Preparation of Enantiomerically Pure Perfluorobutanesulfinamide and Its Application to the Asymmetric Synthesis of α-Amino Acids

Article abstract of DOI:10.1021/acs.joc.5b02700

A high yielding and practical two-step synthesis of enantiomerically pure perfluorobutanesulfinamide from Senanayake's 2-aminoindanol-derived sulfinyl transfer reagent was developed and carried out on a multigram scale. Straightforward condensation of thi

Full text of DOI:10.1021/acs.joc.5b02700

Article
pubs.acs.org/joc
Preparation of Enantiomerically Pure Perfluorobutanesulfinamide
and Its Application to the Asymmetric Synthesis of α‑Amino Acids
Apiwat Wangweerawong,† Joshua R. Hummel,† Robert G. Bergman,‡ and Jonathan A. Ellman*,†
†Department of Chemistry, Yale University, 225 Prospect Street, New Haven, Connecticut 06520-8170, United States
‡Division of Chemical Sciences, Lawrence Berkeley National Laboratory, and Department of Chemistry, University of California,
Berkeley, California 94720, United States
S
* Supporting Information
ABSTRACT: A high yielding and practical two-step synthesis of
enantiomerically pure perfluorobutanesulfinamide from Sena-
nayake’s 2-aminoindanol-derived sulfinyl transfer reagent was
developed and carried out on a multigram scale. Straightforward
condensation of this sulfinamide with ethyl glyoxylate provided the
N-perfluorobutanesulfinyl imino ester. The utility of this activated
N-sulfinyl imino ester was demonstrated for reactions that gave
either no product or very low yields with the corresponding less
electrophilic N-tert-butanesulfinyl derivative. Specifically, the Rh-
(III)-catalyzed C−H bond addition of aromatic compounds to the
N-perfluorobutanesulfinyl imino ester provided arylglycines with
very high diastereoselectivities for a range of directing groups
including pyrrolidine amide, azo, sulfoximine, 1-pyrazole, and 1,2,3-
triazole functionalities. Thermal asymmetric aza-Diels−Alder reactions also proceeded in good yields and with high selectivity,
including for the substituted dienes (E)-1,3-pentadiene and (2E,4E)-2,4-hexadiene.
these more electrophilic imines can be effective substrates for
the addition of a number of nucleophiles.18
INTRODUCTION
■
α-Amino acids were one of the first classes of compounds to be
targeted for asymmetric synthesis due to their pervasive
biological roles,1 and their asymmetric syntheses continue to
be important to numerous drug discovery and chemical biology
applications.2 In this regard, N-tert-butanesulfinyl imino esters
have proven to be extremely versatile intermediates for the
asymmetric synthesis of α-amino acids.3 The addition of a
variety of organometallic reagents proceeds with high
diastereoselectivities, including lithium,4 magnesium,5 indium,6
and zinc7 reagents, and through the use of transition-metal
catalysts, also organoboron reagents.8 Transition-metal catalysts
have also been applied to the addition of allyl alcohols via
isomerization pathways9 and for the hydrogen-mediated
reductive coupling of alkynes.10 Stabilized anions such as
enolates11 and nitronate12 anions also have been added with
good selectivities. Moreover, Lewis acids have been employed
to catalyze Friedel−Craft reactions with electron-rich aro-
matic13 and heteroaromatic compounds,14 Mannich-type
additions of silyl enol ethers,15 and aza-Diels−Alder cyclo-
additions with dienes.16
Herein, we describe a practical two-step synthesis of
perfluorobutanesulfinamide from Senanayake’s 2-aminoinda-
nol-derived sulfinyl transfer reagent in good overall yield and
high enantiopurity.19 Condensation with ethyl glyoxylate to
provide the corresponding N-perfluorobutanesulfinyl imino
ester is also described. We further report that the enhanced
electrophilicity of this N-perfluorobutanesulfinyl imino ester
enables transformations to be performed that are shown not to
proceed with the corresponding N-tert-butanesulfinyl imino
ester. Specifically, Rh(III)-catalyzed, highly diastereoselective
addition of aromatic C−H bonds enables the asymmetric
synthesis of arylglycines, a class of compounds present in many
drugs including glycopeptide antibiotics such as vancomycin,
many β-lactam antibiotics such as cefprozil, and the
cardiovascular agent Plavix.20 Moreover, the asymmetric
synthesis of pipecolic acid derivatives has been accomplished
by thermal aza-Diels−Alder cycloaddition reactions with
substituted dienes, including those that have been reported to
give low cycloaddition yields for the corresponding N-tert-
butanesulfinyl imino ester.16a The pharmaceutical relevance of
these aza-Diels−Alder reactions is highlighted by the AIDs drug
Saquinavir and the blockbuster HCV drug Ledipasvir, each of
which incorporates a pipecolic acid derivative.20
However, for some reactions of N-tert-butanesulfinyl imino
esters, little to no conversion to the desired addition products
was observed because the imines were not sufficiently
electrophilic.16a,17 In seminal work, Liu and co-workers have
reported on the preparation of enantiomerically pure
perfluoroalkanesulfinamides and on their conversion to N-
perfluoroalkanesulfinyl aldimines. They have further shown that
Received: November 25, 2015
© XXXX American Chemical Society
A
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a
RESULTS AND DISCUSSION
Table 1. Addition of Perfluorobutyl Grignard Reagent
■
An effective route to enantiomerically pure perfluoroalkane-
sulfinamides has been developed,21 but significant quantities of
material are difficult to access due to the multistep sequence
that includes several purification steps. For this reason, we
investigated alternative methods for the preparation of
perfluorobutanesulfinamide. The most practical and by far the
most extensively used method for the asymmetric synthesis of
the more commonly used tert-butanesulfinamide is catalytic
enantioselective oxidation of inexpensive tert-butyl disulfide,
followed by addition of LiNH2.22 Unfortunately, this approach
is not relevant to the synthesis of perfluoroalkanesulfinamides
because the corresponding disulfides are not commercially
available and are inconvenient to prepare. The chiral sulfinyl
transfer auxiliary approach developed by Senanayake and co-
workers is an alternative general and efficient method for the
preparation of a broad range of enantiomerically pure
sulfinamides (Scheme 1).19 Addition of a Grignard reagent to
C4F9I
EtMgBr
(equiv)
time
entry
(equiv)
(min)
concn 5 (M) 6 (%) 7 (%)
1
2
3
4
1.1
1.0
1.0
1.0
1.0
30
60
60
60
0.13
0.13
0.13
0.30
79
89
88
90
3
5
3
2
1.1
1.05
1.05
a
Yields of 6 and 7 determined by 1H NMR integration relative to 2,6-
Scheme 1. Senanayake’s Sulfinyl Transfer Approach
dimethoxytoluene as an external standard.
scales (entry 4). The solubility of sulfinyl transfer reagent 5
prevented a concentration higher than 0.3 M from being used.
The only observed impurity was a small amount of byproduct
7, which has no detrimental effects on the subsequent step of
the synthesis (vide infra). Therefore, the crude material
obtained after extractive isolation was employed in the next
step without further purification.
Various amine nucleophiles were next evaluated for cleavage
of 6 to provide the sulfinamide product 8 (Table 2). Initially,
we speculated that the electron-withdrawing perfluorobutyl
group might render sulfinate ester 6 sufficiently reactive for
cleavage with the most practical and inexpensive source of
ammonia, ammonium hydroxide. However, when 6 was treated
with excess ammonium hydroxide, either neat or with THF as a
the sulfinyl transfer reagent 1 proceeds with inversion of
stereochemistry to give sulfinate ester 2. Treatment of 2 with an
amide nucleophile then provides sulfinamide 3 and the chiral
auxiliary 4, which then can be recycled back to the sulfinyl
transfer reagent 1 by reaction with thionyl chloride.
a
Table 2. Sulfinate Ester Cleavage
The key challenge to applying this approach to the
perfluoroalkanesulfinamide is the well-documented instability
of perfluoroalkyl Grignard reagents, which, unless maintained at
low temperature, rapidly decompose through facile elimination
of fluoride.23 We, therefore, investigated the preparation and
reaction of the perfluorobutyl Grignard reagent by trans-
metalation of perfluorobutyl iodide with ethylmagnesium
bromide at −78 °C, followed by slow addition of a THF
solution of the precooled 2-aminoindanol-derived sulfinyl
transfer reagent 5 (Table 1). A slight excess of perfluorobutyl
iodide relative to ethylmagnesium bromide was employed to
prevent competitive formation of the undesired ethanesulfinate
ester byproduct. Moreover, exactly 1 equiv of the Grignard
reagent was used to prevent overaddition of the Grignard
reagent to the desired sulfinate ester product 6, which would
give a sulfoxide byproduct. The duration of the transmetalation
step was evaluated at both 30 and 60 min (entries 1 and 2),
with 60 min providing the highest yield (entry 2). To minimize
reagent waste, the stoichiometry of the perfluorobutyl iodide
was lowered to 1.05 equiv without any reduction in yield (entry
3). Additionally, the reaction can be conducted at a higher
concentration, which is preferable when performed on larger
a
entry
NH2 source
conc 6 (M)
8 (%)
b
1
NH4OH(aq) (excess)
NH4OH(aq) (excess)
LiHMDS (5 equiv)
LiHMDS (2 equiv)
LiHMDS (3 equiv)
NaHMDS (5 equiv)
NaHMDS (3 equiv)
KHMDS (3 equiv)
NaHMDS (3 equiv)
0.05
0.05
0.10
0.10
0.10
0.10
0.10
0.10
0.30
0
0
c
2
d
3
59
41
48
73
74
59
73
d
4
d
5
d
6
d
7
d
8
d
9
a
b
Isolated yields after column chromatography. Neat or with THF as
solvent at rt for 24 h. Neat NH4OH with heating in a pressure tube at
110 °C for 3 h. Workup by treatment with aqueous NH4Cl to cleave
c
d
the N-TMS substituents from the initial addition product.
B
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cosolvent, no reaction was observed at rt (entry 1). While
complete consumption of the sulfinate ester 6 could be
achieved by heating in a sealed tube, and though the alcohol
byproduct 7 was detected, none of the desired sulfinamide 8
was observed (entry 2). The absence of sulfinamide 8 could in
part be due to preferential saponification of 6 under the
reaction conditions. However, control experiments also
established that 8 was not stable to concentrated NH4OH
even at rt. LiHMDS, one of the most commonly used
nucleophiles for sulfinate ester cleavage,19 was next investigated.
Addition of 5 equiv of LiHMDS provided sulfinamide 8 in 59%
yield after chromatography (entry 3). Only 2 equiv of base is
required, 1 equiv to serve as a nucleophile and the second
equivalent to deprotonate the sulfonamide group in 6.
Unfortunately, attempts to reduce the amount of LiHMDS to
either 2.0 or 3.0 equiv led to diminished yields (entries 4 and 5,
respectively). In contrast, addition of 5 equiv of NaHMDS in
place of LiHMDS resulted in a higher yield of 8 (entry 6).
Furthermore, decreasing the amount of NaHMDS to 3.0 equiv
did not significantly affect the reaction yield (entry 7). Because
at least 2 equiv of this strong base is needed, further reduction
in the number of equivalents of base was not investigated. The
more costly KHMDS also gave a slightly lower yield than
NaHMDS under identical reaction conditions (entry 8).
Finally, addition of NaHMDS at triple the reaction
concentration provided pure sulfinamide 8 in the same yield
as observed at the lower concentration (entry 9).
asymmetric synthesis of α-amino acids. Condensation of 8 with
ethyl glyoxylate was performed with molecular sieves as the
dehydrating reagent (eq 1). Although N-sulfinyl imino ester 9 is
not stable to column chromatography, it is sufficiently pure that
it can be directly used in subsequent reactions after filtration to
remove the sieves, followed by concentration.
Recently, we reported on the first asymmetric addition of C−
H bonds to N-perfluorobutanesulfinyl imines.17a This study
included the asymmetric syntheses of the three arylglycines
11a−c by Rh(III)-catalyzed C−H bond addition to perfluor-
obutanesulfinyl imine 9 (Table 3). Here, an expanded set of
Table 3. Asymmetric Synthesis of Arylglycines
With optimal conditions identified for the preparation and
cleavage of sulfinate ester 6, perfluorobutanesulfinamide (8)
was next prepared on a multigram scale from sulfinyl transfer
reagent 5 in a two-step sequence (Scheme 2). Sulfinamide 8
Scheme 2. A Practical Asymmetric Synthesis of
Perfluorobutanesulfinamide
was isolated in 67% overall yield for the two steps with the sole
purification being straightforward chromatographic separation
from the byproduct 7 and its O-TMS ether. Importantly,
sulfinamide 8 was obtained in 99% ee as determined by chiral
HPLC analysis. Chiral auxiliary 7 also can be recovered in pure
form in 76% overall yield from 5 by treating the mixture of 7
and its silyl ether with Bu4NF, followed by extractive isolation
and recrystallization.
a
b
Conditions: in DCE (0.75 M) for 48 h. Conditions: 10 (0.225
We next focused on the preparation of N-perfluorobutane-
sulfinyl imino ester 9 as a versatile intermediate for the
mmol), 9 (0.150 mmol) in DCE (0.75 M) at room temperature for 24
h. Conditions: AgOAc (20 mol %) was added to the reaction mixture.
c
C
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directing groups and compatibility with different functionalities
and substitution patterns has been demonstrated (11d−11m).
All Rh(III)-catalyzed C−H bond additions were performed at
≤60 °C because rapid decomposition of perfluorobutanesul-
finyl imino ester 9 occurs at higher temperatures. A number of
directing groups proved to be effective for this reaction. In
addition to the previously reported benzamide (11a) and azo
(11b and c) directing groups, sulfoximine (11d), pyrazoles
(11e−i), and 1,2,3-triazoles (11j−m) also were shown to be
effective. Good scope was also observed for substitution on the
arene ring with an electron-deficient and reactive keto
functionality (11h) and electron-donating groups (11f, 11g,
11i, and 11k−11m). The desired products were obtained in
moderate to good yield and, in all cases, with excellent
diastereoselectivities, as rigorously determined by HPLC
analysis using an authentic mixture of diastereomer standards.24
The absolute configuration of 11a was established by X-ray
structure determination of its 4-chlorobenzamide derivative.
The stereochemistry of all of the other addition products 11
was assigned by analogy. The sense of induction is consistent
with the stereochemical model that we reported for C−H bond
addition to aromatic imines (Figure 1). Enantiomeric rhoda-
Scheme 3. Attempted C−H Additions to N-tert-
Butanesulfinyl Imino Ester 12
Gautun and co-workers have previously reported highly
diastereoselective aza-Diels−Alder reaction of tert-butanesulfin-
yl imino ester 12 with dienes with TMSOTf as a Lewis acid
catalyst.16 While cycloaddition with unhindered dienes
proceeded in high yields and with high selectivity, for more
hindered diene substrates, the aza-Diels−Alder products were
obtained in very low yields (eq 3).
Figure 1. Stereochemical model consistent with sense of induction.
cycles A and B are based upon the X-ray structures of
corresponding cationic rhodacycles derived from 2-phenyl-
pyridine.25,26 The observed sense of induction is obtained if the
reaction occurs through C with the C4F9 substituent pointing
away from the reaction center. This model is consistent with
prior mechanistic studies on the addition of 2-phenylpyridine to
N-sulfonyl and N-carbamoyl imines.27 The high diastereose-
lectivity requires equilibration between enantiomeric rhoda-
cycles A and B either before or after coordination of N-sulfinyl
iminoester 9.
We and others had previously reported that Rh(III)-
catalyzed C−H bond additions to N-tert-butanesulfinyl
benzaldimine were unsuccessful,17 in contrast to the additions
to the corresponding N-perfluorobutanesulfinyl derivative.17a
However, because the carboxy group of N-sulfinyl imino esters
activates the imine for addition, as a further control, we now
also have evaluated Rh(III)-catalyzed C−H bond additions to
tert-butanesulfinyl imino ester 12 (Scheme 3). The desired
addition products were not obtained for either the amide or
sulfoximine directing groups. At 50 °C, no reaction was
observed, and upon incremental heating up to 120 °C, only
decomposition occurred.
The synthetic utility of N-perfluorobutanesulfinyl imino ester
9 was, therefore, evaluated for aza-Diels−Alder reactions (Table
4). When TMSOTf or BF3·Et2O was employed as Lewis acid
for cycloaddition of 9 with 2-methylbutadiene (14a) under the
conditions previously reported for the aza-Diels−Alder reaction
of N-tert-butanesulfinyl imino ester 12,16 no desired product
was obtained due to the rapid decomposition of 9 (entries 1
and 2, respectively). However, when the reaction solution was
heated to 50 °C without a Lewis acid catalyst, good conversion
to the desired cycloaddition product 15a was observed (entry
3). The higher boiling point solvent 1,2-dichloroethane (DCE)
resulted in higher conversion (entry 4), and increasing the
reaction concentration of 9 to 1.0 M led to a higher yield of 15a
with almost complete consumption of starting material 9 (entry
5). Increasing the temperature above 50 °C resulted in a lower
yield due to competitive decomposition of imino ester 9 (entry
6). The reaction also proceeded at 2.0 M (entry 7) and even
without solvent (entry 8).
The thermal aza-Diels−Alder reaction of the corresponding
N-tert-butanesulfinyl imino ester 12 was also evaluated for
comparison purposes (eq 4). At 50 °C, no reaction occurred,
and incremental heating up to 120 °C only resulted in the
decomposition of imine 12.
As shown in eq 2, the N-perfluorobutanesulfinyl group
readily can be cleaved by treatment with HCl in CH2Cl2 at rt to
provide the hydrochloride salt 13b in high yield and without
any loss in stereochemical purity.17a
D
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a
Table 4. Optimization of Aza-Diels-Alder Reaction
entry
14a (equiv)
Lewis acid
solv
temp (°C)
conc (M)
15a (%)
9 (%)
b
1
2
3
4
5
6
7
8
20
5
TMSOTf
CH2Cl2
CH2Cl2
CH2Cl2
DCE
−78
0
0.13
0.13
0.25
0.25
1.0
0
0
0
7
c
BF3·Et2O
5
50
50
50
75
50
44
61
76
69
70
13
11
3
5
5
DCE
5
DCE
1.0
0
5
DCE
2.0
2
5
50
neat
74
1
a
b
c
Determined by 1H NMR analysis relative to 2,6-dimethoxytoluene as an external standard. 10 equiv of TMSOTF was used. 1 equiv of TMSOTf
was used.
Senanayake’s 2-aminoindanol-derived sulfinyl transfer reagent
was developed and carried out on a multigram scale.
Straightforward preparation of the N-perfluorobutanesulfinyl
imine from ethyl glyoxylate also proceeded cleanly and in high
yield. The enhanced reactivity of the N-perfluorobutanesulfinyl
imino ester allowed for the Rh(III)-catalyzed addition of aryl
C−H bonds using a wide range of directing groups to provide
arylglycines in moderate to good yields and with high
diastereoselectivity. We further demonstrated the utility of
the N-perfluorobutanesulfinyl imino ester for the asymmetric
synthesis of pipecolic acid derivatives via aza-Diels−Alder
reaction. We anticipate that N-perfluorobutanesulfinyl imino
esters may prove effective when the corresponding less
electrophilic N-tert-butanesulfinyl imino esters are determined
to have insufficient reactivity.
The thermal aza-Diels−Alder reaction of the N-perfluor-
obutanesulfinyl imino ester 9 was next evaluated for several
dienes (Table 5). For the reactive dienes 2-methylbutadiene
Table 5. Scope of Aza-Diels-Alder Reaction
EXPERIMENTAL SECTION
■
General Information. Unless noted, all catalytic reactions were set
up inside a nitrogen-filled glovebox using oven-dried (150 °C)
glassware that was evacuated hot prior to use. Unless otherwise
indicated, all reagents and starting materials were obtained from
commercial suppliers and used without further purification. Heating in
addition to workup and isolation of the products of the reactions were
performed on the benchtop using standard techniques. Tetrahydrofur-
an and diethyl ether were purified by passage through activated
alumina using a solvent purification system. [Cp*RhCl2]2,28 AgB-
(C6F5)4,29 benzoylpyrrolidine,30 azobenzenes,31 sulfoximine,32 N-aryl-
1H-pyrazoles,33 and 1-benzyl-4-phenyl-1H-1,2,3-triazoles34 were syn-
thesized according to published procedures. 1,2-Dichloroethane
(DCE) was deoxygenated by sparging with nitrogen gas, followed
by storage over activated 3 Å molecular sieves for 48 h prior to use.
Ethylmagnesium bromide was titrated35 before use, and the
oxathiazolidine oxide chiral sulfinyl transfer auxiliary (5) was prepared
according to a published procedure.36 Ethyl glyoxylate was prepared
following a published procedure.37 Flash column chromatography was
performed with 230−400 mesh silica gel. The products were visualized
on TLC by either UV or staining with KMnO4. Normal phase
chromatography was performed on 230−240 mesh silica gel or
preparative thin-layer chromatography plates (1 mm SiO2, 20 × 20
cm). Reverse phase chromatography was performed with C18 columns
and 2,3-dimethylbutadiene, the aza-Diels−Alder products 15a
and 15b were obtained in high yields and with very high
diastereoselectivity. However, it should be noted that, for these
dienes, the TMSOTF catalyzed aza-Diels−Alder reaction with
tert-butanesulfinyl imino ester 12 had previously been shown to
be efficient.16 Much more significantly, the reaction also
proceeded in good yields and selectivity for the less reactive
dienes (E)-1,3-pentadiene and (2E,4E)-2,4-hexadiene to give
15c and 15d. For these dienes, Lewis acid catalyzed addition to
tert-butanesulfinyl imino ester 12 had previously been shown to
proceed in very low yields (see eq 3).16a The absolute
configuration of the pipecolic acid derivative 15d was rigorously
determined by X-ray crystal structure analysis, and the
remainder of the products were assigned by analogy.
1
using an automated purification system. H, 13C{1H}, and 19F NMR
characterization data were collected at ambient temperature, and
chemical shifts are reported in parts per million relative to CDCl3 (1H
NMR; 7.26 ppm, 13C{1H} NMR; 77.16 ppm) or MeOD (1H NMR;
pentet, 3.31 ppm). Only partial data are provided for IR spectra.
Melting points are reported uncorrected. High-resolution mass spectra
CONCLUSIONS
■
In conclusion, a high yielding and practical two-step synthesis
of enantiomerically pure perfluorobutanesulfinamide from
E
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(HRMS) were obtained using electrospray ionization (ESI) on a time-
of-flight (TOF) mass spectrometer. Enantiomeric excess and
diastereomeric ratio were determined using an HPLC (1.0 mL/min
flow rate) equipped with a multiwavelength detector and a Chiralpak
IB column or an Microsorb 100−5 Si 250 × 4.6 mm silica column,
respectively.
(151 MHz, CDCl3) δ 119.4−107.7 (m); 19F NMR (376 MHz,
CDCl3) δ −80.82 (tt, J = 9.8, 2.3 Hz, 3F), −121.43 to −121.72 (m,
2F), −121.08 to −122.05 (m, 1F), −122.50 to −123.32 (m, 1F),
−126.12 to −126.25 (m, 2F); [α]2D0 = −16.2 (c 0.46, CH3OH); Anal.
Calcd for C4H2F9NOS: C, 16.97; H, 0.71; N, 4.95. Found: C, 17.09;
H, 0.71; N, 5.34.
(1S,2R)-1-(2,4,6-Trimethylbenzenesulfonamido)-2,3-dihy-
dro-1H-inden-2-yl-(S)-nonafluorobutane-1-sulfinate (6). A
flame-dried, 250 mL, three-neck round-bottom flask cooled under
nitrogen was equipped with a magnetic stir bar and rubber septa. The
flask was flushed with nitrogen for 10 min and then charged with
diethyl ether (48 mL) before it was cooled to −78 °C using a dry ice−
acetone bath. The flask was then charged with nonafluoro-1-
iodobutane (5.74 mL, 33.4 mmol, 1.05 equiv) before ethylmagnesium
bromide (12.0 mL, 2.65 M in ether, 31.8 mmol, 1.00 equiv) was added
dropwise with stirring via syringe over 5 min. After the addition, the
flask was covered with aluminum foil to protect it from light, and the
Grignard mixture was stirred for 1 h at −78 °C. While the Grignard
mixture was being stirred, a separate one-neck oven-dried, 100 mL,
round-bottom flask was charged with oxathiazolidine oxide36 (12.0 g,
31.8 mmol, 1.00 equiv) and 45 mL of anhydrous THF, and the
resulting mixture was heated to 50 °C until complete dissolution had
occurred. The resulting THF solution was cooled to −78 °C with a
dry ice−acetone bath before it was transferred via cannula to the 250
mL flask containing the Grignard reagent (1 h after ethylmagnesium
bromide addition). The resulting reaction mixture in the 250 mL flask
was stirred at −78 °C for 1 h before the reaction was quenched by
addition of 15.5 mL of 4.1 M acetic acid in THF (2 equiv) over 5 min.
The solution was allowed to warm to rt over ∼30 min, and then the
mixture was transferred to a separatory funnel. Additional deionized
water (60 mL) was added, and the aqueous layer was separated and
extracted with ethyl acetate (3 × 30 mL). The combined organic layer
was shaken with saturated aqueous Na2S2O3 solution (30 mL) until
the orange color disappeared. The organic layer was then washed with
brine (30 mL), dried over sodium sulfate, and concentrated to dryness
under reduced pressure to afford crude product 6 (17.3 g, 91% yield)
as an off-white solid. The crude product was determined to be of
Recovery of N-((1S,2R)-2-Hydroxy-2,3-dihydro-1H-inden-1-
yl)-2,4,6-trimethylbenzenesulfonamide (7). From the column
chromatography purification of 8, fractions that contain 7 (Rf = 0.59,
10% MTBE in CH2Cl2) or its O-TMS ether (Rf = 0.90, 10% MTBE in
CH2Cl2) were combined and concentrated to give 12.0 g of a dark red-
brown oil. The material was transferred to a one-neck, 250 mL, round-
bottom flask using 100 mL of THF to solubilize the material and assist
with transfer. To the stirred solution at ambient temperature was then
added 30 mL of 1 M TBAF solution in THF. After being stirred at
ambient temperature for 1 h, the mixture was transferred to a 250 mL
separatory funnel. Additional ethyl acetate (50 mL) and deionized
water (50 mL) were used to assist transfer. The aqueous layer was
separated and further extracted with ethyl acetate (2 × 20 mL). The
combined organic layers were washed with deionized water (2 × 30
mL) and saturated aqueous NaCl solution (30 mL) and then dried
over sodium sulfate. The drying agent was removed by vacuum
filtration, and the filtrate was concentrated to dryness on a rotary
evaporator before it was triturated with 50 mL of hexanes and vacuum
filtered through a Buchner funnel equipped with a filter paper to afford
10.0 g of a light brown solid material, which was diluted with 40 mL of
ethyl acetate in a 250 mL Erlenmeyer flask. The mixture was heated to
50 °C with swirling to dissolve all the material, and then 80 mL of
hexanes was layered on top and the flask was covered with aluminum
foil. The flask was stored at −20 °C overnight (16 h). The crystalline
product was isolated by vacuum filtration using a Buchner funnel
equipped with a filter paper. The crystalline solid was crushed to
powder using a porcelain mortar and pestle before it is dried under
high vacuum to provide 8.0 g (76% recovery from 5) of 7 as an off-
white solid; mp 148−150 °C [lit. 149−150 °C].36 The analytical data
for this compound are consistent with previously reported data.36 1H
NMR (400 MHz, CDCl3) δ 7.26−7.10 (m, 4H), 7.01 (s, 2H), 5.33 (d,
J = 9.5 Hz, 1H), 4.63 (dd, J = 9.5, 4.8 Hz, 1H), 4.44−4.39 (m, 1H),
3.09 (dd, J = 16.8, 5.1 Hz, 1H), 2.92 (d, J = 16.5 Hz, 1H), 2.72 (s, 6H),
2.33 (s, 3H), 2.17 (d, J = 4.9 Hz, 1H).
(S,E)-Ethyl-2-(((perfluorobutyl)sulfinyl)imino)acetate (9). To
a 20 mL screw-top scintillation vial equipped with magnetic stir bar
and flushed with nitrogen was weighed out distilled ethyl glyoxylate
(108.2 mg, 1.06 mmol, 1.0 equiv) before addition of anhydrous
CH2Cl2 (3.5 mL, [sulfinyl imino ester] = 0.30 M). To the solution
were added 3 Å molecular sieves and (S)-nonafluorobutanesulfinamide
(300 mg, 1.06 mmol, 1.0 equiv) before the vial was capped. The
resulting mixture was stirred at room temperature over 4 days with the
reaction conversion monitored by 1H NMR. After complete
conversion was observed, the resulting mixture was filtered through
a fine glass frit funnel to remove the molecular sieves and the flask and
funnel were washed with additional CH2Cl2. The combined filtrate was
concentrated under reduced pressure to give crude product 9 (322 mg,
83% yield) as a clear yellow-orange liquid which was of sufficient
purity to be used in subsequent transformations. The analytical data
for this compound are consistent with previously reported data.17a 1H
NMR (400 MHz, CDCl3) δ 8.23 (s, 1H), 4.44 (q, J = 7.1 Hz, 2H),
1.41 (t, J = 7.1 Hz, 3H).
1
sufficient purity by H NMR and was used directly in the subsequent
1
step. H NMR (400 MHz, CDCl3) δ 7.32−7.26 (m, 1H), 7.24−7.20
(m, 2H), 7.18−7.14 (m, 1H), 7.01 (s, 2H), 5.26−5.20 (m, 2H), 5.00
(dd, J = 10.5, 4.3 Hz, 1H), 3.27−3.09 (m, 2H), 2.73 (s, 6H), 2.32 (s,
3H).
(S)-Perfluorobutanesulfinamide (8). To a flame-dried three-
neck, 250 mL, indented style (Morton) round-bottom flask equipped
with a magnetic stir bar and cooled under nitrogen was added 17.3 g of
crude perfluorobutanesulfinate ester 6. The flask was then fitted with
an oven-dried, 125 mL addition funnel and rubber septa before
flushing with nitrogen for 10 min. Anhydrous THF (53 mL) was then
added via syringe with stirring until all the solids had dissolved to give
a clear solution. The solution of 7 in THF was cooled to −78 °C using
a dry ice−acetone bath before 43.4 mL (86.9 mmol, 3 equiv assuming
that crude 6 was 100% pure) of a 2.0 M solution of NaHMDS in THF
was added dropwise via an addition funnel over 10 min. The resulting
reaction mixture was stirred for 3.5 h at −78 °C before it was
quenched by dropwise addition of a saturated aqueous NH4Cl solution
(50 mL). After allowing it to warm to rt over ∼30 min, the biphasic
mixture was stirred at room temperature for 16 h before being
transferred to a separatory funnel. The aqueous layer was separated
and extracted with ethyl acetate (3 × 30 mL). The combined organic
layer was washed with brine (30 mL), dried over sodium sulfate, and
concentrated under reduced pressure to afford a dark red-brown oil.
Purification by flash column chromatography with 10% MTBE in
CH2Cl2 as eluent (8 has an Rf value of 0.31) afforded the product 8
(6.0 g, 67% yield over two steps) as an off-white solid that was
determined to be of >99% ee as determined by chiral HPLC analysis
(Chiralpak IB, EtOH/hexanes 10:90, 1.0 mL/min. 230 nm) of 8: tR =
7.4 min (S) and 11.4 min (R); mp 73−75 °C [lit. 64−66 °C].18d The
analytical data for this compound are consistent with previously
reported data.18d IR (film): 3349, 1264, 1205, 1136, 1021, 731, 700
General Procedure for Synthesis of 1-Benzyl-4-Aryl-1H-
1,2,3-Triazoles. The following procedure was adapted from the
literature.34a In a 20 mL scintillation vial equipped with a magnetic stir
bar was added the indicated benzyl bromide (4.40 mmol, 1.1 equiv) to
a stirred solution of DMF−H2O (10 mL; 4:1). Following this, CuSO4·
5H2O (499 mg, 2.00 mmol, 0.5 equiv), sodium azide (312 mg, 4.80
mmol, 1.2 equiv), L-ascorbic acid (705 mg, 4.00 mmol, 1.0 equiv), and
sodium carbonate (424 mg, 4.00 mmol, 1.0 equiv) were added. After
the solution was stirred for 5 min, the indicated ethynylarene was
added (4.00 mmol, 1.0 equiv), and the reaction mixture was stirred at
ambient temperature for 16 h. The reaction mixture was transferred to
a stirred 0.1 M solution of EDTA (disodium salt, dihydrate) in DI
1
cm−1; H NMR (400 MHz, CDCl3) δ 4.79 (s, 2H); 13C{1H} NMR
F
DOI: 10.1021/acs.joc.5b02700
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The Journal of Organic Chemistry
Article
water (100 mL), followed by the addition of 100 mL of NH4OH (28−
30% v/v). The resulting mixture was then stirred vigorously at 1200
rpm for 30 min before being diluted with CH2Cl2 (200 mL) and
transferred to a separatory funnel. The mixture was extracted with
CH2Cl2 (2 × 50 mL), and the combined organic layers were washed
with DI water (50 mL) and brine (50 mL), dried with MgSO4, and
concentrated under reduced pressure. Purification by flash column
chromatography with EtOAc/hexanes afforded the 1-benzyl-4-aryl-1H-
1,2,3-triazole.
1-Benzyl-4-(4-methoxyphenyl)-1H-1,2,3-triazole (10k). The gen-
eral procedure was followed with benzyl bromide (753 mg, 4.40 mmol,
1.1 equiv) and 4-ethynylanisole (529 mg, 4.00 mmol, 1.0 equiv).
Purification by flash column chromatography (10−30% EtOAc in
hexanes gradient) afforded the product (10k) (729 mg, 69% yield) as
an off-white solid. mp: 142−143 °C [lit.34b 141−142 °C]. The
analytical data for this compound are consistent with previously
reported data.34b
1-Benzyl-4-(p-tolyl)-1H-1,2,3-triazole (10l). The general procedure
was followed with benzyl bromide (753 mg, 4.40 mmol, 1.1 equiv) and
4-ethynyltoluene (465 mg, 4.00 mmol, 1.0 equiv). Purification by flash
column chromatography (10−20% EtOAc in hexanes gradient)
afforded the product (893 mg, 90% yield) as a white solid. mp:
152−154 °C [lit.34b 150−152 °C]. The analytical data for this
compound are consistent with previously reported data.34b
1-Benzyl-4-(m-tolyl)-1H-1,2,3-triazole (10m). The general proce-
dure was followed with benzyl bromide (753 mg, 4.40 mmol, 1.1
equiv) and 3-ethynyltoluene (465 mg, 4.00 mmol, 1.0 equiv).
Purification by flash column chromatography (10−25% EtOAc in
hexanes gradient) afforded the product (758 mg, 76% yield) as a white
solid. 146−147 °C [lit.34c 144−146 °C]. The analytical data for this
compound are consistent with previously reported data.34c
glovebox, perfluorobutanesulfinyl imino ester 9 (55.1 mg, 0.150
mmol, 1.0 equiv) was weighed out into a 1 mL conical screw-capped
vial, followed by benzoylsulfoximine 10d (50.2 mg, 0.225 mmol, 1.5
equiv), [Cp*RhCl2]2 (9.3 mg, 0.015 mmol, 10 mol %), and
AgB(C6F5)4(Et2O)2 (56.1 mg, 0.06 mmol, 40 mol %). To this mixture
were added DCE (0.200 mL, [sulfinyl imine] = 0.750 M) and a
triangular magnetic stir bar before the vial was sealed with a cap
containing a PTFE septum and was removed from the glovebox. The
reaction mixture was stirred at ambient temperature for 24 h before it
was filtered through a plug of Celite in a pipet with CH2Cl2 (4 mL).
The filtrate was then concentrated and subjected to purification by
flash column chromatography on silica gel to afford the product 11d
(45.1 mg, 55% yield) as a yellow oil. IR (film): 1739, 1612, 1595,
1
1573, 1309, 1196, 1093, 746, 723, 692 cm−1; H NMR (600 MHz,
CDCl3) δ 8.10 (d, J = 7.7 Hz, 1H), 7.47 (t, J = 7.5 Hz, 1H), 7.40 (t, J =
7.6 Hz, 1H), 7.30 (d, J = 7.5 Hz, 1H), 6.78 (d, J = 8.5 Hz, 1H), 5.66
(d, J = 7.4 Hz, 1H), 4.16 (q, J = 7.1 Hz, 2H), 3.81−3.73 (m, 1H),
3.72−3.64 (m, 1H), 3.41−3.31 (m, 2H), 2.42−2.32 (m, 2H), 2.35−
2.22 (m, 2H), 1.20 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (151 MHz,
CDCl3) δ 176.8, 170.3, 136.7, 134.4, 132.2, 131.8, 131.1, 128.9,
120.5−106.3 (m), 62.3, 59.9, 53.1, 52.7, 23.9, 23.7, 14.1; 19F NMR
(376 MHz, CDCl3) δ −80.86 (t, J = 9.7 Hz, 3F), −117.84 (dt, J =
249.1, 13.1 Hz, 1F), −121.64 to −121.91 (m, 2F), −122.44 to
−123.39 (m, 1F), −126.12 to −126.35 (m, 2F); HRMS (ESI/[M +
H]+) calcd. for C19H19F9N2O5S2: 591.0664. Found 591.0659.
General Procedure for Synthesis of Arylglycines 11e−11i. In
a N2-filled glovebox, perfluorobutanesulfinyl imino ester 9 (55.1 mg,
0.150 mmol, 1.0 equiv), the indicated 1-aryl-1H-pyrazole (10e−10i)33
(0.300 mmol, 2.0 equiv), [Cp*RhCl2]2 (9.3 mg, 0.015 mmol, 0.10
equiv), and AgB(C6F5)4 (62.0 mg, 0.060 mmol, 0.40 equiv, 23.8% w/w
toluene) were added to a 0.5−2.0 mL microwave vial equipped with a
triangular magnetic stir bar, followed by the addition of 1,2-
dichloroethane (200 μL, [sulfinyl imine] = 0.75 M). The vial was
sealed and removed from the glovebox. The reaction vial was then
placed in a temperature-controlled oil bath preset to 50 °C and was
stirred for 24 h. The vial was removed from the oil bath and cooled to
ambient temperature before the reaction vessel was unsealed. The
crude mixture was purified directly by silica gel chromatography.
Ethyl (S)-2-(2-(1H-Pyrazol-1-yl)phenyl)-2-(((S)-(perfluorobutyl)-
sulfinyl)amino)acetate (11e). The general procedure was followed
with perfluorobutanesulfinyl imino ester 9 (55.1 mg, 0.150 mmol, 1.0
equiv) and 1-phenyl-1H-pyrazole (43.3 mg, 0.300 mmol, 2.0 equiv).
Purification by flash column chromatography (10−20% EtOAc in
hexanes gradient) afforded the product 11e (52.0 mg, 68% yield) as a
light yellow oil. IR (film): 1739, 1521, 1396, 1351, 1195, 1138, 1099,
1015, 941, 864, 758, 723, 692, 619, 577, 515, 428 cm−1; 1H NMR (400
MHz, CDCl3): δ 7.72 (d, J = 1.9 Hz, 1H), 7.68 (d, J = 2.2 Hz, 1H),
7.51−7.40 (m, 4H), 7.33 (dd, J = 7.4, 1.8 Hz, 1H), 6.47 (t, J = 1.9 Hz,
1H), 5.45 (d, J = 9.0 Hz, 1H), 4.00−3.87 (m, 2H), 1.08 (t, J = 7.1 Hz,
3H); 13C{1H} NMR (151 MHz, CDCl3): δ 169.1, 141.2, 138.7, 132.7,
132.2, 130.7, 130.0, 129.0, 125.4, 120.4−106.5 (m), 107.8, 62.4, 58.0,
13.9; 19F NMR (376 MHz, CDCl3): δ −81.81 (t, J = 9.5 Hz, 3F),
−117.51 (dt, J = 249.0, 12.7 Hz, 1F), −122.69 to −122.85 (m, 2F),
−124.30 (dt, J = 249.0, 12.7 Hz, 1F), −126.29 to −128.07 (m, 2F);
HRMS (ESI/[M + H]+) calcd. for C17H15F9N3O3S: 512.0685. Found
512.0684.
Synthesis and Characterization of Arylglycines 11a−11c.
Synthetic procedures, full analytical characterization, and NMR spectra
were previously reported for arylglycines 11a−c.17a
Ethyl (S)-2-(4-Chlorobenzamido)-2-(2-(pyrrolidine-1-carbonyl)-
phenyl)acetate (11a-amide). To a flame-dried, 1 dram vial equipped
with a magnetic stir bar was added 11a (60 mg, 0.11 mmol, 1 equiv).
Anhydrous CH2Cl2 (1 mL) was added, and the solution was cooled to
0 °C with an ice bath, followed by dropwise addition of 4 M HCl in
dioxane (0.14 mL, 0.55 mmol, 5 equiv). The mixture was stirred at 0
°C for 2 h and then concentrated to dryness under reduced pressure.
The resulting solid residue was dissolved in anhydrous CH2Cl2 (1
mL), and Et3N (0.038 mL, 0.28 mmol, 2.5 equiv) was added. After
cooling the mixture to 0 °C with an ice bath, a solution of benzoyl
chloride (20.3 mg, 0.12 mmol, 1.05 equiv) in anhydrous CH2Cl2 (1
mL) was added slowly dropwise. The reaction mixture was warmed up
slowly to room temperature and stirred for 2 h before concentrating to
dryness under reduced pressure. Purification by flash column
chromatography (50% EtOAc in hexanes) afforded the product 11a-
amide (39.5 mg, 86% yield) as an off-white solid; mp 118−120 °C. IR
(film): 3286, 1743, 1660, 1614, 1594, 1521, 1479, 1432, 1338, 1320,
1206, 1180, 1091, 1014, 847, 732 cm−1; 1H NMR (400 MHz, CDCl3)
δ 8.82 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 8.5 Hz, 2H), 7.52 (d, J = 7.4
Hz, 1H), 7.45−7.31 (m, 5H), 6.02 (d, J = 8.8 Hz, 1H), 4.24−4.02 (m,
2H), 3.64−3.53 (m, 2H), 3.38−3.29 (m, 1H), 3.26−3.19 (m, 1H),
2.02−1.77 (m, 4H), 1.22 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (151
MHz, CDCl3) δ 170.7, 170.5, 165.3, 137.9, 136.0, 134.7, 132.3, 132.0,
130.4, 129.0, 128.8, 128.3, 127.7, 61.9, 56.9, 49.7, 46.2, 26.3, 24.7, 14.3;
[α]2D0 = +39.0 (c 0.32, CH3OH); HRMS (ESI/[M + H]+) calcd. for
C22H23ClN2O4: 415.1419. Found 415.1390.
Ethyl (S)-2-(5-Methyl-2-(1H-pyrazol-1-yl)phenyl)-2-(((S)-
(perfluorobutyl)sulfinyl)amino)acetate (11f). The general procedure
was followed with perfluorobutanesulfinyl imino ester 9 (55.1 mg,
0.150 mmol, 1.0 equiv) and 1-(p-tolyl)-1H-pyrazole33a (47.5 mg, 0.300
mmol, 2.0 equiv). Purification by flash column chromatography (10−
20% EtOAc in hexanes gradient) afforded the product 11f (59.6 mg,
76% yield) as a light yellow oil. IR (film): 1738, 1522, 1396, 1351,
1195, 1138, 1099, 1024, 942, 862, 822, 746, 722, 692, 620, 576, 519,
X-ray quality crystals of the 11a-amide were obtained according to
the following procedure: In a flame-dried, 1 dram vial, 10 mg of 11a-
amide was dissolved in 1.0 mL of Et2O with heating. The 1 dram vial
containing the solution of 11a-amide in Et2O was placed inside a 20
mL scintillation vial filled with 5 mL of pentane. The scintillation vial
was sealed and allowed to sit at room temperature for 2 days, after
which single crystals formed.
Procedure for Synthesis of Ethyl (S)-2-(2-((1-Oxido-
tetrahydrothiophen-1-ylidene)carbamoyl)phenyl)-2-(((S)-
(perfluorobutyl)sulfinyl)amino)acetate (11d). In a N2-filled
1
436 cm−1; H NMR (600 MHz, CDCl3): δ 7.70 (d, J = 1.9 Hz, 1H),
7.62 (d, J = 2.2 Hz, 1H), 7.50 (d, J = 9.0 Hz, 1H), 7.30 (s, 1H), 7.26−
7.23 (m, 1H), 7.20 (d, J = 8.0 Hz, 1H), 6.44 (t, J = 2.2 Hz, 1H), 5.39
(d, J = 9.0 Hz, 1H), 3.98−3.87 (m, 2H), 2.40 (s, 3H), 1.08 (t, J = 7.1
Hz, 3H); 13C{1H} NMR (151 MHz, CDCl3): δ 169.1, 140.9, 139.2,
136.3, 132.6, 132.6, 130.7, 130.5, 125.4, 120.4−106.4 (m), 107.6, 62.3,
G
DOI: 10.1021/acs.joc.5b02700
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The Journal of Organic Chemistry
Article
57.6, 21.0, 13.9; 19F NMR (376 MHz, CDCl3): δ −81.86 (tt, J = 9.6,
2.4 Hz, 3F), −117.34 (dt, J = 248.9, 12.9 Hz, 1F), −122.75 to −122.90
(m, 2F), −124.57 (dt, J = 248.9, 11.6 Hz, 1F), −126.32 to −128.10
(m, 2F); HRMS (ESI/[M + H]+) calcd. for C18H17F9N3O3S:
526.0841. Found 526.0840.
dichloroethane (200 μL, [sulfinyl imine] = 0.75 M). The vial was
sealed and removed from the glovebox. The reaction vial was then
placed in a temperature-controlled oil bath preset to 50 °C. After the
solution was stirred for 24 h, the vial was removed from the oil bath
and cooled to ambient temperature before the reaction vessel was
unsealed. The crude mixture was purified directly by chromatography.
Ethyl (S)-2-(2-(1-Benzyl-1H-1,2,3-triazol-4-yl)phenyl)-2-(((S)-
(perfluorobutyl)sulfinyl)amino)acetate (11j). The general procedure
was followed with perfluorobutanesulfinyl imino ester 9 (55.1 mg,
0.150 mmol, 1.0 equiv) and 1-benzyl-4-phenyl-1H-1,2,3-triazole34a
(70.6 mg, 0.300 mmol, 2.0 equiv). Preparative thin-layer silica gel
chromatography using 50% Et2O/pentane provided the first step of
the purification process. Pure product was then obtained by C18
reverse phase column chromatography with loading of the isolated
material onto the column as a solution in 1 mL of DMSO. Reverse
phase purification was performed with 15.5 g of reverse phase media
and a 95 column volume gradient from 10 to 65% CH3CN:H2O
containing 0.1% TFA. Fractions containing product were combined
and diluted with sat. aq. NaHCO3 (50 mL) and extracted with CH2Cl2
(3 × 100 mL). The combined organic layers were then washed with
sat. aq. NaHCO3 (50 mL) and brine (50 mL), dried over MgSO4, and
concentrated to afford the product 11j (52.1 mg, 58% yield) as a
colorless oil. IR (film): 1738, 1352, 1196, 1138, 1014, 763, 721, 692,
Ethyl (S)-2-(5-Methoxy-2-(1H-pyrazol-1-yl)phenyl)-2-(((S)-
(perfluorobutyl)sulfinyl)amino)acetate (11g). The general procedure
was followed with perfluorobutanesulfinyl imino ester 9 (55.1 mg,
0.150 mmol, 1.0 equiv) and 1-(4-methoxyphenyl)-1H-pyrazole33a
(52.3 mg, 0.300 mmol, 2.0 equiv). Purification by preparative thin-
layer silica gel chromatography using 25% EtOAc/hexanes afforded
the product 11g (38.3 mg, 47% yield) as a light yellow oil. IR (film):
1740, 1523, 1196, 1138, 1043, 1018, 943, 864, 816, 746, 723, 692, 613,
1
435 cm−1; H NMR (500 MHz, CDCl3): δ 7.69 (d, J = 1.9 Hz, 1H),
7.58 (d, J = 2.2 Hz, 1H), 7.39 (d, J = 8.8 Hz, 1H), 7.23 (d, J = 8.7 Hz,
1H), 7.00 (d, J = 2.8 Hz, 1H), 6.95 (dd, J = 8.7, 2.8 Hz, 1H), 6.43 (t, J
= 2.2 Hz, 1H), 5.36 (d, J = 8.8 Hz, 1H), 4.00−3.88 (m, 2H), 3.85 (s,
3H), 1.09 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (151 MHz, CDCl3): δ
168.9, 159.7, 140.8, 134.4, 131.9, 131.0, 127.2, 116.7, 115.0, 120.4−
106.4 (m), 107.4, 62.4, 57.3, 55.8, 13.9; 19F NMR (471 MHz, CDCl3):
δ −81.87 (t, J = 9.5 Hz, 3F), −117.38 (dt, J = 249.2, 13.2 Hz, 1F),
−122.71 to −122.88 (m, 2F), −124.49 (ad, J = 249.2, 1F), −126.48 to
−127.98 (m, 2F); HRMS (ESI/[M + H]+) calcd. for C18H17F9N3O4S:
542.0791. Found 542.0790.
1
581 cm−1; H NMR (500 MHz, CDCl3): δ 7.67 (s, 1H), 7.42−7.28
Ethyl (S)-2-(5-Acetyl-2-(1H-pyrazol-1-yl)phenyl)-2-(((S)-
(perfluorobutyl)sulfinyl)amino)acetate (11h). The general procedure
was followed with perfluorobutanesulfinyl imino ester 9 (55.1 mg,
0.150 mmol, 1.0 equiv) and 1-(4-(1H-pyrazol-1-yl)phenyl)ethan-1-
one33b (55.9 mg, 0.300 mmol, 2.0 equiv). Purification by preparative
thin-layer silica gel chromatography using 25% EtOAc/hexanes
afforded the product 11h (50.6 mg, 61% yield) as a light yellow
waxy solid. IR (film): 1726, 1697, 1607, 1524, 1395, 1191, 1137, 1033,
(m, 10H), 5.78 (d, J = 8.0 Hz, 1H), 5.59 (d, J = 14.8 Hz, 1H), 5.55 (d,
J = 14.8 Hz, 1H), 4.01−3.92 (m, 2H), 1.03 (t, J = 7.1 Hz, 3H);
13C{1H} NMR (151 MHz, CDCl3): δ 169.9, 147.4, 135.4, 134.4,
130.4, 130.1, 129.3, 129.3, 129.1, 129.1, 128.3, 122.0, 120.4−106.2
(m), 62.1, 58.6, 54.5, 13.8; 19F NMR (471 MHz, CDCl3): δ −81.88 (t,
J = 9.5 Hz, 3F), −117.99 (dt, J = 249.0, 12.6 Hz, 1F), −122.03 to
−123.54 (m, 2F), −123.56 (ad, J = 249.0 Hz, 1F), −126.52 to
−127.93 (m, 2F); HRMS (ESI/[M + H]+) calcd. for C23H20F9N4O3S:
603.1107. Found 603.1108.
1
943, 759, 746, 722, 692, 613, 514, 457 cm−1; H NMR (500 MHz,
CDCl3): δ 8.08 (d, J = 2.0 Hz, 1H), 8.04 (dd, J = 8.2, 2.0 Hz, 1H),
7.76 (d, J = 2.2 Hz, 1H), 7.74 (d, J = 2.0 Hz, 1H), 7.44 (d, J = 8.2 Hz,
1H), 7.40 (d, J = 9.1 Hz, 1H), 6.51 (t, J = 2.2 Hz, 1H), 5.58 (d, J = 9.1
Hz, 1H), 4.00−3.88 (m, 2H), 2.63 (s, 3H), 1.07 (t, J = 7.1 Hz, 3H);
13C{1H} NMR (151 MHz, CDCl3): δ 196.3, 168.7, 141.9, 141.8,
136.6, 132.9, 132.3, 130.5, 129.8, 124.8, 120.3−106.4 (m), 108.6, 62.5,
58.3, 26.8, 13.9; 19F NMR (471 MHz, CDCl3): δ −82.10 (t, J = 9.5
Hz, 3F), −117.80 (dt, J = 248.9, 13.5 Hz, 1F), −122.93 to −123.09
(m, 2F), −124.53 (ad, J = 248.9 Hz, 1F), −126.72 to −128.91 (m,
2F); HRMS (ESI/[M + H]+) calcd. for C19H17F9N3O4S: 554.0791.
Found 554.0793.
Ethyl (S)-2-(4-Methyl-2-(1H-pyrazol-1-yl)phenyl)-2-(((S)-
(perfluorobutyl)sulfinyl)amino)acetate (11i). The general procedure
was followed with perfluorobutanesulfinyl imino ester 9 (55.1 mg,
0.150 mmol, 1.0 equiv) and 1-(m-tolyl)-1H-pyrazole33a (47.5 mg,
0.300 mmol, 2.0 equiv). Purification by flash column chromatography
(10−20% EtOAc in hexanes gradient) afforded the product 11i (60.1
mg, 76% yield) as a light yellow oil. IR (film): 1738, 1519, 1394, 1351,
1194, 1138, 1101, 1014, 955, 859, 746, 722, 692, 619, 580, 437 cm−1;
1H NMR (600 MHz, CDCl3): δ 7.71 (d, J = 1.8 Hz, 1H), 7.67 (d, J =
2.2 Hz, 1H), 7.38−7.35 (m, 2H), 7.23 (d, J = 7.8 Hz, 1H), 7.14 (s,
1H), 6.46 (t, J = 2.2 Hz, 1H), 5.40 (d, J = 8.9 Hz, 1H), 3.98−3.88 (m,
2H), 2.40 (s, 3H), 1.08 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (151 MHz,
CDCl3): δ 169.2, 141.1, 140.4, 138.5, 131.9, 130.6, 129.7, 129.6, 126.1,
120.4−106.4 (m), 107.6, 62.3, 57.6, 21.1, 14.0; 19F NMR (376 MHz,
CDCl3): δ −81.87 (tt, J = 9.4, 2.6 Hz, 3F), −117.57 (dt, J = 249.1,
13.0 Hz, 1F), −122.72 to −122.89 (m, 2F), −124.33 (dt, J = 249.1,
12.2 Hz, 1F), −126.33 to −128.10 (m, 2F); HRMS (ESI/[M + H]+)
calcd. for C18H17F9N3O3S: 526.0841. Found 526.0842.
Ethyl (S)-2-(2-(1-Benzyl-1H-1,2,3-triazol-4-yl)-5-methoxyphenyl)-
2-(((S)-(perfluorobutyl)sulfinyl)amino)acetate (11k). The general
procedure was followed with perfluorobutanesulfinyl imino ester 9
(55.1 mg, 0.150 mmol, 1.0 equiv) and 1-benzyl-4-(4-methoxyphenyl)-
1H-1,2,3-triazole (79.6 mg, 0.300 mmol, 2.0 equiv). Preparative thin-
layer silica gel chromatography using 50% Et2O/pentane provided the
first step in the purification process. Pure product was then obtained
by C18 reverse phase column chromatography with loading of the
isolated material onto the column as a solution in 1 mL of DMSO.
Reverse phase purification was performed with 15.5 g of reverse phase
media and an 80 column volume gradient from 10 to 70%
CH3CN:H2O containing 0.1% TFA. Fractions containing product
were combined and diluted with sat. aq. NaHCO3 (50 mL) and
extracted with CH2Cl2 (3 × 100 mL). The combined organic layers
were then washed with sat. aq. NaHCO3 (50 mL) and brine (50 mL),
dried over MgSO4, and concentrated to afford the product 11k (53.0
mg, 56% yield) as a yellow oil. IR (film): 1738, 1615, 1493, 1459,
1
1351, 1196, 1138, 864, 814, 746, 721, 693, 580 cm−1; H NMR (400
MHz, CDCl3): δ 7.59 (s, 1H), 7.41−7.30 (m, 7H), 6.93 (d, J = 2.6 Hz,
1H), 6.88 (dd, J = 8.6, 2.6 Hz, 1H), 5.73 (d, J = 7.9 Hz, 1H), 5.58 (d, J
= 14.9 Hz, 1H), 5.53 (d, J = 14.9 Hz, 1H), 4.01−3.93 (m, 2H), 3.81 (s,
3H), 1.03 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (151 MHz, CDCl3): δ
169.8, 160.0, 147.3, 136.8, 134.4, 131.5, 129.3, 129.0, 128.3, 121.8,
121.5, 115.6, 114.7, 120.4−106.4 (m), 62.2, 58.4, 55.5, 54.5, 13.8; 19F
NMR (376 MHz, CDCl3): δ −81.85 (t, J = 9.6 Hz, 3F), −117.85 (dt, J
= 249.0, 13.0 Hz, 1F), −121.83 to −123.66 (m, 2F), −123.74 (ad, J =
249.0 Hz, 1F), −126.35 to −128.08 (m, 2F); HRMS (ESI/[M + H]+)
calcd. for C24H22F9N4O4S: 633.1213. Found 633.1214.
Ethyl (S)-2-(2-(1-Benzyl-1H-1,2,3-triazol-4-yl)-5-methylphenyl)-2-
(((S)-(perfluorobutyl)sulfinyl)amino)acetate (11l). The general pro-
cedure was followed with perfluorobutanesulfinyl imino ester 9 (55.1
mg, 0.150 mmol, 1.0 equiv) and 1-benzyl-4-(p-tolyl)-1H-1,2,3-triazole
(74.8 mg, 0.300 mmol, 2.0 equiv). Preparative thin-layer silica gel
chromatography using 50% Et2O/pentane provided the first step in
the purification process. Pure product was then obtained by C18
reverse phase column chromatography with loading of the isolated
material onto the column as a solution in 1 mL of DMSO. Reverse
General Procedure for the Synthesis of Arylglycines 11j−
11m. In a N2-filled glovebox, perfluorobutanesulfinyl imino ester 9
(55.1 mg, 0.150 mmol, 1.0 equiv), the indicated 1-benzyl-4-aryl-1H-
1,2,3-triazole (10j−10m)34 (0.300 mmol, 2.0 equiv), [Cp*RhCl2]2
(9.3 mg, 0.015 mmol, 0.10 equiv), AgB(C6F5)4 (62.0 mg, 0.060 mmol,
0.40 equiv, 23.8% w/w toluene), and AgOAc (5.0 mg, 0.030 mmol,
0.20 equiv) were added to a 0.5−2.0 mL microwave vial equipped with
a triangular magnetic stir bar, followed by the addition of 1,2-
H
DOI: 10.1021/acs.joc.5b02700
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Article
phase purification was performed with 15.5 g of reverse phase media
and a 70 column volume gradient from 10 to 60% CH3CN:H2O
containing 0.1% TFA. Fractions containing product were combined
and diluted with sat. aq. NaHCO3 (50 mL) and extracted with CH2Cl2
(3 × 100 mL). The combined organic layers were then washed with
sat. aq. NaHCO3 (50 mL) and brine (50 mL), dried over MgSO4, and
concentrated to afford the product 11l (48.3 mg, 52% yield) as a
colorless oil. IR (film): 1739, 1459, 1351, 1232, 1197, 1138, 1015, 820,
3H); 13C{1H} NMR (151 MHz, CDCl3) δ 170.1, 131.4, 116.6, 120.6−
106.3 (m), 62.0, 52.6, 42.9, 32.2, 23.5, 14.2; 19F NMR (376 MHz,
CDCl3) δ −80.88 (t, J = 9.5 Hz, 3F), −114.90 (dt, J = 248.3, 12.9 Hz,
1F), −120.58 to −123.54 (m, 3F), −125.27 to −127.14 (m, 2F);
HRMS (ESI/[M + Na]+) calcd. for C13H14F9NO3S: 458.0443. Found
458.0447.
Ethyl (S)-4,5-Dimethyl-1-((S)-(perfluorobutyl)sulfinyl)-1,2,3,6-
tetrahydropyridine-2-carboxylate (15b). The general procedure
using dimethylbutadiene 14b (0.29 mL, 2.5 mmol, 5.0 equiv) was
followed. Purification by flash column chromatography (10% EtOAc in
hexanes) afforded the product 15b (182 mg, 81% yield) as a colorless
oil. IR (film): 2917, 1742, 1350, 1232, 1196, 1134, 1009, 998, 746,
721, 690 cm−1; 1H NMR (600 MHz, CDCl3) δ 4.51 (s, 1H), 4.19 (qd,
J = 7.1, 2.3 Hz, 2H), 3.89 (d, J = 16.5 Hz, 1H), 3.59 (d, J = 16.6 Hz,
1H), 2.52−2.41 (m, 2H), 1.65 (s, 3H), 1.60 (s, 3H), 1.24 (t, J = 7.1
Hz, 3H); 13C{1H} NMR (151 MHz, CDCl3) δ 170.0, 123.1, 121.6,
120.7−106.0 (m), 61.6, 52.5, 46.2, 33.0, 18.7, 15.9, 14.0; 19F NMR
(376 MHz, CDCl3) δ −80.85 (t, J = 9.5 Hz, 3F), −114.85 (dt, J =
248.6, 12.7 Hz, 1F), −121.46 to −123.53 (m, 3F), −125.28 to
−127.13 (m, 2F); HRMS (ESI/[M + Na]+) calcd. for C14H16F9NO3S:
472.0599. Found 472.0598.
1
721, 692, 578 cm−1; H NMR (400 MHz, CDCl3): δ 7.62 (s, 1H),
7.41−7.28 (m, 7H), 7.22 (s, 1H), 7.17 (d, J = 8.0 Hz, 1H), 5.73 (d, J =
8.0 Hz, 1H), 5.58 (d, J = 14.8 Hz, 1H), 5.53 (d, J = 14.8 Hz, 1H),
4.02−3.91 (m, 2H), 2.36 (s, 3H), 1.03 (t, J = 7.1 Hz, 3H); 13C{1H}
NMR (151 MHz, CDCl3): δ 170.0, 147.5, 139.4, 135.2, 134.4, 131.2,
130.0, 129.9, 129.3, 129.0, 128.3, 126.4, 121.7, 120.4−106.2 (m), 62.1,
58.5, 54.5, 21.2, 13.8; 19F NMR (376 MHz, CDCl3): δ −81.86 (t, J =
9.6 Hz, 3F), −117.83 (dt, J = 248.9, 12.6 Hz, 1F), −121.89 to −123.71
(m, 2F), −123.80 (ad, J = 248.9 Hz, 1F), −126.36 to −128.09 (m,
2F); HRMS (ESI/[M + H]+) calcd. for C24H22F9N4O3S: 617.1263.
Found 617.1261.
Ethyl (S)-2-(2-(1-Benzyl-1H-1,2,3-triazol-4-yl)-4-methylphenyl)-2-
(((S)-(perfluorobutyl)sulfinyl)amino)acetate (11m). The general
procedure was followed with perfluorobutanesulfinyl imino ester 9
(55.1 mg, 0.150 mmol, 1.0 equiv) and 1-benzyl-4-(m-tolyl)-1H-1,2,3-
triazole (74.8 mg, 0.300 mmol, 2.0 equiv). Preparative thin-layer silica
gel chromatography using 50% Et2O/pentane provided the first step in
the purification process. Pure product was then obtained by C18
reverse phase column chromatography with loading of the isolated
material onto the column as a solution in 1 mL of DMSO. Reverse
phase purification was performed with 15.5 g of reverse phase media
and a 75 column volume gradient from 10 to 60% CH3CN:H2O
containing 0.1% TFA. Fractions containing product were combined
and diluted with sat. aq. NaHCO3 (50 mL) and extracted with CH2Cl2
(3 × 100 mL). The combined organic layers were then washed with
sat. aq. NaHCO3 (50 mL) and brine (50 mL), dried over MgSO4, and
concentrated to afford the product 11m (49.1 mg, 53% yield) as a
colorless waxy solid. IR (film): 1739, 1459, 1352, 1197, 1138, 1014,
862, 819, 786, 746, 721, 692, 575 cm−1; 1H NMR (400 MHz, CDCl3):
δ 7.66 (s, 1H), 7.42−7.37 (m, 3H), 7.34−7.28 (m, 3H), 7.24 (d, J =
1.8 Hz, 1H), 7.20−7.17 (m, 2H), 5.73 (d, J = 7.9 Hz, 1H), 5.59 (d, J =
14.8 Hz, 1H), 5.55 (d, J = 14.8 Hz, 1H), 4.02−3.94 (m, 2H), 2.34 (s,
3H), 1.04 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (151 MHz, CDCl3): δ
170.1, 147.5, 139.1, 134.4, 132.4, 130.8, 130.3, 130.0, 129.3, 129.1,
129.1, 128.3, 121.9, 120.4−106.4 (m), 62.1, 58.3, 54.6, 21.1, 13.8; 19F
NMR (376 MHz, CDCl3): δ −81.84 (t, J = 9.5 Hz, 3F), −117.91 (dt, J
= 249.2, 13.3 Hz, 1F), −121.84 to −123.69 (m, 2F), −123.59 (ad, J =
249.2 Hz, 1F), −126.34 to −128.07 (m, 2F); HRMS (ESI/[M + H]+)
calcd. for C24H22F9N4O3S: 617.1263. Found 617.1260.
General Procedure for the Aza-Diels−Alder Reaction. In a
N2-filled glovebox, perfluorobutanesulfinyl imino ester 9 (183.6 mg,
0.50 mmol, 1.0 equiv) was weighed into a 1 mL conical screw-capped
vial. DCE (0.20 mL, [sulfinyl imine] = 1.0 M) and a triangular
magnetic stir bar were then added. The vial was sealed with a screw-
top cap containing a PTFE septum and was removed from the
glovebox. The cap was removed, and the corresponding diene (14a−
14d) (2.5 mmol, 5.0 equiv) was added by syringe before the vial was
sealed again with the cap. The vial was then heated in a temperature-
controlled aluminum-heating block set at 50 °C and was stirred for 16
h, and the vial was removed from the heating block and allowed to
cool to ambient temperature. Excess diene and solvent were removed
under reduced pressure, and the remaining crude material was purified
by silica gel flash column chromatography.
Ethyl (2S,3S,6R)-3,6-Dimethyl-1-((S)-(perfluorobutyl)sulfinyl)-
1,2,3,6-tetrahydropyridine-2-carboxylate (15c). The general proce-
dure using 2,4-hexadiene 14c (0.29 mL, 2.5 mmol, 5.0 equiv) was
followed. Purification by flash column chromatography (10% EtOAc in
hexanes) afforded the product 15c (154 mg, 69% yield) as a colorless
oil. IR (film): 2978, 1749, 1233, 1189, 1137, 1110, 1018, 997, 746,
1
722, 692 cm−1; H NMR (600 MHz, CDCl3) δ 5.71 (ddd, J = 10.4,
5.5, 2.0 Hz, 1H), 5.57−5.51 (m, 1H), 4.60−4.54 (m, 1H), 4.49 (s,
1H), 4.24−4.12 (m, 2H), 2.78 (p, J = 5.8 Hz, 1H), 1.45 (d, J = 6.8 Hz,
3H), 1.24 (t, J = 7.1 Hz, 3H), 1.11 (d, J = 6.9 Hz, 3H); 13C{1H} NMR
(151 MHz, CDCl3) δ 170.2, 129.6, 128.3, 121.7−106.1 (m), 61.5,
54.0, 50.8, 32.7, 20.2, 19.8, 14.1; 19F NMR (376 MHz, CDCl3) δ
−80.88 (t, J = 9.6 Hz, 3F), −108.89 to −115.20 (m, 1F), −122.28 to
−122.42 (m, 2F), −125.14 to −127.34 (m, 3F); HRMS (ESI/[M +
Na]+) calcd. for C14H16F9NO3S: 472.0599. Found 472.0591.
Ethyl (2S,6R)-6-Methyl-1-((S)-(perfluorobutyl)sulfinyl)-1,2,3,6-
tetrahydropyridine-2-carboxylate (15d). The general procedure
using 1,3-pentadiene 14d (0.25 mL, 2.5 mmol, 5.0 equiv) was
followed. Purification by flash column chromatography (10% EtOAc in
hexanes) afforded the product 15d (141 mg, 65% yield) as a colorless
oil and as an inseparable exo/endo diastereomeric mixture (dr = 8/1,
1H NMR). IR (film): 2987, 1742, 1350, 1191, 1136, 1109, 1007, 746,
1
721, 691 cm−1; H NMR (600 MHz, CDCl3) major isomer only δ
5.80−5.73 (m, 1H), 5.65−5.58 (m, 1H), 4.76 (s, 1H), 4.56−4.50 (m,
1H), 4.20 (q, J = 7.1 Hz, 2H), 2.61−2.55 (m, 1H), 2.51−2.45 (m,
1H), 1.43 (d, J = 6.9 Hz, 3H), 1.25 (t, J = 7.1 Hz, 3H); 13C{1H} NMR
(151 MHz, CDCl3, selected signals) δ 170.0, 130.5, 122.9, 121.1−
106.2 (m), 61.7, 50.1, 28.6, 23.4 19.8, 14.1; 19F NMR (376 MHz,
CDCl3) δ −80.86 (t, J = 9.5 Hz, 3F), −110.20 to −115.41 (m, 1F),
−122.29 (app. q, J = 9.6 Hz, 2F), −125.10 to −127.46 (m, 3F);
HRMS (ESI/[M + Na]+) calcd. for C13H14F9NO3S: 458.0443. Found
458.0438. HPLC (Microsorb 100−5 Si, EtOH/hexanes. 2:98, 1.0 mL/
min. 230 nm) of 15d: tR = 4.78 (minor) and 5.05 min (major). A 1:1
mixture of endo/exo diastereomers of 15d was obtained by collecting
enriched fractions (tR = 4.7 to 5.0 min). The enriched fractions from
multiple runs were combined and concentrated to give 2.0 mg of the
1:1 mixture (15d-mix). Relative configurations were determined from
2D NOE experiments of 15d-mix.
The absolute configuration of the major exo diastereomer was
determined by sulfinyl group cleavage and then X-ray structural
analysis of the 2,4,6-trinitrobenzenesulfonate salt of the resulting
amine. To a flame-dried, 1 dram vial equipped with a magnetic stir bar
was added 15d (31.7 mg, 0.073 mmol, 1 equiv), followed by 2 M HCl
in Et2O (0.36 mL, 0.73 mmol, 10 equiv). The mixture was stirred and
heated to 50 °C for 8 h and then concentrated to dryness under
reduced pressure. The concentrate was dissolved in 10 mL of 0.1 M
aqueous HCl, transferred to a separatory funnel, and washed with
Et2O (1 × 5 mL) before aqueous Na2CO3(sat) was added with stirring
until a pH of 10−11 was reached. The basic aqueous layer was
Ethyl (S)-4-Methyl-1-((S)-(perfluorobutyl)sulfinyl)-1,2,3,6-tetra-
hydropyridine-2-carboxylate (15a). The general procedure using
isoprene 14a (0.25 mL, 2.5 mmol, 5.0 equiv) was followed.
Purification by flash column chromatography (10% EtOAc in hexanes)
afforded the product 15a (154 mg, 71% yield) as a colorless oil. IR
(film): 2920, 1740, 1350, 1196, 1138, 1112, 1009, 921, 746, 721, 691
1
cm−1; H NMR (600 MHz, CDCl3) δ 5.42−5.37 (m, 1H), 4.57 (s,
1H), 4.21 (q, J = 7.1 Hz, 2H), 4.00 (d, J = 17.5 Hz, 1H), 3.82 (d, J =
17.1 Hz, 1H), 2.51−2.45 (m, 2H), 1.72 (s, 3H), 1.27 (t, J = 7.1 Hz,
I
DOI: 10.1021/acs.joc.5b02700
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The Journal of Organic Chemistry
Article
extracted with Et2O (3 × 10 mL), and the combined organic layer was
dried over MgSO4 and concentrated under reduced pressure to afford
the free amine (6.7 mg. 54% yield). To 4.8 mg of the unpurified free
amine in a 1 dram vial was added 7.5 mg (0.9 equiv) of 2,4,6-
trinitrobenzenesulfonic acid, followed by 0.5 mL of toluene, which
resulted in a cloudy mixture. To this cloudy mixture was added
methanol dropwise with swirling until the solution turned clear (10
drops). The clear solution was transferred into an NMR tube and
layered with 1.0 mL of HPLC grade hexanes. The NMR tube was
allowed to sit at ambient temperature for 3 days, after which single
crystals were formed.
(7) (a) Huang, W.; Ye, J.-L.; Zheng, W.; Dong, H.-Q.; Wei, B.-G. J.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b02700.
■
S
1H, 13C, and 19F NMR spectra and HPLC chromato-
grams of new compounds, and X-ray structures of the 4-
chlorobenzamide derivative of 11a and the amine salt of
15d (PDF)
Crystallographic data for 11a-amide (CIF)
Crystallographic data for 15d-amine (CIF)
(16) (a) Andreassen, T.; Lorentzen, M.; Hansen, L.-K.; Gautun, O.
R. Tetrahedron 2009, 65, 2806. (b) Andreassen, T.; Haland, T.;
̊
Hansen, L.-K.; Gautun, O. R. Tetrahedron Lett. 2007, 48, 8413.
(17) (a) Wangweerawong, A.; Bergman, R. G.; Ellman, J. A. J. Am.
Chem. Soc. 2014, 136, 8520. (b) Li, Y.; Li, B.-J.; Wang, W.-H.; Huang,
W.-P.; Zhang, X.-S.; Chen, K.; Shi, Z.-J. Angew. Chem., Int. Ed. 2011,
50, 2115.
AUTHOR INFORMATION
Corresponding Author
*E-mail: jonathan.ellman@yale.edu.
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
■
(18) For previous reports on synthesis and reagent additions to N-
perfluorinated sulfinyl imines, see: (a) Yang, K.; Liu, L.-J.; Liu, J.-T. J.
Org. Chem. 2014, 79, 3215. (b) Liu, L.-J.; Liu, J.-T. Tetrahedron 2014,
70, 1236. (c) Liu, Z.-J.; Zhang, F.; Liu, J.-T. J. Fluorine Chem. 2012,
133, 102. (d) Liu, L.-J.; Chen, L.-J.; Li, P.; Li, X.-B.; Liu, J.-T. J. Org.
Chem. 2011, 76, 4675. (e) Li, P.; Liu, L.-J.; Liu, J.-T. Org. Biomol.
Chem. 2011, 9, 74. (f) Wang, X.-J.; Liu, J.-T. Tetrahedron 2005, 61,
6982.
Notes
The authors declare no competing financial interest.
(19) Han, Z.; Krishnamurthy, D.; Grover, P.; Fang, K. Q.; Su, X.;
Wilkinson, S. H.; Lu, Z.-H.; Magiera, D.; Senanayake, C. H.
Tetrahedron 2005, 61, 6386.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the National Institutes of Health
(GM069559) for supporting the development of the
asymmetric Rh(III)-catalyzed C−H bond addition method
and the National Science Foundation (CHE-1464129) for
supporting the development of the asymmetric aza-Diels−Alder
reaction. We are indebted to Dr. Brandon Mercado (Yale
University) for solving the X-ray crystal structures of arylglycine
11a-amide and pipecolic acid 15d-amine.
(20) Typing the names of the following drugs into PubChem
(http://pubchem.ncbi.nlm.nih.gov) provides the chemical and phys-
ical properties, bioactivity, literature, and drug and medication
information: vancomycin, cefprozil, Plavix, Saquinavir, and Ledipasvir.
(21) The perfluoroalkyl iodide is converted to the sodium
perfluoroalkanesulfinate and distilled from concentrated sulfuric acid
to give the sulfinic acid before conversion to the sulfinyl chloride.
Stereoselective sulfinylation of an enantiomerically pure oxazolidinone
is followed by chromatography to obtain the diastereomerically pure
N-sulfinyl oxazolidinone, which is then treated with LiHMDS,
followed by aqueous NH4Cl, to give the desired sulfinamide product
(refs 18d and 18f).
(22) (a) Weix, D. J.; Ellman, J. A. Org. Synth. 2005, 82, 157. (b) Weix,
D. J.; Ellman, J. A. Org. Lett. 2003, 5, 1317.
(23) Smith, C. F.; Soloski, E. J.; Tamborski, C. J. Fluorine Chem.
1974, 4, 35.
(24) An authentic mixture of diastereomers was prepared by methods
previously reported for tert-butanesulfinyl imine addition products;
see: Brak, K.; Barrett, K. T.; Ellman, J. A. J. Org. Chem. 2009, 74, 3606.
(25) Tauchert, M. E.; Incarvito, C. D.; Rheingold, A. L.; Bergman, R.
G.; Ellman, J. A. J. Am. Chem. Soc. 2012, 134, 1482.
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■
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