Optimized Synthetic Route for Enantioselective Preparation of (S)-Metolachlor from Commercially Available (R)-Propylene Oxide

Article abstract of DOI:10.1021/acs.oprd.7b00216

An enantioselective preparation of (S)-metolachlor has been accomplished. The synthetic route featured the asymmetric preparation of chiral intermediates and the final (S)-metolachlor from commercially available (R)-propylene oxide and a key Fukuyama's process. The key steps, control points, separation purifications, and the whole process are optimized, and the target compound has been successfully prepared in five steps in 51-55% overall yield with excellent enantioselectivity (99% ee) up to a 30 g scale. By judicious choice of synthetic route and selection of starting materials and intermediates, no column chromatographic methods are needed for the separation and purification of the intermediates and the final products. The same strategy was extended as a general method for a series of pesticides and herbicide analogs of Metalaxyl-M and Dimethenamid-P.

Full text of DOI:10.1021/acs.oprd.7b00216

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Communication
Optimized Synthetic Route for Enantioselective Preparation of (S)-
Metolachlor from Commercially Available (R)-Propylene Oxide
Peng Yang, Xiao Wang, Lin Peng, Feng Chen, Fang Tian, Chao-Zhe Tang, and Li-Xin Wang
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.7b00216 • Publication Date (Web): 06 Sep 2017
Downloaded from http://pubs.acs.org on September 6, 2017
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Optimized Synthetic Route for Enantioselective
Preparation of (S)-Metolachlor from Commercially
Available (R)-Propylene Oxide
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Peng Yang,†,‡ Xiao Wang,†,‡ Lin Peng,† Feng Chen,†,‡ Fang Tian,†,‡ Chao-Zhe Tang,† and Li-Xin
Wang*,†
†Key Laboratory of Asymmetric Synthesis and Chirotechnology of Sichuan Province, Chengdu
Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, P.R. China
‡University of Chinese Academy of Sciences, Beijing 100049, P.R. China
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Abstract
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An enantioselective preparation of (S)-Metolachlor has been accomplished. The synthetic
route featured the asymmetric preparation of chiral intermediates, and the final (S)-Metolachlor
from commercially available (R)-propylene oxide and a key Fukuyama’s process. The key steps,
control points, separation-purifications and the whole process are optimized, and the target
compound has been successfully prepared in five steps in 51-55% overall yield with excellent
enantioselectivity (99% ee) up to a 30 gram scale. By judicious choice of synthetic route and
selection of starting materials and intermediates, no column chromatographic methods are
needed for separation and purification of the intermediates and the final products. The same
strategy was extended as a general method for a series of pesticides and herbicide analogs of
Metalaxyl-M and Dimethenamid-P.
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Keyword: (S)-Metolachlor, Fukuyama’s process, (R)-propylene oxide, enantioselective
preparation
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Introduction
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Chiral herbicide (S)-Metolachlor (Figure 1) is the active ingredient of Dual Magnum, one of
the most important grass herbicides using in maize and a wide range of other crops. Due to its
great importance in agrochemicals, the synthesis of (S)-Metolachlor has become an area of
intense interests in synthetic chemistry.1–3 The key point for its preparation lies in the effective
construction of amino chiral center. In the past 20 years, most synthetic approaches have focused
on the asymmetric hydrogenations of sterically hindered imines,1d, 1g, 2 and the most outstanding
example is the Ir-xyliphos catalyzed chiral reduction of MEA imine in 1996 and Hans-Ulrich
Blaser has well reviewed the evolution of the current industrial hydrogenation process.2b Other
strategies, such as microbial transformation, chiral agent reduction4 and chiral pool preparations,5
have become a new and powerful reservoir for the potential preparations of (S)-Metolachlor. As
a part of our continued interests in process chemistry,6–8 herein we wish to report an optimized
route for the enantioselective preparation of (S)-Metolachlor and its analogs from commercially
available (R)-propylene oxide and L-lactic acid methyl ester.
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Figure 1. The structure of (S)-Metolachlor
Results and Discussion
In a preliminary study, we tried the potential “optimal” direct nucleophilic substitution of (R)-
methoxyisopropanol Ts/Ms derivatives with 2-methyl-6-ethyl-benzamine.2b The reaction was
conducted with 2.0 equiv. 2-methyl-6-ethyl-benzamine, 1.0 equiv. Ts/Ms derivatives and 1.2
o
equiv. pyridine in DMF at room temperature to 160 C. As a whole, the expected substitution is
disappointedly inactive (generally < 10% conversion) or racemized (58-90% ee) at higher
temperature (with slightly higher conversion) (Scheme 1a). The similar attempt and problems
were also mentioned by Hans-Ulrich Blaser.2b Those results prompted us to carefully reconsider
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this synthetic route centering on modifications to both electrophilic and nucleophilic partners in
the substitution step (Scheme 1b).
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Scheme 1. Strategy for the Preparation of (S)-Metolachlor
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Scheme 2 summarized our synthetic strategy, as well as the key intermediates and starting
materials we identified. To further optimize each reaction step, cheap and easily available aniline
2a, which contained the similar nucleophilicity with 2-ethyl-6-methylaniline, was used as the
model substrate. Based on a well-established hydrolytic ring-opening reaction, we selected (R)-
propylene oxide (99% ee) as the commercial precursor for (R)-1-methoxypropan-2-ol 1, the
starting material required for a Fukuyama-type Mitsunobu alkylation,9 which is known to
proceed with complete inversion of chirality. For synthetic route, we always cherish our
persistence of “separation-purification and process oriented industrial organic syntheses”, and in
every synthetic step, all the reactants, intermediates and the formed substances should be with
obvious differences in physical and chemical characteristics, such as solubility, boiling point,
polarity, acidity and basicity, for easier separation-purifications before synthetic route, reaction,
solvent and technique selections. Based on those considerations, our synthetic route featured the
following characteristics: the starting aromatic amine and pyridine (basic, easy salt formation
and soluble in water), quite different from the sulfonamide 4 and can be easily separated and
purified by simple and general acidification/extraction work-up. After Fukuyama’s process,
sulfonamide 4 and 5, with different solubility in sorts of solvents, and may be separated and
purified by recrystallization of 4 or just washing with solvent. Sulfonamide 5 (neutral) and the
key intermediate 6 (basic, easy salt formation and soluble in water) with obvious differences in
physical and chemical characteristics, can also be easily separated and purified by simple and
general acid/base work-up. Basic amines 6 are also readily separated from the neutral
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sulfonamides 4 and 5 by aqueous extraction at low pH. We expect the described formal synthesis
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of the herbicide targets to be readily scalable.
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Scheme 2. Preparation and optimizations of the model reaction
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For the manufacture of 1 from (R)-2-propylene oxide, there existed some known processes for
nucleophilic substitution in the presence of a base.10 The simplest method was Slayton A. Evans’
procedure.10d (R)-2-propylene oxide was ring opened in catalytic sodium hydroxide in refluxing
methanol. The residue was neutralized, after vacuum distillation, a distillate composed of 88.7%
product and 11.3% of the unwanted 2-methoxy-1-propanol isomer was obtained. To simplify the
work-up process and conveniently to reuse methanol, after termination of the reaction, the
residue was directly rectified with packed column (column length: 15 cm, specification for
spring-like glass packing: diameter 3–8 mm, length 6–20 mm) under atmospheric pressure, the
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desired (R)-1-methoxy-2-propanol was obtained at 113 C in 79% yield with 99% purity (GC),
and methanol may be recycled without further treatment.
For the whole synthetic route and especially the key Fukuyama’s process for the construction
of the chiral center, the selections of protected sulfonylation group and effective desulfonylation
were two key control steps for successful and effective preparation for the target (S)-Metolachlor.
In classic Fukuyama’s process,9 an improved variant of Mitsunobu reaction for an easier
desulfonylation, 4-nitrobenzenesulfonyl, 2-nitrobenzenesulfonyl or 2,4-dinitrobenzenesulfonyl
chloride was generally used. Considering the availability and cost of sulfonyl chlorides, 4-
nitrobenzenesulfonyl chloride 3 instead of 4-methylbenzenesulfonyl chloride or other chlorides
was used for the sulfonylation of 2a, and 4-nitro-N-phenylbenzenesulfonamide 4a was readily
prepared in the presence of 1.0 equiv. pyridine and 0.9 equiv. 3 in DCM in 96–98% yields.11 As
a typical preparation method, this process had been reported by several literatures and generally
gave good results.11 However, the purifications were usually limited to column chromatographic
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methods, or used only with crude product without purification. We found the crude product of 4a
could be recrystallized with ethanol in 80% yield or just washing with cold ethanol in 95% yield
with 98% HPLC purity.
9
Table 1. Screening for Mitsunobu Reaction of 4aa
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entry
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PPh3 (eq)
1.0
DIAD (eq)
1.0
T (oC)
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solvent
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
THF
yieldb (%)
50
eec (%)
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1 (eq)
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1.5
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1.5
1.5
1.5
1.5
1.5
1.5
1.2
1.5
1.5
1.5
2.0
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
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70
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99
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trace
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nd
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25d
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DCE
toluenee
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aUnless otherwise noted, the reaction was performed with 4a (1.0 mmol), in anhydrous toluene (2.8 mL) for 2 h. Isolated yield.
b
cDetermined by chiral HPLC. d reaction time was increased to 24 h eCommercial grade toluene.
After Mitsunobu reaction of 1 and 4a in the presence of triphenylphosphine and diisopropyl
azodicarboxylate (DIAD), the key intermediate 5a was successfully obtained. Based on
Mitsunobu reaction conditions,12 some important reaction parameters were furtherly investigated
(Table 1). The model reaction initially proceeded with 1.0 equiv. 4a, 1.0 equiv. PPh3 and 1.0
equiv. DIAD at 80 oC in toluene, and product 5a was obtained in only 50% yield (Table 1, entry
1). To furtherly raise the yield, there were generally two strategies: excessive 1 or excessive 4a
was used and in most and generally regarded opinions, excessive cheaper 4a was better
compared with excessive 1. In our strategy, the easy separation and purification of any mixture is
the most top consideration. Therefore, an excess of water soluble and volatile 1 was used; 4a and
5 being similar in structure and physical properties. Hence, excessive 1 is more easily separated
from 5a by water washings or distillation. Based on those considerations, various material ratios
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were studied (Table 1, entries 2–6), and 88% yield was obtained in 1.2 equiv. 1, 1.5 equiv. PPh3
and DIAD (Table 1, entry 4). Higher material ratio gave almost equal results (Table 1, entries 5–
6). The temperature also showed some effects on Mitsunobu process, a higher or lower
temperature was not suitable (Table 1, entries 7–12), and best result of 99% yield with 99% ee
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was achieved at 50 C (Table 1, entry 9). Other solvents for Mitsunobu reaction were also
studied, and inferior results were obtained (Table 1, entries 13–14). When the commercial grade
toluene was used, almost the same excellent result was achieved (Table 1, entry 15, 99% yield,
99% ee).
Another key step of Fukuyama’s process was the mild and effective desulfonylation.
According to Fukuyama’s procedures, the intermediate 5a could be treated with different bases
and thiols in acetonitrile (Table 2).11a, 12, 13 When 5a was treated with 4.0 equiv. DBU and 2.0
equiv. 2-mercaptoacetic acid (to reduce the loading of DBU, such as a slightly lower to 3.0
equiv., leads to incomplete reaction conversion to 68% yield ) at room temperature for 1 h, the
desired secondary amine 6a was obtained in the best result (85% yield, 99% ee, Table 2, entry 3).
Table 2. Desulfonylation of Sulfonamide 5aa
entrya
1
2
3
base
K2CO3
LiOH
DBU
R-SH
benzenethiol
yieldb (%)
eec (%)
99
72
82
85
2-mercaptoacetic acid
2-mercaptoacetic acid
99
99
aUnless otherwise noted, the reaction was performed with 5a (1.0 mmol), base (4.0 mmol) and thiol (2.0 mmol) in CH3CN (5 mL)
for 2 h. bIsolated yield. cDetermined by chiral HPLC.
Scheme 3. Enantioselective Preparation of (S)-Metolachlor
Under the optimal reaction conditions, we broaden the synthetic route to the preparation of
chiral herbicide (S)-Metolachlor intermediate 6b (Scheme 3) and attended to the process and
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separation-purification optimizations. In the sulfonylation step, the reaction mixture containing
4b and other excessive reactants, excessive 2b and pyridine was acidified to pH = 3 or lower for
complete salt formation and separated by washing with water, product 4b stayed in organic
phase. After removal of solvent, the crude product was obtained and purified by washing with
ethanol to give pure 4b in 97% yield with 98% HPLC purity. In Mitsunobu step, 4b displayed
the similar reactivity as 4a. Treatment of 4b with 1 in toluene smoothly afforded key
intermediate 5b in 99% conversion. After strip of solvent and excessive 1 under reduced pressure,
the residue, containing phosphorous byproducts (neutral), quite different with the target 6b (basic)
in physical and chemical properties, was directly used for the subsequent desulfonylation step in
one-pot without separation and purification. The desulfonylation was operated in CH3CN with
2.0 equiv. mercaptoacetic acid and 4.0 equiv. DBU11a at room temperature for 1 h, and the
residue was treated as the following procedures: The solvent was removed and the residue was
acidified to pH = 1 or lower to ensure the desired 6b to fully form its hydrochloride salt (over 2 h
with stirring) and sufficiently soluble in enough water. DCM was added and all neutral
byproducts and organic wastes were extracted and separated with 6b hydrochloride in water. The
aqueous phase, containing the needed product, DBU-HCl and mercaptoacetic acid, was basified
and extracted with DCM, product 6b in DCM was separated while water soluble DBU and
mercaptoacetic acid stayed in the aqueous phase. The crude product was purified by vacuum
distillation and the desired 6b was obtained in 74%–80% total separated yield14 for two steps
with 99% ee. The principles and strategies for the separation-purification of the needed 6b with
other materials were outlined in Chart 1. Operated as the reported method,15 6b was easily
transformed to (S)-Metolachlor in 80% yield with 98% HPLC purity in 99% ee.
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Chart 1. Material flow and separation-purification strategies for target 6b.
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Further applications of this method to the preparations of other chiral bactericides of
Metalaxyl-M and Benalaxyl-M were examined (Scheme 4). The whole process and results of this
synthetic route were similar to those of (S)-Metolachlor, while using commercially available L-
lactic acid methyl ester as the chiral pool starting material, 6c was obtained in 70–74% total yield
in three steps. Using different chlorides and after general work-up, the key chiral intermediate of
6c was easily transformed to Metalaxyl-M16 and Benalaxyl-M.17
Scheme 4. Preparations of Metalaxyl-M and Benalaxyl-M
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Conclusions
In conclusion, an optimized enantioselective preparation of (S)-Metolachlor from
commercially available (R)-propylene oxide via Fukuyama’s processes has been successfully
accomplished. Our synthesis characterized by the careful choice of synthetic route and starting
materials and intermediates with simple and general work-up procedures. After optimizations of
the key Fukuyama’s processes, especially optimizations for every separation-purification, the
target compound has been successfully prepared for five steps in 51-55% overall yield with
excellent enantioselectivity (99% ee) up to a 30 gram scale without column chromatographic
methods. Furthermore, this route can be used as a general method for a series of pesticides and
herbicide analogs such as Metalaxyl-M and Benalaxyl-M.
Experimental Section
Materials and Instruments. Unless otherwise noted, all solvents and reagents were purchased
from the suppliers and used without further purifications. (R)-2-propylene oxide was
1
commercially available with 99% ee. Mechanic stirrers were used for all stirrings. H NMR
spectra were recorded on a Bruker DPX 300 MHz spectrometer in CDCl3, DMSO-d6 with Me4Si
(TMS) as internal standard at room temperature. Mass spectra were recorded on a Bruker micro
TOF-Q mass spectrometer. Reaction process and purity were monitored by HPLC analysis on
C18 columns. Enantiomeric excess was determined by HPLC analysis on chiralpak AD-H, AS-H,
or IC-H columns.
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(R)-1-Methoxypropan-2-ol (1).
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In a 500 mL three necked bottle with condenser, (R)-2-propylene oxide (75 g, 1.3 mol, 99% ee),
sodium hydroxide (1.0 g, 2.5 mmol) and methanol 250 mL were combined and heated to reflux.
The mixture was stirred for 5 h, and the condenser was replaced by distillation apparatus. The
product was obtained by atmospheric rectification (15 cm packed column, specification for
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spring-like glass packing: diameter 3–8 mm, length 6–20 mm) at 113 C as a colorless liquid
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(92.2 g, 79% yield, GC 99%). Boiling point in literature:18 116-119 C (760 mm Hg). Boiling
o
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point of 2-methoxy-1-propanol in literature:18 127-129 C (760 mm Hg). H NMR (300 MHz,
DMSO-d6) δ 4.55 (d, J = 4.6 Hz, 1H), 3.75–3.68 (m, 1H), 3.24 (s, 3H), 3.22–3.17 (m, 1H), 3.11
(dd, J = 9.5, 5.3 Hz, 1H), 1.01 (d, J = 5.4 Hz, 3H). 13C NMR (75 MHz, DMSO-d6) δ 78.2, 64.8,
58.3, 20.2.
4-Nitro-N-phenylbenzenesulfonamide (4a).
To a stirred solution of aniline (46.5 g, 0.5 mol) and pyridine (39.6 g, 0.5 mol) in
dichloromethane (460 mL), 4-nitrobenzene-1-sulfonyl chloride (99.8 g, 0.45 mol) was added.
After mechanic stirring at ambient temperature for 2.5 h, the reaction mixture was acidified to
pH = 3 with 1 N HCl. The resulting organic phase was washed with water (460 mL x 3) and
concentrated in vacuum. The residue solid was washed with cold ethanol (80 mL) by stirring and
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filtered to afford the product as a yellow solid (119 g, 95% yield, HPLC 98%). Mp 177–178 C
(174–176 oC11a); 1H NMR (300 MHz, DMSO-d6) δ 10.57 (s, 1H), 8.35 (d, J = 8.9 Hz, 1H), 7.97
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(d, J = 8.9 Hz, 1H), 7.32–7.19 (m, 2H), 7.14–6.99 (m, 3H). C NMR (75 MHz, DMSO-d6) δ
149.8, 144.9, 136.9, 129.4, 128.3, 124.8, 124.6, 120.7.
N-(2-ethyl-6-methylphenyl)-4-nitrobenzenesulfonamide (4b).
Preparation of 4b was similar to that of 4a. 4b (279.8 g, 97% yield, HPLC 98%) was obtained
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from 2-ethyl-6-methylaniline (135.2 g, 1.0 mol) as a yellow solid; Mp 193–195 C; H NMR
(300 MHz, DMSO-d6) δ 9.79 (s, 1H), 8.44–8.39 (m, 2H), 7.96–7.92 (m, 2H), 7.17–7.07 (m, 2H),
7.04–7.01 (m, 1H), 2.41 (q, J = 7.4 Hz, 2H), 1.90 (s, 3H), 0.97 (t, J = 7.5 Hz, 3H). 13C NMR (75
MHz, DMSO-d6) δ 149.6, 147.4, 143.7, 137.6, 132.0, 128.4, 128.0, 127.9, 126.7, 124.7, 24.1,
18.6, 14.6. HRMS (ESI) m/z calcd for C15H17N2O4S+ (M+H)+ 321.0904, found 321.0903.
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N-(2,6-dimethylphenyl)-4-nitrobenzenesulfonamide (4c).
Preparation of 4c was similar to that of 4a. Product 4c (265.8 g, 96% yield, 90% HPLC) was
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obtained from 2,6-dimethylaniline (121.2 g, 1.0 mol) as a yellow solid; Mp 189–190 C; H
NMR (300 MHz, DMSO-d6) δ 9.76 (s, 1H), 8.41 (d, J =8.9 Hz, 2H), 7.94 (dd, J = 9.4, 2.4 Hz,
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2H), 7.12–7.02 (m, 3H), 1.96 (s, 6H). C NMR (75 MHz, DMSO-d6) δ 149.6, 147.4, 137.6,
132.8, 128.5, 128.0, 127.6, 124.7, 18.5. HRMS (ESI) m/z calcd for C14H15N2O4S+ (M+H)+
307.0747, found 307.0746.
(S)-N-(1-methoxypropan-2-yl)-4-nitro-N-phenylbenzenesulfonamide (5a).
For reaction condition screening: To a stirred solution of 4a (278 mg, 1 mmol),
triphenylphosphine (393 mg, 1.5 mmol) and (R)-1-methoxypropan-2-ol 1 (108 mg, 1.2 mmol) in
toluene (3.2 mL), diisopropyl azodicarboxylate (303 mg, 1.5 mmol) was added at room
temperature. The reaction mixture was stirred at 50 oC for 2 h. The solvent was removed and the
residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc =
20:1–10:1) and 349 mg (99% yield, 99% ee, HPLC 96.5%) of 5a was obtained as a white solid;
Mp 121–122 oC; [α]D20 = 45.0 (c = 1.75, CHCl3). The ee value was determined by a chiral HPLC
(Chiralcel AD-H column, hexane/i-PrOH = 98/2, flow rate 1.0 mL/min, λ = 254 nm, 99% ee:
tmajor = 25.2 min, tminor = 23.0 min; 1H NMR (300 MHz, CDCl3) δ 8.26 (d, J = 8.9 Hz, 2H), 7.90
(d, J = 8.9 Hz, 2H), 7.40–7.32 (m, 3H), 7.03 (dd, J = 7.8, 1.2 Hz, 2H), 4.78–4.71 (m, 1H), 3.17–
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3.10 (m, 4H), 3.00 (t, J = 10.0 Hz, 1H), 1.09 (d, J = 6.9 Hz, 3H). C NMR (75 MHz, CDCl3) δ
149.7, 146.7, 133.6, 132.4, 129.3, 129.16, 129.15, 123.4, 73.4, 58.1, 55.2, 16.9. HRMS (ESI) m/z
calcd for C16H19N2O5S+ (M+H)+ 351.1009, found 351.1010.
Scale up preparations: To a mechanic stirred solution of 4a (55.6 g, 0.2 mol),
triphenylphosphine (78.6 g, 0.3 mol) and (R)-1-methoxypropan-2-ol 1 (21.6 g, 0.24 mol) in
toluene (640 mL), diisopropyl azodicarboxylate (60.7 g, 0.3 mol) was added in ice bath. The
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addition was completed within 5 min and the reaction mixture was allowed to reach 25 C. The
reaction mixture was mechanic stirred for additional 2 h at 50 oC. The solvent was removed and
the residue was directly used for the next step without further purification.
1-Ethyl-2-((2S)-3-methoxy-2-methyl-1-((4-nitrophenyl)sulfonyl)propyl)-3-methylbenzene (5b).
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Preparation of 5b was similar to that of 5a. Product 5b (391 mg, 99% yield, HPLC 95.6%) was
obtained from 4b (320 mg, 1.0 mmol) as a semisolid. In the scale up preparation, 5b was
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obtained as a crude product and used directly for the next step; [α]D = –9.6 (c = 1.35, CHCl3);
dr = 53/47. The ee value was determined by a chiral HPLC (Chiralcel IC column, hexane/i-PrOH
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= 80/20, flow rate 1.0 mL/min, λ = 254 nm, major diastereomer 98% ee: tmajor = 33.2 min, tminor
=
28.6 min; minor diastereomer 99% ee: tmajor = 51.2 min, tminor = 25.5 min); 1H NMR (300 MHz,
CDCl3) δ 8.38 (d, J = 8.6 Hz, 2H), 7.98–7.93 (m, 2H), 7.24–7.20 (m, 2H), 7.11–7.07 (m, 1H),
4.29–4.23 (m, 1H), 3.42–3.38 (m, 1H), 3.35–3.32 (m, 1H), 3.06–3.04 (s, 3 H, Major + Minor),
2.48–2.45 (m, 1H), 2.33–2.31 (m, 1H), 2.10–1.97 (s, 3H, Major + Minor), 1.13–1.01 (m, 6H).
13C NMR (75 MHz, CDCl3) δ 149.7, 146.72, 146.66, 146.1, 145.3, 140.0, 139.3, 134.2, 134.0,
129.18, 129.15, 128.9, 128.8, 128.61, 128.59, 126.9, 126.8, 124.4, 124.3, 74.5, 74.4, 57.9, 57.79,
57.75, 57.7, 24.7, 23.6, 20.09, 19.0, 15.9, 15.8, 15.0, 14.8. HRMS (ESI) m/z calcd for
C18H21N2O6S+ (M+H)+ 393.1115, found 393.1116.
Methyl N-(2,6-dimethylphenyl)-N-((4-nitrophenyl)sulfonyl)-L-alaninate (5c).
Preparation of 5c was similar to that of 5a. Product 5c (382 mg, 97% yield, HPLC 92.4%) was
obtained from 4c (306 mg, 1.0 mmol) and L-lactic acid methyl ester (156 mg, 1.5 mmol) as a
white solid. In the scale up preparation, 5c was obtained as a crude product and used directly for
the next step; Mp 129–130 oC; [α]D20 = 4.8 (c = 1.05, CHCl3). The ee value was determined by a
chiral HPLC (Chiralcel OD column, hexane/i-PrOH = 95/5, flow rate 1.0 mL/min, λ = 254 nm,
98% ee: tmajor = 15.8 min, tminor = 17.8 min; 1H NMR (300 MHz, DMSO-d6) δ 8.41–8.37 (m, 2H),
7.83–7.78 (m, 2H), 7.21 (t, J = 7.5 Hz, 1H), 7.18–7.07 (m, 2H), 4.78 (dd, J = 14.3, 7.1 Hz, 1H),
3.72 (s, 3H), 2.08 (s, 3H), 1.93 (s, 3H), 0.94 (d, J = 7.2 Hz, 3H). 13C NMR (75 MHz, DMSO-d6)
δ 172.5, 150.0, 144.6, 140.9, 140.3, 133.2, 129.4, 129.1, 129.0, 128.8, 124.3, 57.6, 52.3, 18.9,
18.4, 16.7. HRMS (ESI) m/z calcd for C19H25N2O5S+ (M+H)+ 393.1479, found 393.1478.
(S)-N-(1-methoxypropan-2-yl)aniline (6a).
For reaction condition screening: To a stirred solution of 5a (349 mg, 1.0 mmol) in acetonitrile
(3.5 mL), a solution of DBU (608 mg, 4.0 mmol) and mercaptoacetic acid (184 mg 2.0 mmol) in
acetonitrile (1.0 mL) was added. After stirring at ambient temperature for 10–15 min, the solvent
was removed and the residue was purified by flash column chromatography on silica gel
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(petroleum ether/EtOAc = 20: 1) to afford 140.0 mg (85% yield, 99% ee) of the product 6a as a
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colorless oil.
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Scale up preparation: To a mechanic stirred solution of crude 5a (the residue from the previous
step) in acetonitrile (700 mL), a solution of DBU (122 g, 0.8 mol) and mercaptoacetic acid (37 g
0.4 mol) in acetonitrile (200 mL) was added. After stirring at ambient temperature for 2 h, the
solvent was removed and the residue was acidified by 6M HCl to pH = 1 or lower. The mixture
was extracted with dichloromethane (400 mL x 3). The resulting aqueous layer was basified with
5 M NaOH to pH 10 above and extracted with dichloromethane (400 mL x 3). The organic layer
was evaporated and purified by vacuum distillation (107 oC, 5 mm Hg) to afford the product as a
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colorless oil (23.1 g, 70% yield, GC 99%); [α]D = –0.9 (c = 0.75, CHCl3). The ee value was
determined by a chiral HPLC (Chiralcel OD column, hexane/i-PrOH = 99.5/0.5, flow rate 1.0
mL/min, λ = 254 nm, 99% ee: tmajor = 20.0 min, tminor = 11.9 min; 1H NMR (300 MHz, CDCl3) δ
7.07–7.02 (m, 2H), 6.57 (d, J = 7.7 Hz, 2H), 6.49 (t, J = 7.2 Hz, 1H), 5.27 (d, J = 8.0 Hz, 1H),
3.61–3.52 (m, 1H), 3.38–3.37 (m, 1H), 3.26 (s, 3H), 3.23–3.17 (m, 1H) 1.11 (d, J = 6.4 Hz, 3H).
13C NMR (75 MHz, CDCl3) δ 148.0, 128.9, 115.5, 112.3, 75.6, 58.3, 47.0, 17.9.
(S)-2-Ethyl-N-(1-methoxypropan-2-yl)-6-methylaniline (6b).
Preparation of 6b was similar to that of 6a. Product 6b (167.7 mg, 81% yield) was obtained from
5b (392 mg, 1.0 mmol) as a colorless oil. In the scale up preparation, 6b (30.7 g, 74% yield, GC
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96%) was obtained by vacuum distillation (120 oC, 5 mm Hg); [α]D = 10.6 (c = 1.40, CHCl3).
The ee value was determined by a chiral HPLC (Chiralcel OD column, hexane/i-PrOH =
1
99.5/0.5, flow rate 1.0 mL/min, λ = 254 nm, 99% ee: tmajor = 5.5 min, tminor = 5.1 min; H NMR
(300 MHz, DMSO-d6) δ 7.26–7.01 (m, 2H), 6.90 (t, J = 7.5 Hz, 1H), 3.43–3.37 (m, 6H), 2.69 (q,
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J = 7.6 Hz, 2H), 2.33 (s, 3H), 1.30 (t, J = 7.6 Hz, 3H), 1.25–1.21 (m, 3H). C NMR (75 MHz,
DMSO-d6) δ 144.2, 135.4, 129.7, 128.6, 126.4, 121.6, 76.1, 58.9, 52.8, 24.1, 18.8, 18.4, 14.5.
Methyl (2,6-dimethylphenyl)-L-alaninate (6c).
Preparation of 6c was similar to that of 6a. Product 6c (154.7 mg, 75% yield) was obtained from
6c (392 mg, 1.0 mmol) as a colorless oil. In the scale up preparation, 6c (29.8 g, 72% yield, GC
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98%) was obtained by vacuum distillation (120 oC, 5 mm Hg); [α]D = –0.5 (c = 0.61, CHCl3);
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dr = 71/29. The ee value was determined by a chiral HPLC (Chiralcel AD-H column, hexane/i-
PrOH = 99.5/0.5, flow rate 1.0 mL/min, λ = 254 nm, 99% ee: tmajor = 11.7 min, tminor = 9.3 min;
1H NMR (300 MHz, DMSO-d6) δ 6.91 (d, J = 7.4 Hz, 2H), 6.72 (t, J = 7.4 Hz, 1H), 4.11 (d, J =
11.0 Hz, 1H), 3.91–3.80 (m, 1H), 3.56 (s, 3H), 2.22 (s, 6H), 1.33 (d, J = 6.9 Hz, 3H). 13C NMR
(75 MHz, DMSO-d6) δ 175.3, 144.3, 129.0, 128.7, 121.5, 54.8, 51.7, 19.1, 18.5.
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(S)-2-chloro-N-(2-ethyl-6-methylphenyl)-N-(1-methoxypropan-2-yl)acetamide (S-Metolachlor)
The acylation of 6b was prepared according to the reported procedures.[15] Crude (S)-
Metolachlor (30.9 g, 90% yield, HPLC 94%) was obtained from 6b (25.0 g, 0.12 mol) as a
colorless oil. After distillation under vacuum (164–167 oC, 5 mmHg). Qualified (S)-Metolachlor
(27.5 g, 80% yield, HPLC 98%) was obtained. [α]D20 = 5.8 (c = 0.71, CH2Cl2). The ee value was
determined by a chiral HPLC (Chiralcel OD+AS column, hexane/i-PrOH = 80/20, flow rate 1.0
mL/min, λ = 254 nm, major diastereomer >99% ee: tmajor = 28.2 min, tminor = 33.5 min; minor
diastereomer >99% ee: tmajor = 27.1 min, tminor = 43.8 min; 1H NMR (300 MHz, Chloroform-d) δ
7.26–7.09 (m, 3H), 4.20–4.18 (m, 1H), 3.73–3.63 (m, 1H), 3.58–3.57 (s, 2H, Major + Minor),
3.48–3.43 (m, 1H), 3.25–3.22 (s, 3H, Major + Minor), 2.58–2.52 (m, 2H), 2.22–2.20 (s, 3H,
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Major + Minor), 1.22 (t, J = 7.5 Hz, 3H), 1.14–1.10 (m, 3H). C NMR (75 MHz, CHCl3) δ
166.7, 142.5, 142.4, 137.1, 136.9, 136.8, 128.9, 128.8, 126.8, 126.7, 74.5, 58.5, 58.4, 55.3, 55.1,
42.8, 42.7, 23.8, 23.5, 18.82, 18.79, 15.4, 15.3, 14.1, 13.9.
Associated Content
Supporting Information
The spectra of intermediate and product are listed in the Supporting Information, which is available free of
charge on the ACS Publications website.
Author Information
Corresponding Author
*E-mail: wlxioc@cioc.ac.cn.
Notes
The authors declare no competing financial interest.
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