Chiral GAP catalysts of phosphonylated imidazolidinones and their applications in asymmetric Diels-Alder and Friedel-Crafts reactions

Article abstract of DOI:10.1039/c6ob02801b

The design and synthesis of recyclable imidazolidinone catalysts using GAP chemistry/technique was described. Their applications in asymmetric Diels-Alder and Friedel-Crafts reactions with α,β-unsaturated aldehydes resulted in excellent yields and higher enantioselectivities than previous processes. As recyclable small molecular catalysts, phosphonylated imidazolidinones can be recovered and reused for up to three runs without costing significant decrease in catalytic activity.

Full text of DOI:10.1039/c6ob02801b

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Chiral GAP catalysts of phosphonylated imidazolidinones and
their applications in asymmetrical Diels-Alder and Friedel-Craft
reactions
Received 00th January 20xx,
Accepted 00th January 20xx
Shuo Qiao,a Junming Mo,a Cody B. Wilcox,a Bo Jiang,*,a,c and Guigen Li*,a,b
DOI: 10.1039/x0xx00000x
The design and synthesis of recyclable imidazolidinone catalysts using GAP chemistry/technique was described. Their
applications in asymmetric Diels-Alder and Friedel-Craft reactions with α,β-unsaturated aldehydes resulted in excellent
yields and higher enantioselectivities than previous processes. As recyclable small molecular catalysts, the phosphonylated
imidazolidinones can be recovered and reused for up to three runs without costing significant decrease in catalytic activity.
www.rsc.org/
and phosphinyl groups were introduced into starting materials,
the solubility of the desired products can be adjusted in
various solvents, and their purification can be achieved simply
Introduction
Among the most attractive and appealing synthetic strategies,
organocatalysis has drawn a special attention due to its
characteristics of foreseeable non-toxicity, invulnerability to
moisture/air, convenience and less expense for modification
and synthesis.1 However, most of these successful applications
showed higher catalyst loadings than corresponding transition
metal catalytic systems besides the difficulty in catalyst
separation.2 Thus, these drawbacks weaken the merits of
organocatalyst and limit the application scope of
orgnocatalysis for chemical and pharmaceutical industry. In
view of this practical limit, the development of organocatalysts
that can be recovered and recycled after reaction is highly
desired but full of challenging task.3 Notably, MacMillan’s
group reported pioneering work on chiral imidazolidinone
catalysts (Type I, Figure 1) depending on the iminium
activation model,4 which has been proved to be an efficient
organocatalyst in various asymmetrical reactions.5 Later on,
several groups have contributed in this field using polymer-
supported (Type II)6,7 or ionic-liquid immobilized (Type III)
chiral imidazolidinone scaffold.8 However, in addition to
complicated route for imidazolidinone preparation, these
known catalysts may still suffer from either non-recovery or
complex recovery process, thereby limiting their flexible
potential.
by washing with combinational solvents of hexane and ethyl
acetate. Based on these practical significant observations, we
proposed the concept of group-assisted purification (GAP)
chemistry so as to encourage synthetic community to perform
synthesis by avoiding traditional purification methods such as
chromatography and/or recrystallization.9 In our continuous
effort on the GAP chemistry, we decided to install phosphonyl
groups on the chiral imidazolidinone framework (Type IV and
Type V) to explore their catalytic activities and the feasibility of
recovery potential for asymmetric reactions such as Diels-
Alder and Field-Craft reactions. After several attempts, we
were pleased to find that the preformed diphenylphosphoryl
(DPP) imidazolidinone (Type IV) showed high catalytic
performance and can be recycled and recovered three times
without loss of catalytic activity. Note that this is first example
of small neutral and recoverable catalysts, which would find
broad applications in asymmetrical synthesis based on the fact
that the GAP catalysts can improve not only transformation
efficiency and enantioselectivity but also lower production
costs. Herein, we would like to report our preliminary results
of this project.
Previous works
Bu
N
R
N
R
N
N
()3
N
O
O
X
Polymer
O
Me
Me
Me
Me
Over the past few years, our group found when phosphonyl
Me
Me
Ph
N
Ph
N
H
N
H
H
I
II
III
Our design
O
Ph
Ph
FG
()3
N
P
Me
N
DPP =
H
N
O
O
FG
Me
Me
1-Np
Me
Me
Ph
O
N
N
N
P
H
V
DNP =
1-Np
H
IV
N
FG = DPP and DNP
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Scheme 1 Design of chiral phosphonylated imidazolidinone
catalysts
desired product 4a with 90% endo ee and 84% yield, along
with the maintenance of the catalyst recovery of 77%. The use
of catalyst 1b led to 92% endo ee and 77% yield, but lowered
catalyst recovery (51%, entry 2). The latter two catalysts 1c-d
gave inferior outcomes with regard to enantioselectivity and
yield of product 4a, especially the recovery of these both
catalysts. Next, five types of protic acids, including TfOH, (D)-
10-camphorsulfonic acid (CSA), HBF4, and trifluoroacetic acid
(TFA), were investigated as the reaction co-catalysts by using
catalyst 1a (Table 1, entry 1 vs entries 5–8). In comparison to
HCl, it was found that better yields and enantioselectivities
were obtained when CSA, TfOH and TFA behaved as reaction
co-catalysts whereas the use of HBF4 completely suppressed
the reaction process. Among all the acids screened, TFA was
proven to be the most efficient one, delivering 98% endo ee
and 98% yield of product 4a under the reaction conditions
(entry 8) with 92% catalyst recovery. Therefore, TFA was
selected as a reaction co-catalyst in further transformations.
Table 1 Optimization of reaction conditions for Diels-Alder reaction
Results and discussion
In an initial effort on installing phosphonyl group on the phenyl
ring of imidazolidinone skeleton (MacMillan’s catalyst), we
designed two different synthetic pathways for their
preparation with the use of diphenylphosphoryl (DPP) and 2-
oxido-1,3- bis(1-naphthalenylmethyl)-1,3,2-diazaphospholidin-
2-yl (DNP, 1-naphthalenyl (1-Np)) groups as GAP auxiliary
functionality (Scheme 1). As shown in Scheme 1, the synthesis
of imidazolidinone catalysts 1a-b involved multiple steps
consisted of nitration, amination, and cyclization as well as
hosphinic amide formation using commercial available L-
phenylalanine as starting materials (route i) whereas
imidazolidinone catalysts 1c-d were generated via an
amidization/de-protection/ cyclization sequence (route ii).
Notably, during the synthesis of catalysts 1a-b, the last step
did not require protection of the diakyl amine group due to its
bulky effect. Generally, these multi-step pathways toward
catalysts
1 enable high conversion in almost each step except
for the last step. Specifically, the pure catalyst 1a could be
obtained by washing with hexane/ether system in the last step
without any column chromatography, which corresponds to
the definition of our GAP chemistry. However, the other types
of catalysts (1b-d) require column chromatography at the final
stage of their synthesis.
Entry Cat.
(mol %)
Acid
endo:exob endo (ee Yield Recycle
%)c
90
92
83
78
-
91
94
98
93
(%)d
84
yield (%)e
1
2
3
4
5
6
7
8
9
1a (20)
1b (20)
2a (20)
2b (20)
1a (20)
1a (20)
1a (20)
1a (20)
HCl
HCl
HCl
HCl
HBF4
TfOH
CSAf
TFA
1.1:1
1.0:1
1.3:1
1.2:1
-
1.0:1
1.0:1
1.9:1
1.3:1
77
51
trace
trace
-
90
87
92
-
77
78
61
trace
85
88
98
99
I (20, Lit.)g HCl
aThe reactions were carried out at 23 oC for 12 h using catalyst (0.2
mmol, 20 mol %), HX (0.2 mmol, 20 mol %), cinnamaldehyde (2a, 1.0
mmol), cyclopentadiene (3, 5.0 mmol), MeOH (2.0 mL), and H2O (0.1
mL). bEndo/exo ratio was determined by 1H NMR analysis of crude
reaction mixture. cProduct enantiomer excesses was determined by
HPLC using chiral IC column after reduction of the aldehyde to alcohol
with NaBH4. dIsolated yield based on substrate 2. eResult of first
Scheme 1. Synthesis of phosphonylated imidazolidinone
catalysts
f
recycling experiment with catalyst 1a. CSA = D-(+)-10-camphorsulfonic
acid. gRef.4.
After the successful synthesis of catalysts, we set out to
evaluate their catalytic capability and the recovery application
Next, the synthetic utility of this asymmetrical Diels-Alder reaction
was investigated by the adoption of four examples of
representative α,β-unsaturated aldehydes 2b-e as the reaction
partners. As described in Table 2, α,β-unsaturated aldehydes
bearing both electron-donating (methoxy 2b and methyl 2c) and
electron-withdrawing (nitro 2d, 2e) groups effectively underwent
the Diels-Alder reaction with cyclopentadiene in the presence of
phosphonylated imidazolidinone catalyst 1a and acid co-catalyst
in
asymmetric
Diels-Alder
cycloaddition
between
cinnamaldehyde (2a) and cyclopentadiene (
3
), following the
original protocol by MacMillan’s group.10 The Diels-Alder
reaction was conducted at room temperature for 24 h with
loading of 20 mol % catalyst and acid as additive (Table 1),
searching for the optimized conditions. As shown in Table 1,
when HCl was used as an acid co-catalyst (Table 1, entry 1), the
reaction employing catalyst 1a proceeded readily to give the
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o
TFA in MeOH-H2O at 23 C. The target bridged cyclic products 4b-e Notably, in all cases, high catalyst recovery (87%-98%) was
were provided in good to excellent yields with excellent endo ee. conducted without loss of catalytic activity.
Table 2. The synthetic utility of asymmetrical Diels-Alder reaction
Entry
4
Ar
endo: exob
1.9:1
1.6:1
1.7:1
13:1
1.1:1
Endo ee (%)c
Exo ee (%)c
Yield d/%
Cat. Recovery (%)e
1
2
3
4
5
4a
4b
4c
4d
4e
C6H5 (2a)
98
91
92
97
92
99
75
90
-
98
81
87
92
95
92
88
91
87
83
p-MeOC6H4(2b)
p-MeC6H4 (2c)
o-NO2C6H4 (2d)
p-NO2C6H4 (2e)
90
aThe reactions were carried out at 23 oC for 12 h using catalyst 1a (0.2 mmol, 20 mol %), TFA (0.2 mmol, 20 mol %), aldehydes 2 (1.0
mmol), cyclopentadiene 3 (5.0 mmol), MeOH (2.0 mL) and H2O (0.1 mL). bEndo/exo ratio was determined by 1H NMR analysis of
crude reaction mixture. cProduct enantiomer excesses was determined by HPLC using chiral IC column after reduction of the
aldehyde to alcohol with NaBH4. dIsolated yield based on substrate 2. eResult of first recycling experiment with catalyst 1a
With the success of the above reactions, we then explored the
recyclability of chiral phosphonylated imidazolidinone catalyst 1a in
Diels-Alder reaction. As illustrated in Table 3, after reaction the
remaining imidazolidinone catalyst 1a was recovered and recycled
in subsequent reactions with only a slight decrease in catalytic
activity being observed. For instance, the recycling procedure
involving cinnamaldehyde and cyclopentadiene was found to
provide the product 4a in 98% yield, 98% endo ee, 92% catalyst
recovery (1st run), 97% yield, 96% endo ee, 90% catalyst recovery
(2nd run), 98% yield, 95% endo ee, 95% catalyst recovery (3rd run).
phase. Nevertheless, the products 6 could be isolated from the
catalyst when non-polar solvent was applied after
neutralization. In addition, the first recovered catalyst 1a could
showed a highly catalytic activity in the Friedel-Craft alkylation,
giving 88% ee of product 6a
.
Table 4 Substrate scope of Friedel-Craft alkylation of N-methyl
pyrrole
Table 3. Recycling of catalyst 1a in Diels-Alder reaction
entry
6
R
Yield(%)b
ee (%)c
87
1
2
3
4
5
6a
6b
6c
6d
6e
6a
C6H5 (2a)
p-OMeC6H4 (2b)
p-NO2C6H4 (2e)
CO2Et (2f)
Pr (2g)
89
77
96
83
90
77
Time
Yield (%)d endo: exob
ee (%)c
98
96
95
Cat. Recovery (%)e
80
77
1
2
3
98
97
98
1.9:1
1.8:1
1.9:1
92
90
95
85d
99
6e
C6H5 (2a)
88
aThe reactions were carried out at 23 oC for 12 h using catalyst 1a
(reused from last run), TFA (0.2 mmol, 20 mol %), aldehydes 2 (1.0
mmol), cyclopentadiene 3 (5.0 mmol), MeOH (2.0 mL) and H2O (0.1
mL). bEndo/exo ratio was determined by 1H NMR analysis of crude
reaction mixture. cProduct enantiomer excesses was determined by
HPLC using chiral IC column after reduction of the aldehyde to alcohol
with NaBH4. dIsolated yield based on substrate 2. eRecovery of
catalyst 1a with method 1 in the supporting information.
a
Reaction conditions: aldehyde (0.5 mmol, 1.0 equiv), N-methylpyrrole
(2.50 mmol, 5.0 equiv), catalyst 1a (20 mol %), aq TFA (1 M; 20 mol %), -
30 °C, 48 hours. bIsolated yield based on substrate 2. cProduct
enantiomer excesses were determined by HPLC using chiral IC column
after reduction of aldehydes to alcohols with NaBH4. dUsing cyanoacetic
acid as co-catalyst. eResult with recycled catalyst with method 2.
Conclusions
To broaden the application of the preformed chiral GAP
phosphonylated imidazolidinone catalyst, the Friedel-Craft
alkylation of pyrrole was also studied under the previously
reported conditions.11 The reactions worked well to access the
In conclusion, we have designed and synthesized chiral GAP
catalysts of phosphonylated imidazolidinones and applied to two
target products 6a-e in 77%-96% yields and 77%-99% ee asymmetric reactions. We found the GAP catalyst 1a showed a
determined by the corresponding alcohols through reduction
(Table 4) Among them, Pr-substituted counterpart 2g was
converted into the corresponding product 6g with 90% yield
and 99% ee (Table 3, entry 5). The purification and recovery of
the phosphonylated catalyst is different from the above Diels-
Alder cycloaddition due to the target product containing
nitrogen will be extracted along with the catalyst to the water
highly catalytic activity in enantioselective Diels-Alder and Friedel-
Craft reactions. Most importantly, the recovery and recycling of the
phosphonylated imidazolidinone catalyst 1a in further operations
were successfully realized and the catalyst can be reused for at least
three runs without significant dropping in both chemical yields and
enantioselectivity. We believed that the present chiral GAP
catalysts with easy recycling for re-usable characteristics would find
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great synthetic potential in asymmetric field. Further study on 16.4 Hz, 1H), 3.31 (d, J = 4 Hz, 1H), 2.92-2.89 (m, 1H), 2.78 (d, J = 5.6
Hz, 3H), 1.23 (s, 2H) ppm. 13C NMR (100 MHz, CDCl3): δ 173.9,
design and applications of new GAP catalysts for more asymmetric
147.1, 145.9, 130.2, 130.1, 123.9, 123.8, 56.2, 40.9, 25.9 ppm
transformations is under study in our laboratory.
1.3 Synthesis of (S)-2,2,3-trimethyl-5-(4-nitrobenzyl)imidazolidin-4-
one (1-3)
Experiment
(S)-2-amino-N-methyl-3-(4-nitrophenyl)propanamide (1-2) (10 g,
44.8 mmol) was dissolved in acetone (60 mL) followed by adding
PTSA (2 mmol, 0.46 g). The reaction mixture was stirred under
General Information
refluxing for overnight. After reaction, the solvent was removed
All commercially available chemicals were used as received without
under vacuo and the residue was dissolved in CH2Cl2, washed with
further purification. Flash chromatography was carried out using
saturated NaHCO3 and brine, and dried over MgSO4. After removal
flash grade silica gel. Subsequent to elution, plates were visualized
of organic solvent under vacuo, the product was directly used for
using UV radiation (254 nm) on Spectroline Model ENF-24061/F 254
the next step without further purification. (98%, 11 g) 1H NMR (400
nm. All reactions were carried out in flame dried flask under
MHz, CDCl3): δ 8.13 (d, J = 9.2 Hz, 2H), 7.42 (d, J = 9.2 Hz, 2H), 3.83
nitrogen atmosphere. The 1H and 13C NMR spectra were recorded
in CDCl3 on a 400 MHz instrument with TMS as internal standard.
Chemical shifts (δ) were reported in ppm with respect to TMS. Data
(t, J = 3.6 Hz, 1H), 3.22 (d, J = 4 Hz, 1H), 2.97-2.95 (m, 1H), 2.73 (s,
3H), 1.32 (s, 3H), 1.21 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3): δ
172.4, 146.9, 145.8, 130.5, 130.4, 123.6, 123.5, 75.7, 59.1, 38.1,
are represented as follows: chemical shift, mutiplicity (s = singlet, d
27.8, 25.5, 25.3 ppm
= doublet, t = triplet, m = multiplet), coupling constant (J, Hz) and
integration. 31P NMR spectra were referenced to external H3PO4
1.4 Synthesis of (S)-5-(4-aminobenzyl)-2,2,3-trimethylimidazolidin-
(0.00 ppm). HRMS analyses were carried out using a TOF-MS
4-one (1-4)
instrument with an ESI source. For HPLC analysis of the
(S)-2,2,3-trimethyl-5-(4-nitrobenzyl)imidazolidin-4-one (1-3) (11 g,
enantioselectivity of the products, the corresponding racemic
40.8 mmol) was dissolved in methanol (50ml), followed by adding
compounds were synthesized by using pyroline as catalyst in THF.
Pd/C (0.5g, 10%) and purged with H2 three times, this mixture was
stirred at room temperature for 24 h. The resulting mixture was
1. General Procedure for the Synthesis of Catalyst 1a:
filter through celite, and condensed to dryness as a colorless oil
1
(96%, 9.5 g) for next step. H NMR (400 MHz, CDCl3): δ 6.95 (d, J =
20.0 Hz, 2H), 6.59 (d, J = 20.0 Hz, 2H), 3.68 (s, 1H), 2.94 (d, J = 8.0
Hz, 2H), 2.66 (s, 3H), 1.21 (s, 3H), 1.18 (s, 3H), ppm. 13C NMR (100
MHz, CDCl3): δ 173.7, 145.2, 130.5, 130.4, 126.5, 115.4, 115.3, 75.5,
59.4, 35.9, 27.1, 25.3, 25.2 ppm.
1.1 Synthesis of (L)-p-Nitrophenylalanine (1-1)
L-Phenylalanine (20.0 g, 0.12 mol) was dissolved in 96% sulfuric acid
o
(50 mL) with vigorous stirring at 10 C and concentrated nitric acid
(6 mL) was added over a period of 35 min with vigorous stirring at
o
0–5 C; the reaction mixture was then stirred for an additional 1 h.
The reaction mixture was poured on 200 mL of ice cold water and
neutralized with 30% ammonium hydroxide. During neutralization
precipitation started; the reaction mixture was kept at room
temperature for 45 min and then filtered to separate out the
precipitate. The precipitate was washed with water until the
washings were neutral to litmus. The solid product was
recrystallized from hot water to yield (L)-p-nitrophenylalanine as
white solid (22.4g, 88%).10
1.5 Synthesis of (S)-P,P-diphenyl-N-(4-((1,2,2-trimethyl-5-
oxoimidazolidin-4-yl)methyl)phenyl)phosphinic amide 1a
A solution of (S)-5-(4-aminobenzyl)-2,2,3-trimethylimidazolidin-4-
one (1-4) (9 g, 38 mmol) and triethyl amine (16 ml, 115 mmol) in dry
CH2Cl2 (200 mL) under argon atmosphere was cooled to 0 °C,
diphenyl phosphorate chloride (11 g , 46 mmol) was added
dropwise through an addition funnel, and was stirred at room
temperature for 72 h. The resulting solution was condensed to
dryness after washed with H2O twice and brine. The residue was
added hexane and ether slurry until the product precipitated as
white solid; the solid was collected as the title catalyst 1a. (15.2 g,
68% overall yield) 31P NMR (CDCl3 162 MHz): δ 18.7 1H NMR (400
MHz, CDCl3): δ7.88-7.83 (m, 4H), 7.45-7.43 (m, 2H), 7.43-7.41 (m,
4H), 6.99 (d, J = 8.4 Hz, 2H), 6.88 (d, J = 8 Hz 2H), 5.26 (s, 1H), 3.68
(t, J = 5.2 Hz, 1H), 2.94 (d, J = 10.4 Hz, 2H), 2.70 (s, 3H), 1.21 (s, 3H),
1.11 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3): δ 173.4, 139.1, 132.5,
132.4, 132.3, 132.0, 131.9, 131.8, 131.7, 131.6, 131.3, 130.5, 130.4,
130.2, 128.9, 128.8, 118.8, 118.7, 75.5, 59.1, 36.0, 27.2, 25.3, 25.2
ppm. HRMS (TOF ES+) m/z calcd for C25H29N3O2P [(M + H)+],
434.1992; found, 434.1983.
1.2 Synthesis of (S)-2-amino-N-methyl-3-(4-nitrophenyl)propan
amide (1-2)
A solution of (L)-p-Nitrophenylalanine (20.0 g, 95.5 mmol) in dry
methanol (200 mL) under argon atmosphere was cooled to
0 °C
and thionyl chloride (38.8 mL, 285 mmol) was added dropwise
through an addition funnel. After the addition was complete, the
cooling bath was removed and stirring was continued at room
temperature overnight. The reaction mixture was concentrated
under vacuum and the solid residue was stirred with acetone
(2 x 150 mL) for one hour. Then it was concentrated in vacuum, and
the process was repeated (dissolve in acetone, stir for 1 hour and
evaporate). The solid was filtered off and washed with acetone (3 x
100 mL). The separated solid was dried under vacuum to afford
(L)-p-Nitrophenylalanine methyl ester hydrochloride as a yellow
solid. This above solid was treated with methylamine (60 mL, 60 %)
and the resulting mixture was stirred at roomtemperature for 24
hours. After extracted with dichloromethane, the excess
methylamine was removed by concentration in vacuo overnight and
the product was directly used for the next step without further
purification. (91%, 19 g) 1H NMR (400 MHz, CDCl3): δ 8.10 (d, J =
16.4 Hz, 2H), 7.38 (d, J = 16.4 Hz, 2H), 7.20 (s, 1H NH), 3.60 (t, J =
2. Diels-Alder Reaction (Table 2)
The cinnamaldehydes (1.0 mmol) and pentadiene (0.36 ml, 5 mmol)
were added sequentially to the catalyst 1a (85 mg, 0.2 mmol, 20
mol %) and TFA (15 µL, 20 mol %) in the methanol (2 mL) and water
(0.2 ml). After 12 h, the mixture was diluted with Et2O and washed
with H2O and brine. The organic phases were dried (Na2SO4),
concentrated, and then purified by flash chromatography. The
enantioselectivity was determined by the corresponding alcoholic
product after reduction with NaBH4 (83 mg, 2.2 mmol). To recycle
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the catalyst 1a, the resulting reaction mixture was extracted with (1R,2S,3S,4S)-3-(2-Nitrophenyl)bicyclo[2.2.1]hept-5-ene-2-
HCl (1 M), and aqueous phase was added saturated NaHCO3, and
extracted with dichloromethane. The organic phase was condensed
to dryness and treated with ether/hexane to get the cycled catalyst
1a as white solid after filtration. The reaction was repeated three
times using recycled catalyst 1a as catalyst. The solid catalyst was
used directly for the next run.
carbaldehyde and (1S,2S,3S,4R)-3-(2-nitrophenyl) bicyclo[2.2.1]
hept-5-ene-2-carbaldehyde (4d, Table 2, entry 4)
1
Yellow liquid, 223 mg, 92 % yield, H NMR (400 MHz, CDCl3): (endo
isomer) δ 9.39 (d, J = 2.4 Hz, 1H), 7.81-7.24 (m, 4H), 6.48 (d, J = 3.6
Hz, 1H), 6.21 (d, J = 3.6 Hz, 1H), 3.42 (t, J = 5.2 Hz, 1H), 3.31 (dd, J =
3.6 Hz, 1H), 3.10 (t, J = 4.8 Hz, 1H), 2.94 (d, J = 3.8 Hz, 1H), 1.84-1.81
(m, 1H), 1.65-1.61 (m, 1H) ppm. 13C NMR (100 MHz, CDCl3): (endo
isomer) δ 203.6, 150.4, 139.2, 137.3, 134.2, 132.9, 127.9, 127.4,
124.8, 59.1, 49.8, 47.3, 46.6, 41.7 ppm. Enantiomeric ratio was
determined by HPLC using Chiral IC column after reduction with
NaBH4/MeOH (1:99 i-PrOH/hexane, 1 mL/min flow rate), endo
isomers tr = 101.6 min (minor enantiomer) and 113.5 min (major
enantiomer) ee = 97 %.
(1R,2S,3S,4S)-3-phenylbicyclo[2.2.1]hept-5-ene-2-carbaldehyde
and (1S,2S,3S,4R)-3-phenylbicyclo[2.2.1] hept-5-ene-2-
carbaldehyde (4a, Table 2, entry 1)
Pale yellow liquid, 190 mg, 98 % yield; 1H NMR (400 MHz, CDCl3):
(endo isomer) δ 9.92 (d, J = 2.4 Hz, 1H), 7.29-7.16 (m, 5H), 6.33 (d, J
= 2.8 Hz, 1H), 6.06 (d, J = 2.8 Hz, 1H), 3.74 (t, J = 4 Hz, 1H), 3.22 (t, J
= 1.2 Hz, 1H), 3.10 (d, J = 2 Hz, 1H), 2.61 (t, J = 5.2 Hz, 1H), 1.64-1.55
(m, 2H) ppm. 13C NMR (100 MHz, CDCl3): (endo isomer) δ 203.5,
143.6, 142.6, 139.3, 136.6, 133.9, 128.2, 127.4, 126.3, 59.5, 48.5,
48.1, 47.6, 45.7 ppm. Enantiomeric ratio was determined by HPLC
using Chiracel IC column (x 2) after reduction with NaBH4/MeOH
(1:99 i-PrOH/hexane, 1 mL/min flow rate), endo isomers tr = 87.9
min (minor enantiomer) and 116.2 min (major enantiomer) ee =
98%; exo isomers tr = 73.1 min (minor enantiomer) and 103.6 min
(major enantiomer) ee = 99%.
(1R,2S,3S,4S)-3-(4-Nitrophenyl)bicyclo[2.2.1]hept-5-ene-2-
carbaldehyde and (1S,2S,3S,4R)-3-(4-nitrophenyl) bicyclo[2.2.1]
hept-5-ene-2-carbaldehyde (4e, Table 2, entry 5)
1
Yellow liquid, 231 mg, 95 % yield; H NMR (400 MHz, CDCl3): (endo
isomer) δ 9.89 (d, J = 1.6 Hz, 1H), 8.14-7.28 (m, 4H), 6.39 (d, J = 3.2
Hz, 1H), 6.01 (d, J = 3.8 Hz, 1H), 3.87 (t, J = 4.4 Hz, 1H), 3.28 (m, 1H),
2.93 (t, J = 2.8 Hz, 1H), 2.61-2.60 (m, 1H), 1.69-1.61 (m, 2H) ppm. 13
C
NMR (100 MHz, CDCl3): (endo isomer) δ 202.2, 151.6, 146.6, 139.1,
137.0, 136.0, 134.0, 128.7, 123.8, 61.25, 59.6, 48.4, 45.6, 45.2 ppm.
Enantiomeric ratio was determined by HPLC using Chiral IC column
after reduction with NaBH4/MeOH (1:99 i-PrOH/hexane, 1 mL/min
flow rate), endo isomers tr = 81.5 min, and 176.1 min (major
enantiomer) ee = 92 %; exo isomers tr = 115.9 min (minor
enantiomer) and 176.1 min (major enantiomer) ee = 92 %.
(1R,2S,3S,4S)-3-(4-Methoxyphenyl)bicyclo[2.2.1]hept-5-ene-2-
carbaldehyde and (1S,2S,3S,4R)-3-(4-methoxyphenyl)bicycle
[2.2.1]hept-5-ene-2-carbaldehyde (4b, Table 2, entry 2)
Pale yellow liquid, 184 mg, 81 % yield; 1H NMR (400 MHz, CDCl3):
(endo isomer) δ 9.89 (d, J = 2.4 Hz, 1H), 7.18-6.79 (m, 4H), 6.31 (d, J
= 2.8 Hz, 1H), 6.04 (d, J = 2.8 Hz, 1H), 3.77 (s, 3H), 3.64 (t, J = 3.6 Hz,
3 Friedel–Crafts Alkylation (Table 4)
Catalyst 1a (43 mg, 0.1 mmol, 20 mol %) was dissolved in THF (5
1H), 3.18 (d, J = 1.6 Hz, 2H), 2.52-2.51 (m, 1H), 1.57-1.54 (m, 2H) mL), H2O (0.5 mL) and aqueous TFA solution (1 M, 0.1 ml, 0.1 mmol,
ppm. 13C NMR (100 MHz, CDCl3): (endo isomer) δ 203.8, 158.1, 20 mol %) was added. The mixture was stirred for 10 min, and then
139.3, 136.6, 136.3, 128.8, 128.3, 114.1, 113.6, 61.1, 59.7, 55.4, N-methylpyrrole (0.2 ml, 2.5 mmol) was added. Next, trans-
48.6, 47.1, 45.1 ppm. Enantiomeric ratio was determined by HPLC cinnamaldehyde derivatives (0.5 mmol) was added dropwise to the
using Chiracel IC column after reduction with NaBH4/MeOH (1:99 i-
PrOH/hexane, 1 mL/min flow rate), endo isomers tr = 34.7 min
(major enantiomer) and 36.3 min (minor enantiomer) ee = 91 %;
exo isomers tr = 38.8 min (major enantiomer) and 40.6 min (minor
enantiomer) ee = 75 %.
reaction vial. The suspension was stirred at -30 ℃, and the reaction
was monitored by thin layer chromatography (TLC). After 48 h,
NaBH4 (84 g, 2.2 mmol) was added, the reaction proceed for 2 h at
room temperature, followed by washing with H2O, brine and
purification with gel column chromatography to get the alcoholic
product for HPLC. To recycle the catalyst 1a, the resulting reaction
mixture before reduction was extracted with HCl (1 M), and
aqueous phase was added saturated NaHCO3, and extracted with
dichloromethane. The organic phase was condensed to dryness and
treated with ether/hexane to get the cycled catalyst 1a as white
solid after filtration. The solid catalyst was used directly for the next
run. The filtrate was condensed to dryness and purified with gel
column chromatography to get the product which was used for
reduction.
(1R,2S,3S,4S)-3-(p-Tolyl)bicyclo[2.2.1]hept-5-ene-2-carbaldehyde
and (1S,2S,3S,4R)-3-(p-tolyl)bicyclo[2.2.1] hept-5-ene-2-
carbaldehyde (4c, Table 2, entry 3)
Pale yellow liquid, 184 mg, 87 % yield; 1H NMR (400 MHz, CDCl3):
(endo isomer) δ 9.92 (d, J = 1.6 Hz, 1H), 7.18-7.06 (m, 4H), 6.33 (d, J
= 2.8 Hz, 1H), 6.07 (d, J = 2.8 Hz, 1H), 3.69 (t, J = 2 Hz, 1H), 3.21 (dd,
J = 2 Hz, 1H), 3.09 (d, J = 2 Hz, 1H), 2.57 (d, J = 2 Hz, 1H), 2.31 (s, 3H),
1.64-1.54 (m, 2H) ppm. 13C NMR (100 MHz, CDCl3): (endo isomer) δ
202.9, 139.6, 139.3, 136.3, 135.9, 133.8, 129.3, 128.9, 127.3, 59.6,
48.6, 48.5, 45.5, 45.2 21.2 ppm. Enantiomeric ratio was determined
by HPLC using Chiracel IC column after reduction with NaBH4/MeOH
(1:99 i-PrOH/hexane, 1 mL/min flow rate), endo isomers tr = 59.1
min (major enantiomer) and 73.6 min (minor enantiomer) ee = 92
%; exo isomers tr = 47.1 min (major enantiomer) and 64.2 min
(minor enantiomer) ee = 90 %.
(S)-3-(1-Methyl-1H-pyrrol-2-yl)-3-phenylpropan-1-ol (7a, Table 4,
entry 1)
Colorless liquid, 93 mg, 89 % yield; 1H NMR (400 MHz, CDCl3): δ
7.27-7.12 (m, 5H), 6.52 (s, 1H), 6.13 (s, 1H), 6.11 (d, J = 3.6 Hz, 1H),
4.12 (t, J = 7.6 Hz, 1H), 3.70-3.68 (m, 1H), 3.67-3.62 (m, 1H), 3.29 (s,
3H), 2.37-2.32 (m, 1H), 2.08-2.04 (m, 1H) ppm. 13C NMR (100 MHz,
CDCl3): δ 143.5, 134.9, 128.6, 128.4, 128.1, 127.9, 126.4, 121.9,
106.3, 105.8, 60.8, 39.6, 39.1, 33.9 ppm. Enantiomeric ratio was
determined by HPLC using Chiracel IC column after reduction with
NaBH4/MeOH (5:95 i-PrOH/hexane, 1 mL/min flow rate), isomers tr
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DOI: 10.1039/C6OB02801B
ARTICLE
Journal Name
1
2
(a) Special Issue about Asymmetric Organocatalysis (Eds.: K.
N. Houk and B. List), Acc. Chem. Res., 2004, 37, 487-681; (b)
= 9.0 min (minor enantiomer) and 10.4 min (major enantiomer) ee
= 87 %.
P. I. Dalko and Moisan. L. Angew. Chem. Int. Ed., 2004, 43
,
(S)-3-(1-Methyl-1H-pyrrol-2-yl)-3-phenylpropan-1-ol (7b, Table 4,
5138; (c) A. M. Rouhi, Chem. Eng. News, 2004, 82, 41; (d) S.
France, D. J. Guerin, S. J. Miller and T. Lectka, Chem. Rev.,
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Science, 2002, 298, 1904; (f) E. R. Jarvo and S. J. Miller,
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Jørgensen, Chem. Soc. Rev., 2009, 38, 2178. (c) A. Berkessel
and H. Groger, Asymmetric Organocatalysis, VCH, Weinheim,
2004. (d) H. Groger and J. Wilken, Angew. Chem. Int. Ed.,
2001, 40, 529.
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103, 3401; (b) D. J. Cole-Hamilton, Science, 2003, 299, 1702.
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Rev., 2007, 107, 5416. (c) Y. Zhu, X. Chen, M. Xie, S. Dong, Z.
entry 2)
Colorless liquid, yield 94 mg, 77 %, 1H NMR (400 MHz, CDCl3): δ 7.05
(m, 2H), 6.81 (d, J = 8.4 Hz, 2H), 6.51 (s, 1H), 6.11 (t, J = 3.2 Hz, 2H),
4.07 (t, J = 7.2 Hz, 1H), 3.75 (s, 3H), 3.67-3.61 (m, 1H), 3.59-3.51 (m,
1H), 2.28 (s, 3H), 2.31-2.29 (m, 1H), 2.06-2.01 (m, 1H) ppm. 13C
NMR (100 MHz, CDCl3): δ 158.1, 135.5, 135.3 128.9, 121.8, 114.2,
114.1, 106.4, 106.3, 105.6, 60.8, 55.3, 39.1, 38.7, 33.9 ppm.
Enantiomeric ratio was determined by HPLC using Chiracel IC
column after reduction with NaBH4/MeOH (5:95 i-PrOH/hexane, 1
mL/min flow rate), isomers tr = 26.6 min (minor enantiomer) and
30.7 min (major enantiomer) ee= 80 %.
3
4
5
(S)-3-(1-methyl-1H-pyrrol-2-yl)-3-(4-nitrophenyl)propan-1-ol (7c,
Table 4, entry 3)
Colorless liquid, yield 124 mg, 96 %, 1H NMR (400 MHz, CDCl3): δ
8.13 (d, J = 2 Hz, 2H), 7.32 (m, J = 2 Hz, 2H), 6.55 (s, 1H), 6.16 (d, J =
2.8 Hz, 2H), 4.32 (t, J = 8 Hz, 1H), 3.74-3.72 (m, 1H), 3.71-3.67 (m,
1H), 3.29 (s, 3H), 2.34-2.30 (m, 1H), 2.07-2.02 (m, 1H) ppm. 13C
NMR (100 MHz, CDCl3): δ 151.5, 146.6, 133.2, 128.8, 128.7, 123.9,
122.5, 106.8, 106.4, 106.3, 60.1, 39.1, 38.6, 33.9 ppm. Enantiomeric
ratio was determined by HPLC using Chiracel IC column after
reduction with NaBH4/MeOH (5:95 i-PrOH/hexane, 1 mL/min flow
rate), isomers tr = 39.7 min (minor enantiomer) and 51.1 min (major
enantiomer) ee = 77 %.
Qiao, L. Lin, X. Liu and X. M. Feng, Chem. Eur. J., 2010
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M. Feng, Angew. Chem. Int. Ed., 2015 54, 4032. (e) T. F. Kang, Z.
Wang, L. L. Lin, Y. T. Liao, Y. H. Zhou, X. H. Liu and X. M. Feng,
Adv. Synth. Catal., 2015 357, 2045. (f) Y. Lu, Y. H. Zhou, L. L. Lin,
H. F. Zheng, K. Fu, X. H. Liu and X. M. Feng, Chem. Commun.,
, 16,
,
,
2016
2009
,
,
52, 8255.(g) Y. Wang, X. Xu and W. Pei, Synth. Commun.,
39, 2032. (h) H. Hagiwara, T. Kuroda, T. Hoshi and T.
Suzuki, Adv. Synth. Catal., 2010, 352, 909.
6
(a) M. Benaglia, G. Celentano, M. Cinquini, A. Puglisi and F.
Cozzi, Adv. Synth. Catal., 2002, 344, 149; (b) S. A. Selkala, J.
Tois, P. M. Pihko and A. M. P. Koskinen, Adv. Synth. Catal.,
2002, 344, 941; (c) A. Puglisi, M. Benaglia, M. Cinquini, F.
Cozzi and G. Celentano, Eur. J. Org. Chem., 2004, 567; (d) C.
S. Pecinovsky, G. D. Nicodemus and D. L. Gin, Chem. Mater.,
2005, 17, 4889. (e) Y. Zhang, L. Zhao, S. Lee and Y. Ying, Adv.
Synth. Catal., 2006, 348, 2027. (f) T. Pecchioli, M. Muthyala,
(R)-Ethyl 4-hydroxy-2-(1-methyl-1H-pyrrol-2-yl)butanoate (7d,
Table 4, entry 4)
Colorless liquid, yield 91 mg, 87 %, 1H NMR (400 MHz, CDCl3): δ,
6.62 (s, 1H), 6.07 (t, J = 2.4 Hz, 1H), 6.04 (d, J = 2 Hz, 1H), 4.51-4.48
(m, 1H), 4.37-4.35 (m, 1H), 3.85 (t, J = 6.5 Hz 1H), 3.68 (s, 3H), 3.45-
3.42 (m, 2H), 2.63-2.53 (m, 2H), 1.21 (t, J = 6.8 Hz, 3H) ppm. 13C
NMR (100 MHz, CDCl3): δ 175.9, 126.7, 123.5, 107.1, 106.4, 66.8,
65.9, 37.8, 34.3, 29.2, 15.3 ppm. Enantiomeric ratio was determined
by HPLC using Chiracel IC column after reduction with NaBH4/MeOH
(5:95 i-PrOH/hexane, 1 mL/min flow rate), isomers tr = 34.9 min
(minor enantiomer) and 44.7 min (major enantiomer) ee = 85 %.
R. Haag and M. Christmann, Beilstein J. Org. Chem., 2015, 11
730.
(a) P. Riente, J. Yadav and M. A. Pericás, Org. Lett., 2012, 14
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7
8
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3668. (b) S. Ranjbar, P. Riente and M. A. Pericás, Org. Lett.,
2016, 18, 1602.
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4
, 1184; (b) A. Winkel, P. V. G. Reddy and R. Wilhelm, Synlett,
(R)-3-(1-Methyl-1H-pyrrol-2-yl)hexan-1-ol (7e, Table 4, entry 5)
Colorless liquid, yield 86 mg, 90 %, 1H NMR (400 MHz, CDCl3): δ 6.48
(d, J = 2.4 Hz, 1H), 6.06 (t, J = 3.2 Hz, 1H), 5.85 (t, J = 2 Hz, 1H), 3.62-
3.59 (m, 1H), 3.55 (s, 3H), 3.54-3.53 (m, 1H), 2.85-2.82 (m, 1H),
1.90-1.76 (m, 2H), 1.59-1.53 (m, 2H), 1.29-1.21 (m, 2H), 0.87 (t, J =
7.2 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3): δ 136.8, 121.1, 106.7,
104.3, 61.1, 38.6, 33.8, 33.7, 32.9, 20.5, 14.2 ppm. Enantiomeric
ratio was determined by HPLC using Chiracel IC column after
reduction with NaBH4/MeOH (5:95 i-PrOH/hexane, 1 mL/min flow
rate), isomers tr = 19.5 min (major enantiomer) and 23.7 min (minor
enantiomer).
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9
Tetrahedron Lett., 2010, 51, 4403. (b) Y. Xiong, H. Mei, C. Xie,
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Acknowledgements
Kattamuri, T. Ai, S. Pindi, Y. W. Sun, P. Gu, M. Shi and G. Li, J.
Org. Chem., 2011, 76, 2792. (d) Y. Xiong, H. Mei, C. Xie, J.
Han, G. Li and Y. Pan, Beilstein J. Org. Chem., 2014, 10, 653.
We are grateful for financial support from the NSFC (Nos. 21332005
and 21672100), NSF of Jiangsu Province (BK20151163), PAPD of
Jiangsu Higher Education Institutions, Robert A. Welch Foundation
(D-1361, USA) and NIH (R33DA031860, USA)
(e) G. An, C. Seifert and G. Li, Org. Biomol. Chem., 2015, 13
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10 J. Qiu, B. Xu, Z. Huang, W. Pan, P. Cao, C. Liu, X. Hao, B. Song
and J. Liang, Bioorg. Med. Chem., 2011, 19, 5352.
Notes and references
6 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C6OB02801B
Journal Name
ARTICLE
11 K. A. Ahrendt, C. J. Borths and D. W. C. MacMillan, J. Am.
Chem. Soc., 2000, 122, 4243.
12 (a) N. A. Paras and D. W. C. MacMillan, J. Am. Chem. Soc.
2001, 123, 4370. (b) J. Zheng, L. Lin, L. Dai, X. Yuan, X. Liu and
X. M. Feng, Chem. Eur. J. 2016, 22, 18254. (c) Y. L. Zhang, X. H.
Liu, X. H. Zhao, J. L. Zhang, L. Zhou, L. L. Lin and X. M. Feng,
Chem. Commun., 2013, 49, 11311.
This journal is © The Royal Society of Chemistry 20xx
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