Highly diastereoselective Friedel-Crafts reaction of arenes with N-tert-butanesulfinylimino ester towards the efficient synthesis of α-arylglycines

Article abstract of DOI:10.1039/c1ob06450a

Lewis acid-catalyzed highly diastereoselective asymmetric Friedel-Crafts alkylation of arenes with a chiral N-tert-butanesulfinylimino ester is described. The reaction can be accomplished with ease in the presence of a catalytic amount of In(OTf)₃

Full text of DOI:10.1039/c1ob06450a

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PAPER
Highly diastereoselective Friedel–Crafts reaction of arenes with
N-tert-butanesulfinylimino ester towards the efficient synthesis of
a-arylglycines†
Yi Li, Du-Ming Ji and Ming-Hua Xu*
Received 24th August 2011, Accepted 16th September 2011
DOI: 10.1039/c1ob06450a
Lewis acid-catalyzed highly diastereoselective asymmetric Friedel–Crafts alkylation of arenes with a
chiral N-tert-butanesulfinylimino ester is described. The reaction can be accomplished with ease in the
presence of a catalytic amount of In(OTf)3 at room temperature, providing a series of enantiomerically
enriched a-arylglycines in good yields and with excellent diastereoselectivities (up to 99% de). Highly
stereoselective double Friedel–Crafts alkylation to afford dialkylation product was also investigated.
alkylation for synthesis of a-arylglycines remains a significant
Introduction
challenge. Herein, we report our efforts to address this issue by
employing simple Lewis acid to catalyze the asymmetric Friedel–
Crafts reaction of arenes with an N-tert-butanesulfinylimino ester
to produce various enantioenriched a-arylglycines directly at room
temperature.
In recent years, optically active non-proteinogenic amino acids
have attracted much attention, not only because of their significant
biological activities, but also because they can be incorporated
into the peptide chain for intriguing protein property studies
as well as be used as fundamental building blocks for extensive
applications in organic synthesis and new drug discovery.1 Among
them, a-arylglycines and their derivatives are key structural
components of many biologically active natural products and
pharmaceutical compounds.2 Due to this importance, a great num-
ber of approaches have been developed to access these valuable
compounds,3–6 mainly including asymmetric catalysis,4 enzymatic
resolution5 and chiral auxiliary-mediated induction.6 While some
of these methods can be highly stereoselective, many require
special reagents/conditions,6d–f,6n or need to involve extra multi-
transformations.4p,6p Further development of new methods that
allow efficient synthesis of enantiomerically pure a-arylglycines
from easily accessible precursors under mild and practical condi-
tions has been certainly a desirable subject. In general, asymmetric
Friedel–Crafts reaction of arenes with glyoxylate imines represents
the simplest and most direct approach for the stereoselective
preparation of a-arylglycines in terms of reagent availability. To
our knowledge, despite the fact that the strategies of transition
metal catalysis,4r–t organocatalysis,4h,4n,6f and Lewis acid-promoted
induction6e,6m have been employed, the results are far from satisfac-
tory, and achieving high stereoselectivity through Friedel–Crafts
N-tert-Butanesulfinyl imines have recently shown versatile ap-
plication in the asymmetric synthesis of various chiral amines.7,8
In our previous work, we demonstrated the successful use of N-
tert-butanesulfinylimino ester as a chiral glycine cation equiva-
lent for the asymmetric synthesis of synthetically useful diverse
amino acids such as D-allylglycine,8g b-vinyl-a-arylalanines,8j a-
(3-indolyl)glycines,8l and a-allenylglycines.8m In continuation of
our interest in this area, we considered to prepare a-arylglycines
especially a-phenylglycine analogues via asymmetric Friedel–
Crafts alkylation of arenes with N-tert-butanesulfinylimino ester.
It is worth noting that the same strategy has been examined
to synthesize heteroaromatic glycine derivatives in the presence
of stoichiometric amounts of TMSOTf, but the only exam-
ple of anisole addition showed very low diastereoselectivity
◦
(1 : 2.6 dr ratio) even at -20 C.6m Taking account of our
earlier successes involving metal chelation,8 we anticipated that
a high reaction stereocontrol might be achieved with a proper
transition-metal-based Lewis acid catalyst under mild conditions
(Scheme 1).
State key Laboratory of Drug Research, Shanghai Institute of Materia
Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai
201203, People’s Republic of China. E-mail: xumh@mail.shcnc.ac.cn;
Fax: +86 21 5080 7388; Tel: +86 21 5080 7388
† Electronic supplementary information (ESI) available: Experimental
details including copies of 1H and 13C NMR and HPLC spectra. See DOI:
10.1039/c1ob06450a
Scheme 1 Synthetic strategies to chiral a-arylglycine derivatives.
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Table 1 Screening of reaction conditions for diastereoselective Friedel–Crafts reaction of 1,3-dimethoxybenzene 1a with (R)-N-tert-butanesulfinylimino
ester 2a
Entry
Catalyst
mol (%)
1a (equiv)
T/◦C
Time (h)
Solvent
Yield (%)b
de (%)c
1
2
3
4
5
6
7
8
Cu(OTf)2
InBr3
Zn(OTf)2
FeCl3
15
15
15
15
15
15
15
15
15
15
15
15
15
15
20
30
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.1
2.0
1.5
1.5
rt
rt
rt
rt
rt
rt
rt
50
rt
rt
rt
rt
rt
rt
rt
rt
12
12
12
12
12
12
12
12
12
12
12
12
12
12
8
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
CHCl3
CH3CN
THF
23
22
18
16
20
n.r.d
36
16
38
45
12
12
27
38
61
89
97
76
84
62
53
—
98
92
94
95
43
71
97
98
98
98
AlCl3
AgNO3
In(OTf)3
In(OTf)3
In(OTf)3
In(OTf)3
In(OTf)3
In(OTf)3
In(OTf)3
In(OTf)3
In(OTf)3
In(OTf)3
9
10
11
12
13
14
15
16
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
1
a The reaction was performed with 0.25 mmol of glyoxylate imine 2 and 0.375 mmol of 1,3-dimethoxybenzene 1a in dry solvent (2.0 mL) at room
temperature. b Yield of isolated and purified products. c The diastereoselectivity of the product was determined by measuring the enantiomeric excess of
its acetyl derivative. d No reaction.
Having identified the optimal reaction conditions, a wide range
of electron-rich aromatic ring compounds were examined to inves-
tigate the reaction generality and substrate scope; the results are
summarized in Table 2. To our delight, in all examples of diverse
arenes, the reactions worked well. Generally, the phenyl arenes
reacted exclusively at the expected electrophilic site giving the
corresponding N-sulfinyl addition products in good to high yields
Results and discussion
Inspired by the previous findings on the synthesis of optically
active a-(3-indolyl)glycines,8l we began our survey by examin-
ing the reaction of 1,3-dimethoxybenzene 1a with (R)-N-tert-
butanesulfinylimino ester of ethyl glyoxylate (2) in the presence
of 15 mol% of Cu(OTf)2 in CH2Cl2 at ambient temperature.9 The
reaction proceeded slowly, affording the desired a-arylglycine 3a
as the sole product in 23% yield after 12h. Although the yield was
not ideal, a very high diastereoselectivity (97% de) of the reaction
was observed (Table 1, entry 1). To achieve better results, a series
of transition-metal Lewis acids were carefully screened (entries 2–
(60–91%), regardless of the manner of substitution on the benzene
ring. Among them, excellent diastereoselectivities (93–98% de)
were achieved with the 1,3,5- and 1,2,4-trisubstituted benzene
compounds (entries 2–6). In contrast, the 1,2,3-trisubstituted
benzene substrates usually gave slightly lower yields and di-
astereoselectivities (entries 7–9). The naphthalene derivatives can
be suitable substrates as well, providing the desired products
with excellent diastereoselectivities (98–99% de) (entries 10–14).
Notably, with 1-methoxynaphthalene and 1-naphthol as reactant,
a regioselective ratio of 3 : 1 and 5 : 1 in favor of a-alkylation
product was observed, respectively. In both cases, each regioisomer
was isolated with great diastereoselectivity (97–99% de) (entries 10
and 12). The current system was also applicable to heteroaromatic
substrates, which afforded a-heteroarylglycine derivatives in good
yields with up to 90% de (entries 15 and 16).
Encouraged by the above results, we next turned our atten-
tion to explore more challenging stereoselective double Friedel–
Crafts alkylation. As illustrated in Scheme 2, the reaction of
dimethoxybenzene 1a with (R)-N-tert-butanesulfinylimino ester 2
was examined. Initially, the desired dialkylation product 4 was only
obtained in less than 5% yield under the standard conditions using
30 mol% In(OTf)3 as Lewis acid catalyst even after prolonging the
reaction time to 12 h. Interestingly, when the amount of In(OTf)3
was increased to 1 equiv, the reaction was promoted and afforded
10
7). While AgNO3 catalyst was ineffective, 15 mol% of In(OTf)3
provided a clearly better yield over Cu(OTf)2, along with the
best de of 98% (entry 7). Unfortunately, elevating the reaction
◦
temperature to 50 C did not result in further improvement, but
caused lower yield and diminished diastereoselectivity (entry 8).
The investigation of various solvents indicated that the use of
CH2Cl2 as solvent was the best choice (entries 9–12). In addition,
the optimal ratio of imino ester 2 to 1,3-dimethoxybenzene 1a was
determined to be 1 : 1.5 in terms of atom economy and efficiency
(entries 7, 13 and 14). Gratifyingly, when the loading amount
of catalyst was increased, the Friedel–Crafts reaction between
1a and 2 was significantly promoted to gave 3a in high yield
(entries 15–16). It was found that the employment of 30 mol%
of In(OTf)3 was essential to achieve the reaction with both high
yield and excellent diastereoselectivity (89% yield, 98% de) (entry
16). After these studies, the optimal conditions were determined
to be performing the reaction with 1.5 equiv of alkylating arene
using CH2Cl2 as solvent in the presence of 30 mol% of In(OTf)3 at
room temperature.
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Table 2 Diastereoselective Friedel–Crafts reaction of arenes 1 with (R)-
N-tert-butanesulfinylimino ester 2a
Table 2 (Contd.)
Entry Product 3 Ar
Time (h)
8
Yield (%)b de (%)c
Entry Product 3 Ar
Time (h)
1
Yield (%)b de (%)c
16
3p
74%
79%
1
3a
89%
98%
a Reactions were performed with 30 mol% of In(OTf)3, 0.25 mmol of
glyoxylate imine 2 and 0.375 mmol of arene 1 in 2.0 mL of dry CH2Cl2
at room temperature. b Yield of isolated and purified products. c The
diastereoselectivity of the products was determined by measuring the
enantiomeric excess of their acetyl or sulfonyl derivatives. d The regioisomer
b-alkylation product 3j¢ was obtained in 22% yield with >99% de. e The
regioisomer b-alkylation product 3l¢ was obtained in 15% yield with 97%
de.
2
3b
1
8
8
91%
97%
3
4
3c
3d
84%
80%
95%
98%
5
6
7
3e
3f
1
86%
72%
60%
98%
93%
70%
0.5
8
Scheme 2 Stereoselective double Friedel–Crafts alkylation.
3g
4 in a significantly increased yield (43%) with an extremely high
diastereo- and enantioselectivity (anti : syn > 99 : 1, >99% ee).
To realize the stereochemical outcome of the reaction, removal
of the ethyl and N-sulfinyl groups was subsequently carried out.
As exemplified by 3a, the reactions proceeded smoothly under very
mild conditions and yielded the free amino acid 5. The absolute
configuration of 3a at a-stereogenic center was unambiguously
determined to be R by comparison of the optical rotation of 5
with that of the known compound4n (Scheme 3). Assuming an
analogous reaction mechanism, the same absolute configuration
of the obtained a-arylglycines could be assigned.
8
3h
8
74%
73%
9
3i
3j
8
8
72%
79%
10d
66%d
>99%
11
3k
8
72%
>99%
12e
13
3l
1
1
74%e
70%
98%
98%
Scheme 3 Removal of ethyl and N-sulfinyl groups.
3m
To explain the observed diastereofacial selectivity of this asym-
metric Friedel–Crafts alkylation, a plausible five-membered chela-
tion transition state model as previously proposed8l is illustrated
(Fig. 1), in which the activation of imino ester by the coordination
of the Lewis acidic metal to both the imine nitrogen and carbonyl
oxygen is considered. Since the uncoordinated N-sulfinyl group
adopts an approximately synperiplanar configuration,11 in the case
of (R)-N-tert-butanesulfinyl imino ester, the bulky tert-butyl group
is positioned at the si-face of imine molecule. As a result, the arene
14
15
3n
3o
8
1
74%
90%
98%
90%
addition to the sterically unblocked re-face of the imine C
N
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General procedure for determination of the diastereoselectivity/
enantiomeric excess
The diastereoselectivities of the a-arylglycine products were
measured as enantiomeric excess for their acetate or N-sulfonylate
derivatives after the removal or oxidation of the sulfinyl group by
chiral HPLC analysis. a-Arylglycines 3e and 4 were converted to
the corresponding N-sulfonylate, all others were converted to their
acetate. The HPLC reference compound was a mixture of related
products consisting of R and S enantiomers.
Fig. 1 Mechanistic proposals for stereocontrol.
(R)-Ethyl 2-(2,4-dimethoxyphenyl)-2((R)-1,1-
dimethylethylsulfinamido)acetate (3a)
bond would be preferred, thereby facilitating (R)-a-arylglycine
product formation.
89% yield, yellow oil. 1H NMR (300 MHz, CDCl3): d 1.15 (s, 9H),
1.18 (t, 3H), 3.77 (s, 3H), 3.79 (s, 3H), 4.13–4.20 (m, 2H), 4.51 (d,
J = 4.2 Hz, 1H), 5.19 (d, J = 4.2 Hz, 1H), 6.43–6.45 (m, 2H),
7.10 (d, J = 9.0 Hz, 1H); 13C NMR (100 MHz, CDCl3): d 14.14,
22.51, 55.39, 55.55, 55.82, 56.00, 61.85, 98.94, 104.22, 118.74,
130.12, 158.21, 161.03, 172.03; ESI-MS (m/z, %) 344 [M + H]+;
ESI-HRMS calcd for C16H25NNaO5S [M + Na+] 366.1351, found
366.1351.
Conclusion
In summary, we have developed a highly diastereoselective syn-
thesis of a-arylglycines via asymmetric Friedel–Crafts alkylation
of arenes with a chiral N-tert-butanesulfinylimino ester. The
reaction could be accomplished with ease in the presence of
a catalytic amount of In(OTf)3 at room temperature. It allows
exceptionally mild, efficient and ready access to various enan-
tiomerically enriched a-arylglycines. By this method, we have also
successfully explored the potential of highly stereoselective double
Friedel–Crafts alkylation to afford dialkylation product. Given the
importance of a-arylglycines in medicinal chemistry and organic
synthesis, application of this methodology is currently ongoing in
our laboratory.
(R)-Ethyl 2-((R)-1,1-dimethylethylsulfinamido)-2-(2,4,6-
trimethoxyphenyl)acetate (3b)
1
91% yield, colorless oil. H NMR (300 MHz, CDCl3): d 1.10 (s,
9H), 1.17 (t, 3H), 3.77 (s, 6H), 3.80 (s, 3H), 4.09–4.22 (m, 2H),
4.58 (d, J = 5.1 Hz, 1H), 5.49 (d, J = 5.1 Hz, 1H), 6.09 (s, 2H);
13C NMR (100 MHz, CDCl3): d 14.27, 22.44, 51.35, 55.39, 55.76,
55.85, 61.59, 90.68, 107.92, 158.83, 161.38, 172.55; ESI-MS (m/z,
%) 374 [M + H]+; ESI-HRMS calcd for C17H27NNaO6S [M + Na+]
396.1457, found 396.1454.
Experimental
(R)-Ethyl 2-(2,4-dimethoxy-6-methylphenyl)-2-((R)-1,1-
dimethylethylsulfinamido)acetate (3c)
General methods
1
84% yield, colorless oil. H NMR (300 MHz, CDCl3): d 1.11 (s,
Unless otherwise specified, all reactions were carried out in flame-
dried glassware with magnetic stirring under an atmosphere of
nitrogen. Solvents were dried and distilled by standard procedures.
NMR spectra were recorded on Varian spectrometers (300 MHz
for 1H, and 100 MHz for 13C). Chemical shifts are reported
in d (ppm) referenced to an internal SiMe4 standard for 1H
NMR and chloroform-d (d 77.16) for 13C NMR. HPLC was
performed on a JASCO 2000 instrument by using Daicel AS-H,
AD-H and AD-3 column with 2-propanol/hexane as the eluent at
214 nm.
9H), 1.16 (t, 3H), 2.36 (s, 3H), 3.73 (s, 3H), 3.78 (s, 3H), 4.09–
4.21 (m, 2H), 4.63 (d, J = 3.0 Hz, 1H), 5.33 (d, J = 3.9 Hz,
1H), 6.29 (d, J = 5.7 Hz, 2H); 13C NMR (100 MHz, CDCl3): d
14.24, 20.24, 22.50, 53.44, 55.26. 55.63, 55.71, 61.79, 96.58, 107.05,
117.52, 139.22, 158.74, 160.17, 172.34; ESI-MS (m/z, %) 358 [M +
H]+; ESI-HRMS calcd for C17H28NO5S [M + H+] 358.1688, found
358.1697.
(R)-Ethyl 2-(2-chloro-4,6-dimethoxyphenyl)-2-((R)-1,1-
dimethylethylsulfinamido)acetate (3d)
80% yield, yellow oil. 1H NMR (300 MHz, CDCl3): d 1.12 (s, 9H),
1.18 (t, 3H), 3.76 (s, 3H), 3.79 (s, 3H), 4.09–4.23 (m, 2H), 4.59 (d,
J = 4.2 Hz, 1H), 5.60 (d, J = 4.2 Hz, 1H), 6.34 (d, J = 2.1 Hz, 1H),
6.52 (d, J = 2.4 Hz, 1H); 13C NMR (100 MHz, CDCl3): d 14.22,
22.44, 55.65, 55.91, 56.01, 62.07, 97.93, 106.12, 117.96, 135.60,
159.09, 160.55, 171.42; ESI-MS (m/z, %) 378 [M + H]+; ESI-
HRMS calcd for C16H24ClNNaO5S [M + Na+] 400.0961, found
400.0945.
General procedure for In(OTf)3-catalyzed Friedel–Crafts reaction
of arenes 1 with (R)-N-tert-butanesulfinylimino ester 2
Under a nitrogen atmosphere, In(OTf)3 (0.075 mmol, 30 mol%)
was placed into a glass reaction vessel, glyoxylate imine 2 (0.25
mmol) in 2 mL of dry CH2Cl2 and arene 1 (0.375 mmol) were
added successively. The mixture was stirred at room temperature
and monitored by TLC. When the reaction was over, a saturated
aq. NH4Cl solution was added and the mixture was extracted
with CH2Cl2 (10 mL ¥ 3). The combined organic phase was dried
over Na2SO4, filtered, and concentrated. The residue was purified
by silica gel flash chromatography to afford the corresponding
a-arylglycine product 3.
(R)-Ethyl 2-((R)-1,1-dimethylethylsulfinamido)-2-(2,4,5-
trimethoxyphenyl)acetate (3e)
1
86% yield, colorless oil. H NMR (300 MHz, CDCl3): d 1.16
(s, 9H), 1.17 (t, 3H), 3.79 (s, 3H), 3.80 (s, 3H), 3.87 (s, 3H),
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4.11–4.21 (m, 2H), 4.51 (d, J = 3.3 Hz, 1H), 5.30 (d, J = 3.9 Hz,
1H), 6.51 (s, 1H), 6.74 (s, 1H); 13C NMR (100 MHz, CDCl3): d
14.15, 22.56, 55.13, 55.85, 56.09, 56.57, 56.93, 61.97, 97.96, 112.45,
117.52, 143.19, 149.81, 151.89, 171.98; ESI-MS (m/z, %) 396 [M +
Na]+; ESI-HRMS calcd for C17H27NNaO6S [M + Na+] 396.1457,
found 396.1455.
55.79, 59.32, 62.33, 102.97, 122.79, 123.90, 124.34, 125.33, 126.33,
126.95, 128.62, 131.90, 156.24, 172.41; ESI-MS (m/z, %) 364 [M
+ H]+; ESI-HRMS calcd for C19H25NNaO4S [M + Na+] 386.1402,
found 386.1411.
(R)-Ethyl 2-((R)-1,1-dimethylethylsulfinamido)-2-(1-
methoxynaphthalen-2-yl)acetate (3j¢)
(R)-Ethyl 2-((R)-1,1-dimethylethylsulfinamido)-2-(2-hydroxy-4,5-
dimethoxyphenyl)acetate (3f)
22% yield, white solid. 1H NMR (300 MHz, CDCl3): d 1.13 (t, 3H),
1.21 (s, 9H), 4.00 (s, 3H), 4.07–4.21 (m, 2H), 5.73 (d, J = 3.9 Hz,
1H), 6.77 (d, J = 7.8 Hz, 1H), 7.47–7.61 (m, 3H), 8.18 (d, J = 8.4
Hz, 1H), 8.31 (d, J = 8.4 Hz, 1H); 13C NMR (100 MHz, CDCl3):
d 14.12, 22.65, 55.68, 56.46, 56.74, 61.88, 103.27, 122.85, 123.40,
125.06, 125.51, 126.11, 127.19, 127.46, 131.78, 156.21, 172.01; ESI-
MS (m/z, %) 364 [M + H]+; ESI-HRMS calcd for C19H25NNaO4S
[M + Na+] 386.1402, found 386.1390.
72% yield, yellow oil. 1H NMR (300 MHz, CDCl3): d 1.21 (t, 3H),
1.25 (s, 9H), 4.10–4.28 (m, 2H), 4.52 (d, J = 1.5 Hz, 1H), 5.21 (d,
J = 2.7 Hz, 1H), 5.89 (s, 2H), 6.46 (s, 1H), 6.62 (s, 1H), 7.90 (br, 1H);
13C NMR (100 MHz, CDCl3): d 14.16, 22.71, 55.87, 56.30, 62.49,
99.56, 101.35, 108.15, 113.68, 141.28, 148.77, 150.90, 171.63; ESI-
MS (m/z, %) 344 [M + H]+; ESI-HRMS calcd for C15H21NNaO6S
[M + Na+] 366.0987, found 366.0963.
(R)-Ethyl 2-((R)-1,1-dimethylethylsulfinamido)-2-(2-
methoxynaphthalen-1-yl)acetate (3k)
(R)-Ethyl 2-((R)-1,1-dimethylethylsulfinamido)-2-(2,3,4-
trimethoxyphenyl)acetate (3g)
72% yield, white solid. 1H NMR (300 MHz, CDCl3): d 1.06–1.10
(m, 12H), 3.98 (s, 3H), 4.11–4.18 (m, 2H), 4.76 (s, 1H), 6.10 (s,
1H), 7.28–7.36 (m, 2H), 7.46 (dd, J = 8.4 Hz, 7.2 Hz, 1H), 7.78
(d, J = 8.1 Hz, 1H), 7.84 (d, J = 9.0 Hz, 1H), 7.93 (d, J = 9.0
Hz, 1H); 13C NMR (100 MHz, CDCl3): d 14.14, 22.51, 52.18,
55.69, 57.17, 62.12, 113.67, 118.42, 123.34, 123.76, 127.09, 128.75,
129.47, 130.90, 132.31, 155.83, 172.77; ESI-MS (m/z, %) 364 [M +
H]+; ESI-HRMS calcd for C19H26NO4S [M + H+] 364.1582, found
364.1578.
60% yield, yellow oil. 1H NMR (300 MHz, CDCl3): d 1.17 (s, 9H),
1.18 (t, 3H), 3.84 (s, 6H), 3.88 (s, 3H), 4.11–4.24 (m, 2H), 4.59
(d, J = 3.9 Hz, 1H), 5.18 (d, J = 3.6 Hz, 1H), 6.60 (d, J = 8.4
Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H); 13C NMR (100 MHz, CDCl3):
d 14.13, 22.61, 55.75, 55.84, 55.98, 60.77, 61.14, 62.06, 106.98,
123.75, 123.90, 142.15, 151.91, 154.07, 171.84; ESI-MS (m/z, %)
374 [M + H]+; ESI-HRMS calcd for C17H27NNaO6S [M + Na+]
396.1457, found 396.1467.
(R)-Ethyl 2-((R)-1,1-dimethylethylsulfinamido)-2-(2,3,4-
trimethoxy-6-methylphenyl)acetate (3h)
(R)-Ethyl 2-((R)-1,1-dimethylethylsulfinamido)-2-(4-
hydroxynaphthalen-1-yl)acetate (3l)
1
74% yield, yellow oil. H NMR (300 MHz, CDCl3): d 1.15 (s,
1
74% yield, yellow solid. H NMR (300 MHz, CDCl3): d 1.06 (t,
9H), 1.18 (t, 3H), 2.34 (s, 3H), 3.79 (s, 3H), 3.83 (s, 3H), 3.85
(s, 3H), 4.08–4.22 (m, 2H), 4.73 (d, J = 1.2 Hz, 1H), 5.29 (d,
J = 2.7 Hz, 1H), 6.46 (s, 1H); 13C NMR (100 MHz, CDCl3):
d 14.22, 19.97, 22.61, 53.61, 55.76, 55.82, 60.70, 60.98, 61.99,
109.11, 122.28, 132.79, 139.91, 152.28, 153.17, 172.08; ESI-MS
(m/z, %) 388 [M + H]+; ESI-HRMS calcd for C18H30NO6S [M +
H+] 388.1794, found 388.1791.
3H), 1.18 (s, 9H), 4.09–4.18 (m, 2H), 4.77 (d, J = 2.1 Hz, 1H),
5.49 (d, J = 2.1 Hz 1H), 6.78 (d, J = 7.8 Hz 1H), 7.32 (d, J =
7.8 Hz, 1H), 7.43–7.46 (m, 2H), 7.92–7.96 (m, 1H), 8.18 (s, 1H),
8.28–8.32 (m, 1H); 13C NMR (100 MHz, CDCl3): d 14.04, 22.74,
56.03, 59.76, 62.42, 107.83, 122.59, 123.16, 123.86, 124.93, 125.69,
126.80, 129.66, 132.14, 153.98, 172.40; ESI-MS (m/z, %) 350 [M
+ H]+; ESI-HRMS calcd for C18H23NNaO4S [M + Na+] 372.1246,
found 372.1244.
(R)-Ethyl 2-(2,4-dimethoxy-3-methylphenyl)-2-((R)-1,1-
dimethylethylsulfinamido)acetate (3i)
(R)-Ethyl 2-((R)-1,1-dimethylethylsulfinamido)-2-(1-
hydroxynaphthalen-2-yl)acetate (3l¢)
1
72% yield, yellow oil. H NMR (300 MHz, CDCl3): d 1.16–1.18
(m, 12H), 2.15 (s, 3H), 3.77 (s, 3H), 3.81 (s, 3H), 4.09–4.23 (m, 2H),
4.59 (d, J = 3.0 Hz, 1H), 5.27 (d, J = 3.9 Hz, 1H), 6.60 (d, J = 8.4
Hz, 1H), 7.06 (d, J = 8.1 Hz, 1H); 13C NMR (100 MHz, CDCl3): d
9.56, 14.15, 22.67, 55.09, 55.66, 55.84, 61.55, 62.10, 106.18, 119.99,
123.10, 126.58, 157.46, 159.03, 172.15; ESI-MS (m/z, %) 380 [M +
Na]+; ESI-HRMS calcd for C17H27N1NaO5S [M + Na+] 380.1508,
found 380.1506.
1
15% yield, yellow solid. H NMR (300 MHz, CDCl3): d 1.19 (t,
3H), 1.28 (s, 9H), 4.11–4.29 (m, 2H), 4.59 (s, 1H), 5.36 (d, J = 2.7
Hz, 1H), 7.25 (d, J = 8.4 Hz, 1H), 7.39 (d, J = 8.7 Hz, 1H), 7.45–
7.52 (m, 2H), 7.76–7.79 (m, 1H), 8.26–8.30 (m, 2H); 13C NMR
(100 MHz, CDCl3): d 14.11, 22.68, 56.53, 57.25, 62.76, 114.46,
120.34, 122.67, 125.57, 126.79, 127.07, 127.51, 134.83, 151.71,
171.29; ESI–MS (m/z, %) 372 [M + Na]+; ESI-HRMS calcd for
C18H23NNaO4S [M + Na+] 372.1246, found 372.1253.
(R)-Ethyl 2-((R)-1,1-dimethylethylsulfinamido)-2-(4-
methoxynaphthalen-1-yl)acetate (3j)
(R)-Ethyl 2-((R)-1,1-dimethylethylsulfinamido)-2-(2-
hydroxynaphthalen-1-yl)acetate (3m)
1
66% yield, white solid. H NMR (300 MHz, CDCl3): d 1.10 (t,
3H), 1.13 (s, 9H), 4.01 (s, 3H), 4.08–4.21 (m, 2H), 4.66 (s, 1H),
5.50 (s, 1H), 6.76 (d, J = 8.1 Hz, 1H), 7.41 (d, J = 8.4 Hz, 1H),
7.47–7.51 (m, 2H), 7.98 (d, J = 7.8 Hz, 1H), 8.30 (d, J = 7.8
Hz, 1H); 13C NMR (100 MHz, CDCl3): d 14.08, 22.63, 55.63,
1
70% yield, yellow solid. H NMR (300 MHz, CDCl3): d 1.05 (t,
3H), 1.21 (s, 9H), 4.05–4.18 (m, 2H), 4.82 (s, 1H), 6.22 (s, 1H),7.17
(d, J = 8.7 Hz, 1H), 7.26 (dd, J = 6.6 Hz, 8.4 Hz, 1H), 7.39 (dd,
8456 | Org. Biomol. Chem., 2011, 9, 8452–8458
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J = 8.4 Hz, 7.2 Hz, 1H), 7.67–7.74 (dd, J = 8.7 Hz, 8.4 Hz, 2H), 7.80
(d, J = 8.4 Hz, 1H), 9.55 (br, 1H); 13C NMR (100 MHz, CDCl3):
d 14.07, 22.72, 52.00, 55.76, 62.32, 112.46, 118.40, 122.77, 122.90,
126.69, 128.74, 128.95, 130.81, 132.61, 155.18, 173.00; ESI-MS
(m/z, %) 372 [M + Na]+; ESI-HRMS calcd for C18H23NNaO4S
[M + Na+] 372.1246, found 372.1246.
3 h. The reaction mixture was then concentrated to remove the
dioxane, and the remaining material was diluted with distilled H2O
(3 mL) and EtOAc (3 mL) and placed in a separatory funnel. 1 N
NaHSO4 (2 mL) was added and the aqueous layer was extracted
with EtOAc (5 ¥ 4 mL). The combined organic layers were dried
over Na2SO4, filtered, and concentrated under reduced pressure.
The crude product was isolated with no further purification as
a white solid. Subsequently, the crude product was treated with
5 mL solution of dry HCl in 1,4-dioxane at room temperature
for 1 h. The reaction mixture was concentrated in vacuo, and the
amine hydrochloride was precipitated with dry diethyl ether. The
precipitate was collected by filtration and washed with diethyl
ether to yield the (R)-5 (20 mg, 91% yield) as a white solid.
(R)-Ethyl 2-(2,7-dimethoxynaphthalen-1-yl)-2-((R)-1,1-
dimethylethylsulfinamido)acetate (3n)
74% yield, white solid. 1H NMR (300 MHz, CDCl3): d 1.05–1.24
(m, 12H), 3.86 (s, 3H), 3.95 (s, 3H), 4.10–4.17 (m, 2H), 4.71 (s, 1H),
6.06 (s, 1H), 6.96–7.00 (dd, J = 1.5 Hz, 8.7 Hz, 1H), 7.11 (d, J =
8.7 Hz, 1H), 7.25 (d, J = 1.5 Hz, 1H), 7.64 (d, J = 9.3 Hz, 1H), 7.74
(d, J = 6.9 Hz, 1H); 13C NMR (100 MHz, CDCl3): d 14.16, 14.29,
22.55, 52.14, 55.33, 55.57, 57.00, 62.09, 101.66, 110.87, 116.61,
124.82, 130.20, 130.53, 133.79, 156.50, 158.59, 172.88; ESI-MS
(m/z, %) 416 [M + Na]+; ESI-HRMS calcd for C20H27NNaO5S
[M + Na+] 416.1508, found 416.1516.
(R)-2-(Chloroamino)-2-(2,4-dimethoxyphenyl)acetic acid ((R)-5)
91% yield, white solid. [a]2D0 -111.2 (c 0.5, MeOH); The absolute
configuration was determined to be (R) according to literature
[lit4n[a]D22 = +106.6 (c 1.0 MeOH)]. 1H NMR (300 MHz, CD3OD):
d 3.83 (s, 3H), 3.88 (s, 3H), 5.10 (s, 1H), 6.58–6.61 (dd, J = 2.4 Hz,
8.4 Hz, 1H), 6.64 (d, J = 2.1 Hz, 1H), 7.27 (d, J = 8.4 Hz, 1H); 13
C
(R)-Ethyl 2-((R)-1,1-dimethylethylsulfinamido)-2-(5-methylfuran-
NMR (100 MHz, CD3OD): d 53.75, 56.06, 56.24, 99.73, 106.42,
2-yl)acetate (3o)
114.21, 132.48, 159.90, 164.16, 171.17.
1
90% yield, colorless oil. H NMR (300 MHz, CDCl3): d 1.22 (s,
9H), 1.25 (t, 3H), 2.25 (s, 3H), 4.19–4.28 (m, 2H), 4.41 (d, J =
4.8 Hz, 1H), 5.03 (d, J = 5.4 Hz, 1H), 5.91 (s, 1H), 6.18 (s, 1H);
13C NMR (100 MHz, CDCl3): d 13.07, 14.13, 22.57, 55.36, 56.23,
62.52, 106.53, 109.86, 147.66, 153.04, 169.70; ESI-MS (m/z, %)
310 [M + Na]+; ESI-HRMS calcd for C13H21NNaO4S [M + Na+]
310.1089, found 310.1094.
Acknowledgements
Financial support from the National Natural Science Foundation
of China (21021063), the Chinese Academy of Sciences, State key
Laboratory of Drug Research, SIMM and National Science &
Technology Major Project is greatly acknowledged.
(R)-Ethyl 2-((R)-1,1-dimethylethylsulfinamido)-2-(5-
methylthiophen-2-yl)acetate (3p)
Notes and References
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74% yield, colorless oil. 1H NMR (300 MHz, CDCl3): d 1.26 (m,
12H), 2.44 (s, 3H), 4.18–4.28 (m, 2H), 4.57 (d, J = 4.8 Hz, 1H), 5.20
(d, J = 4.8 Hz, 1H), 6.60–6.61 (m, 1H), 6.84 (d, J = 3.3 Hz, 1H);
13C NMR (100 MHz, CDCl3): d 14.14, 15.54, 22.73, 56.35, 56.95,
62.60, 125.18, 126.38, 137.78, 140.82, 170.57; ESI-MS (m/z, %)
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326.0860, found: 326.0862.
(2R,2¢R,26R)-Diethyl-2,2¢-(4,6-dimethoxy-1,3-phenylene)bis(2-
((R)-1,1-dimethylethylsulfinamido)acetate) (4)
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(m, 24H), 3.85 (s, 6H), 4.08–4.21 (m, 4H), 4.51 (d, J = 4.2 Hz,
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found 571.2133.
The synthesis of (R)-2-(chloroamino)-2-(2,4-dimethoxyphenyl)-
acetic acid ((R)-5)
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mmol, 1.0 equiv) in dioxane (5.0 mL) was cannulated into the
reaction flask. The resulting solution was stirred at 0 ◦C for
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9 Reaction conducted in the absence of Lewis acid catalysts gave no
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8458 | Org. Biomol. Chem., 2011, 9, 8452–8458
This journal is
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©