A general strategy for the synthesis of cyclic N-aryl hydroxamic acids via partial nitro group reduction

Article abstract of DOI:10.1021/jo200530j

We describe a generalized approach to stereocontrolled synthesis of substituted cyclic hydroxamic acids (3-amino-1-hydroxy-3,4-dihydroquinolinones) by selective reduction of substituted 2-nitrophenylalanine substrates. Compounds in this series have antibacterial properties and have also recently been reported as KAT II inhibitors. The key nitrophenyl alanine intermediates are prepared enantioselectively in excellent yield by phase transfer catalyzed alkylation of the corresponding nitrobenzyl bromides. The scope and limitations of the reductive cyclization transformation have been explored with attention to the effects of substitution pattern and electronics on reaction efficiency and byproduct formation. In addition, a novel activated trifluoroethyl ester cyclization strategy has been developed as an alternate approach to the most sterically demanding systems in this series.

Full text of DOI:10.1021/jo200530j

ARTICLE
pubs.acs.org/joc
A General Strategy for the Synthesis of Cyclic N-Aryl Hydroxamic Acids
via Partial Nitro Group Reduction
Laura A. McAllister,* Bruce M. Bechle, Amy B. Dounay, Edelweiss Evrard, Xinmin Gan, Somraj Ghosh,
Ji-Young Kim, Vinod D. Parikh, Jamison B. Tuttle, and Patrick R. Verhoest
Neuroscience Chemistry, Pfizer Worldwide R&D, Eastern Point Rd., Groton, Connecticut 06340, United States
S Supporting Information
b
ABSTRACT:
We describe a generalized approach to stereocontrolled synthesis of substituted cyclic hydroxamic acids (3-amino-1-hydroxy-3,4-
dihydroquinolinones) by selective reduction of substituted 2-nitrophenylalanine substrates. Compounds in this series have
antibacterial properties and have also recently been reported as KAT II inhibitors. The key nitrophenyl alanine intermediates are
prepared enantioselectively in excellent yield by phase transfer catalyzed alkylation of the corresponding nitrobenzyl bromides. The
scope and limitations of the reductive cyclization transformation have been explored with attention to the effects of substitution
pattern and electronics on reaction efficiency and byproduct formation. In addition, a novel activated trifluoroethyl ester cyclization
strategy has been developed as an alternate approach to the most sterically demanding systems in this series.
’ INTRODUCTION
oxidizing reagents such as PIFA.2,4 A significant limitation of
this approach is that it is only applicable to electron-rich aromatic
systems. In addition, unsymmetrical substitution patterns give
rise to a mixture of regioisomeric products. Tomkinson and co-
workers have reported Pd-catalyzed amination conditions for
the addition of protected hydroxylamine derivatives onto aryl
halides.5 We attempted to use this approach in the context of our
targets of interest, but it proved unsuccessful.
Reductive cyclization of the synthetically accessible 2-nitro-
phenylalanine derivatives 4 has offered the most flexible approach
to the 3-amino-1-hydroxy-3,4-dihydroquinolinones. One challenge
associated with reductive cyclization is the propensity of the nitro
group to be over-reduced to the aniline product, resulting in
formation of a lactam. To overcome this issue, we carried out
hydrogenations using a sulfided platinum catalyst reported by the
Davis group.6 Although these conditions are suitable for some
substitution patterns, the reductive cyclization reaction process is
strongly influenced by the steric and electronic nature of the aryl
The synthesis of N-hydroxy-3-amino-3,4-dihydroquinoli-
nones as antibacterial agents was first reported by Davis and
co-workers over thirty years ago (1, Figure 1).1 More recently,
these scaffolds have been identified as potent inhibitors of kynur-
enine aminotransferase II (KAT II), an enzyme currently being
investigated as a therapeutic target for cognitive impairment asso-
ciated with schizophrenia, among other disorders.2,3 As part of our
program to identify optimal KAT II inhibitors, we have extensively
explored synthetic approaches to differentially substituted 3-amino-
1-hydroxy-3,4-dihydroquinolinones. Herein we describe a general-
ized approach to synthesis of substituted cyclic hydroxamic acids 1by
selective reduction of substituted 2-nitrophenylalanine substrates.
The scope and limitations of this transformation have been explored,
with attention to the effects of substitution pattern and electronics on
reaction efficiency. In addition, a novel activated ester cyclization
strategy has provided synthetic access to the most sterically hindered
and electronically disfavored systems in this series.
Several synthetic approaches to the hydroxamic acid core 1
were pursued (Figure 1). In one approach, cyclization of
phenylalanine hydroxamic acids 2 is achieved using SET
Received: March 14, 2011
Published: March 31, 2011
r
2011 American Chemical Society
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|

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Figure 1. Strategies for the preparation of cyclic hydroxamic acids.
Scheme 1. Asymmetric Synthesis of Substituted 2-Nitro-
phenylalanines Using Phase Transfer Catalyzed Asymmetric
Alkylation
Table 1. Asymmetric Alkylation of 2-Nitrobenzyl Bromides
Using Cinchonidine Phase Transfer Catalyst
entry bromide 5
R1
R2
R3
R4 % yieldd of 7aꢀk % eea
1
2
5a
5b
5c
5d
5e
5f
H
H
H
Me
F
72
79
74
50
72
60
89
89
49
92
82
91b
89b
100b
75b
90c
86b
94b
93b
90b
96b
96c
H
H
H
3
H
H
Me
Cl
H
H
H
H
H
H
H
H
H
4
H
H
5
H
H
CF3
OCF3
H
6
H
H
7
5g
5h
5i
H
OMe
Me
Cl
H
8
H
H
9
H
H
10
11
5j
OCF3
CF3
H
5k
H
H
a Racemic versions of compounds 7aꢀk were prepared from bromides
5aꢀk using TBAF instead of chiral catalyst 6. b ee values were
determined using chiral supercritical fluid chromatography (SFC;
Chiracel OD-H, 4.6 mm ꢁ 25 cm column, Mobile phase 95/5 CO2/
propanol). c ee determined using chiral HPLC (Chirobiotic V column,
4.6 mm ꢁ 25 cm; mobile phase 50/50 MeOH/MeCN) after conversion
to 8e (for 7e) or 8k (for 7k). d Yields are reported for isolated material
obtained after chromatographic purification.
ring. Specifically, electron-rich systems are readily over-reduced to
generate the lactam product, while compounds substituted at C-8
do not undergo cyclization.
’ RESULTS AND DISCUSSION
We report herein two new approaches toward the cyclization
of 2-nitrophenylalanines to 3-amino-1-hydroxy-3,4-dihydroquinoli-
nones 1. First, the application of a SnCl2/NaOAc reducing system
has enabled the efficient, selective synthesis of cyclic hydroxamic
acids without over-reduction to lactams. These conditions expanded
the substrate scope to include C-5, C-6, and C-7 substituted
hydroxamic acids of electron-rich, electron-poor, and neutral elec-
tronic character. Second, a method for synthesis of the problematic
C-8 substituted hydroxamic acids has been identified. This subset of
targets, especially those bearing electron-rich substituents, is parti-
cularly challenging due to steric hindrance around the nitro group
slowing the reduction rate, which leads to undesired side reactions.
To address this limitation, we employed a novel activated ester
reductive cyclization approach that provides access to these com-
pounds in excellent yields while suppressing the formation of
byproduct.
Asymmetric Synthesis of 2-Nitrophenylalanine Derivatives.
Because our target compounds of interest contain a (3S)-amino
group, an asymmetric synthesis of the 2-nitrophenylalanine sub-
strates was required. Chiral phase transfer catalysis has been
established as a robust methodology for the asymmetric synthesis
of R-amino acids.7 For example, the asymmetric alkylation of tert-
butyl N-(diphenylmethylidene)glycinate with simple 2-nitrobenzyl
bromides using the commercially available cinchonidine alkaloid 68
as catalyst has been reported to give the protected amino acid of the
desired configuration in excellent yield and enantiomeric excess.9,10
In an extension of the scope of these alkylations, a wide variety of
2-nitrobenzyl bromides (5aꢀk) underwent asymmetric alkylation
at ꢀ30 °C to afford the desired amino acids 7aꢀk in respectable
yields and excellent enantioselectivities (generally >90%) (Scheme 1);
Table 1 provides representative examples. Higher ee values for this
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Scheme 2. Process of Reduction of Nitroaromatics
Scheme 3. SnCl2 Reduction of 2-Nitrophenylalanine Derivatives
step can be achieved by conducting the alkylation at ꢀ78 °C;
however, the reaction proceeds significantly more slowly and in
lower yields.
NaOAc trihydrate. The reaction proceeded at room temperature
and did not result in aniline formation. Additionally, only minor
quantities of azoxy compound impurities were observed. Applica-
tion of these conditions has, however, been limited. Gratifyingly,
when applied to our systems these conditions cleanly gave the
desired hydroxamic acid product (Table 2). Crucially, no over-
reduction to the lactam was observed over the time course necessary
for complete consumption of starting material. Furthermore, these
conditions effected reduction at room temperature for substrates
8aꢀi, whereas the SnCl2/EtOH system required a reaction tem-
perature of 60 °C. This observation suggests that the SnCl2/NaOAc
conditions provide a more activated reducing system than the more
conventional SnCl2/EtOH system. As shown in Table 2, use of
SnCl2/NaOAc enabled the synthesis of a wide range of substituted
cyclic hydroxamic acids bearing substituents at the R2, R3, and R4
positions with varied electronic properties. For ease of isolation and
purification, the crude amino hydroxamic acids were protected
in situ as the di-Boc derivatives; after chromatographic purification,
deprotection was carried out with acid. This reaction sequence
furnished our desired products 19aꢀi in high purity, without
concomitant generation of byproduct.
Synthesis of C-8 Substituted Cyclic Hydroxamic Acids. In
the cases of substrates 8k and 8l (Table 2, entries 11 and 12), which
bear a substituent ortho to the nitro group, the mild SnCl2/NaOAc
reductive cyclization conditions did not yield any reduction pro-
ducts; starting material remained unchanged under these condi-
tions. We attributed this low reactivity to the steric hindrance around
the nitro group. Indeed, in the case where R1 = CF3 (Table 2, entry
11), cyclization could be achieved using SnCl2 in EtOH at 60 °C.
However, this process was sluggish, requiring 1ꢀ2 days for starting
material to be consumed and leading to a mixture of the hydroxamic
Discovery of a SnCl2/NaOAc System for Selective Reduction
to Cyclic Hydroxamic Acids. Many reagent systems have been
reported, with varying efficiencies, to reduce nitroaryl groups to
hydroxylamines. These include SnCl2,11 H2ꢀPt/C,12 Zn/NH4Cl,13
hydrazine with Pd/C,14 and enzymatic reduction using Baker’s
yeast.15 The main challenge in this transformation is achieving
selective reduction to the hydroxylamine without over-reduction to
the aniline or the formation of byproduct such as azoxy or diazo
compounds. Scheme 2 depicts the mechanisms by which a range of
products can be obtained upon reduction of a simple nitroaromatic.16
To achieve selective reduction and maximize yield it is often
necessary to carefully control the reaction temperature, monitor
reaction progress, and terminate prior to complete conversion, to
minimize byproduct formation. In our system, identification of a
reagent system that could be generally applied to all of our
substrates proved challenging. Moderate product yields could be
obtained by treating some substrates with SnCl2 in ethanol at
60 °C (Scheme 3). However, the efficiency of the reduction/
cyclization and the nature and quantity of the byproduct were
highly dependent on the electronic and steric nature of the amino
acid substrate. In some cases, reaction progress was monitored
very closely and reactions were terminated as soon as over-
reduction was observed (Scheme 3). This protocol led to
mixtures of product 1, starting material 15 and lactam 17
byproduct, which were difficult to separate chromatographically.
In a related method aimed at the synthesis of 7-hydroxyamino-
benzodiazepines, Walser and co-workers17 reported the reduction of
a nitroaryl group to the hydroxylamine using SnCl2 buffered with
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Table 2. Reductive Cyclization of 2-Nitrophenylalanine Derivatives to Hydroxamic Acids Using a SnCl2/NaOAc System
ARTICLE
entry
substrate
R1
R2
R3
R4
% yield of 18aꢀla
% yield of 19aꢀl
1
2
8a
8b
8c
8d
8e
8f
H
H
H
Me
F
86
60
80
H
H
H
73
3
H
H
Me
Cl
H
H
H
H
H
H
H
H
H
H
45
85
4
H
H
42
86
5
H
H
CF3
OCF3
H
65
94
6
H
H
72
86
7
8g
8h
8i
H
OMe
Me
Cl
H
75
90
8
H
H
35
91
9
H
H
18
86
10
11
12
8j
OCF3
CF3
OMe
H
N/Ab
0c
N/A
N/A
N/A
8k
H
H
8l
H
H
0c
a Values represent isolated yields obtained after chromatographic purification. b A mixture of desired product and lactam was obtained. The mixture
could not be separated chromatographically. c No reaction, starting material remained.
ester in place of the carboxylic acid, would minimize the problem
of over-reduction and subsequent isolation of the lactam by-
product; elimination of the hydroxylamine oxygen atom, either
via the lone pair participation mechanism described in Scheme 4
or by direct reduction, is much less favored in the cyclized
hydroxamic acid product 28a as compared with the uncyclized
systems 26a or 27a (Scheme 5).
Scheme 4. Proposed Reduction Mechanism for Electron-
Rich Aromatic Nitro Groups
To test this hypothesis, amino acid 8j was N-protected as the Boc
derivative, and converted to the methyl ester (24a) and the
corresponding trifluoroethyl ester (25a) (Scheme 5). These com-
pounds were subjected to a screen of various reductive cyclization
conditions and the outcome was monitored by LC-MS (Table 3).
Treatment of methyl ester 24a and trifluoroethyl ester 25a with
SnCl2 at 60 °C gave sluggish reactions, which required 24 h for the
majority of the starting materials to be consumed (Table 3, entries 1
and 2). In both cases, significant amounts of the over-reduced
lactam 29 were observed. Trifluoroethyl ester substrate 25a did give
improved results over the simple methyl ester, however (Table 3,
entries 1 and 2). We therefore sought improved conditions to
further minimize the formation of lactam 29.
Selective reduction of nitroaromatics to hydroxylamines using
Pt-catalyzed hydrogenation procedures has been reported.18 The
key to selectivity in these examples was the use of solvent
additives such as N-methylmorpholine, pyridine, or DMSO,
which act to dope the Pt catalyst. Upon further investigation of
this strategy, we found that use of pyridine as the hydrogenation
solvent was optimal for these cyclic hydroxamic acid systems.
Subjecting the N-Boc-protected trifluoroethyl ester 25a to
catalytic hydrogenation conditions using 5% Pt/C in pyridine
solvent gave excellent results (Table 3, entry 4). This reagent
system provided clean conversion to the desired product 28a,
with no lactam byproduct 29 observed (Table 3, entry 4 and
Table 4, entry 1). Under these conditions, reductive cyclization
acid and the lactam derived from over-reduction. For R1 = OMe
(Table 2, entry 12), the use of higher reaction temperatures gave
complete conversion to the lactam product, and the desired
hydroxamic acid product was never observed. In such electron-rich
ortho-substituted systems, lone pair donation from the electron-
donating group may result in rapid elimination of the hydroxyl
group of the hydroxylamine (Scheme 4). The cationic intermediate
thus formed (21) can then undergo a second reduction to give the
aniline 22, which would subsequently cyclize to lactam 23. Clearly,
for substrates bearing R1 substituents, an alternative strategy was
required.
Activated Ester Strategy: Increasing Cyclization Rate. We
postulated that more rapid cyclization of the challenging ortho-
substituted substrates such as 8j, 8k, and 8l, through use of an
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Scheme 5. Activated Ester Strategy for Increasing Cyclization Rate
reductive cyclization of activated trifluoroethyl ester substrates under
mild hydrogenation conditions. Both approaches furnish the hydro-
xamic acid product without production of the undesired lactam or
other byproduct.
Table 3. Reductive Cyclization of Ester Substrates Using
Hydrogenation Conditions
product
entry substrate
conditions
ratioa (28a:29)
1
2
3
4
5
24a
25a
24a
25a
8j
SnCl2, EtOH, 60 °C, 24 h
SnCl2, EtOH, 60 °C, 24 h
H2 (30 psi), 5% Pt/C, pyridine, 3 h
H2 (30 psi), 5% Pt/C, pyridine, 3 h
H2 (30 psi), 5% Pt/C, pyridine, 3 h
2:1
4:1b
’ EXPERIMENTAL SECTION
General Experimental Details. Unless otherwise stated, all
starting materials and solvents were obtained from commercial sources
and used without further purification. Proton and carbon NMR spectra
were obtained using 500 and 400 MHz machines. Enantiomeric excess
values were measured using either Chiral SFC [Chiralcel OD-H column
(4.6 mm ꢁ 25 cm)] or Chiral HPLC [Chirobiotic V column, 4.6 mm ꢁ
25 cm]. Flash chromatography was carried out on either an ISCO or
BiotageCompanion automated purification system using prepacked
ISCO brand silica gel cartridges.
2:1
1:0
1:2.3
a Values represent ratios obtained from the UV trace of LC-MS analysis.
b Approximately 20% starting material 25a remains.
of methyl ester substrate 24a gave inferior selectivity (Table 3,
entry 3), although complete consumption of starting material
was observed in only 3 h. The pyridine solvent is crucial to the
success of the reaction, as it provides milder reaction conditions
by slightly poisoning the hydrogenation catalyst. Employing
other solvents such as MeOH produced 29 as a major byproduct.
Use of the ester is also key to the success of this transformation:
under these conditions, the parent amino acid 8j yields the
undesired lactam as the major product (Table 3, entry 5).
Upon the successful application of these conditions to the efficient
synthesis of 28a, we sought to apply these conditions to the synthesis
of further examples of electronically activated and/or sterically
hindered substrates. Trifluoroethyl esters 25bꢀf were prepared and
subjected to these hydrogenation conditions (Table 4). Gratifyingly,
cyclized hydroxamic products 28bꢀf were obtained in good yields
and again no lactam byproduct was observed. These Boc-protected
products were readily deprotected with acid to give 30bꢀf.Inthecase
of 25d (R1 = OPh; Table 4, entry 4), the cyclization reaction
proceeded sluggishly, resulting in only 33% yield of the desired
product 28d after 10 h. Starting material 25d could be recovered and
recycled. We attributed this sluggish reaction to the considerable
steric hindrance around the nitro group in this molecule. In the
remainder of the examples in Table 4, complete conversion of starting
material to cyclized product was observed.
Preparation of 2-Nitrobenzyl Bromides: Preparation of 5aꢀk
2-(Bromomethyl)-1-methyl-3-nitrobenzene (5a): To a solu-
tion of 2-methyl-6-nitrobenzoic acid (5 g, 28 mmol) in THF (25 mL)
cooled to 0 °C was added NaBH4 (3.13 g, 82.8 mmol) in small portions.
BF3ꢀMe2O (7.60 mL, 82.8 mmol) was then added dropwise at 0 °C,
and the reaction mixture was allowed to stir overnight, while warming
from 0 °C to rt. The reaction mixture was cooled with iceꢀwater, and
solid NH4Cl was added in small portions. Water (100 mL) and EtOAc
(500 mL) were added and the water layer was basified using solid
NaHCO3. The organic layer was dried over Na2SO4 and concentrated in
vacuo. The crude product mixture was purified on a silica gel column (80
g), eluting with 30% EtOAc/heptane, to give (2-methyl-6-nitrophe-
nyl)methanol (3.90 g, 85% yield) as a light yellow solid. To a solution of
(2-methyl-6-nitrophenyl)methanol (3.90 g, 23.3 mmol) in CH2Cl2
(30 mL) at 0 °C was added a solution of 1 M PBr3 in CH2Cl2
(46.7 mL, 46.7 mmol). The reaction mixture was allowed to stir
overnight at rt, then was diluted with 200 mL of CH2Cl2 and poured
onto iceꢀwater. After neutralization with solid NaHCO3, the organic
layer was separated and washed with H2O (2 ꢁ 25 mL) and saturated aq
NaCl (1 ꢁ 25 mL), dried over Na2SO4, and concentrated in vacuo. The
crude product mixture was purified on a silica gel column (120 g),
eluting with 20% EtOAc/heptane to give 2-(bromomethyl)-1-methyl-3-
nitrobenzene (4.6 g, 86% yield) as a light yellow solid. 1H NMR (500
MHz, CDCl3) δ 2.54 (s, 3H), 4.73 (s, 2H), 7.35ꢀ7.39 (m, 1H), 7.47 (d,
J = 7.8 Hz, 1H), 7.75 (d, J = 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3)
δ 149.9, 140.5, 135.5, 130.2, 129.3, 123.1, 24.9, 19.6. Anal. Calcd for
C8H8BrNO2: C, 41.77; H, 3.50; Br, 34.73, N, 6.09. Found: C, 42.00; H,
3.58; Br, 34.52; N, 5.99.
In conclusion, we have described two efficient asymmetric
synthetic approaches toward the biologically active cyclic hydro-
xamic acids, both employing a selective nitro group reductive
cyclization. In the case of unhindered substrates, a buffered SnCl2
reduction system efficiently provides the desired product. We have
also demonstrated that the more challenging ortho-substituted,
electron-rich cyclic N-aryl hydroxamic acids can be accessed by
2-(Bromomethyl)-1-fluoro-3-nitrobenzene (5b): To a solu-
tion of 2-fluoro-6-nitrobenzoic acid (2.7 g, 15 mmol) in anhydrous THF
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Table 4. Reductive Cyclization of Trifluoroethyl Ester Substrates to Hydroxamic Acids
entry
substrate
R1
% yield of 28aꢀfa
% yield of 30aꢀf
1
2
3
4
5
6
25a
25b
25c
25d
25e
25f
OCF3
OMe
CF3
OPh
Me
88
64
82
70
66
33b
56
94
46
100
69
Cl
60
a Values represent isolated yields after chromatographic purification. b 30% of starting material 25d was recovered unchanged after 10 h.
(5 mL) at 0 °C was added sodium borohydride (1.67 g, 43.8 mmol) in
MHz, CDCl3) δ 140.2, 135.0, 132.7, 129.8, 127.2, 28.2. Anal. Calcd for
C7H5BrClNO2: C, 33.57; H, 2.01; N, 5.59. Found: C, 33.69; H, 1.95;
N, 5.46.
two portions. After all the gas evolution subsided, BF3 OMe2 (4.1 mL,
3
43.8 mmol) was added dropwise at 0 °C. The reaction was stirred at 0 °C
for 30 min, then warmed to rt and stirred overnight. The mixture was
quenched with aq ammonium chloride (10 mL). The aqueous layer was
extracted with EtOAc (50 mL), then washed with brine (3 ꢁ 50 mL) and
water (3 ꢁ 50 mL). The organic layer was dried over sodium sulfate and
purified by flash chromatography on silica gel to provide (2-fluoro-6-
nitrophenyl)methanol in 88% yield. To a solution of (2-fluoro-6-
nitrophenyl)methanol (2.1 g, 12 mmol) in 8 mL of anhydrous CH2Cl2
was added CBr4 (10.3 g, 30.7 mmol) and PPh3 (8.1 g, 30.7 mmol) and
the reaction was stirred for 2 h at rt. The mixture was diluted with EtOAc
(50 mL), then washed with brine (3 ꢁ 50 mL) and water (3 ꢁ 50 mL).
The organic layer was dried over sodium sulfate and concentrated under
reduced pressure. The crude product mixture was purified by flash
chromatography on silica gel eluting with 0ꢀ50% EtOAc/heptane to
give 2-(bromomethyl)-1-fluoro-3-nitrobenzene in 77% yield. 1H NMR
(400 MHz, CDCl3) δ 7.83 (d, J = 8.2 Hz, 1H), 7.46 (dt, J = 5.5, 8.3 Hz,
1H), 7.42ꢀ7.34 (m, 1H), 4.80 (s, 2H); 13C NMR (100 MHz, CDCl3) δ
161.0, 130.4, 121.4, 121.4, 121.3, 121.1, 19.4.
2-(Bromomethyl)-1-nitro-4-(trifluoromethyl)benzene (5e):
To a solution of 2-methyl-1-nitro-4-(trifluoromethyl)benzene (6.25 g,
30.5 mmol, 1 equiv) in DMF (10 mL) was added DMFꢀDMA (9.06 mL,
60.9 mmol, 2 equiv). The reaction mixture was heated at 100 °C for 24 h.
The DMF was evaporated off and the residue was dissolved in 1:1
THFꢀH2O (10 mL:10 mL). NaIO4 was added to the solution and the
mixture was allowed to stir at rt for 18 h. The mixture was then filtered to
remove the solids. Water was added to the filtrate, which was then
extracted with EtOAc. The EtOAc layer was dried (MgSO4), filtered, and
concentratedto give crude 2-nitro-5-(trifluoromethyl)benzaldehyde. To a
solution of the crude 2-nitro-5-(trifluoromethyl)benzaldehyde in THF
(100 mL) at 0 °C was added NaBH4 (2.35 g, 61 mmol, 2 equiv). The
mixture was allowed to stir at rt for 2 h then quenched slowly with water
and 1 M HCl. The mixture was then extracted with EtOAc, dried
(MgSO4), filtered and concentrated. The crude product mixture was
purified byflash chromatography onsilica gel (80 g) eluting with 0ꢀ100%
EtOAc/heptane to give [2-nitro-5-(trifluoromethyl)phenyl]methanol
(3.66 g, 54% over 3 steps). To a solution of [2-nitro-5-(trifluoromethyl)-
phenyl]methanol (3.66 g, 16.6 mmol, 1 equiv) in CH2Cl2 (20 mL) was
added CBr4 (7.14 g, 21.5 mmol, 1.3 equiv) then PPh3 (5.64 g, 21.5 mmol,
21.5 equiv). The reaction was allowed to stir at rt for 16 h. The reaction
mixture was adsorbed onto silica and purified by flash chromatography
on silica gel (80 g) eluting with 0ꢀ20% EtOAc/heptane to give
2-(bromomethyl)-1-nitro-4-(trifluoromethyl)benzene (3.72 g, 79%). 1H
NMR (400 MHz, CDCl3) δ 8.09 (d, J = 8.4 Hz, 1H), 7.83 (d, J = 1.6 Hz,
1H), 7.72 (dd, J = 1.8, 8.6 Hz, 1H), 4.79 (s, 2H); 13C NMR (100 MHz,
CDCl3) δ 149.9, 135.1, 133.8, 129.6, 126.6, 126.0, 123.9, 27.4. Anal. Calcd
for C8H5BrF3NO2: C, 33.83; H, 1.77; N, 4.93. Found: C, 33.91; H, 1.71;
N, 4.86.
2-(Bromomethyl)-4-methyl-1-nitrobenzene (5c): To a solu-
tion of (5-methyl-2-nitrophenyl)methanol (5.30 g, 31.7 mmol) in
CH2Cl2 (100 mL) was added CBr4 (13.3 g, 50.7 mmol, 1.6 equiv) then
PPh3 (17.0 g, 50.7 mmol, 1.6 equiv). The reaction was allowed to stir at
rt for 16 h. The reaction mixture was adsorbed onto silica and purified by
flash chromatography on silica gel (120 g) eluting with 0ꢀ20% EtOAc/
heptane to give 2-(bromomethyl)-4-methyl-1-nitrobenzene (7.29 g,
1
76%). H NMR (500 MHz, CDCl3) δ 7.99 (d, J = 8.3 Hz, 1H), 7.36
(d, J = 1.2 Hz, 1H), 7.28 (dd, J = 1.7, 8.3 Hz, 1H), 4.83 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 145.6, 145.1, 133.0, 132.8, 130.1, 125.7, 29.3, 21.3.
Anal. Calcd for C8H8BrNO2: C, 41.77; H, 3.50; N, 6.09. Found: C,
41.99; H, 3.55; N, 6.03.
2-(Bromomethyl)-4-chloro-1-nitrobenzene (5d): To a solu-
tion of (5-chloro-2-nitrophenyl)methanol (1.04, 5.54 mmol) in CH2Cl2
(20 mL) was added CBr4 (3.34 g, 9.98 mmol, 1.8 equiv) then PPh3 (2.63
g, 9.98 mmol, 1.8 equiv). The reaction was allowed to stir at rt for 16 h.
The reaction mixture was adsorbed onto silica and purified by flash
chromatography on silica gel (40 g) eluting with 0ꢀ20% EtOAc/
heptane to give 2-(bromomethyl)-4-chloro-1-nitrobenzene (0.7 g,
2-(Bromomethyl)-1-nitro-4-(trifluoromethoxy)benzene (5f):
To a solution of methyl 2-amino-5-(trifluoromethoxy)benzoate (15 g,
63.80 mmol) in toluene (150 mL) was added m-CPBA (44.02 g, 255
mmol) at 0 °C. The reaction mixture was stirred at rt for 12 h, then was
concentrated and adjusted to basic pH with aq NaHCO3 solution. The
mixture was extracted with EtOAc and the combined organic layers were
dried over Na2SO4, filtered, and concentrated to obtain crude methyl
2-nitro-5-(trifluoromethoxy)benzoate (13.5 g). To a solution of methyl
2-nitro-5-(trifluoromethoxy)benzoate (5.0 g, 19 mmol) in THF (150 mL)
1
50%). H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 8.6 Hz, 1H), 7.56
(s, 1H), 7.43 (dd, J = 2.1, 8.8 Hz, 1H), 4.77 (s, 2H); 13C NMR (100
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ARTICLE
was added a solution of LiBH4 in THF (2 M, 10.4 mL, 20.8 mmol) at 0 °C.
The reaction mixture was stirred at rt for 6 h. The mixture was quenched
with 1 N HCl solution at ꢀ40 °C and extracted with EtOAc. The combined
organic layers were dried over Na2SO4, filtered, and concentrated to obtain
crude material, which was purified by flash chromatography on silica gel,
eluting with 5% EtOAc in petroleum ether to afford [2-nitro-
5-(trifluoromethoxy)phenyl]methanol (1.6 g, 35% yield). To a solution
of [2-nitro-5-(trifluoromethoxy)phenyl]methanol (1.5 g, 10 mmol) in
toluene (20 mL) was added PBr3 (2.9 mL, 30.0 mmol) at 0 °C and the
reaction mixture was stirred at rt for 48 h. The reaction mixture was then
concentrated, quenched with water, and extracted with EtOAc. The organic
layer was dried over Na2SO4, filtered, and concentrated to obtain crude
product, which was purified by silica gel chromatography, eluting with 5%
EtOAc in petroleum ether to afford 2-(bromomethyl)-1-nitro-4-(trifluoro-
methoxy)benzene (640 mg, 31% yield). 1H NMR (400 MHz, CDCl3) δ
8.13 (d, J = 9.0 Hz, 1H), 7.42 (d, J = 2.3 Hz, 1H), 7.36ꢀ7.26 (m, 1H), 4.81
(s, 2H); 13C NMR (100 MHz, CDCl3) δ 152.3, 145.6, 135.9, 128.0, 124.2,
120.8, 120.3, 28.2. Anal. Calcd for C8H5BrF3NO3: C, 32.04; H, 1.58; N,
4.59. Found: C, 32.03; H, 1.68; N, 4.68.
1-(Bromomethyl)-4-methoxy-2-nitrobenzene (5g): To a
solution of (4-methoxy-2-nitrophenyl)methanol (5.00 g, 27.3 mmol, 1
equiv) in Et2O at 0 °C was added PBr3 (8.87 g, 32.8 mmol, 1.2 equiv).
The mixture was allowed to stir for 3 h then poured onto iceꢀwater. The
aqueous layer was extracted with Et2O, washed with brine, dried
(MgSO4), filtered, and concentrated. The crude product mixture was
purified by flash chromatography on silica gel (40 g), eluting with
0ꢀ50% EtOAc/heptane to give 1-(bromomethyl)-4-methoxy-2-nitro-
benzene (4.4 g, 66% yield). 1H NMR (400 MHz, CDCl3) δ 7.56 (d, J =
2.7 Hz, 1H), 7.47 (d, J = 8.2 Hz, 1H), 7.14 (dd, J = 2.7, 8.6 Hz, 1H), 4.81
(s, 2H), 3.89 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 159.8, 148.3,
133.3, 124.4, 119.6, 110.0, 55.7, 28.8. Anal. Calcd for C8H8BrNO3: C,
39.05; H, 3.28; N, 5.69. Found: C, 39.20; H, 3.24; N, 5.61.
(1.45 mL, 15.5 mmol, 3 equiv). The mixture was allowed to stir at rt then
quenched with saturated aq NH4Cl solution. The aqueous layer was
extracted with EtOAc and the combined organic layers were washed with
brine, dried (MgSO4), filtered, and concentrated to give [2-nitro-
3-(trifluoromethoxy)phenyl]methanol (870 mg, 71% yield). To a solution
of [2-nitro-3-(trifluoromethoxy)phenyl]methanol (870 mg, 3.67 mmol, 1
equiv) in CH2Cl2 (70 mL) at 0 °C was added PBr3 (2.05 g, 7.34 mmol, 2
equiv) and the reaction was allowed to stir at rt overnight. The reaction
mixture was quenched by dropwise addition of saturated aq NaHCO3 until
the pH reached 8, followed by dilution with CH2Cl2 (10 mL). The
separated aqueous phase was washed with EtOAc (2 ꢁ 10 mL) and the
combined organic layers were washed with water (10 mL), dried over
Na2SO4, filtered, and concentrated to give 1-(bromomethyl)-2-nitro-
3-(trifluoromethoxy)benzene (780 mg, 71%). 1H NMR (400 MHz,
CDCl3) δ 7.55ꢀ7.49 (m, 1H), 7.48ꢀ7.44 (m, 1H), 7.37 (td, J = 1.6, 8.2
Hz, 1H), 4.44 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 143.4, 140.7, 132.4,
132.1, 129.5, 120.6, 120.3, 25.5.
1-(Bromomethyl)-2-nitro-3-(trifluoromethyl)benzene (5k):
A suspension of NaBO3 (22.49 g, 146.2 mmol) in AcOH (30 mL) was
heated at 85 °C. A solution of 2-amino-3-(trifluoromethyl)benzoic acid
(5.0 g, 24.37 mmol) in acetic acid (20 mL) was then added and the
reaction mixture was heated at 95 °C for 24 h. The reaction mixture was
poured into water, then extracted with EtOAc and diethyl ether. The
combined organic layers were dried over Na2SO4, filtered, and concen-
trated to afford crude compound, which was purified by flash chroma-
tography on silica gel, eluting with 10% MeOH in CH2Cl2, to afford
2-nitro-3-(trifluoromethyl)benzoic acid (2.1 g, 36.6%). To a solution of
2-nitro-3-(trifluoromethyl)benzoic acid (0.50 g, 2.1 mmol) in dry THF
(20.0 mL) was added BH3ꢀDMS (0.40 mL, 4.2 mmol) in a small amount
of THF (5.0 mL) dropwise at 0 °C. The reaction mixture was slowly
heated to 60 °C and stirred for 2 h. (The reaction progressed to
completion with the formation of two nonpolar spots by TLC.) The
reaction mixture was poured into water and 1 N HCl, then extracted with
EtOAc. The combined organic layers were dried over Na2SO4, filtered,
concentrated, and purified by flash chromatography on silica gel to afford
[2-nitro-3-(trifluoromethyl)phenyl]methanol (300 mg, 64%). To a solu-
tion of [2-nitro-3-(trifluoromethyl)phenyl]methanol (0.15 g, 0.67 mmol)
in CH2Cl2 was added PPh3 and CBr4 at 0 °C and the reaction was stirred
for 20 min. The reaction mixture was washed with water, dried over
Na2SO4, filtered, and concentrated to obtain crude product, which was
purified by flash chromatography on silica gel, eluting with 10% EtOAc in
petroleum ether to give 1-(bromomethyl)-2-nitro-3-(trifluoromethyl)-
benzene (100 mg, 52%). 1H NMR (400 MHz, CDCl3) δ 7.73 (dd, J = 1.0,
7.8 Hz, 1H), 7.70ꢀ7.65 (m, 1H), 7.60 (dd, J = 0.6, 7.8 Hz, 1H), 4.37 (s,
2H); 13C NMR (100 MHz, CDCl3) δ 135.3, 131.1, 129.4, 127.5, 123.4,
123.4, 121.9, 25.0.
1-(Bromomethyl)-4-methyl-2-nitrobenzene (5h): To a solu-
tion of (4-methyl-2-nitrophenyl)methanol (5.28 g, 31.6 mmol) in
CH2Cl2 (100 mL) was added CBr4 (16.9 g, 50.5 mmol, 1.6 equiv) then
PPh3 (13.3 g, 50.5 mmol, 1.6 equiv). The reaction was allowed to stir at
rt for 16 h. The reaction mixture was adsorbed onto silica and purified by
flash chromatography on silica gel (120 g) eluting with 0ꢀ20% EtOAc/
heptane to give 1-(bromomethyl)-4-methyl-2-nitrobenzene (2.87 g,
1
39.5%). H NMR (400 MHz, CDCl3) δ 7.86 (s, 1H), 7.49ꢀ7.38 (m,
2H), 4.81 (s, 2H), 2.45 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 147.8,
140.4, 134.4, 132.4, 129.9, 125.8, 28.9, 21.0. Anal. Calcd for
C8H8BrNO2: C, 41.77; H, 3.50; N, 6.09. Found: C, 42.23 H, 3.16;
N, 6.05.
1-(Bromomethyl)-4-chloro-2-nitrobenzene (5i): To a solu-
tion of (4-chloro-2-nitrophenyl)methanol (1.26 g, 6.72 mmol) in
CH2Cl2 (20 mL) was added CBr4 (4.05 g, 12.1 mmol, 1.8 equiv) then
PPh3 (3.17 g, 12.1 mmol, 1.8 equiv). The reaction was allowed to stir at
rt for 16 h. The reaction mixture was adsorbed onto silica and purified by
flash chromatography on silica gel (40 g) eluting with 0ꢀ20% EtOAc/
heptane to give 1-(bromomethyl)-4-chloro-2-nitrobenzene (1.68 g,
77%). 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 2.0 Hz, 1H),
7.59ꢀ7.53 (m, 1H), 7.53ꢀ7.47 (m, 1H), 4.76 (s, 2H); 13C NMR (100
MHz, CDCl3) δ 148.4, 135.6, 134.0, 133.8, 131.6, 125.9, 28.1.
1-(Bromomethyl)-2-nitro-3-(trifluoromethoxy)benzene (5j):
To a suspension of sodium perborate (3.59 g, 22.2 mmol, 5 equiv) in
trifluoroacetic acid (6 mL) was added 2-amino-3-(trifluoromethoxy)-
benzoic acid (0.982 g, 4.43 mmol, 1 equiv). The mixture was heated at
reflux overnight. The mixture was cooled and poured onto water. The
aqueous layer was then extracted with Et2O and the organic layer was dried
(MgSO4), filtered, and concentrated to give 2-nitro-3-(trifluoromethoxy)-
benzoic acid (quantitative yield). To a solution of 2-nitro-3-(trifluoro-
methoxy)benzoic acid (1.30 g, 5.16 mmol, 1 equiv) in THF (3 mL) at 0 °C
Asymmetric Alkylation Reactions: Preparation of 7aꢀk
tert-Butyl N-(diphenylmethylidene)-2-methyl-6-nitro-L-
phenylalaninate (7a)—General Procedure A: To a solution of
2-(bromomethyl)-1-methyl-3-nitrobenzene (5a) (1.02 g, 4.41 mmol, 1
equiv) in CH2Cl2 (10 mL) cooled to ꢀ30 °C was added tert-butyl
N-(diphenylmethylidene)glycinate (1.43 g, 4.86 mmol, 1.1 equiv)
and (ꢀ)-(O)-(9)-allyl-N-(9-anthracenylmethyl)cinchodinium bromide
(281 mg, 0.44 mmol, 0.1 equiv). CsOHꢀH2O (1.10 g, 6.62 mmol, 1.5
equiv) was added and the mixture was allowed to stir for 18 h. The
reaction mixture was washed with water, dried (Na2SO4), filtered, and
concentrated. The crude mixture was purified by flash chromatography
on silica gel, eluting with CH2Cl2 (isocratic) to give tert-butyl
N-(diphenylmethylidene)-2-methyl-6-nitro-L-phenylalaninate (7a)
1
(1.41 g, 72% yield, 91% ee). H NMR (500 MHz, CDCl3) δ 1.47 (s,
9H), 2.38 (s, 3H), 3.54 (dd, J = 13.9, 3.4 Hz, 1H), 3.67ꢀ3.72 (m, 1H),
4.28 (dd, J = 10.5, 3.4 Hz, 1H), 7.20ꢀ7.40 (m, 12H), 7.48ꢀ7.52 (m,
1H), 7.55ꢀ7.62 (m, 5H), 7.81ꢀ7.84 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ 197.0, 170.9, 170.6, 151.7, 140.9, 139.1, 135.9, 134.5,
was added NaBH4 (593 mg, 15.5 mmol, 3 equiv) then BF3 OMe2
3
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ARTICLE
132.7,130.5, 130.2, 129.0, 128.2, 127.6, 127.0, 122.5, 81.6, 66.2, 31.3,
28.3. Anal. Calcd for C27H28N2O4: C, 72.95; H, 6.35; N, 6.30. Found: C,
72.94; H, 6.51; N, 6.70.
10.1 mmol, 1 equiv) according to general procedure A to give tert-butyl
N-(diphenylmethylidene)-O-methyl-2-nitro-L-tyrosinate (7g) (4.15 g,
89% yield, 94% ee). 1H NMR (400 MHz, CDCl3) δ 7.58ꢀ7.51 (m, 2H),
7.38ꢀ7.21 (m, 8H), 6.96 (dd, J = 2.7, 8.6 Hz, 1H), 6.63 (d, J = 6.6 Hz,
2H), 4.26 (dd, J = 4.1, 9.2 Hz, 1H), 3.79 (s, 3H), 3.59 (dd, J = 4.1, 13.5
Hz, 1H), 3.30 (dd, J = 9.4, 13.7 Hz, 1H), 1.40 (s, 9H); 13C NMR (100
MHz, CDCl3) δ 171.2, 170.7, 158.8, 150.1, 139.6, 136.4, 135.2, 130.6,
129.0, 128.7, 128.5, 128.2, 127.7, 125.8, 119.5, 109.4, 81.6, 66.3, 56.1,
36.2, 28.3; HRMS (m/z) [M þ H]þ calcd for C27H29N2O5 461.2070,
found 461.2081; [R]20D ꢀ171.9 (c 0.725, MeOH).
tert-Butyl N-(diphenylmethylidene)-2-fluoro-6-nitro-L-
phenylalaninate (7b): The title compound was prepared from 5b
(1.2 g, 5.1 mmol, 1 equiv) according to general procedure A to give tert-
butyl N-(diphenylmethylidene)-2-fluoro-6-nitro-L-phenylalaninate (7b)
(1.8 g, 79% yield, 89% ee). 1H NMR (400 MHz, CDCl3) δ 7.84ꢀ7.74
(m, 1H), 7.63ꢀ7.57 (m, 1H), 7.54ꢀ7.51 (m, 1H), 7.47 (dd, J = 0.6, 7.4
Hz, 1H), 7.37ꢀ7.15 (m, 7H), 6.66 (d, J = 7.0 Hz, 2H), 4.25 (ddd, J = 0.9,
4.5, 9.2 Hz, 1H), 3.81ꢀ3.42 (m, 2H), 1.59ꢀ1.20 (m, 9H); 13C NMR
(100 MHz, CDCl3) δ 171.2, 169.9, 160.2, 150.8, 139.1, 135.8, 130.3,
130.0, 128.8, 128.5, 128.2, 127.8, 127.4, 122.2, 120.3, 119.8, 119.6, 81.5,
65.1, 28.0; HRMS (m/z) [M þ H]þ calcd for C26H26FN2O4 449.1871,
found 449.1861.
tert-Butyl N-(diphenylmethylidene)-5-methyl-2-nitro-L-
phenylalaninate (7c): The title compound was prepared from 5c
(4.19 g, 18.2 mmol, 1 equiv) according to general procedure A to give
tert-butyl N-(diphenylmethylidene)-5-methyl-2-nitro-L-phenylalaninate
(7c) (5.97 g, 74% yield, 100% ee). 1H NMR (400 MHz, CDCl3) δ 7.81
(d, J = 8.2 Hz, 1H), 7.61ꢀ7.54 (m, 2H), 7.42ꢀ7.25 (m, 6H), 7.18 (d, J =
1.8 Hz, 1H), 7.11 (dd, J = 1.5, 8.3 Hz, 1H), 6.63 (d, J = 7.2 Hz, 2H), 4.32
(dd, J = 4.3, 9.4 Hz, 1H), 3.69 (dd, J = 4.2, 13.2 Hz, 1H), 3.39 (dd, J = 9.4,
13.3 Hz, 1H), 2.30 (s, 3H), 1.45 (s, 9H); 13C NMR (100 MHz, CDCl3)
δ 170.9, 170.3, 147.2, 143.5, 139.2, 136.0, 134.9, 133.6, 130.2, 128.7,
128.4, 128.1, 127.9, 127.9, 127.4, 124.8, 81.3, 65.8, 36.6, 28.0, 21.1;
HRMS (m/z) [M þ H]þ calcd for C27H28N2O4 445.2121, found,
445.2117. [R]20D ꢀ187.9 (c 0.28, MeOH).
tert-Butyl N-(diphenylmethylidene)-4-methyl-2-nitro-L-
phenylalaninate (7h): The title compound was prepared from 5h
(2.45 g, 10.65 mmol, 1 equiv) according to general procedure A to give
tert-butyl N-(diphenylmethylidene)-4-methyl-2-nitro-L-phenylalaninate
(7h) (4.2 g, 89% yield, 93% ee). 1H NMR (400 MHz, CDCl3) δ 7.68 (s,
1H), 7.61ꢀ7.54 (m, 2H), 7.42ꢀ7.24 (m, 10H), 6.64 (d, J = 7.0 Hz, 2H),
4.30 (dd, J = 4.1, 9.2 Hz, 1H), 3.65 (dd, J = 4.1, 13.5 Hz, 1H), 3.36 (dd,
J = 9.3, 13.4 Hz, 1H), 2.38 (s, 3H), 1.44 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 170.8, 170.2, 149.2, 139.1, 137.6, 135.9, 133.7, 133.2, 130.3,
130.1, 128.6, 128.3, 128.0, 127.8, 127.3, 124.7, 81.2, 65.9, 36.0, 27.9,
20.6; HRMS (m/z) [M þ H]þ calcd for C27H28N2O4 445.2121, found
445.2135; [R]20D ꢀ120 (c 0.23, MeOH).
tert-Butyl 4-chloro-N-(diphenylmethylidene)-2-nitro-L-phenyl-
alaninate (7i): The title compound was prepared from 5i (1.5 g, 3.2
mmol, 1 equiv) according to general procedure A to give tert-butyl
4-chloro-N-(diphenylmethylidene)-2-nitro-L-phenylalaninate (7i)
1
(1.19 g, 49% yield, 90% ee). H NMR (400 MHz, CDCl3) δ 7.83 (d,
J = 2.1 Hz, 1H), 7.59ꢀ7.49 (m, 2H), 7.41ꢀ7.24 (m, 8H), 6.66 (d, J = 6.8
Hz, 2H), 4.26 (dd, J = 4.1, 9.2 Hz, 1H), 3.61 (dd, J = 4.2, 13.4 Hz, 1H),
3.35 (dd, J = 9.2, 13.5 Hz, 1H), 1.40 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 171.4, 170.2, 150.0, 139.2, 136.0, 135.4, 133.3, 132.7, 132.3,
130.6, 129.0, 128.8, 128.5, 128.2, 127.6, 124.8, 81.9, 65.9, 36.1, 28.2;
HRMS (m/z) [M þ H]þ calcd for C26H26ClN2O4 465.1575, found
465.1573.
tert-Butyl 5-chloro-N-(diphenylmethylidene)-2-nitro-L-
phenylalaninate (7d): The title compound was prepared from 5d
(1.33 g, 5.31 mmol, 1 equiv) according to general procedure A to give
tert-butyl 5-chloro-N-(diphenylmethylidene)-2-nitro-L-phenylalaninate
(7d) (1.24 g, 50% yield, 75% ee). 1H NMR (400 MHz, CDCl3) δ 7.80
(d, J = 8.6 Hz, 1H), 7.57ꢀ7.50 (m, 2H), 7.41ꢀ7.22 (m, 8H), 6.72 (d, J =
6.6 Hz, 2H), 4.27 (dd, J = 4.3, 9.0 Hz, 1H), 3.63 (dd, J = 4.5, 13.5 Hz,
1H), 3.42 (dd, J = 9.0, 13.7 Hz, 1H), 1.42 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 171.6, 170.1, 148.1, 139.2, 138.9, 136.2, 135.9, 134.1, 130.6,
130.3, 129.0, 128.8, 128.5, 128.2, 127.7, 126.3, 81.9, 65.8, 36.5, 28.2.
Anal. Calcd for C26H25ClN2O4: C, 67.17; H, 5.42; N, 6.03. Found: C,
66.96; H, 5.38; N, 5.93.
tert-Butyl N-(diphenylmethylidene)-2-nitro-3-(trifluoro-
methoxy)-L-phenylalaninate (7j): The title compound was pre-
pared from 5j (3.0 g, 10 mmol, 1 equiv) according to general procedure
Atogivetert-butyl N-(diphenylmethylidene)-2-nitro-3-(trifluoromethoxy)-
L-phenylalaninate (7j) (4.8 g, 92% yield, 96% ee). 1H NMR (400 MHz,
CDCl3) δ 7.64ꢀ7.57 (m, 2H), 7.45ꢀ7.23 (m, 9H), 6.69 (d, J = 7.0 Hz,
2H), 4.23 (dd, J = 5.3, 8.2 Hz, 1H), 3.31ꢀ3.17 (m, 2H), 1.44 (s, 9H);
13C NMR (100 MHz, CDCl3) δ 171.7, 169.8, 144.6, 140.2, 139.2, 135.9,
133.2, 132.6, 130.8, 130.7, 130.6, 130.2, 129.0, 128.8, 128.5, 128.2, 127.5,
119.5, 120.3, 82.0, 66.0, 34.8, 28.2; HRMS (m/z) [M þ H]þ calcd for
tert-Butyl N-(diphenylmethylidene)-2-nitro-5-(trifluoromethyl)-
L-phenylalaninate (7e): The title compound was prepared from 5e
(40.8 g, 143 mmol, 1 equiv) according to general procedure A to give
tert-butyl N-(diphenylmethylidene)-2-nitro-5-(trifluoromethyl)-L-phe-
C27H26N2O5F3 515.1788, found 515.1775; [R]20 ꢀ138.68 (c 0.61,
1
nylalaninate (7e) (51.56 g, 72% yield, 90% ee). H NMR (400 MHz,
D
MeOH).
CDCl3) δ 7.91ꢀ7.84 (m, 1H), 7.70ꢀ7.65 (m, 1H), 7.60ꢀ7.24 (m, 9H),
6.71ꢀ6.59 (m, 2H), 4.30ꢀ4.21 (m, 1H), 3.65ꢀ3.57 (m, 1H),
3.53ꢀ3.44 (m, 1H), 1.40 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
171.8, 170.0, 152.0, 139.0, 137.8, 134.7, 134.2, 133.9, 132.6, 131.4, 130.8,
130.3, 128.9, 128.5, 128.5, 128.2, 127.6, 124.3, 123.1, 82.1, 65.8,
36.1, 28.2.
tert-Butyl N-(diphenylmethylidene)-2-nitro-5-(trifluoro-
methoxy)-L-phenylalaninate (7f): The title compound was pre-
pared from 5f (810 mg, 2.70 mmol, 1 equiv) according to general
procedure A to give tert-butyl N-(diphenylmethylidene)-2-nitro-
5-(trifluoromethoxy)-L-phenylalaninate (7f) (700 mg, 50.4% yield,
86% ee). 1H NMR (400 MHz, CD3OD) δ 8.03ꢀ7.96 (m, 1H),
7.54ꢀ7.44 (m, 2H), 7.43ꢀ7.18 (m, 8H), 6.71ꢀ6.52 (m, 2H),
4.38ꢀ4.22 (m, 1H), 3.69ꢀ3.57 (m, 1H), 3.43ꢀ3.31 (m, 1H), 1.42 (s,
9H); 13C NMR (100 MHz, CD3OD) δ 172.7, 170.3, 151.3, 147.9, 138.9,
137.7, 136.3, 135.9, 132.6, 130.6, 129.8, 128.8, 128.6, 128.3, 127.9, 127.2,
127.1, 125.3, 121.6, 119.7, 81.9, 65.4, 35.9, 27.0.
tert-Butyl N-(diphenylmethylidene)-2-nitro-3-(trifluoro-
methyl)-L-phenylalaninate (7k): The title compound was prepared
from 5k (970 mg, 3.4 mmol, 1 equiv) according to general procedure A
to give tert-butyl N-(diphenylmethylidene)-2-nitro-3-(trifluoromethyl)-
L-phenylalaninate (7k) (1.4 g, 82% yield, 96% ee). 1H NMR (400 MHz,
DMSO-d6) δ 7.95ꢀ7.84 (m, 1H), 7.76ꢀ7.68 (m, 2H), 7.53ꢀ7.29 (m,
8H), 6.67ꢀ6.48 (m, 2H), 4.17ꢀ4.07 (m, 1H), 3.26ꢀ3.04 (m, 2H), 1.37
(s, 9H); 13C NMR (101 MHz, DMSO-d6) δ 170.7, 169.0, 147.3, 138.5,
137.3, 135.1, 131.2, 131.0, 130.6, 129.6, 128.7, 128.4, 128.3, 128.2, 126.8,
126.2, 123.5, 120.7, 120.7, 120.3, 81.3, 65.5, 33.8, 27.5; HRMS (m/z)
[M þ H]þ calcd for C27H26N2O4F3 499.1839, found 499.1841.
Determination of ee for Asymmetric Alkylation Reactions.
Chiral SFC was used to determine ee values of the products 7aꢀd and
7fꢀj (Chiralcel OD-H (4.6 mm ꢁ 25 cm) column, mobile phase 95/5
CO2/ propanol, flow rate 2.5 mL/min). In the case of 7e and 7k, chiral
HPLC was used to determine ee (Chirobiotic V column, 4.6 mm ꢁ
25 cm, mobile phase 50/50 MeOH/MeCN, flow rat: 1 mL/min) after
conversion to 8e and 8k, respectively.
tert-Butyl N-(diphenylmethylidene)-O-methyl-2-nitro-L-
tyrosinate (7g): The title compound was prepared from 5g (2.5 g,
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ARTICLE
Racemic alkylation products were prepared as standards according to
the following general procedure: To a solution of the relevant alkyl
bromide 5aꢀk (1 equiv) in CH2Cl2 (10 mL) cooled to ꢀ30 °C was
added tert-butyl N-(diphenylmethylidene)glycinate (1.1 equiv) and
tetrabutylammonium bromide (0.1 equiv). CsOH (1.5 equiv) was then
added and the mixture was allowed to stir for 18 h. The reaction mixture
was washed with water, dried (Na2SO4), filtered, and concentrated. The
crude mixture was purified by flash chromatography on silica gel eluting
with CH2Cl2 (isocratic) to give the respective racemic products of
7aꢀk.
(8f) (0.8 g, 70% yield). 1H NMR (400 MHz, CD3OD) δ 8.30ꢀ8.22 (m,
1H), 7.56ꢀ7.46 (m, 2H), 4.43ꢀ4.30 (m, 1H), 3.75ꢀ3.62 (m, 1H),
3.54ꢀ3.43 (m, 1H); 13C NMR (100 MHz, CD3OD) δ 169.2, 151.8,
147.2, 133.2, 127.6, 124.8, 121.5, 120.3, 52.8, 33.5; HRMS (m/z) [M þ
H]þ calcd for C10H10F3N2O5 295.0536, found 295.0531.
O-Methyl-2-nitro-L-tyrosine (8g): The title compound was
prepared from 7g (3.6 g, 7.81 mmol, 1 equiv) according to general
procedure B to give O-methyl-2-nitro-L-tyrosine (8g) (1.24 g, 57%
yield). 1H NMR (400 MHz, CD3OD) δ 7.63 (d, J = 2.5 Hz, 1H), 7.44 (d,
J = 8.6 Hz, 1H), 7.28 (dd, J = 2.7, 8.6 Hz, 1H), 4.30 (t, J = 7.4 Hz, 1H),
3.58 (dd, J = 7.0, 14.3 Hz, 1H), 3.35 (t, J = 7.8 Hz, 1H), 3.38ꢀ3.33 (m,
1H); 13C NMR (100 MHz, CD3OD) δ 170.7, 161.0, 151.0, 135.2, 122.5,
120.7, 111.2, 56.3, 54.2, 34.2; HRMS (m/z) [M þ H]þ calcd for
Preparation of Chiral Amino Acids 8aꢀk
2-Methyl-6-nitro-L-phenylalanine (8a)—General Procedure
B: To a solution of tert-butyl N-(diphenylmethylidene)-2-methyl-6-nitro-L-
phenylalaninate (7a) (190 mg, 0.43 mmol, 1 equiv) in CH2Cl2 (5 mL) was
added TFA (5 mL). The reaction was allowed to stir at rt for 18 h. The
reaction mixture was concentrated to remove TFA. The residue was
partitioned between 4 M HCl and Et2O. The aqueous layer was washed
several times with Et2O. The aqueous layer was then concentrated to give
2-methyl-6-nitro-L-phenylalanine (8a) (95 mg, 99% yield) as the HCl salt.
1H NMR (500 MHz, CD3OD) δ 2.53 (s, 3H), 3.43 (dd, J = 14.2, 7.1 Hz,
1H), 3.62 (dd, J = 14.3, 8.9 Hz, 1H), 4.26 (t, J = 8.0 Hz, 1H), 7.44 (t, J = 7.9
Hz, 1H), 7.60 (d, J = 7.6 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H); 13C NMR (100
MHz, CD3OD) δ 169.8, 151.2, 140.7, 135.5, 128.3, 122.9, 52.2, 29.6, 19.1;
LC-MS m/e 224 (M þ 1). Anal. Calcd for C10H13ClN2O4: C, 46.08; H,
5.03; Cl, 13.60; N, 10.75. Found; C, 45.89; H, 4.92; Cl, 13.92; N, 10.58.
[R]20D ꢀ62.6 (c 0.11, MeOH).
C10H13N2O5 241.0818, found 241.0823; [R]20 þ0.157 (c 0.58,
D
MeOH).
4-Methyl-2-nitro-L-phenylalanine (8h): The title compound
was prepared from 7h (4.3 g, 9.49 mmol, 1 equiv) according to general
procedure B to give 4-methyl-2-nitro-L-phenylalanine (8h) (2.29 g, 93%
1
yield). H NMR (400 MHz, CD3OD) δ 7.94 (s, 1H), 7.58ꢀ7.50 (m,
1H), 7.41 (d, J = 7.8 Hz, 1H), 4.32 (t, J = 7.5 Hz, 1H), 3.61 (dd, J = 7.2,
14.1 Hz, 1H), 3.35 (dd, J = 7.8, 14.1 Hz, 1H), 2.45 (s, 3H); 13C NMR
(100 MHz, CD3OD) δ 171.1, 150.6, 141.4, 135.9, 134.5, 128.3, 126.9,
54.6, 34.9, 20.9; HRMS (m/z) [M þ H]þ calcd for C10H12N2O4
225.0875, found 225.0876; [R]20D þ16.1 (c 0.385, MeOH).
4-Chloro-2-nitro-L-phenylalanine (8i): The title compound
was prepared from 7i (23 mg, 0.094 mmol, 1 equiv) according to
general procedure B to give 4-chloro-2-nitro-L-phenylalanine (8i) (24
mg, 91% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.10 (d, J = 2.0 Hz,
1H), 7.79 (dd, J = 2.3, 8.6 Hz, 1H), 7.65 (d, J = 8.6 Hz, 1H), 4.07 (t, J =
7.4 Hz, 1H), 3.46 (dd, J = 7.4, 14.1 Hz, 1H), 3.32 (dd, J = 7.4, 14.1 Hz,
1H); HRMS (m/z) [M þ H]þ calcd for C9H10ClN2O4 245.0323, found
245.0319.
2-Fluoro-6-nitro-L-phenylalanine (8b): The title compound
was prepared from 7b (1.5 g, 3.3 mmol, 1 equiv) according to general
procedure B to give 2-fluoro-6-nitro-L-phenylalanine (8b) (55 mg, 66%
yield). 1H NMR (400 MHz, CD3OD) δ 7.92 (td, J = 1.3, 8.0 Hz, 1H),
7.64ꢀ7.49 (m, 2H), 4.27 (dd, J = 7.0, 8.4 Hz, 1H), 3.61 (ddd, J = 2.0, 8.4,
13.9 Hz, 1H), 3.47ꢀ3.37 (m, 1H); 13C NMR (100 MHz, CD3OD) δ
169.3, 161.9, 150.3, 130.1, 121.1, 120.8, 120.5, 52.3, 26.3; HRMS (m/z)
[M þ H]þ calcd for C9H9FN2O4 228.0546, found 228.0544.
5-Methyl-2-nitro-L-phenylalanine (8c): The title compound
was prepared from 7c (5.92 g, 13.3 mmol, 1 equiv) according to general
procedure B to give 5-methyl-2-nitro-L-phenylalanine (8c) (3.46 g,
2-Nitro-3-(trifluoromethoxy)-L-phenylalanine hydrochloride
a solution of tert-butyl N-(diphenylmethylidene)-2-nitro-
(8j): To
3-(trifluoromethoxy)-L-phenylalaninate (7j) (2.3 g, 4.5 mmol, 1 equiv) in
CH2Cl2 (20 mL) was added TFA (3 mL). The reaction was allowed to stir at
rt for 18 h. The reaction mixture was concentrated to remove TFA, and the
residue was partitioned between 4 M HCl and Et2O. The aqueous layer was
washed several times with Et2O, and then concentrated to give 2-nitro-
3-(trifluoromethoxy)-L-phenylalanine (8j) (1.48 g, 74% yield) as the HCl
salt. 1H NMR (400 MHz, CD3OD) δ 7.75ꢀ7.69 (m, 1H), 7.62ꢀ7.54 (m,
2H), 4.28 (t, J = 7.4 Hz, 1H), 3.38ꢀ3.34 (m, 1H), 3.25ꢀ3.15 (m, 1H); 13C
NMR (100 MHz, CD3OD) δ 170.0, 145.5, 141.3, 133.3, 131.0, 130.8, 122.1,
120.1, 54.0, 32.5; HRMS (m/z) [M þ H]þ calcd for C10H10F3N2O5
295.0536, found 295.0525; [R]20D þ6.55 (c 0.57, MeOH).
1
100% yield). H NMR (400 MHz, CD3OD) δ 8.04 (d, J = 8.4 Hz,
1H), 7.38 (d, J = 8.4 Hz, 1H), 7.36 (s, 1H), 4.31 (t, J = 7.4 Hz, 1H), 3.65
(dd, J = 7.0, 13.9 Hz, 1H), 3.38 (dd, J = 7.8, 13.9 Hz, 1H), 2.46 (s, 3H);
13C NMR (100 MHz, CD3OD) δ 171.3, 148.5, 146.9, 135.2, 131.7,
131.0, 126.9, 54.8, 35.4, 21.5; HRMS (m/z) [M þ H]þ calcd for
C10H12N2O4 225.0875, found 225.0884. [R]20 ꢀ28.5 (c 0.435,
D
MeOH).
5-Chloro-2-nitro-L-phenylalanine (8d). The title compound
was prepared from 7d (560 mg, 2.29 mmol, 1 equiv) according to
general procedure B to give 5-chloro-2-nitro-L-phenylalanine (8d) (360
mg, 56% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.04 (d, J = 8.6 Hz,
1H), 7.75 (d, J = 2.3 Hz, 1H), 7.60 (dd, J = 2.3, 9.0 Hz, 1H), 4.12 (t, J =
7.4 Hz, 1H), 3.52 (dd, J = 7.4, 14.1 Hz, 1H), 3.33 (dd, J = 7.4, 14.1 Hz,
1H); 13C NMR (100 MHz, DMSO-d6) δ 170.5, 148.4, 138.9, 133.7,
129.4, 127.6, 52.9, 33.2. Anal. Calcd for C9H10Cl2N2O4: C, 38.46; H,
3.59; N, 9.97. Found C, 38.49; H, 3.48; N, 10.06.
2-Nitro-5-(trifluoromethyl)-L-phenylalanine (8e): The title
compound was prepared from 7e (6.33 g, 12.7 mmol, 1 equiv) according
to general procedure B to give 2-nitro-5-(trifluoromethyl)-L-phenylala-
nine (8e) (3.49 g, 87% yield). 1H NMR (400 MHz, CD3OD) δ 8.26 (d,
J = 8.6 Hz, 1H), 8.01ꢀ7.85 (m, 2H), 4.37 (s, 1H), 3.72 (s, 1H),
3.58ꢀ3.45 (m, 1H); 13C NMR (100 MHz, CD3OD) δ 168.3, 151.5,
134.3, 131.3, 131.0, 130.3, 126.0, 123.1, 52.8, 33.1; HRMS (m/z) [M þ
H]þ calcd for C27H26N2O4F3 499.1839, found 499.1833.
2-Nitro-3-(trifluoromethyl)-L-phenylalanine (8k): The title
compound was prepared from 7k (1.4 g, 2.8 mmol, 1 equiv) according to
general procedure B to give 2-nitro-3-(trifluoromethyl)-L-phenylalanine
1
(8k) (598 mg, 77% yield). H NMR (400 MHz, DMSO-d6) δ 8.02ꢀ
7.95 (m, 2H), 7.91ꢀ7.84 (m, 1H), 4.27ꢀ4.11 (m, 1H), 3.29ꢀ3.14
(m, 1H), 3.13ꢀ2.99 (m, 1H); 13C NMR (75 MHz, DMSO-d6) δ
171.5, 169.3, 136.6, 131.8, 129.3, 126.9, 120.9, 52.2, 30.9, 22.5;
HRMS (m/z) [M þ H]þ calcd for C10H10F3N2O4 279.0587, found
279.0586.
SnCl2 Reductive Cyclization Procedure: Preparation of
Hydroxamic Acids 19aꢀi
(3S)-3-Amino-1-hydroxy-5-methyl-3,4-dihydroquinolin-2(1H)-
one (19a)—General Procedure C (preparation of di-Boc-pro-
tected hydroxamic acid intermediate): To a solution of 2-methyl-6-
nitro-L-phenylalanine (8a) (450 mg, 1.73 mmol, 1 equiv) in THF:
MeOH (50 mL:50 mL) at 0 °C was added SnCl2 (1.64 g, 8.63 mmol, 5
2-Nitro-5-(trifluoromethoxy)-L-phenylalanine (8f): The title
compound was prepared from 7f (2 g, 3.89 mmol, 1 equiv) according to
general procedure B to give 2-nitro-5-(trifluoromethoxy)-L-phenylalanine
equiv) and NaOAc 3H2O (2.35 g, 17.3 mmol, 10 equiv). The mixture
3
was allowed to stir, gradually warming to rt over 5 h. NEt3 (2.4 mL, 17.3
mmol, 10 equiv) and Boc2O (1.13 g, 5.13 mmol, 3 equiv) were then
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ARTICLE
added and the mixture was allowed to stir overnight at rt. The mixture
was concentrated and the residue was taken up in EtOAc and H2O. The
organic layer was washed several times with water, dried (MgSO4),
filtered, and concentrated. The crude product was purified by flash
chromatography on silica gel, eluting with 0ꢀ100% EtOAc/heptane
(containing 1% NEt3) to give di-Boc-protected product 18a (660 mg,
89% yield). General Procedure D: To a solution of product 18a (600
mg, 1.53 mmol, 1 equiv) in Et2O (10 mL) was added 2 M HCl/Et2O
(10 mL). The reaction mixture was stirred overnight at rt. The solid
precipitate was filtered off and washed with Et2O to give (3S)-3-amino-
1-hydroxy-5-methyl-3,4-dihydroquinolin-2(1H)-one (19a) (280 mg,
(br s, 3H), 7.74 (s, 1H), 7.69 (d, J = 8.6 Hz, 1H), 7.42 (d, J = 8.6 Hz, 1H),
4.44 (dd, J = 6.4, 14.6 Hz, 1H), 3.44ꢀ3.30 (m, 1H), 3.29ꢀ3.14 (m, 1H);
13C NMR (100 MHz, DMSO-d6) δ 162.8, 143.0, 126.0, 125.9, 124.6,
124.3, 121.7, 114.2, 48.4, 29.1. Anal. Calcd for C10H10F3N2O2Cl: C,
42.49; H, 3.57; N, 9.91. Found: C, 42.21; H, 3.35; N, 9.70.
(3S)-3-Amino-1-hydroxy-6-(trifluoromethoxy)-3,4-dihydroqui-
nolin-2(1H)-one (19f): 2-Nitro-5-(trifluoromethoxy)-L-phenylalanine
(8f) (203 mg, 0.67 mmol, 1 equiv) was treated according to general
procedure C to give di-Boc protected product 18f (203 mg, 72% yield).
Di-Boc-protected product 18f (106 mg, 0.22 mmol, 1 equiv) was treated
according to general procedure D to give (3S)-3-amino-1-hydroxy-
6-(trifluoromethoxy)-3,4-dihydroquinolin-2(1H)-one (19f) (61 mg,
89% yield). 1H NMR (400 MHz, DMSO-d6) δ 11.01 (br s, 1H), 8.77
(br s, 3H), 7.40 (s, 1H), 7.31 (s, 2H), 4.40 (dd, J = 6.6, 14.4 Hz, 1H),
3.32ꢀ3.21 (m, 1H), 3.20ꢀ3.06 (m, 1H); 13C NMR (101 MHz, DMSO-
d6) δ 162.3, 144.5, 138.9, 122.8, 122.0, 121.8, 121.5, 115.3, 48.4, 29.1;
HRMS (m/z) [M þ H]þ calcd for C10H10F3N2O3 263.0638, found
263.0640.
(3S)-3-Amino-1-hydroxy-7-methoxy-3,4-dihydroquinolin-
2(1H)-one (19g): 4-Methyl-2-nitro-L-phenylalanine (8g) (1.2 g, 4.33
mmol, 1 equiv) was treated according to general procedure C to give di-
Boc protected product 18g (1.33 g, 75% yield). Di-Boc-protected
product 18g (600 mg, 1.47 mmol, 1 equiv) was treated according to
general procedure D to give (3S)-3-amino-1-hydroxy-7-methoxy-3,4-
dihydroquinolin-2(1H)-one (19g) (323 mg, 90% yield). 1H NMR (400
MHz, CD3OD) δ 7.20 (d, J = 8.2 Hz, 1H), 6.95 (d, J = 2.5 Hz, 1H), 6.69
(dd, J = 2.5, 8.4 Hz, 1H), 4.29 (dd, J = 6.4, 14.6 Hz, 1H), 3.81 (s, 3H),
3.25ꢀ3.16 (m, 1H), 3.13ꢀ3.00 (m, 1H); 13C NMR (100 MHz, DMSO-
d6) δ 162.0, 159.5, 140.3, 129.2, 112.0, 108.8, 100.0, 55.6, 48.6, 28.2;
HRMS (m/z) [M þ H]þ calcd for C10H13N2O3 209.0920, found
209.0915; [R]20D ꢀ36.79 (c 0.41, MeOH).
1
80% yield). H NMR (500 MHz, CD3OD) δ 2.36 (s, 3H), 2.89 (t,
J = 14.2 Hz, 1H), 3.40 (dd, J = 15.0, 4.3 Hz, 1H), 4.14 (br s, 1H),
7.00ꢀ7.04 (m, 1H), 7.21ꢀ7.29 (m, 2H); 13C NMR (500 MHz,
CD3OD) δ 139.1, 136.1, 127.8, 126.2, 118.8, 111.6, 99.9, 49.0, 27.0,
18.2; HRMS (m/z) [M þ H]þ calcd for C10H12N2O2 193.0971, found
193.0970; [R]20D ꢀ18.3 (c 0.11, MeOH)
(3S)-3-Amino-5-fluoro-1-hydroxy-3,4-dihydroquinolin-2(1H)-
one (19b): 2-Fluoro-6-nitro-L-phenylalanine (8b) (307 mg, 1.34 mmol,
1 equiv) was treated according to general procedure C to give di-Boc-
protected product (320 mg, 60% yield). The di-Boc-protected product
(150 mg, 0.51 mmol) was treated according to general procedure D to
give (3S)-3-amino-5-fluoro-1-hydroxy-3,4-dihydroquinolin-2(1H)-one
(19b) (72 mg, 73% yield). 1H NMR (400 MHz, CD3OD) δ
7.39ꢀ7.28 (m, 1H), 7.18 (d, J = 8.2 Hz, 1H), 6.89 (t, J = 8.7 Hz, 1H),
4.35 (dd, J = 6.6, 14.6 Hz, 1H), 3.53 (dd, J = 6.6, 15.2 Hz, 1H), 2.93 (t, J =
14.9 Hz, 1H); 13C NMR (100 MHz, CD3OD) δ 161.7, 159.5, 140.4,
129.7, 111.0, 109.5, 107.4, 48.5, 22.0; HRMS (m/z) [M þ H]þ calcd for
C9H10FN2O2 197.0721, found 197.0716.
(3S)-3-Amino-1-hydroxy-6-methyl-3,4-dihydroquinolin-2(1H)-
one hydrochloride (19c): 5-Methyl-2-nitro-L-phenylalanine (8c) (925
mg, 4.13 mmol, 1 equiv) was treated according to general procedure C to
give di-Boc-protected product 18c (724 mg, 44% yield). Diboc-pro-
tected product 18c (256 mg, 0.65 mmol, 1 equiv) was treated according
to general procedure D to give (3S)-3-amino-1-hydroxy-6-methyl-3,4-
dihydroquinolin-2(1H)-one hydrochloride (19c) (126 mg, 85% yield).
1H NMR (400 MHz, CD3OD) δ 7.27 (d, J = 8.4 Hz, 1H), 7.19 (d, J = 8.4
Hz, 1H), 7.13 (s, 1H), 4.30 (dd, J = 6.6, 14.4 Hz, 1H), 3.23 (dd, J = 6.6,
14.8 Hz, 1H), 3.14 (t, J = 14.6 Hz, 1H), 2.32 (s, 3H); 13C NMR (100
MHz, CD3OD) δ 162.9, 137.8, 135.8, 130.2, 129.9, 120.9, 115.0, 50.4,
30.6, 20.9; HRMS (m/z) [M þ H]þ calcd for C10H12N2O2 193.0977,
found 193.0970; [R]20D ꢀ55.7 (c 0.28, MeOH).
(3S)-3-Amino-1-hydroxy-7-methyl-3,4-dihydroquinolin-2(1H)-
one hydrochloride (19h): 4-Methyl-2-nitro-L-phenylalanine (8h)
(2.27 g, 10.2 mmol, 1 equiv) was treated according to general procedure
C to give di-Boc protected product 18h (1.40 g, 35% yield). Di-Boc-
protected product 18h (529 mg, 1.35 mmol, 1 equiv) was treated
according to general procedure D to afford (3S)-3-amino-1-hydroxy-7-
methyl-3,4-dihydroquinolin-2(1H)-one hydrochloride (19h) (289 mg,
91% yield). 1H NMR (400 MHz, CD3OD) δ 7.23 (s, 1H), 7.18 (d, J =
7.6 Hz, 1H), 6.96 (dd, J = 0.7, 7.5 Hz, 1H), 4.30 (dd, J = 6.6, 14.6 Hz,
1H), 3.25 (dd, J = 6.5, 14.7 Hz, 1H), 3.12 (t, J = 14.7 Hz, 1H), 2.36 (s,
3H); 13C NMR (100 MHz, CD3OD) δ 163.2, 140.2, 140.0, 129.2, 126.4,
118.0, 115.5, 50.5, 30.2, 21.6; HRMS (m/z) [M þ H]þ calcd for
(3S)-3-Amino-6-chloro-1-hydroxy-3,4-dihydroquinolin-2(1H)-
one (19d): 5-Chloro-2-nitro-L-phenylalanine (8d) (320 mg, 1.3 mmol,
1 equiv) was treated according to general procedure C to give di-Boc-
protected product 18d (230 mg, 43% yield). Di-Boc-protected product
18d (180 mg, 0.43 mmol, 1 equiv) was treated according to general
procedure D to give (3S)-3-amino-6-chloro-1-hydroxy-3,4-dihydroqui-
nolin-2(1H)-one (19d) (93 mg, 86% yield). 1H NMR (400 MHz,
DMSO-d6) δ 10.95 (s, 1H), 8.69 (br s, 3H), 7.43 (d, J = 2.0 Hz, 1H),
7.38ꢀ7.32 (m, 1H), 7.22 (d, J = 8.6 Hz, 1H), 4.36 (dd, J = 6.6, 14.4 Hz,
1H), 3.25ꢀ3.00 (m, 2H); 13C NMR (100 MHz, DMSO-d6) δ 162.2,
137.7, 128.5, 128.1, 122.8, 115.5, 48.5, 29.1. Anal. Calcd for
C9H10Cl2N2O2: C, 43.40; H, 4.05; N, 11.25. Found C, 43.46; H,
3.60; N, 11.03. HRMS (m/z) [M þ H]þ calcd for C9H10ClN2O2
213.0425, found 213.0420.
(3S)-3-Amino-1-hydroxy-6-(trifluoromethyl)-3,4-dihydroqui-
nolin-2(1H)-one (19e). 2-Nitro-5-(trifluoromethyl)-L-phenylalanine
8e (457 mg, 1.64 mmol, 1 equiv) was treated according to general
procedure C to give di-Boc protected product 18e (424 mg, 65% yield).
Di-Boc-protected product 18e (226 mg, 0.5 mmol, 1 equiv) was treated
according to general procedure D to give (3S)-3-amino-1-hydroxy-
6-(trifluoromethyl)-3,4-dihydroquinolin-2(1H)-one (19e) (134 mg,
94% yield). 1H NMR (400 MHz, DMSO-d6) δ 11.15 (br s, 1H), 8.88
C10H12N2O2 193.0977, found 193.0980; [R]20 ꢀ29.1 (c 0.45,
D
MeOH).
(3S)-3-Amino-7-chloro-1-hydroxy-3,4-dihydroquinolin-2(1H)-
one (19i): 4-Chloro-2-nitro-L-phenylalanine (8i) (403 mg, 1.4 mmol, 1
equiv) was treated according to general procedure C to give di-Boc
protected product 18i (107 mg, 18% yield). Di-Boc-protected product
18i (77 mg, 0.19 mmol, 1 equiv) was treated according to general
procedure D to provide (3S)-3-amino-7-chloro-1-hydroxy-3,4-dihydro-
1
quinolin-2(1H)-one (19i) (40 mg, 86% yield). H NMR (400 MHz,
DMSO-d6) δ 11.02 (br s, 1H), 8.73 (br s, 2H), 7.32 (d, J = 7.8 Hz, 1H),
7.20 (s, 1H), 7.10 (d, J = 7.8 Hz, 1H), 4.36 (dd, J = 5.7, 14.4 Hz, 1H),
3.20 (dd, J = 6.2, 15.2 Hz, 1H), 3.11ꢀ2.97 (m, 1H); 13C NMR (100
MHz, DMSO-d6) δ 162.5, 141.0, 133.2, 130.4, 123.8, 119.6, 113.4, 48.5,
28.9; HRMS (m/z) [M þ H]þ calcd for C9H10ClN2O2 213.0425, found
213.0423.
Preparation of Methyl N-(tert-butoxycarbonyl)-2-nitro-
3-(trifluoromethoxy)-L-phenylalaninate (24a): To a solution
of N-(tert-butoxycarbonyl)-2-nitro-3-(trifluoromethoxy)-L-phenylala-
nine (183 mg, 0.465 mmol, 1 equiv; see below for preparation) in
CH2Cl2 (3 mL) was added EDCI (109 mg, 0.558 mmol, 1 equiv),
DMAP (29 mg, 0.233 mmol, 0.5 equiv), and MeOH (3 mL). The
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reaction was allowed to stir at rt overnight. The mixture was then washed
with brine, dried (MgSO4), filtered, and concentrated. The crude
product mixture was purified by flash chromatography on silica gel
(12 g) eluting with 0ꢀ40% EtOAc/heptane to give methyl N-(tert-
butoxycarbonyl)-2-nitro-3-(trifluoromethoxy)-L-phenylalaninate (24a)
(119 mg, 63% yield). 1H NMR (400 MHz, CDCl3) δ 7.46 (d, J = 7.8 Hz,
1H), 7.39ꢀ7.26 (m, 2H), 5.20ꢀ5.09 (m, 1H), 4.62ꢀ4.52 (m, 1H),
3.21ꢀ3.10 (m, 1H), 3.03ꢀ2.92 (m, 1H), 1.36 (s, 9H); 13C NMR (100
MHz, CDCl3) δ 170.2, 153.8, 143.9, 139.2, 130.5, 130.1, 128.2, 118.9,
119.2, 79.3, 52.9, 51.6, 33.3, 27.1. Anal. Calcd for C16H19F3N2O7: C,
47.06; H, 4.69; N, 6.86. Found: C, 47.20; H, 4.33; N, 6.55.
[M þ H]þ calcd for C27H29N2O5 461.20701, found 461.2069;
[R]20D ꢀ128.8 (c 0.182, MeOH).
N-(tert-Butoxycarbonyl)-3-methoxy-2-nitro-L-phenylalanine:
To a solution of tert-butyl N-(diphenylmethylidene)-3-methoxy-2-nitro-L-
phenylalaninate (396 mg, 0.86 mmol, 1 equiv) in CH2Cl2 (20 mL) was
added TFA (3 mL). The reaction was allowed to stir at rt for 18 h. The
reaction mixture was concentrated to remove TFA. The residue was
partitioned between 4 M HCl and Et2O. The aqueous layer was washed
several times with Et2O. The aqueous layer was then concentrated to give
3-methoxy-2-nitro-L-phenylalanine (8l) as the HCl salt. The amino acid was
dissolved in THF (10 mL) and 1 M NaOH (10 mL). Boc2O (375 mg, 1.72
mmol, 2 equiv) was added and the mixture was allowed to stir at rt
overnight. The reaction mixture was neutralized using aq NH4Cl solution
and extracted with EtOAc. The organic layers were dried (MgSO4), filtered,
and concentrated to give N-(tert-butoxycarbonyl)-3-methoxy-2-nitro-L-
phenylalanine (240 mg).
Preparation of Trifluoroethyl Ester Amino Acids 25aꢀf
Table 4, entry 1: N-(tert-Butoxycarbonyl)-2-nitro-3-(trifluoro-
methoxy)-L-phenylalanine: To a solution of 2-nitro-3-(trifluoro-
methoxy)-L-phenylalanine in water (10 mL) was added NEt3 (0.85 mL,
6.05 mmol, 4 equiv) and Boc2O (363 mg, 1.66 mmol, 1.1 equiv) and the
reaction was stirred at rt overnight. The reaction was acidified with 10%
citric acid to pH ∼5, and extracted with EtOAc. The organic layers were
washed with H2O and brine, dried over MgSO4, filtered, and concentrated
in vacuo. The crude product mixture was purified on silica gel eluting with
5% CH3OH/CH2Cl2 to give N-(tert-butoxycarbonyl)-2-nitro-3-(trifluoro-
2,2,2-Trifluoroethyl N-(tert-butoxycarbonyl)-3-methoxy-
2-nitro-L-phenylalaninate (25b): To a solution of N-(tert-
butoxycarbonyl)-3-methoxy-2-nitro-L-phenylalanine (100 mg, 0.294
mmol, 1 equiv) in THF (10 mL) was added NEt3 (0.102 mL, 0.735
mmol, 2.5 equiv) and trifluoroethyl trifluoromethanesulfonate (89 mg,
0.382 mmol, 1.3 equiv). The reaction was heated at 60 °C overnight. The
reaction mixture was partitioned between EtOAc and water. The organic
layer was washed with water, dried (MgSO4), filtered, and concentrated.
The crude product mixture was purified on a 12 g silica column eluting
with 0ꢀ100% EtOAc/heptane to give 2,2,2-trifluoroethyl N-(tert-
butoxycarbonyl)-3-methoxy-2-nitro-L-phenylalaninate (25b) as a white
solid (84 mg, 67% yield). 1H NMR (400 MHz, CDCl3) δ 7.38 (t, J = 8.1
Hz, 1H), 7.00ꢀ6.87 (m, 2H), 5.17 (d, J = 7.6 Hz, 1H), 4.67ꢀ4.57 (m,
1H), 4.57ꢀ4.43 (m, 2H), 3.88 (s, 3H), 3.16ꢀ3.06 (m, 1H), 2.95 (dd, J =
8.5, 14.3 Hz, 1H), 1.40 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 170.1,
155.2, 151.2, 142.3, 131.4, 129.6, 122.3, 122.8, 111.7, 80.7, 61.6, 56.6,
54.2, 33.3, 28.4. Anal. Calcd for C17H21F3N2O7: C, 48.34; H, 5.01; N,
6.63. Found: C, 48.55; H, 5.00; N, 6.54. [R]20D ꢀ6.6 (c 0.11, MeOH).
Table 4, entry 3: N-(tert-Butoxycarbonyl)-2-nitro-3-(triflu-
oromethyl)-L-phenylalanine: To a solution of 2-nitro-3-(trifluo-
romethyl)-L-phenylalanine (8k) (1.5 g, 5.39 mmol) in dioxane and water
(1:1) (100 mL) was added Et3N (4.3 mL 32.34 mmol) followed by
Boc2O (2.9 mL 13.47 mmol) at rt and the reaction was stirred for 1 h.
The reaction mixture was quenched with saturated NH4Cl solution and
extracted with EtOAc. The organic solution was dried over Na2SO4,
filtered, and concentrated to obtain crude N-(tert-butoxycarbonyl)-2-
nitro-3-(trifluoromethyl)-L-phenylalanine, which was used without
further purification.
1
methoxy)-L-phenylalanine (510 mg, 86% yield). H NMR (400 MHz,
CD3OD) δ 7.66ꢀ7.57 (m, 1H), 7.47 (d, J = 8.0 Hz, 2H), 4.41 (dd, J = 4.7,
10.0 Hz, 1H), 3.24 (dd, J = 4.7, 14.4 Hz, 1H), 2.96 (dd, J = 10.0, 14.4 Hz,
1H), 1.37 (s, 9H); 13C NMR (100 MHz, CD3OD) δ 174.0, 157.5, 145.8,
141.0, 133.6, 132.5, 131.3, 121.1, 121.5, 80.6, 55.0, 34.2, 28.6; HRMS (m/z)
[M þ Na]þ calcd for C17H17F3N2O7Na 417.0880, found 417.0882;
[R]20D þ5.64 (c 0.55, MeOH).
2,2,2-Trifluoroethyl N-(tert-butoxycarbonyl)-2-nitro-3-(trifluo-
romethoxy)-L-phenylalaninate (25a): To a solution of N-(tert-
butoxycarbonyl)-2-nitro-3-(trifluoromethoxy)-L-phenylalanine (450
mg, 1.14 mmol, 1 equiv) in THF (10 mL) was added NEt3 (0.41 mL,
2.85 mmol, 2.5 equiv) and 2,2,2-trifluoroethyl trifluoromethanesulfo-
nate (344 mg, 1.48 mmol, 1.3 equiv). The reaction was heated at 60 °C
overnight. The reaction mixture was partitioned between EtOAc and
water, and the organic layer was washed with water, dried (MgSO4),
filtered, and concentrated. The crude product mixture was purified by
chromatography on silica gel (12 g), eluting with 0ꢀ100% EtOAc/
heptane to give 2,2,2-trifluoroethyl N-(tert-butoxycarbonyl)-2-nitro-
3-(trifluoromethoxy)-L-phenylalaninate (25a) as a white solid (429
mg, 79% yield). 1H NMR (400 MHz, CD3OD) δ 7.69ꢀ7.59 (m,
1H), 7.56ꢀ7.42 (m, 2H), 4.63 (q, J = 8.8 Hz, 2H), 4.49 (dd, J = 5.4, 9.9
Hz, 1H), 3.24ꢀ3.16 (m, 1H), 3.06 (dd, J = 10.0, 14.3 Hz, 1H), 1.39 (s,
9H); 13C NMR (100 MHz, CD3OD) δ 169.8, 156.3, 144.6, 139.9, 132.2,
131.8, 131.6, 130.1, 124.7, 120.4, 79.8, 60.7, 54.0, 32.3, 27.4; HRMS
(m/z) [M þ Na]þ calcd for C17H18F6N2O7Na 499.0910, found
499.0894; [R]20D þ4.00 (c 0.55, MeOH).
2,2,2-Trifluoroethyl N-(tert-butoxycarbonyl)-2-nitro-3-(triflu-
oromethyl)-L-phenylalaninate (25c): To a solution of N-(tert-
butoxycarbonyl)-2-nitro-3-(trifluoromethyl)-L-phenylalanine (0.1 g,
0.264 mmol) in dry THF (20 mL) was added Et3N (0.08 mL, 0.65
mmol) followed by trifluoroethyl trifluoromethanesulfonate (0.08 mL,
0.343 mmol), and the mixture was heated at reflux for 12 h. The reaction
mixture was quenched with water and extracted with EtOAc. The
organic layer was dried over Na2SO4, filtered, and concentrated. The
crude product mixture was purified by flash chromatography on silica gel
eluting with EtOAc to give 2,2,2-trifluoroethyl N-(tert-butoxycarbonyl)-
2-nitro-3-(trifluoromethyl)-L-phenylalaninate (25c) as a white solid
Table 4, entry 2: tert-Butyl N-(diphenylmethylidene)-3-
methoxy-2-nitro-L-phenylalaninate: To a solution of 1-(bromo-
methyl)-3-methoxy-2-nitrobenzene (494 mg, 2.01 mmol, 1 equiv) in
CH2Cl2 (10 mL) cooled to ꢀ30 °C was added tert-butyl N-(diphenyl-
methylidene)glycinate (890 mg, 3.01 mmol, 1.5 equiv) and (ꢀ)-(O)-(9)-
allyl-N-(9-anthracenylmethyl)cinchodinium bromide (128 mg, 0.201
mmol, 0.1 equiv). CsOH (439 mg, 2.61 mmol, 1.3 equiv) was then added
and the mixture was allowed to stir for 18 h. The reaction mixture was
washed with water, dried (Na2SO4), filtered, and concentrated. The crude
mixture was purified by flash chromatography on silica gel eluting with
CH2Cl2 (isocratic) to give tert-butyl N-(diphenylmethylidene)-3-methoxy-
2-nitro-L-phenylalaninate (870 mg, 94%). 1H NMR (400 MHz, CDCl3) δ
7.63ꢀ7.58 (m, 2H), 7.41ꢀ7.18 (m, 7H), 6.86 (d, J = 8.2 Hz, 2H), 6.71 (d,
J = 7.0 Hz, 1H), 4.21 (dd, J = 4.7, 8.8 Hz, 1H), 3.85 (s, 3H), 3.34ꢀ2.95 (m,
2H), 1.42 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 171.3, 170.2, 150.9,
139.5, 136.2, 131.7, 130.5, 130.4, 130.3, 129.1, 128.7, 128.4, 128.2, 127.8,
123.9, 110.7, 81.8, 77.6, 76.9, 66.3, 56.6, 34.7, 28.2; HRMS (m/z)
1
(0.120 g, 99%). H NMR (300 MHz, DMSO-d6) δ 8.01ꢀ7.77 (m,
2H), 7.66ꢀ7.54 (m, 1H), 4.85ꢀ4.66 (m, 2H), 4.42ꢀ4.28 (m, 1H),
3.11ꢀ2.96 (m, 2H), 1.33 (s, 9H); 13C NMR (100 MHz, DMSO-d6) δ
169.6, 155.1, 147.2, 136.5, 131.5, 130.7, 126.3, 124.6, 121.9, 120.3, 78.4,
60.2, 53.4, 31.3, 27.9; HRMS (m/z) [M þ NH4]þ calcd for
C17H22F6N3O6 478.1407, found 478.1409.
Table 4, entry 4: 3-Fluoro-2-nitro-L-phenylalanine: To a
solution of 1-(bromomethyl)-3-fluoro-2-nitrobenzene (3.72 g, 15.9 mmol,
1 equiv) in CH2Cl2 (30 mL) cooled to ꢀ30 °C was added tert-butyl
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N-(diphenylmethylidene)glycinate (6.23 g, 20.7 mmol, 1.3 equiv)
and (ꢀ)-(O)-(9)-allyl-N-(9-anthracenylmethyl)cinchodinium bromide
7.22ꢀ7.14 (m, 1H), 7.10ꢀ6.98 (m, 3H), 6.85 (dd, J = 0.9, 8.3 Hz, 1H),
5.24ꢀ5.14 (m, 1H), 4.71ꢀ4.60 (m, 1H), 4.57ꢀ4.45 (m, 2H), 3.23ꢀ3.11
(m, 1H), 3.09ꢀ2.98 (m, 1H), 1.40 (s, 9H); 13C NMR (100 MHz, CDCl3)
δ 169.8, 155.5, 154.9, 149.3, 143.6, 131.1, 130.0, 126.7, 124.7, 124.0, 121.2,
119.5, 117.8, 80.6, 61.0, 54.0, 33.3, 28.2; HRMS (m/z) [M þ Na]þ calcd
(1.01 g, 1.59 mmol, 0.1 equiv). CsOH H2O (3.47 g, 20.7 mmol, 1.3
3
equiv) was then added and the mixture was allowed to stir for 18 h. The
reaction mixture was washed with water, dried (Na2SO4), filtered, and
concentrated. The crude mixture was purified by flash chromatography
on silica gel eluting with CH2Cl2 (isocratic) to give tert-butyl N-(di-
phenylmethylidene)-3-fluoro-2-nitro-L-phenylalaninate (1.72 g, 32%).
To a solution of tert-butyl N-(diphenylmethylidene)-3-fluoro-2-nitro-L-
phenylalaninate (678 mg, 1.5 mmol, 1 equiv) was added TFA (4 mL)
and the reaction was allowed to stir at rt overnight, then concentrated to
remove TFA. The residue was partitioned between 4 M HCl and Et2O.
The aqueous layer was washed several times with Et2O, and concen-
trated to give 3-fluoro-2-nitro-L-phenylalanine (273 mg, 68% yield, 96%
ee). 1H NMR (400 MHz, CD3OD) δ 7.80ꢀ7.51 (m, 1H), 7.45ꢀ7.26
(m, 2H), 4.26 (t, J = 7.4 Hz, 1H), 3.36 (dd, J = 7.2, 14.6 Hz, 1H), 3.20
(dd, J = 7.7, 14.7 Hz, 1H); 13C NMR (100 MHz, CD3OD) δ 169.2,
153.1, 133.2, 133.1, 130.2, 127.3, 116.7, 53.2, 31.7; HRMS (m/z) [M þ
H]þ calcd for C9H10N2O4F 229.0619, found 229.0620; [R]20D þ13.3
(c 0.35, MeOH).
N-(tert-Butoxycarbonyl)-3-fluoro-2-nitro-L-phenylalanine:
To solution of 3-fluoro-2-nitro-L-phenylalanine (1.91 g, 1.5 mmol, 1
equiv) in water (10 mL) was added NEt3 (3.5 mL, 25.1 mmol, 3 equiv)
and Boc2O (2.8 mg, 12.6 mmol, 1.1 equiv) and the reaction was stirred at
room temperature overnight. The reaction was acidified with 10% citric
acid to pH∼5, and extracted with EtOAc. The organic layers were washed
with H2O and brine, dried over MgSO4, filtered, and concentrated in
vacuo. The crude product mixture was purified on silica gel eluting with
0ꢀ40% EtOAc/heptane to give N-(tert-butoxycarbonyl)-3-fluoro-2-ni-
tro-L-phenylalanine (1.84 g, 67% yield). 1H NMR (400 MHz, CD3OD) δ
7.59ꢀ7.37 (m, 1H), 7.36ꢀ7.15 (m, 2H), 4.44ꢀ4.28 (m, 1H), 3.24ꢀ3.18
(m, 1H), 2.97 (?, 1H), 1.37 (s, 9H); 13C NMR (100 MHz, CD3OD) δ
173.0, 156.4, 155.2, 138.1, 132.7, 132.0, 127.3, 115.3, 79.5, 53.9, 33.1, 27.4;
HRMS (m/z) [M þ Na]þ calcd for C15H20N2O6Na 347.1213, found
347.1203; [R]20D þ33 (c 0.46, MeOH).
for C22H23N2O7F3Na 507.1349, found 507.1351; [R]20 ꢀ7.6 (c 0.63,
D
MeOH).
Table 4, entry 5: 1-(Bromomethyl)-3-methyl-2-nitrobenzene:
To a solution of (3-methyl-2-nitrophenyl)methanol (2.5 g, 15 mmol, 1
equiv) in CH3CN (50 mL) was added CBr4 (4.96 g, 15 mmol, 1 equiv)
followed by PPh3 (3.92 g, 15 mmol, 1 equiv). The reaction was allowed to stir
at rt for 18 h. The reaction mixture was washed with water, dried (MgSO4),
filtered, and concentrated. The crude product mixture was purified via
chromatography (40 g silica), eluting with 0ꢀ30% EtOAc/heptane to give
1-(bromomethyl)-3-methyl-2-nitrobenzene (2.56 g, 74%). 1H NMR (400
MHz, CDCl3) δ7.36ꢀ7.29 (m, 2H), 7.25ꢀ7.20 (m, 1H), 4.42 (s, 2H), 2.30
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 150.7, 132.1, 131.0, 131.0, 129.8,
129.2, 27.2, 17.9. Anal. Calcd for C8H8NO2Br: C, 41.77; H, 3.51; N, 6.09.
Found: C, 41.86; H, 3.69; N, 6.09.
tert-Butyl N-(diphenylmethylidene)-3-methyl-2-nitro-L-
phenylalaninate. To a solution of 1-(bromomethyl)-3-methyl-2-
nitrobenzene (1.21 g, 5.26 mmol, 1 equiv) in CH2Cl2 (30 mL) cooled
to ꢀ30 °C was added tert-butyl N-(diphenylmethylidene)glycinate
(2.06 g, 6.84 mmol, 1.3 equiv) and (ꢀ)-(O)-(9)-allyl-N-(9-anthrace-
nylmethyl)cinchodinium bromide (335 mg, 0.525 mmol, 0.1 equiv).
CsOH (1.13 g, 6.84 mmol, 1.3 equiv) was added and the mixture was
allowed to stir for 18 h. The reaction mixture was washed with water,
dried (Na2SO4), filtered, and concentrated. The crude mixture was
purified by flash chromatography on silica gel eluting with CH2Cl2
(isocratic) to give tert-butyl N-(diphenylmethylidene)-3-methyl-2-ni-
1
tro-L-phenylalaninate (620 mg, 27%, 96% ee). H NMR (400 MHz,
CD3OD) δ 7.50ꢀ7.41 (m, 1H), 7.39ꢀ7.29 (m, 2H), 4.24ꢀ4.13 (m,
1H), 3.25ꢀ3.19 (m, 1H), 3.08 (dd, J = 8.1, 14.7 Hz, 1H), 2.30 (s, 3H);
13C NMR (100 MHz, CD3OD) δ 169.0, 139.1, 132.8, 129.7, 127.1,
126.6, 126.3, 34.0, 28.8, 21.2; HRMS (m/z) [M þ H]þ calcd for
C27H29N2O4 445.2121, found 445.2129; [R]20D ꢀ211 (c 0.28, MeOH).
3-Methyl-2-nitro-L-phenylalanine hydrochloride: To a so-
lution of tert-butyl N-(diphenylmethylidene)-3-methyl-2-nitro-L-pheny-
lalaninate (289 mg, 0.65 mmol) in CH2Cl2 (7 mL) was added TFA
(7 mL). The reaction was allowed to stir at rt for 18 h, then concentrated
to remove TFA. The residue was partitioned between 4 M HCl and
Et2O. The aqueous layer was washed several times with Et2O and then
concentrated to give 3-methyl-2-nitro-L-phenylalanine (140 mg, 96%
yield) as its HCl salt. 1H NMR (400 MHz, CD3OD) δ 7.50ꢀ7.41 (m,
1H), 7.39ꢀ7.29 (m, 2H), 4.24ꢀ4.13 (m, 1H), 3.25ꢀ3.19 (m, 1H), 3.08
(dd, J = 8.1, 14.7 Hz, 1H), 2.30 (s, 3H); 13C NMR (100 MHz, CD3OD)
δ 169.0, 139.1, 132.8, 129.7, 127.1, 126.6, 126.3, 34.0, 28.8, 21.2; HRMS
(m/z) [M þ H]þ calcd for C10H12N2O4 225.0877, found 225.0869;
[R]20D þ1.25 (c 0.32, MeOH).
N-(tert-Butoxycarbonyl)-2-nitro-3-phenoxy-L-phenylalanine:
To a solution of N-(tert-butoxycarbonyl)-3-fluoro-2-nitro-L-phenylalanine
(400 mg, 1.2 mmol, 1 equiv) in DMF (2 mL) was added phenol (206 mg,
2.19 mmol, 1.8 equiv) and Cs2CO3 (1.19 g, 3.65 mmol, 3 equiv). The
reaction was heated at 70 °C for 18 h. The reaction mixture was diluted with
water and the aqueous layer was washed with EtOAc (1ꢁ) to remove excess
phenol. The aqueous phase was then acidified with 10% citric acid to pH 6
and extracted with EtOAc. The combined organic layers were washed twice
with brine, dried (MgSO4), filtered, and concentrated to give N-(tert-
butoxycarbonyl)-2-nitro-3-phenoxy-L-phenylalanine (347 mg, 70% yield).
1H NMR (400 MHz, CD3OD) δ 7.38ꢀ7.29 (m, 3H), 7.23ꢀ7.18 (m, 1H),
7.19ꢀ7.10 (m, 1H), 7.03ꢀ6.98 (m, 2H), 6.84ꢀ6.78 (m, 1H), 4.43ꢀ4.03
(m, 1H), 3.25ꢀ3.17 (m, 1 H), 2.91ꢀ2.81 (m, 1 H), 1.34 (s, 9H); 13CNMR
(100MHz, CD3OD) δ175.8, 156.3, 155.9, 148.4, 141.8, 132.1, 130.5, 129.6,
125.6, 124.1, 118.6, 117.3, 78.8, 55.8, 34.0, 27.3; HRMS (m/z) [M þ Na]þ
calcd for C20H22N2O7Na 425.1319, found 425.1309; [R]20D ꢀ5 (c 0.42,
MeOH).
2,2,2-Trifluoroethyl N-(tert-butoxycarbonyl)-3-methyl-2-
nitro-L-phenylalaninate (25e): To a solution of 3-methyl-2-nitro-
L-phenylalanine (115 mg, 0.51 mmol, 1 equiv) in water (10 mL) was
added NEt3 (0.2 mL, 1.47 mmol, 3 equiv) and Boc2O (164 mg, 0.735
mmol, 1.5 equiv) and the reaction was stirred at room temperature
overnight. The reaction was acidified with 10% citric acid to pH ∼5, then
extracted with EtOAc. The organic layers were washed with H2O and
brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude
product mixture was purified by chromatography on silica gel, eluting
with 0ꢀ40% EtOAc/heptane to give N-(tert-butoxycarbonyl)-3-methyl-
2-nitro-L-phenylalanine (141 mg, 85% yield). To a solution of N-(tert-
butoxycarbonyl)-3-methyl-2-nitro-L-phenylalanine (91 mg, 0.28 mmol,
1 equiv) in THF (5 mL) was added NEt3 (0.1 mL, 0.70 mmol, 2.5 equiv)
and trifluoroethyl trifluoromethanesulfonate (85 mg, 0.365 mmol,
1.3 equiv). The reaction was heated at 60 °C overnight. The reaction
2,2,2-Trifluoroethyl
N-(tert-butoxycarbonyl)-2-nitro-3-
phenoxy-L-phenylalaninate (25d): To a solution of N-(tert-
butoxycarbonyl)-2-nitro-3-phenoxy-L-phenylalanine (280 mg, 0.862 mmol,
1 equiv) in THF (5 mL) was added NEt3 (0.309 mL, 2.16 mmol, 2.5 equiv)
and trifluoroethyl trifluoromethanesulfonate (260 mg, 1.12 mmol, 1.3
equiv). The reaction was heated at 60 °C overnight. The reaction mixture
was partitioned between EtOAc and water. The organic layer was washed
with water, dried (MgSO4), filtered, and concentrated. The crude product
mixture was purified by chromatography on silica (12 g), eluting with
0ꢀ100% EtOAc/heptane to give 2,2,2-trifluoroethyl N-(tert-butoxycarbo-
nyl)-2-nitro-3-phenoxy-L-phenylalaninate (25d) as a white solid (280 mg,
67% yield). 1H NMR (400 MHz, CDCl3) δ 7.41ꢀ7.28 (m, 3H),
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mixture was partitioned between EtOAc and water. The organic layer was
washed with water, dried (MgSO4), filtered, and concentrated. The crude
product mixture was purified by silica gel chromatography (12 g silica),
eluting with 0ꢀ100% EtOAc/heptane to give 2,2,2-trifluoroethyl N-(tert-
butoxycarbonyl)-3-methyl-2-nitro-L-phenylalaninate (25e) as a white solid
(81 mg, 71% yield). 1H NMR (400 MHz, CDCl3) δ 7.35ꢀ7.28 (m, 1H),
7.18 (d, J = 7.4 Hz, 2H), 5.13 (d, J = 7.4 Hz, 1H), 4.60 (d, J = 6.2 Hz, 1H),
4.53ꢀ4.40 (m, 2H), 3.13ꢀ3.04 (m, 1H), 2.94 (dd, J = 8.6, 14.1 Hz, 1H),
2.29 (s, 3H), 1.37 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 170.2, 155.2,
152.1, 130.6, 130.6, 130.3, 128.9, 128.1, 121.4, 80.7, 61.3, 54.3, 33.7, 28.4,
17.9; HRMS (m/z) [M þ Na]þ calcd for C17H21F3N2O6Na 429.1243,
found 429.1248; [R]20D þ2.9 (c 0.25, MeOH).
J = 8.0 Hz, 1H), 6.84 (d, J = 7.4 Hz, 1H), 4.37ꢀ4.24 (m, 1H), 3.88 (s,
3H), 3.03ꢀ2.89 (m, J = 9.4 Hz, 2H), 1.46 (s, 9H); 13C NMR (100 MHz,
CD3OD) δ 167.6, 150.3, 128.3, 127.3, 126.1, 119.3, 112.1, 79.2, 55.3,
50.6, 32.1, 27.1.
tert-Butyl [(3S)-1-hydroxy-2-oxo-8-(trifluoromethyl)-1,2,3,4-
tetrahydroquinolin-3-yl]carbamate (28c): The title compound was
prepared from 25c (100 mg, 0.217 mmol) according to general procedure E
to give tert-butyl [(3S)-1-hydroxy-2-oxo-8-(trifluoromethyl)-1,2,3,4-tetra-
hydroquinolin-3-yl]carbamate (28c) (50 mg, 66% yield). 1H NMR (400
MHz, CD3OD) δ 7.71ꢀ7.63 (m, 1 H), 7.54ꢀ7.47 (m, 1 H), 7.28ꢀ7.21
(m, 1 H), 4.47ꢀ4.35 (m, 1 H), 3.17ꢀ2.97 (m, 2 H), 1.47 (s, 9 H); 13C
NMR (100 MHz, CDCl3) δ 165.8, 155.5, 132.0, 127.8, 126.6, 125.4, 124.8,
122.1, 119.6, 80.7, 49.6, 33.3, 28.5; HRMS (m/z) [M þ Na]þ calcd for
C15H17F3N2NaO4 369.1033, found 369.1037.
Table 4, entry 6: N-(tert-Butoxycarbonyl)-3-chloro-2-ni-
tro-L-phenylalanine: To a solution of 3-chloro-2-nitro-L-phenylala-
nine (1.5 g, 5.36 mmol) in water:dioxane (1:2) (27 mL) was added NEt3
(3.0 mL, 21 mmol) and Boc2O (3.04 mL, 13.4 mmol) at rt and the
reaction was stirred for 30 min. The reaction mixture was concentrated,
diluted with EtOAc, and washed with saturated aq NH4Cl solution. The
organic layer was dried over Na2SO4, filtered, and concentrated to obtain
crude compound, which was triturated with n-pentane to afford N-(tert-
butoxycarbonyl)-3-chloro-2-nitro-L-phenylalanine (1.2 g, 66% yield).
2,2,2-Trifluoroethyl N-(tert-butoxycarbonyl)-3-chloro-2-
tert-Butyl [(3S)-1-hydroxy-2-oxo-8-phenoxy-1,2,3,4-tetra-
hydroquinolin-3-yl]carbamate (28d): The title compound was
prepared from 25d (80 mg, 0.16 mmol) according to general procedure
E to give tert-butyl [(3S)-1-hydroxy-2-oxo-8-phenoxy-1,2,3,4-tetrahy-
droquinolin-3-yl]carbamate (28d) (20 mg, 33% yield) and 25d (24 mg,
1
30% yield). H NMR (400 MHz, CD3OD) δ 7.35ꢀ7.22 (m, 2H),
7.15ꢀ6.98 (m, 3H), 7.00ꢀ6.89 (m, 2H), 6.89ꢀ6.76 (m, 1H),
4.49ꢀ4.28 (m, 1H), 3.09ꢀ2.95 (m, 2H), 1.45 (s, 9H); 13C NMR
(100 MHz, CD3OD) δ 167.2, 157.9, 156.3, 145.7, 131.2, 129.2, 127.4,
125.6, 122.8, 122.4, 120.9, 117.4, 79.4, 50.3, 32.1, 27.2; HRMS (m/z)
[M þ Na]þ calcd for C20H22N2O5Na 393.1421, found 393.1412;
[R]20D ꢀ57.2 (c 0.63, MeOH).
nitro-L-phenylalaninate (25f): To
a solution of N-(tert-
butoxycarbonyl)-3-chloro-2-nitro-L-phenylalanine (1 g, 2.91 mmol)
and Et3N (1.0 mL, 7.267 mmol) in THF (25 mL) was added 2,2,2-
trifluoroethyl trifluoromethanesulfonate (1.18, 4.941 mmol). The mix-
ture was stirred at 60 °C for 12 h. The reaction mixture was cooled to rt
and the solvent was evaporated. The residual oil was partitioned between
EtOAc and water, and the organic layer was washed with brine, dried
over Na2SO4, filtered, and concentrated to obtain crude compound. The
crude product was triturated with n-pentane to afford 2,2,2-trifluor-
tert-Butyl [(3S)-1-hydroxy-8-methyl-2-oxo-1,2,3,4-tetra-
hydroquinolin-3-yl]carbamate (28e): The title compound was
prepared from 25e (70 mg, 0.17 mmol) according to general procedure
E to give tert-butyl [(3S)-1-hydroxy-8-methyl-2-oxo-1,2,3,4-tetrahydro-
quinolin-3-yl]carbamate (28e) (23 mg, 46% yield). 1H NMR (400
MHz, CD3OD) δ 7.12ꢀ7.07 (m, 1H), 7.07ꢀ7.02 (m, 1H), 7.02ꢀ6.95
(m, 1H), 4.31 (s, 1H), 3.07ꢀ2.76 (m, 2H), 2.45 (s, 3H), 1.45 (s, 9H);
13C NMR (100 MHz, CD3OD) δ 167.7, 156.7, 137.8, 131.5, 128.4,
125.8, 125.3, 125.0, 79.6, 50.3, 32.6, 27.5, 19.8; HRMS (m/z) [M þ
oethyl
N-(tert-butoxycarbonyl)-3-chloro-2-nitro-L-phenylalaninate
(25f) (560 mg, 45% yield). 1H NMR (400 MHz, CDCl3) δ 7.39 (d, J
= 7.0 Hz, 3H), 5.16ꢀ5.02 (m, 1H), 4.67ꢀ4.56 (m, 1H), 4.49 (dd, J = 2.1,
8.4 Hz, 2H), 3.18ꢀ3.06 (m, 1H), 3.03ꢀ2.90 (m, 1H), 1.38 (s, 9H); 13C
NMR (100 MHz, CDCl3) δ 169.8, 154.9, 131.2, 130.4, 129.8, 129.7,
124.1, 121.2, 81.0, 61.3, 54.0, 33.8, 28.3. Anal. Calcd for C16H18-
ClF3N2O6: C, 45.03; H, 4.25; N, 6.56. Found: C, 44.85; H, 4.06;
N. 6.50.
Na]þ calcd for C15H20N2O4Na 315.1315, found 315.1320; [R]20
D
ꢀ31.6 (c 0.28, MeOH).
tert-Butyl [(3S)-8-chloro-1-hydroxy-2-oxo-1,2,3,4-tetrahy-
droquinolin-3-yl]carbamate (28f): The title compound was pre-
pared from 25f (0.45 g, 1.03 mmol) according to general procedure E to
give tert-butyl [(3S)-8-chloro-1-hydroxy-2-oxo-1,2,3,4-tetrahydroqui-
Reductive Cyclization of Trifluoroethyl Ester Amino Acids:
Preparation of 28aꢀf
1
nolin-3-yl]carbamate (28f) (0.2 g, 60% yield). H NMR (400 MHz,
tert-Butyl
[(3S)-1-hydroxy-2-oxo-8-(trifluoromethoxy)-
CD3OD) δ 7.35ꢀ7.28 (m, 1H), 7.20ꢀ7.13 (m, 1H), 7.10ꢀ7.01 (m,
1H), 4.40ꢀ4.23 (m, 1H), 3.06ꢀ2.93 (m, 2H), 1.43 (s, 9H); 13C NMR
(100 MHz, CD3OD) δ 168.2, 156.4, 136.6, 130.7, 128.7, 126.3, 126.0,
124.0, 79.7, 50.5, 32.5, 27.5; HRMS (m/z) [M þ Na]þ calcd for
C14H17ClN2O4Na 335.0769, found 335.0796.
1,2,3,4-tetrahydroquinolin-3-yl]carbamate (28a)—General
Procedure E: To solution of 2,2,2-trifluoroethyl N-(tert-
a
butoxycarbonyl)-2-nitro-3-(trifluoromethoxy)-L-phenylalaninate (25a)
(324 mg, 0.68 mmol, 1 equiv) in pyridine (10 mL) was added 5% Pt/C
catalyst (33 mg). The reaction was shaken on a Parr shaker at 30 psi of
H2 for 3 h. The reaction mixture was filtered through Celite and
concentrated. The crude product mixture was purified by flash chroma-
tography on silica gel (25 g) eluting with 0ꢀ100% EtOAc/heptane to
give tert-butyl [(3S)-1-hydroxy-2-oxo-8-(trifluoromethoxy)-1,2,3,4-tet-
rahydroquinolin-3-yl]carbamate (28a) (218 mg, 88% yield). 1H NMR
(400 MHz, CD3OD) δ 7.30ꢀ7.24 (m, 2H), 7.21ꢀ7.14 (m, 1H), 4.38
(dd, J = 7.0, 13.3 Hz, 1H), 3.15ꢀ2.99 (m, 2H), 1.47 (s, 9H); 13C NMR
(100 MHz, CD3OD) δ 168.2, 157.9, 138.7, 133.2, 128.8, 127.8, 126.5,
123.5, 123.3, 120.7, 80.8, 51.4, 33.2, 28.6; HRMS (m/z) [M þ Na]þ
calcd for C15H17F3N2O5Na 385.0981, found 385.0983; [R]20D ꢀ25.95
(c 0.42, MeOH).
tert-Butyl [(3S)-1-hydroxy-8-methoxy-2-oxo-1,2,3,4-tetra-
hydroquinolin-3-yl]carbamate (28b): The title compound was
prepared from 25b (29 mg, 0.069 mmol) according to general procedure
E to give tert-butyl [(3S)-1-hydroxy-8-methoxy-2-oxo-1,2,3,4-tetrahy-
droquinolin-3-yl]carbamate (28b) (13.4 mg, 64% yield). 1H NMR (400
MHz, CD3OD) δ 7.16ꢀ7.09 (m, 1H), 7.00 (d, J = 8.2 Hz, 1H), 6.93 (d,
Preparation of 30aꢀe
(3S)-3-Amino-1-hydroxy-8-(trifluoromethoxy)-3,4-dihydroqui-
nolin-2(1H)-one (30a)—General Procedure F: To a solution of tert-
butyl [(3S)-1-hydroxy-2-oxo-8-(trifluoromethoxy)-1,2,3,4-tetrahydroquino-
lin-3-yl]carbamate (28a) (178 mg, 0.49 mmol) in Et2O was added 2 M
HCl in Et2O. The reaction mixture was allowed to stir overnight at rt. The
solid precipitate was filtered and washed with Et2O to give (3S)-3-amino-1-
hydroxy-8-(trifluoromethoxy)-3,4-dihydroquinolin-2(1H)-one (30a) (120
1
mg, 82% yield). H NMR (400 MHz, CD3OD) δ 7.39ꢀ7.30 (m, 2H),
7.30ꢀ7.22 (m, 1H), 4.37 (dd, J= 7.2, 13.5 Hz, 1H), 3.28ꢀ3.19 (m, 2H); 13C
NMR (100 MHz, CD3OD) δ 163.4, 137.7, 131.7, 127.0, 126.0, 125.3, 123.0,
120.8, 48.9, 29.8; HRMS (m/z) [M þ H]þ calcd for C10H9F3N2O3
263.0638, found 263.0633; [R]20D ꢀ25.37 (c 0.46, MeOH).
(3S)-3-Amino-1-hydroxy-8-methoxy-3,4-dihydroquinolin-
2(1H)-one (30b): The title compound was prepared from 28b (13 mg,
0.042 mmol) according to general procedure F to give (3S)-3-amino-1-
hydroxy-8-methoxy-3,4-dihydroquinolin-2(1H)-one (30b) (7.1 mg, 70%
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The Journal of Organic Chemistry
ARTICLE
yield). 1H NMR (300 MHz, DMSO-d6) δ 10.38 (br s, 1H), 8.61 (br s,
3H), 7.20ꢀ7.11 (m, 1H), 7.10ꢀ7.01 (m, 1H), 6.92 (d, J = 7.7 Hz, 1H),
4.40ꢀ4.22 (m, 1H), 3.81 (s, 3H), 3.16ꢀ2.99 (m, 2H); 13C NMR (101
MHz, DMSO-d6) δ 163.8, 150.0, 128.3, 126.2, 125.3, 119.7, 113.0, 56.2,
48.5, 29.7; HRMS (m/z) [M þ H]þ calcd for C10H13N2O3 209.0920,
found 209.0918.
support. We thank Dr. Katherine E. Brighty for her editing
assistance.
’ REFERENCES
(1) (a) Davis, A. L.; Choun, O. H. P.; Cook, D. E.; McCord, T. J.
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1, 134.
(3S)-3-Amino-1-hydroxy-8-(trifluoromethyl)-3,4-dihydro-
quinolin-2(1H)-one (30c): The title compound was prepared from
28c (50 mg, 0.144 mmol) according to general procedure F to give (3S)-
3-amino-1-hydroxy-8-(trifluoromethyl)-3,4-dihydroquinolin-2(1H)-
1
one (30c) (20 mg, 56% yield). H NMR (400 MHz, DMSO-d6) δ
11.12ꢀ10.93 (m, 1H), 8.74ꢀ8.59 (m, 2H), 7.76ꢀ7.71 (m, 1H), 7.69ꢀ
7.64 (m, 1H), 7.39ꢀ7.25 (m, 1H), 4.57ꢀ4.41 (m, 1H), 3.27ꢀ3.05 (m,
2H); 13C NMR (100 MHz, CD3OD) δ 162.9, 137.0, 131.7, 127.6, 125.0,
124.7, 124.4, 122.0, 48.4, 29.7; HRMS (m/z) [M þ H]þ calcd for
C10H10F3N2O2 247.0687, found 247.0689.
(3S)-3-Amino-1-hydroxy-8-phenoxy-3,4-dihydroquinolin-
2(1H)-one (30d): The title compound was prepared from 28d (280
mg, 0.75 mmol) according to general procedure F to give (3S)-3-amino-
1-hydroxy-8-phenoxy-3,4-dihydroquinolin-2(1H)-one (30d) (190 mg,
(5) Porzelle, A.; Woodrow, M. D.; Tomkinson, N. C. O. Org. Lett.
2009, 11, 233.
(6) Davis, A. L.; Chambers, W. H.; Kelley, D. H.; Fell, D. A.; Haynes,
J. R.; Hulmw, K. L.; Gage, L. G.; McCord, T. J. J. Med. Chem. 1975,
18, 752.
1
94% yield). H NMR (400 MHz, CD3OD) δ 7.36ꢀ7.24 (m, 2H),
7.17ꢀ7.03 (m, 3H), 6.96ꢀ6.92 (m, 2H), 6.92ꢀ6.88 (m, 1H), 4.43ꢀ4.26
(m, 1H), 3.23ꢀ3.15 (m, 2H); 13C NMR (100 MHz, CD3OD) δ 163.4,
157.7, 146.2, 130.8, 129.3, 126.3, 125.0, 123.0, 122.7, 121.4, 117.6, 49.0,
29.9; HRMS (m/z) [M þ H]þ calcd for C15H15N2O3 271.1077, found
271.1077; [R]20D ꢀ38.3 (c 0.34, MeOH).
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(3S)-3-Amino-1-hydroxy-8-methyl-3,4-dihydroquinolin-2(1H)-
one (30e): The title compound was prepared from 28e (12 mg, 0.041
mmol) according to general procedure F to afford (3S)-3-amino-1-
hydroxy-8-methyl-3,4-dihydroquinolin-2(1H)-one (30e) (10 mg,100%
yield). 1H NMR (400 MHz, CD3OD) δ 7.20ꢀ7.09 (m, 2H), 7.09ꢀ7.01
(m, 1H), 4.30ꢀ4.07 (m, 1H), 3.19ꢀ3.07 (m, 2H), 2.47 (s, 3H); 13C
NMR (100 MHz, CD3OD) δ 164.3, 137.5, 132.2, 128.6, 125.6, 125.5,
123.5, 49.4, 30.6, 19.8; HRMS (m/z) [M þ H]þ calcd for C10H13N2O2
193.0971, found 193.0971; [R]20D ꢀ9.25 (c 0.4, MeOH).
(3S)-3-Amino-8-chloro-1-hydroxy-3,4-dihydroquinolin-2(1H)-
one hydrochloride (30f): The title compound was prepared from 28f
(200 mg, 0.641 mmol) according to general procedure F to afford (3S)-3-
amino-8-chloro-1-hydroxy-3,4-dihydroquinolin-2(1H)-one as its hydro-
1
chloride salt (30f) (110 mg, 69% yield). H NMR (400 MHz, DMSO-
d6) δ 9.00 (br s, 1H), 7.42 (d, J = 7.9 Hz, 1H), 7.33 (d, J = 7.4 Hz, 1H),
7.22ꢀ7.04 (m, 1H), 4.40 (dd, J = 7.0, 13.0 Hz, 1H), 3.34ꢀ3.05 (m, 2H);
13C NMR (100 MHz, DMSO-d6) δ164.0, 136.4, 130.9, 126.9, 126.6, 126.1,
122.6, 48.1, 29.6. Anal. Calcd for C9H10Cl2N2O2: C, 43.40; H, 4.05; N,
11.25. Found: C, 43.10; H, 3.81; N, 11.06. [R]20D ꢀ6.23 (c 0.39, MeOH).
(17) Walser, A.; Zenchoff, G.; Fryer, R. I. J. Med. Chem. 1976,
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’ ASSOCIATED CONTENT
Supporting Information. 1H and 13C NMR spectra for
S
b
all compounds and chiral SFC and HPLC traces. This material is
available free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: laura.mcallister@pfizer.com.
’ ACKNOWLEDGMENT
We thank Professor Andrew Myers for helpful discussions. We
also thank Geeta Yalamanchi and Qi Yan for analytical services.
We are grateful to Dr. R. Bagepalli Madhu, Mr. C. Suresh Kumar,
Mr. K. Venkateswarlu, Mr. B. Rajasekhara Rao, and Mrs. C.
Aruna of GVK Biosciences Private Limited for resynthesis
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dx.doi.org/10.1021/jo200530j |J. Org. Chem. 2011, 76, 3484–3497