap was found to be
responsible for the enantioselectivity. This observation was also
in agreement with our initial screening results of the bifunctional
tertiary-amine catalysts (entry 3 in Table 1).
Conclusion
In summary, we have presented a highly enantioselective Michael
addition reaction of 3-substituted benzofuran-2(3H)-ones to
nitroolefins by a simple bifunctional tertiary-amine thiourea
organocatalyst. The reaction scope is substantial and a number of
aryl or alkyl substituted benzofuran-2(3H)-ones and nitroolefins
could be successfully applied to give multifunctional chiral
benzofuran-2(3H)-one compounds with an all carbon-substituted
quaternary stereocenter and a tertiary stereocenter with moderate
to very good enantioselectivities. Theoretical calculations with
Fig. 6 Transition state geometries for the reaction of 3-methylbenzofu-
ran-2(3H)-one (1a) and nitrostyrene (2a) (units: kcal mol-1).
Among these transition states, TS2 shows the lowest energy
(Fig. 6). We hypothesized that the hydrogen bonding interaction
between the key proton abstracted from the developing enolate
by the dimethylamino group of catalyst 4g and the nitro group
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the DFT method on the current Michael strategy was also
conducted. More endeavors demonstrating the further derivations
and reactions of the Michael products are in progress in our
laboratory.
J = 7.82 Hz), 7.23–7.20 (1H, t, J = 7.56 Hz), 7.09 (1H, d, J =
7.38 Hz), 7.02 (1H, d, J = 7.91 Hz), 6.88 (4H, d, J = 6.77 Hz), 4.97
(1H, d, J = 4.04 Hz), 4.89–4.83 (1H, t, J = 12.13 Hz), 4.02 (1H,
d, J = 3.69 Hz), 1.59 (3H, s); 13C NMR (100.6 MHz, CDCl3): d
177.5, 164.0, 161.6, 152.7, 130.6, 130.5, 130.1, 130.0, 129.6, 128.7,
124.6, 123.7, 115.7, 115.5, 111.4, 75.5, 49.9, 49.7, 21.7 ppm; HRMS
(ESI+): calcd. for [C17H14FNO4 + Na]+ 338.0799, found 338.0804.
The enantiomeric excess was determined by HPLC with an AD-H
column at 210 nm (2-propanol : hexane = 1 : 19), 1.0 mL min-1; tR =
20.8 min (major), 16.5 min (minor).
3d: The Michael product was synthesized according to the
general procedure as a white solid in 90% overall yield. [a]1D5 -207.8
(c 0.23, CHCl3); 1H NMR (400 MHz, CDCl3): d 7.52 (2H, d, J =
7.65 Hz), 7.43–7.39 (4H, t, J = 7.73 Hz), 7.36–7.31 (2H, m), 7.21–
7.18 (1H, t, J = 7.38 Hz), 7.08 (1H, d, J = 7.65 Hz), 7.03–6.97 (3H,
m), 5.02 (1H, d, J = 3.34 Hz), 4.97–4.91 (1H, t, J = 11.87 Hz), 4.06
(1H, d, J = 4.04 Hz), 1.61 (3H, s); 13C NMR (100.6 MHz, CDCl3): d
177.7, 152.7, 141.5, 140.1, 132.8, 129.9, 129.3, 129.0, 128.8, 127.6,
127.2, 127.0, 124.6, 123.9, 111.3, 75.5, 50.0, 49.9, 21.7 ppm; HRMS
(ESI+): calcd. for [C23H19NO4 + Na]+ 396.1206, found 396.1207.
The enantiomeric excess was determined by HPLC with an AD-H
column at 210 nm (2-propanol : hexane = 1 : 9), 1.0 mL min-1; tR =
29.9 min (major), 18.4 min (minor).
Experimental section
General remarks
Commercial reagents were used as received, unless otherwise
stated. Chemical shifts are reported in ppm from tetramethyl-
silane with the solvent resonance as the internal standard.
The following abbreviations were used to designate chemical
shift multiplicities: s = singlet, d = doublet, t = triplet, q =
quartet, h = heptet, m = multiplet, br = broad. All first-order
splitting patterns were assigned on the basis of the appearance
of the multiplet. Splitting patterns that could not be easily
interpreted are designated as multiplet (m) or broad (br). Mass
spectra were obtained using an electrospray ionization (ESI) mass
spectrometer. Bifunctional tertiary-amine thiourea/urea catalysts
were synthesized from the literature methods.5 3p was a known
compound.5h
3e: The Michael product was synthesized according to the
General experimental procedure of Michael reaction
general procedure as a white solid in 87% overall yield. [a]1D5 -369.1
1
To a stirred solution of 3-substituted benzofuran-2(3H)-one
(0.1 mmol) and nitroolefin (1.5 equiv.) in dry toluene (400 uL)
was added thiourea-catalyst (0.1 equiv.) at -60 ◦C with 40 mg
(c 0.23, CHCl3); H NMR (400 MHz, CDCl3): d 7.39–7.35 (1H,
t, J = 7.73 Hz), 7.24–7.09 (4H, m), 7.03 (1H, d, J = 7.91 Hz),
6.97–6.92 (1H, m), 6.85 (1H, d, J = 8.26 Hz), 5.07–4.96 (1H, m),
4.90–4.84 (1H, t, J = 11.95 Hz), 4.03–3.97 (1H, m), 1.59 (3H,
s); 13C NMR (100.6 MHz, CDCl3): d 178.5, 177.4, 152.7, 152.1,
134.9, 134.5, 132.7, 132.3, 130.2, 130.1, 129.7, 129.6, 129.5, 128.8,
128.6, 124.7, 124.6, 123.7, 123.6, 111.4, 111.1, 75.3, 75.0, 50.0,
49.8, 22.9, 21.8 ppm; HRMS (ESI+): calcd. for [C17H14ClNO4 +
Na]+ 354.0504, found 354.0510. The enantiomeric excess was
determined by HPLC with an AD-H column at 210 nm (2-
propanol : hexane = 1 : 19), 1.0 mL min-1; tR = 25.0 min (major),
18.2 min (minor).
3f: The Michael product was synthesized according to the
general procedure as a white solid in 87% overall yield. 1H NMR
(400 MHz, CDCl3): d 7.42–7.38 (1H, t, J = 7.63 Hz), 7.28–7.24
(2H, m), 7.14 (1H, d, J = 7.39 Hz), 7.07 (1H, d, J = 8.13 Hz),
6.98 (1H, s), 6.80 (1H, d, J = 8.13 Hz), 4.99–4.92 (1H, m), 4.85–
4.79 (1H, t, J = 11.94 Hz), 3.98–3.95 (1H, m), 1.59 (3H, s); 13C
NMR (100.6 MHz, CDCl3): d 177.1, 152.7, 134.1, 133.3, 132.8,
130.8, 130.6, 130.3, 129.9, 128.2, 124.9, 123.6, 111.6, 75.2, 49.7,
49.6, 21.9 ppm; HRMS (ESI+): calcd. for [C17H13Cl2NO4 + Na]+
388.0114, found 388.0120. The ee was not determined because the
two enantiomers could not be separated on the Daicel chiralpak
columns.
3g: The Michael product was synthesized according to the
general procedure as a white solid in 91% overall yield. [a]1D5 -114.3
(c 0.23, CHCl3); 1H NMR (400 MHz, CDCl3): d 8.14 (1H, d, J =
7.94 Hz), 7.84 (1H, s), 7.44–7.38 (2H, m), 7.31–7.16 (3H, m), 7.02
(1H, d, J = 8.13 Hz), 5.21–5.07 (1H, m), 5.02–4.90 (1H, m), 4.17–
4.13 (1H, m), 1.68 (3H, s); 13C NMR (100.6 MHz, CDCl3): d 177.9,
177.0, 152.6, 152.0, 148.0, 147.9, 136.6, 136.1, 135.4, 133.5, 130.5,
129.9, 129.8, 129.7, 128.0, 125.1, 124.9, 124.0, 123.8, 123.6, 123.5,
123.4, 111.6, 111.2, 75.1, 74.6, 50.3, 50.1, 49.7, 22.7, 22.0 ppm;
HRMS (ESI+): calcd. for [C17H14N2O6 + Na]+ 365.0744, found
˚
4 A molecular sieves. After the reaction completed, the reaction
solution was concentrated in vacuo and the crude was purified by
flash chromatography to afford the product.
3a: The Michael product was synthesized according to the
general procedure as a white solid in 96% overall yield. [a]1D5 -42.6
1
(c 0.23, CHCl3); H NMR (400 MHz, CDCl3): d 7.35–7.31 (1H,
t, J = 7.91 Hz), 7.26–7.15 (4H, m), 7.03–6.98 (2H, m), 6.91 (2H,
d, J = 7.38 Hz), 5.01 (1H, d, J = 4.57 Hz), 4.95–4.89 (1H, t, J =
11.95 Hz), 4.00 (1H, d, J = 4.57 Hz), 1.58 (3H, s); 13C NMR
(100.6 MHz, CDCl3): d 177.7, 152.7, 133.9, 129.8, 129.0, 128.9,
128.8, 128.5, 124.5, 124.0, 111.2, 75.5, 50.3, 49.8, 21.6 ppm; HRMS
(ESI+): calcd. for [C17H15NO4 + Na]+ 320.0893, found 320.0896.
The enantiomeric excess was determined by HPLC with an AD-H
column at 210 nm (2-propanol : hexane = 1 : 9), 1.0 mL min-1; tR =
10.5 min (major), 12.3 min (minor).
3b: The Michael product was synthesized according to the
general procedure as a white solid in 92% overall yield. [a]1D5 -202.5
(c 0.2, CHCl3); 1H NMR (400 MHz, CDCl3): d 7.36–7.32 (1H, t,
J = 7.73 Hz), 7.21–7.17 (1H, t, J = 7.38 Hz), 7.06–7.00 (2H, m),
6.81 (2H, d, J = 8.00 Hz), 6.70 (2H, d, J = 8.00 Hz), 4.98 (1H,
d, J = 4.31 Hz), 4.89–4.83 (1H, t, J = 11.87 Hz), 3.96 (1H, d, J =
4.04 Hz), 3.74 (3H, s), 1.58 (3H, s); 13C NMR (100.6 MHz, CDCl3):
d 177.7, 159.7, 152.7, 130.0, 129.8, 129.1, 125.6, 124.5, 123.9, 113.9,
111.2, 75.7, 55.2, 50.0, 49.7, 21.6 ppm; HRMS (ESI+): calcd. for
[C18H17NO5 + Na]+ 350.0999, found 350.1004. The enantiomeric
excess was determined by HPLC with an AD-H column at 210 nm
(2-propanol : hexane = 1 : 9), 1.0 mL min-1; tR = 18.2 min (major),
15.8 min (minor).
3c: The Michael product was synthesized according to the
general procedure as a white solid in 90% overall yield. [a]1D5 -135.0
(c 0.2, CHCl3); 1H NMR (400 MHz, CDCl3): d 7.38–7.34 (1H, t,
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365.0735. The enantiomeric excess was determined by HPLC with
an AD-H column at 210 nm (2-propanol : hexane = 1 : 4), 1.0 mL
min-1; tR = 13.5 min (major), 16.8 min (minor).
132.5, 131.5, 130.6, 129.7, 129.4, 129.2, 129.1, 128.9, 126.7, 126.6,
125.9, 124.8, 124.5, 124.4, 124.3, 124.1, 124.0, 123.9, 123.0, 122.8,
111.1, 110.8, 76.3, 76.2, 50.6, 49.4, 43.0, 42.3, 23.6, 21.3 ppm;
HRMS (ESI+): calcd. for [C21H17NO4 + Na]+ 370.1050, found
370.1043. The enantiomeric excess was determined by HPLC with
an AD-H column at 210 nm (2-propanol : hexane = 1 : 9), 1.0 mL
min-1; tR = 9.9 min (major), 10.8 min (minor).
3h: The Michael product was synthesized according to the
general procedure as a white solid in 95% overall yield. [a]1D5 -179.1
(c 0.23, CHCl3); 1H NMR (400 MHz, CDCl3): d 7.37 (1H, d, J =
7.51 Hz), 7.25–7.23 (1H, m), 7.20–7.15 (3H, m), 7.11–7.06 (2H,
m), 6.89 (1H, d, J = 7.88 Hz), 5.07 (1H, d, J = 4.37 Hz), 5.02–4.97
3m: The Michael product was synthesized according to the
(1H, t, J = 12.12 Hz), 4.92 (1H, d, J = 4.37 Hz), 1.69 (3H, s); 13
C
general procedure as a white solid in 90% overall yield. [a]1D5 -114.0
1
NMR (100.6 MHz, CDCl3): d 178.8, 151.9, 135.2, 133.3, 130.2,
129.5, 129.2, 127.4, 126.5, 124.2, 110.6, 75.6, 50.4, 44.9, 23.2 ppm;
HRMS (ESI+): calcd. for [C17H14ClNO4 + Na]+ 354.0504, found
354.0500. The enantiomeric excess was determined by HPLC with
an AD-H column at 210 nm (2-propanol : hexane = 1 : 19), 1.0 mL
min-1; tR = 12.2 min (major), 11.1 min (minor).
3i: The Michael product was synthesized according to the
general procedure as a white solid in 98% overall yield. [a]1D5 -181.5
(c 0.2, CHCl3); 1H NMR (400 MHz, CDCl3): d 7.44–7.37 (2H, m),
7.23–7.17 (3H, m), 7.11–7.07 (1H, t, J = 7.51 Hz), 7.02–6.98 (1H,
t, J = 7.26 Hz), 6.90 (1H, d, J = 8.00 Hz), 5.11–5.07 (1H, m),
4.00–4.88 (2H, m), 1.70 (3H, s); 13C NMR (100.6 MHz, CDCl3): d
178.8, 151.9, 135.0, 133.7, 129.8, 129.6, 129.2, 128.1, 126.6, 126.4,
124.5, 124.2, 110.6, 75.8, 50.4, 47.7, 23.4 ppm; HRMS (ESI+):
calcd. for [C17H14BrNO4 + Na]+ 397.9998, found 397.9995. The
enantiomeric excess was determined by HPLC with an AD-H
column at 210 nm (2-propanol : hexane = 1 : 19), 1.0 mL min-1;
tR = 12.8 min (major), 11.8 min (minor).
(c 0.2, CHCl3); H NMR (400 MHz, CDCl3): d 7.36–7.32 (1H,
m), 7.26 (2H, d, J = 6.89 Hz), 7.21–7.13 (4H, m), 7.10 (2H, d, J =
7.63 Hz), 4.52 (1H, d, J = 5.29 Hz), 4.37 (1H, d, J = 6.53 Hz), 2.93
(1H, d, J = 5.42 Hz), 2.69–2.52 (2H, m), 1.91–1.83 (1H, m), 1.62–
1.55 (1H, m), 1.53 (3H, s); 13C NMR (100.6 MHz, CDCl3): d 178.3,
152.6, 140.3, 129.7, 129.5, 128.6, 128.3, 126.4, 124.8, 123.5, 111.4,
76.0, 49.4, 43.9, 33.7, 31.1, 22.6 ppm; HRMS (ESI+): calcd. for
[C19H19NO4 + Na]+ 348.1206, found 348.1206. The enantiomeric
excess was determined by HPLC with an AD-H column at 210 nm
(2-propanol : hexane = 1 : 9), 1.0 mL min-1; tR = 11.6 min (major),
10.0 min (minor).
3n: The Michael product was synthesized according to the
general procedure as a white solid in 88% overall yield. [a]1D5 +323.0
(c 0.2, CHCl3); 1H NMR (400 MHz, CDCl3): d 7.38–7.34 (1H, t,
J = 7.63 Hz), 7.24–7.15 (3H, m), 4.50 (1H, d, J = 6.28 Hz), 4.31
(1H, d, J = 5.54 Hz), 3.01–2.94 (1H, m), 1.54 (3H, s), 1.25–1.08
(2H, m), 0.91 (3H, d, J = 6.53 Hz), 0.86 (3H, d, J = 6.53 Hz); 13
C
NMR (100.6 MHz, CDCl3): d 178.4, 152.6, 129.6, 124.7, 123.5,
111.3, 76.3, 49.7, 42.3, 38.2, 25.7, 23.4, 22.4, 21.3 ppm; HRMS
(ESI+): calcd. for [C15H19NO4 + Na]+ 300.1206, found 300.1205.
The enantiomeric excess was determined by HPLC with an AD-H
column at 210 nm (2-propanol : hexane = 1 : 19), 1.0 mL min-1; tR =
7.5 min (major), 6.9 min (minor).
3j: The Michael product was synthesized according to the
general procedure as a white solid in 85% overall yield. [a]1D5 -30.5
1
(c 0.2, CHCl3); H NMR (400 MHz, CDCl3): d 7.36–6.96 (6H,
m), 6.82–6.78 (1H, m), 5.26 (1H, d, J = 3.69 Hz), 5.14–5.08 (1H,
t, J = 11.33 Hz), 4.92 (1H, d, J = 3.20 Hz), 1.78 (3H, s); 13C NMR
(100.6 MHz, CDCl3): d 177.7, 162.6, 160.2, 152.2, 136.3, 136.2,
130.6, 130.3, 130.1, 129.8, 129.6, 129.4, 126.3, 126.0, 124.4, 124.2,
124.0, 123.6, 122.6, 122.4, 115.6, 115.4, 115.0, 114.9, 114.7, 111.0,
110.8, 110.7, 74.7, 74.6, 73.5, 73.4, 73.2, 48.5, 45.3, 25.4 ppm;
HRMS (ESI+): calcd. for [C17H13ClFNO4 + Na]+ 372.0209, found
372.0402. The enantiomeric excess was determined by HPLC with
an OD-H column at 210 nm (2-propanol : hexane = 1 : 9), 1.0 mL
min-1; tR = 15.0 min (major), 18.4 min (minor).
3k: The Michael product was synthesized according to the
general procedure as a white solid in 87% overall yield. [a]1D5 -205.7
(c 0.23, CHCl3); 1H NMR (400 MHz, CDCl3): d 7.20–7.18 (1H, m),
7.10–7.06 (1H, t, J = 7.88 Hz), 6.99–6.89 (4H, m), 6.83–6.80 (1H,
t, J = 7.39 Hz), 5.53–5.34 (2H, m), 5.22–5.19 (1H, m), 1.75 (3H, s);
13C NMR (100.6 MHz, CDCl3): d 178.5, 152.2, 137.6, 134.7, 132.5,
129.7, 129.2, 128.8, 124.1, 123.6, 110.9, 73.8, 48.0, 46.9, 28.4 ppm;
HRMS (ESI+): calcd. for [C17H13Cl2NO4 + Na]+ 388.0114, found
388.0118. The enantiomeric excess was determined by HPLC with
an OD-H column at 210 nm (2-propanol : hexane = 1 : 9), 1.0 mL
min-1; tR = 12.6 min (major), 17.9 min (minor).
3o: The Michael product was synthesized according to the
general procedure as a white solid in 91% overall yield. [a]1D5 -37.1
(c 0.27, CHCl3); 1H NMR (400 MHz, CDCl3): d 7.41–6.66 (14H,
m), 5.06–4.96 (2H, m), 4.27–4.17 (1H, m), 3.44–3.05 (2H, m); 13
C
NMR (100.6 MHz, CDCl3): d 177.9, 176.1, 153.1, 152.7, 134.2,
133.9, 133.7, 133.6, 130.0, 129.9, 129.5, 129.3, 128.8, 128.7, 128.6,
128.5, 128.2, 127.3, 127.1, 126.8, 126.6, 125.1, 124.4, 124.3, 123.9,
111.0, 110.7, 75.9, 75.5, 56.8, 56.7, 50.6, 50.1, 47.3, 42.6, 41.7
pm; HRMS (ESI+): calcd. for [C23H19NO4 + Na]+ 396.1206, found
396.1201. The enantiomeric excess was determined by HPLC with
an OD-H column at 210 nm (2-propanol : hexane = 1 : 9), 1.0 mL
min-1; tR = 38.3 min (major), 42.2 min (minor) and tR = 74.2 min
(major), 81.1 min (minor).
3q: The Michael product was synthesized according to the
general procedure as a white solid in 91% overall yield. [a]2D3 +21.0
1
(c 1.0, CHCl3); H NMR (400 MHz, CDCl3): d 7.72 (2H, d,
J = 8.05 Hz), 7.51–7.43 (3H, m), 7.29 (1H, s), 7.22 (2H, d, J =
5.58 Hz), 7.14 (3H, t, J = 7.22 Hz), 6.89 (3H, t, J = 9.25 Hz),
4.99 (1H, d, J = 12.26 Hz), 4.86 (1H, d, J = 11.75 Hz), 4.76 (1H,
s, J = 12.70 Hz), 2.85 (2H, q, J = 7.62 Hz, 7.47 Hz), 1.40 (3H,
t, J = 7.70 Hz); 13C NMR (100.6 MHz, CDCl3): d 175.4, 151.7,
140.7, 134.8, 133.0, 129.8, 129.5, 129.0, 128.8, 128.5, 127.5, 125.5,
111.4, 75.7, 59.2, 51.4, 28.8, 16.3 ppm; HRMS (ESI+): calcd. for
[C24H21NO4 + Na]+ 410.1363, found 410.1357. The enantiomeric
excess was determined by HPLC with an OD-H column at 210 nm
(2-propanol : hexane = 2 : 98), 1.0 mL min-1; tR = 12.5 min (major),
15.3 min (minor).
3l: The Michael product was synthesized according to the
general procedure as a white solid in 85% overall yield. [a]1D5 +216.5
(c 0.23, CHCl3); 1H NMR (400 MHz, CDCl3): d 8.27 (1H, d, J =
8.74 Hz), 7.81–7.70 (2H, m), 7.58–7.55 (1H, t, J = 7.14 Hz), 7.46–
7.43 (1H, m), 7.41–7.36 (1H, m), 7.31–7.25 (1H, m), 7.11–6.97 (2H,
m), 6.89 (1H, d, J = 7.88 Hz), 6.78 (1H, d, J = 7.75 Hz), 5.22–5.16
(1H, m), 5.11–4.96 (2H, m), 1.60 (1H, s), 1.56 (2H, s); 13C NMR
(100.6 MHz, CDCl3): d 179.3, 177.7, 152.7, 152.1, 133.9, 132.6,
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3r: The Michael product was synthesized according to the
general procedure as a white solid in 87% overall yield. [a]2D3 +42.1
(c 1.0, CHCl3); H NMR (400 MHz, CDCl3): d 7.69 (2H, d, J =
Notes and references
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1
7.15 Hz), 7.53–7.44(5H, m), 7.29–7.23 (1H, m), 7.20–7.17 (2H, m),
6.93 (3H, t, J = 8.72 Hz), 4.98 (1H, t, J = 12.33 Hz), 4.88 (1H, d,
J = 11.81 Hz), 4.73 (1H, d, J = 12.50 Hz); 13C NMR (100.6 MHz,
CDCl3): d 174.5, 152.0, 133.9, 132.5, 130.6, 129.7, 129.3, 129.0,
128.9, 128.7, 127.3, 126.3, 112.9, 75.2, 59.5, 51.3 ppm; HRMS
(ESI+): calcd. for [C22H16ClNO4 + Na]+ 416.0660, found 416.0658.
The enantiomeric excess was determined by HPLC with an AD-H
column at 210 nm (2-propanol : hexane = 2 : 98), 1.0 mL min-1; tR =
16.5 min (minor), 17.4 min (major).
3s: The Michael product was synthesized according to the
general procedure as a white solid in 98% overall yield. [a]2D3 -11.7
1
(c 1.0, CHCl3); H NMR (400 MHz, CDCl3): d 7.65 (2H, d, J =
8.32 Hz), 7.56 (2H, d, J = 7.21 Hz), 7.49–7.42 (3H, m), 7.21
(1H, d, J = 7.21 Hz), 7.15 (2H, t, J = 7.21 Hz), 6.89–6.84 (3H,
m), 4.93 (1H, t, J = 12.20 Hz), 4.84 (1H, d, J = 12.20 Hz), 4.96
(1H, d, J = 12.20 Hz); 13C NMR (100.6 MHz, CDCl3): d 174.3,
152.5, 133.9, 133.5, 132.5, 129.7, 129.4, 129.1, 129.0, 128.9, 128.7,
127.9, 127.3, 116.9, 113.3, 75.2, 59.4, 51.3 ppm; HRMS (ESI+):
calcd. for [C22H16BrNO4 + Na]+ 460.0155, found 460.0157. The
enantiomeric excess was determined by HPLC with an OD-H
column at 210 nm (2-propanol : hexane = 2 : 98), 1.0 mL min-1;
tR = 21.2 min (major), 26.7 min (minor).
3t: The Michael product was synthesized according to the
general procedure as a white solid in 90% overall yield. [a]2D3 -24.7
1
(c 0.5, CHCl3); H NMR (400 MHz, CDCl3): d 7.67 (2H, d, J =
7.20 Hz), 7.47–7.37 (5H, m), 7.23 (1H, s), 7.15 (2H, s), 7.01 (1H, d,
J = 6.40 Hz), 6.86 (2H, d, J = 6.40 Hz), 4.98 (1H, t, J = 11.82 Hz),
4.79 (1H, d, J = 11.60 Hz), 4.70 (1H, d, J = 12.40 Hz); 13C NMR
(100.6 MHz, CDCl3): d 174.7, 153.7, 135.4, 133.2, 132.6, 130.7,
129.7, 128.9, 128.5, 126.1, 124.5, 111.9, 75.4, 58.7, 51.6 ppm;
HRMS (ESI+): calcd. for [C22H16ClNO4 + Na]+ 416.0660,
found 416.0656. The enantiomeric excess was determined by
HPLC with an AD-H column at 210 nm (2-propanol : hexane =
2 : 98), 1.0 mL min-1; tR = 31.2 min (major), 33.0 min
(minor).
Computation details
All calculations were performed at the B3LYP/6-311++G(d,p)//
B3LYP/6-31G(d) level by means of the Gaussian 03 suite of
program package.13 This level of theory was demonstrated to be
appropriate for studying the thiourea-based chiral bifunctional
organocatalyst promoted asymmetric addition reactions.10 All the
-1
˚
bond lengths are in angstroms (A), and energies in kcal mol .
Structures were generated using CYLview.14
Acknowledgements
This work was supported by National Natural Science Foun-
dation of China (Grant Nos. 20902091, 21172112, 21172118
and 21102101), the National Basic Research Program of China
(973 Program, No. 2010CB833300 and 2012CB821600), and the
State Key Laboratory on Elemento-organic Chemistry (Nankai
University, China). X. Li also thanks the Fundamental Research
Funds for the Central Universities for support.
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