Synthesis of Highly Substituted 3-Pyrrolin-2-ones from N,N-Disubstituted α-Amino Acids

Article abstract of DOI:10.1021/acs.joc.7b03187

Highly functionalized 5-membered N-heterocyclic compounds, 4-aryl-3-chloro-5-methoxy-1-methyl-3-pyrrolin-2-ones, have been synthesized in moderate to high yields by the reaction of N,N-dimethylated aromatic α-amino acids with oxalyl chloride, followed by solvolysis with MeOH. The products possess a number of functional groups such as an amide, a mixed amido/alkoxy acetal, a vinyl halide, and an alkene and thus are promising candidates to be used as starting materials for the synthesis of diverse five-membered N-heterocyclic compounds.

Full text of DOI:10.1021/acs.joc.7b03187

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Article
Synthesis of Highly Substituted 3-Pyrrolin-2-
ones from N,N-Disubstituted #-Amino Acids
Víctor Samper Barceló, and Stefan Bienz
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b03187 • Publication Date (Web): 06 Feb 2018
Downloaded from http://pubs.acs.org on February 6, 2018
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Synthesis of Highly Substituted 3-Pyrrolin-2-ones from N,N-
Disubstituted α-Amino Acids
by Víctor Samper Barceló and Stefan Bienz*
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Department of Chemistry, University of Zurich, Winterthurerstrasse 190, CHꢀ8057
Zurich, Switzerland
stefan.bienz@chem.uzh.ch
Table of Contents/Abstract Graphic
Aryl
Cl
Aryl
1. (COCl)2
2
5–94 %
2. MeOH
MeO
O
HO C
NMe2
N
2
Me
Abstract
Highly functionalized 5ꢀmembered Nꢀheterocyclic compounds, 4ꢀarylꢀ3ꢀchloroꢀ5ꢀ
methoxyꢀ1ꢀmethylꢀ3ꢀpyrrolinꢀ2ꢀones, have been synthesized in moderate to high yields
by the reaction of N,Nꢀdimethylated aromatic αꢀamino acids with oxalyl chloride,
followed by solvolysis with MeOH. The products possess a number of functional groups
such as an amide, a mixed amido/alkoxy acetal, a vinyl halide, and an alkene, and thus
are promising candidates to be used as starting materials for the synthesis of diverse
fiveꢀmembered Nꢀheterocyclic compounds.
Introduction
Fiveꢀmembered Nꢀcontaining heterocycles are important chemical frameworks that
represent the core structures of many natural products, pharmaceutically active
1ꢀ8
compounds, or agrochemicals. Some examples of biologically active compounds that
contain differently substituted Nꢀheterocycles with different degrees of unsaturation and
levels of oxidation are shown in Figure 1. The fully saturated pyrrolidine, for instance, is
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the common structure of a number of hNK1 antagonists represented with structure 1,
and the aromatic pyrrole is contained in the naturally occurring pyrrolnitrin (2), which
10ꢀ13
shows antimycobacterial and antifungal activities.
Pyrrolidinꢀ2ꢀones and pyrrolinꢀ2ꢀ
ones are found in compounds such as (−)ꢀclausenamide (3), isolated from Clausena
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4,15
16,17
18
lansium,
and related derivatives,
which are multiꢀtarget nootropics or in
19
structures of the type 4, acting as mineralocorticoid receptor antagonists, respectively.
Also, fiveꢀmembered cyclic imides are found as frameworks in biologically active
compounds. For instance, succinimide represents the core structure of tivantinib (5), a
drug against hepatocellular carcinoma that presently is in phase III of clinical
20,21
studies,
or the maleimide framework is found in MPOꢀ0029 (6), a highly potent and
22
selective COXꢀ2 inhibitor.
CF3
F
Cl
O
Cl
OH
CF3
O N
2
CH3
H
O
N
N
H
N
OH Me
1
2
3
O
R2
O
F
Cl
SO NH
2 2
H
N
N
O
HN
Me
N
O
O
O
O
O
N
H
N
R1
Me
4
5
6
Figure 1. Selected examples of biologically active compounds that contain differently
substituted Nꢀheterocycles with different degrees of unsaturation and levels of oxidation.
In light of the widespread occurrence of fiveꢀmembered Nꢀheterocycles and their
importance as diversely substituted structural cores, any new access to these
compounds is of particular interest. Such a new access was accidently found in the
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attempt to convert N,Nꢀdimethylphenylalanine (7a) into its corresponding methyl ester
2
by treatment of the amino acid with a large excess of (COCl) followed by quenching
with MeOH. Instead of the expected ester, 3ꢀpyrrolineꢀ2ꢀone derivative 8a was obtained
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in 74% yield (Scheme 1).
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R
Cl
R
1
. (COCl)2
. MeOH
2
MeO
O
HO C
NMe2
N
2
Me
7a
R = Ph
8a R = Ph
Scheme 1
The formation of 3ꢀpyrrolinꢀ2ꢀone derivative 8a from amino acid derivative 7a attracted
our attention immediately. 3ꢀPyrrolinꢀ2ꢀone itself represents the core structure of many
natural products and biologically active materials, and numerous approaches for the
synthesis of 3ꢀpyrrolinꢀ2ꢀone derivatives have been published. This is excellently
5
reviewed in a recent monograph by Pelkey et al. Some selected examples of natural
products that contain the 3ꢀpyrrolin2ꢀone framework and illustrate the structural variety
of this class of compounds are shown in Figure 2.
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H C
3
CH3
H C
CH3
3
H C
O
3
N
O
H
CH3
H C
3
O
NH
HN
NH
HO
H
CH3 CH3
N
HO C
HO
HO
2
O
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N
O
H C
3
Ph
N
CH3
H
HO C
2
Bilirubin
Oteromycin
Leuconolam
OH
CH3
H C
3
CH3
N
OCH3
HO
OH
O
H
N
O
N
O
N
O
HO
O
OCH3
Phenopyrrozin
Pukeleimide A
Phaeosphaeride A
H C
CH3
3
Ph
CH3
N
O
CH3
O
O
CH3
N
OCH3
H C
3
N
N
H C
3
CH3
HO
HO CH3
CH3
O
HN
H C
CH3
Ph
O
O
3
Belamide A
PI-091
Figure 2. Selected examples of natural products that contain the 3ꢀpyrrolinꢀ2ꢀone
2
4
25
26
27
framework (Bilirubin, Oteromycin, Leuconolam, Phenopyrrozin, Pukeleimide
28
29
30
31
A, Phaeosphaeride A, Belamide A, PI-091 ).
Because of the highly functionalized framework of 8a and the way of its formation, we
expected the unprecedented reaction to allow a flexible access to a variety of 3ꢀpyrrolinꢀ
2
ꢀones and other fiveꢀmembered Nꢀheterocycles by variation of the starting materials
and by conversion of the compounds of the type 8 into further derivatives by
subsequent transformations. We thus decided to explore the reaction more deeply,
particularly with regards to its mechanism and its scope upon variation of the R group in
the starting amino acids 7.
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Results and Discussion
Evidently, the reaction of compound 7a to the heterocyclic product 8a involves
decarboxylation and Nꢀdemethylation of the starting amino acid and condensation of the
1
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formed intermediate with (COCl) . Scheme 2 shows two mechanistic paths that were
considered to rationalize the transformation.
O
O
O
+
(COCl)2
– MeCl
R
OH
R
O
R
O
N
Me
Me
N
N
Me
Me
O
Me
O
Cl
7
O
O
9
9’
– CO2
– 2 CO
R
Cl
R
N
N
Me
Me
Me
R
R
N
Me
NH
Me
Me
10
10’
+
(COCl)2
R
Cl
R
Cl
–
MeCl
Cl
O
Cl
O
N
N
Cl
Me Me
Me
11
11’
MeOH
8
Scheme 2
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Condensation of amino acids of the type 7 with (COCl)
intermediates of the type 9 that could decompose directly or after loss of MeCl
formation of 9') to imine/iminium/enamine intermediates of the type 10 and 10',
respectively. Condensation of the enamines with a second equivalent of (COCl)
2
may form 6ꢀmembered cyclic
(
2
could
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provide 3ꢀpyrrolinꢀ2ꢀones of the type 11 or 11', the former delivering compounds of the
type 11' by loss of MeCl. Methanolysis would then lead to the observed compounds of
the type 8.
Similar reactions as those proposed above are described in literature. The oxidative
decarboxylation of N,Nꢀdisubstituted αꢀamino acids was, e.g., synthetically exploited by
32
33ꢀ36
Weinstein and Craig, the condensation of enamines with oxalyl cloride
or with
37
fumarates delivering 3ꢀpyrrolinꢀ2ꢀones has been published as well, and also Nꢀ
38
dealkylating ring closure finds its precedence. The combination of these reactions in a
cascade, however, is new, and also new is the formation of 3ꢀchloroꢀ3ꢀpyrrolinꢀ2ꢀone
derivatives.
Evidence for the formation of compounds of the type 11' is found for 11a' (R = Ph). The
1
13
Hꢀ and CꢀNMR spectra of the virtually pure crude product obtained after treatment of
a with (COCl) showed signal distributions analogous to those that are observed for
the products of hydrolysis or methanolysis of this intermediate, and in the HRꢀEIꢀMS,
7
2
+•
the respective signal for the M ion at m/z 241.0052 (−1.51 ppm) is found.
Both mechanistic paths above suggest that two equivalents of (COCl) are required and
2
sufficient for the transformation. Thus, a 20ꢀfold excess of the reagent — as used in the
original procedure — should not be necessary, and in fact it turned out that the use of
three equivalents of the acid chloride is appropriate. Treatment of 7a with 3.1
2
equivalents of (COCl) delivered the final product 8a in as much as 94% yield.
To test whether compounds of the type 9', 10, and/or 10' are in fact intermediates in the
reaction, Nꢀmonomethylated amino acid 12a and enamines 10a and 10a', prepared
from the respective aldehydes by condensation with dimethlyamine or methylamine,
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were treated with (COCl)
2
under standard conditions (Scheme 3). Amino acid 12a
delivered under these conditions almost quantitatively the proposed intermediate 9a' but
no product of the type 8. Thus, a heterocyclic compound of the type 9' cannot be an
intermediate in the formation of the 2ꢀpyrrolinꢀ2ꢀones 8. Also, no product of the type 8
but full decomposition of the starting material was observed when enamine 10a' was
1
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9
0
2
treated with (COCl) . Thus, a reaction path proceeding via an intermediate of the type
10' can also be excluded. Treatment of enamine 10a with (COCl) , on the other hand,
2
provided the expected heterocyclic product 8a in substantial amounts. The yield,
however, remained much lower than the one obtained with the amino acid precursor 7a;
even after extensive optimization of the reaction conditions, not more than 36% of the
desired product 8a was attained.
O
O
+(COCl)2
Ph
OH
Ph
O
NH
N
Me
Me
O
O
12a
9a’
Ph
+(COCl)2
decomposition
NH
Me
10a’
Ph
Ph
Cl
+
(COCl)2
MeO
O
N
N
Me
+
MeOH
Me
Me
10a
8a
Scheme 3
Since the "short cut" to compounds of the type 8 using enamines of the type 10 did not
turn out to be beneficial, the scope of the title reaction was investigated with starting
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materials of the type 7, varied in the group R. To this purpose, the aromatic N,Nꢀ
dimethylated amino acids 7b–7n and N,Nꢀdimethylated leucine (7o) were prepared
either by reductive methylation of the respective commercial nonꢀmethylated amino acid
precursors or, in the case of 7k, analogous to literature procedures by a threeꢀstep
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9ꢀ41
synthesis starting from N,Nꢀdimethyl glycine.
treated under standardized conditions with (COCl)
subsequently, after removal of the solvent by evaporation, with an excess of MeOH at
°C for 2 h. The results of these experiments are summarized in Table 1, together with
The several amino acids were then
2
in CH Cl for 24 h at 20–22 °C, and
2
2
0
the yields that were attained in the syntheses of the starting amino acids of the type 7.
Table 1
R
Suffix
Starting Amino Acids 3ꢀPyrrolinꢀ2ꢀones
7a–7p
8a–8p
yield / %
yield / %
a
b
c
commercial
94
87
94
99
87
84
F
Br
d
79
HO
e
f
95
75
95
98
71
87
MeO
75
BnO
MeO
g
h
i
71
MeO
81**
77
2
O N
j
94
92
O
k
l
96
25
33
52
O
69*
93
S
m
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S
n
o
p
96
75
0
H
N
86
N
Me
100
2
Me
*
*
synthesized from N,Nꢀdimethylglycine
* after 48 h of reaction with (COCl)
1
1
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0
2
Evidently, aromatic R groups are required to effect an efficient conversion of
compounds of the type 7 to pyrrolinones of the type 8. Except for the histidine derived
amino acid 7o, all the starting materials with aromatic R groups (7a–7n) delivered the
desired products with reasonable to very high yields. When the R group was aliphatic,
in the case of the leucine derivative 7p, mostly decomposition of the starting material
was observed and only a trace amount of pyrrolinone 8p was obtained. This
corresponds to our observations with other aliphatic amino acids that we studied in a
preliminary substrate evaluation.
With regards to the phenylalanine derivatives, the success of the reaction is largely
independent of the nature of the substituents attached to the aromatic ring. The lower
yields obtained with the benzyloxy and bismethoxyꢀsubstituted compounds 7f and 7g is
attributed to partial cleavage of the O–Bn or O–Me bonds under the strongly acidic
reaction conditions, rather than to electronic effects. A somewhat more sluggish, but still
highꢀyielding reaction was observed with the nitro derivative 7h, for which the reaction
time had to be doubled to attain full conversion.
The results obtained with starting materials that carry heteroaromatic R groups are not
fully conclusive. All the furyl and thiophenyl derivatives 7k–7n delivered the expected
products, but the obtained yields were markedly lower than those attained with the
phenyl derivatives. Particularly with the furyl compounds, pronounced decomposition
was observed already during the reaction, and substantial amounts of the products
were lost in the course of their chromatographic purification. In addition, the products
turned out to be rather reactive: they already decomposed partly during the acquisition
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6
of their analytical data. A similar high reactivity of a 4ꢀ(2ꢀfuryl)pyrrolinone under acidic
42
conditions had already been reported previously. The behavior of histidine derivative
7o was quite different. No reaction whatsoever was observed upon treatment of the
compound with (COCl) . The reason for the special behavior of the heteroaromatically
2
0
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3
4
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7
8
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substituted starting materials is not clear, but evidently the reaction is most successful
with phenyl and substituted phenyl derivatives.
Conclusion
We have shown that N,Nꢀdimethylated αꢀamino acids of the type 7 can readily be
converted into pyrrolinones of the type 8 if the starting amino acids are substituted in βꢀ
position with an aryl group. Thus, the new reaction allows the efficient synthesis of
differently 4ꢀarylꢀsubstituted 3ꢀpyrrolinꢀ2ꢀones of the type 8 by variation of the structure
of the starting material. The distinctively functionalized compounds of the type 8 can be
regarded as structural units prone for further modifications and, thus, as starting
materials to access diverse target molecules containing the pyrrole,
pyrroline/pyrrolinone, or pyrrolidine/pyrrolidone moiety.
Experimental
General Information. Unless otherwise stated, all chemicals were of reagent grade
and purchased from commercial suppliers and used without further purification.
Reactions were carried out under Ar or N2, in dried glass equipment with dry solvents
(puriss. grade over molecular sieve). Extracts were washed with H
2
O and/or brine,
and dried over anhydrous Na SO . Evaporation of the solvents in vacuo was done
2
4
with the rotary evaporator. Chromatography: Merck silica gel 60 (40–63 ꢁm, 0.1%
Ca) with the indicated solvent system. Thin layer chromatography (TLC): Merck TLC
plates silica gel 60 on aluminum with the indicated solvent system; the spots were
4
visualized by UV light (254 and 365 nm) and a stain of KMnO . Specific optical
rotation [ : JASCO Polarimeter P-2000. M.p.: Mettler FP 5 + FP 52, coupled to an
α]
D
–1
Olympus HSC microscope, heating rate 2 ºC min ; range 2/3 to fully molten. IR
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spectra: FT/IR-4100 Spectrometer (JASCO) equipped with a JASCO MODEL ATR
(attenuated total reflection) PRO 410-S single reflection measuring attachment;
–
1 1
applied as neat samples; 1/
λ
in cm . HꢀNMR spectra: Bruker AV-300 (300 MHz);
7.26), CD OD ( 3.31), CD CN ( 1.94), or D
4.75), J in Hz. CꢀNMR spectra: Bruker AV-300 (75.5 MHz); in ppm rel. to TMS
0.00), CDCl 77.00), CD OD ( 49.15), CD CN ( 1.39), or DMSOꢀd 39.51);
δ
in ppm rel. to TMS (
δ
0.00), CDCl
3
(δ
3
δ
3
δ
2
O
1
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1
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9
0
1
3
(
(
δ
δ
δ
3
(
δ
3
δ
3
δ
6
(δ
multiplicities from DEPTꢀ135 and DEPTꢀ90 measurements. The signal assignments
given for 7c, 8c, 8i, 8j, 8k, and 8n are based on HSQC and HMBC data, for 8k
additionally on COSY and NOESY data (see supporting information). Mass
spectrometry (MS): MS (ESI/quadrupole ion trap) spectra were performed on a
Bruker ESQUIRE-LC quadrupole ion trap instrument (Bruker Daltonik GmbH,
Bremen, Germany), equipped with a combined Hewlett-Packard Atmospheric
Pressure Ion (API) source (Hewlett-Packard Co., Palo Alto, CA, USA); the solutions
−
1
(about 0.1–1 ꢁmol mL ) were continuously introduced through the electrospray
interface with a syringe infusion pump (Cole-Parmer 74900ꢀ05, Cole-Parmer
−
1
Instrument Company, Vernon Hills, Illinois, USA) at a flow rate of 5 ꢁL min ; the
−
1
MSꢀconditions were: nebulizer gas (N ) 15 psi, dry gas (N ) 7 L min , dry
2
2
temperature 300 °C, capillary voltage 4000 V, end plate 3500 V, capillary exit 100 V,
skimmer1 30 V, and trap drive 70; the MS acquisitions were performed at normal
resolution (0.6 u at half peak height), under ion charge control (ICC) conditions
(10000) in the mass range from m/z 100 to 2000; to get representative mass spectra,
8 scans were averaged. High resolution mass spectrometry (HRMS): HRMS
(ESI/Orbitrap) spectra were performed on a QExactive (Thermo Fisher Scientific,
Bremen, Germany) Orbitrap mass spectrometer equipped with a heated electrospray
ionization (ESI) source and connected to a Dionex Ultimate 3000 UHPLC system;
–1
2
the samples were dissolved in MeOH or H O at a concentration of ca. 50 ꢁg mL
thereof 1 ꢁL was injected onꢀflow with an autoꢀsampler; the mobile phase (120 ꢁL
–1
2
min flow rate) consisting of MeOH + 0.1% AcOH or MeCN/H O 2:8 + 0.1% AcOH,
chosen according to the solubility; ion source parameters were set as follows: spray
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6
–1
voltage, 3.0 kV; capillary temperature, 320 °C; sheath gas 5 L min ; and sꢀlens RF
level, 55.0; full scan MS were acquired in the alternating (+)/(–)ꢀESI mode and over
the ranges m/z 80–1200 at 70000 resolution (full width halfꢀmaximum) and with
6
automatic gain control (AGC) target of 3.00 — 10 ; the maximum allowed ion transfer
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9
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time (IT) was 30 ms; masses were calibrated below 2 ppm accuracy between m/z
130.0662 and 1621.9651 in positive and between 265.1479 and 1779.9653 in the
®
negative ESI mode using the Pierce ESI calibration solns. (ThermoFisher Scientific,
Rockford, USA); additionally, contamination of erucamide (m/z 338.3417, (+)ꢀESI)
and palmitic acid (m/z 255.2330, (–)ꢀESI) were used as lock masses in (+)ꢀ and (–)ꢀ
ESI, respectively. HRMS (ESI/QꢀTOF) spectra were performed on a Bruker maXis
QTOF highꢀresolution mass spectrometer (Bruker Daltonics, Bremen, Germany); the
samples were dissolved in an appropriate solvent at a concentration of around
−
1
−1
1 ꢁmol mL and measured at continuous flow at 3 ꢁL min ; the mass spectrometer
was operated in the positive electrospray ionization mode at 4000 V capillary voltage,
–
500 V endplate offset, with a N
2
nebulizer pressure of 0.8 bar and dry gas flow of 4
L min at 180 °C; MS acquisitions were performed in the mass range from m/z 50 to
000 at 20000 resolution (full width at half maximum) and 1.0 Hz spectra rate;
masses were calibrated between m/z 158 and 1450 or 2721 prior analysis below 2
ppm accuracy, with a 2 m solution of sodium formate or with a Fluka electrospray
−
1
2
M
calibration solution that has been 100 times diluted with MeCN, respectively. HRMS
(EI/doubleꢀfocusing magnetic sector) spectra were performed on a Thermo DFS
(ThermoFisher Scientific, Bremen, Germany) doubleꢀfocusing magnetic sector mass
spectrometer (geometry BE); mass spectra were measured in electron impact (EI)
mode at 70 eV, with solid probe inlet, a source temperature of 200 °C, an
acceleration voltage of 5 kV, and a resolution of 10000; the instrument was scanned
between e.g. m/z 300 and 350 at scan rate of 100–200 s / decade in the electric
scan mode; perfluorokerosene (PFK, Fluorochem, Derbyshire, UK) served for
calibration.
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.2. 3ꢀ(4ꢀFluorophenyl)ꢀ2ꢀ(dimethylamino)propanoic Acid (7b)
Na(CN)BH
suspension of 2ꢀaminoꢀ3ꢀ(4ꢀfluorophenyl)propanoic acid (pꢀfluoroꢀDLꢀphenylalanine, 834
mg, 4.55 mmol) and formaldehyde (37% aq. soln., 5.0 mL, 67 mmol) in H O (100 mL)
and MeCN (100 mL), upon which in a clear soln. was formed. The mixture was stirred at
1 ºC for 1 h, while the pH was kept at approx. 7 by the successive addition of glacial
AcOH. MeCN was evaporated, and the residual aq. soln. was acidified with conc. aq.
HCl. After the vigorous effervescence ceased, it was washed with Et O (2 × 150 mL),
and the H O was evaporated under reduced pressure. The residue was dissolved in
O (40 mL) and applied onto a column of DOWEX 50WX8 (H form, 50–100 mesh, 30
mL). The column was washed with H O (200 mL) and then eluted with an aq. soln. of
NH (1 , 350 mL). The fractions containing the product were combined, the solvent
3
(1518 mg, 24.16 mmol) was added at 21 °C in small portions to a stirred
1
1
1
1
1
1
1
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1
1
2
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2
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2
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3
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3
4
4
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5
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5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
2
2
2
+
H
2
2
3
M
was evaporated under reduced pressure, and the residue was dried at high vacuum to
afford pure 7b (951 mg, 4.50 mmol, 99%) as a colorless, amorphous solid.
m.p. (decomp.): ≥216 ºC (after ion exchange chromatography upon evaporation of the
1
solvents). IR: 1619. HꢀNMR (CD
3
OD): 7.36 (ddꢀlike m, “J” = 8.7, 5.4, 2 H); 7.04 (tꢀlike
13
m, “J” = 8.8, 2 H); 3.77 (t, J = 6.9, 1 H); 3.22 (d, J = 6.9, 2 H); 2.86 (s, 6 H). CꢀNMR
(CD
3
OD): 172.1 (s); 163.6 (sD, JCF = 243.7); 133.7 (sD, JCF = 3.1); 132.3 (dD, JCF = 8.6,
2
C); 116.5 (dD, JCF = 21.0, 2 C); 73.3 (d); 42.5 (q, 2 C); 34.5 (t). HRMS (ESI/Orbitrap)
+
+
2
m/z: [M + H] Calcd for C11H15FNO 212.1081; Found 212.1083.
4.3. 3ꢀ(4ꢀBromophenyl)ꢀ2ꢀ(dimethylamino)propanoic Acid (7c)
Analogous to the preparation of 7b, 2ꢀaminoꢀ3ꢀ(4ꢀbromophenyl)propanoic acid (pꢀ
bromoꢀDLꢀphenylalanine, 906 mg, 3.71 mmol) was reacted with formaldehyde (37% aq.
soln., 5.0 mL, 67 mmol) and Na(CN)BH
3
(1504 mg, 23.93 mmol) in H
2
O (100 mL) and
MeCN (100 mL) for 1 h at 21 ºC. To redissolve the crude product, H
2
O (270 mL),
acidified with conc. HCl (5 drops), was needed. Ion exchange column chromatography
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on DOWEX 50WX8 (30 mL) afforded 7c (880 mg, 3.23 mmol, 87%) as a colorless,
amorphous solid.
m.p. (decomp.): ≥257 ºC (after ion exchange chromatography upon evaporation of the
1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
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7
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1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
solvents). IR: 1614. HꢀNMR (CD
3
OD): 7.47, 7.28 (2 dꢀlike m, “J” = 8.5, AA’BB’, 2 × 2
13
2 2
arom. H); 3.77 (t, J = 6.9, CHN); 3.20 (d, J = 6.9, CH ); 2.86 (s, N(Me) ). CꢀNMR
–
5
(
(
(
CD
3
OD/(DCl in D
2
O (10
M
)) 1:1): 170.2 (s, COOH); 134.4 (s, arom. C); 132.9, 132.2
2 d, 2 × 2 arom. C); 122.3 (s, arom. CBr); 69.5 (d, CHN); 43.4, 42.0 (2 q, N(Me)
2
); 33.7
+
+
t, CH
2
). HRMS (ESI/Orbitrap) m/z: [M + H] Calcd for C11
2
H15BrNO 272.0281; Found
272.0279.
4.4. (S)ꢀ2ꢀ(Dimethylamino)ꢀ3ꢀ(4ꢀhydroxyphenyl)propanoic Acid (7d)
Analogous to the preparation of 7b, (S)ꢀ2ꢀaminoꢀ3ꢀ(4ꢀhydroxyphenyl)propanoic acid (
tyrosine, 1000 mg, 5.52 mmol) was reacted with formaldehyde (37% aq. soln., 4.5 mL,
60 mmol) and Na(CN)BH (1200 mg, 19.10 mmol) in H O (100 mL) and MeCN (100
mL) for 1 h at 23 ºC. Purification by ion exchange chromatography and recrystallization
in H O/acetone afforded 7d (1036 mg, 4.64 mmol, 84%) as a colorless, amorphous
Lꢀ
3
2
2
solid.
28
D
1
m.p. (decomp.): ≥180 ºC (H
2
O/acetone). [
α]
2
= 70.0 (c = 0.99, H O). IR: 1610. Hꢀ
2
NMR (500 MHz, D O): 7.18, 6.86 (2 d, J = 8.3, 2 × 2 H); 3.79 (dd, X of ABX, J = 8.8, 5.9,
1 H); 3.25, 3.05 (AB of ABX, JAB = 13.9, JAX = 9.0, JBX = 5.8, 2 × 1 H); 2.95, 2.92 (2 br. s,
13
2 × 3 H). CꢀNMR (125 MHz, D
2
O): 172.8 (s); 155.3 (s); 131.2 (d, 2 C); 127.5 (s); 116.3
(
(
d, 2 C); 72.7 (d); 43.4, 41.1 (2 brd. q); 33.8 (t). MS (ESI/quadrupole ion trap) m/z: 231.9
+
+
100; [M + Na] ), 210.0 (56; [M + H] ).
4.5. (S)ꢀ2ꢀ(Dimethylamino)ꢀ3ꢀ(4ꢀmethoxyphenyl) propanoic Acid (7e)
Analogous to the preparation of 7b, (S)ꢀ2ꢀaminoꢀ3ꢀ(4ꢀmethoxyphenyl)propanoic acid
Oꢀmethylꢀ ꢀtyrosine, 890 mg, 4.47 mmol) was reacted with formaldehyde (37% aq.
soln., 5.0 mL, 67 mmol) and Na(CN)BH (1522 mg, 24.22 mmol) in H O (100 mL) and
(
L
3
2
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MeCN (100 mL) for 1 h at 22 ºC to deliver, after ion exchange chromatography, 7e (963
mg, 4.31 mmol, 95%) as a colorless, amorphous solid.
m.p. (decomp.): ≥214 ºC (after ion exchange chrom. upon evaporation of the solvents).
26
1
–5
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
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5
6
7
8
9
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
[α]
D
= 26.9 (c = 1.00, MeOH). IR: 1609. HꢀNMR (DCl in D
O (10
M)): 6.25, 5.94 (2 d,
2
J = 8.2, 2 × 2 H); 3.27 (dd, X of ABX, J = 8.7, 6.2, 1 H); 2.77 (s, 3 H); 2.36, 2.16 (AB of
13
ABX, JAB = 13.9, JAX = 9.1, JBX = 5.7, 2 × 1 H); 2.01, 1.93 (2 s, 2 × 3 H). CꢀNMR
(CD
3
OD): 172.4 (s); 160.5 (s); 131.5 (d, 2 C); 129.4 (s); 115.3 (d, 2 C); 73.4 (d); 55.8
+
+
(
q); 42.5 (q, 2 C); 34.5 (t). HRMS (ESI/Orbitrap) m/z: [M + H] Calcd for C12
H
18NO
3
224.1281; Found 224.1282.
4.6. (S)ꢀ3ꢀ(4ꢀBenzyloxyphenyl)ꢀ2ꢀ(dimethylamino)propanoic Acid (7f)
Analogous to the preparation of 7b, (S)ꢀ2ꢀaminoꢀ3ꢀ(4ꢀbenzyloxyphenyl)propanoic acid
(Oꢀbenzylꢀ ꢀtyrosine, 1232 mg, 4.54 mmol) was reacted with formaldehyde (37% aq.
soln., 5.0 mL, 67 mmol) and Na(CN)BH (1555 mg, 24.75 mmol) in H O (100 mL) and
MeCN (100 mL) for 1 h at 22 ºC to deliver, after ion exchange chromatography, 7f
1025 mg, 3.42 mmol, 75%) as a colorless, amorphous solid.
L
3
2
(
m.p. (decomp.): ≥208 ºC (after ion exchange chromatography upon evaporation of the
26
1
solvents). [
DCl (37% in D
H); 5.07 (s, 2 H); 4.30 (dd, X of ABX, J = 8.9, 5.5, 1 H); 3.38, 3.19 (AB of ABX, JAB
α
]
D
= 17.9 (c = 0.10, MeOH). IR: 3400, 1609. HꢀNMR (CD
3
OD + 1 drop
2
O)): 7.44–7.28 (m, 5 H); 7.26, 6.97 (2 dꢀlike m, “J” = 8.7, AA’XX’, 2 × 2
=
13
14.2, JAX = 8.9, JBX = 5.5, 2 × 1 H); 3.02, 2.95 (2 br. s, 2 × 3 H). CꢀNMR (CD
3
OD + 5
drops DCl (37% in D
2
O)): 170.0 (s); 159.5, 138.4 (2 s); 131.7, 129.6 (2 d, 2 × 2 C);
1
3
3
29.1 (d); 128.7 (d, 2 C); 127.6 (s); 116.4 (d, 2 C); 71.1 (t); 69.9 (d); 43.2, 42.4 (2 q);
+
+
4.1 (t). HRMS (ESI/Orbitrap) m/z: [M + H] Calcd for C18
H
22NO
3
300.1594; Found
00.1592.
4.7. (S)ꢀ3ꢀ(3,4ꢀDimethoxyphenyl)ꢀ2ꢀ(dimethylamino)propanoic Acid (7g).
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Analogous to the preparation of 7b, (S)ꢀ2ꢀaminoꢀ3ꢀ(3,4ꢀdimethoxyphenyl)propanoic acid
(
m,pꢀdimethoxyꢀ
L
ꢀphenylalanine, 829 mg, 3.68 mmol) was reacted with formaldehyde
(1350 mg, 21.48 mmol) in H O (100
(37% aq. soln., 4.0 mL, 54 mmol) and Na(CN)BH
3
2
mL) and MeCN (100 mL) for 1 h at 22 ºC to deliver, after ion exchange chromatography,
a product (963 mg) that was redissolved in MeOH and dried over anhydrous MgSO to
deliver, after evaporation of the solv. and drying of the residue in vacuo in a desiccator,
g (885 mg, 3.49 mmol, 95%) as a colorless, amorphous solid.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
4
7
m.p. (decomp.): ≥184 ºC (after ion exchange chromatography upon evaporation of the
26
D
1
solvents). [
α]
= 27.0 (c = 0.50, MeOH). IR: 1611. HꢀNMR (TFAꢀd): 7.08–6.99 (m, 3
H); 4.59 (t, X of ABX, J = 7.4, 1 H); 3.98 (s, 6 H); 3.59, 3.46 (AB of ABX, JAB = 15.1, JAX
13
=
8.0, JBX = 6.9, 2 × 1 H); 3.27, 3.18 (2 s, 2 × 3 H). CꢀNMR (100 MHz, CD
3
OD): 172.3
(s); 150.9, 149.9, 130.4 (3 s); 122.9, 114.3, 113.4 (3 d); 73.3 (d); 56.64, 56.62 (2 q);
+
+
42.5 (q, 2 C); 34.9 (t). HRMS (ESI/Orbitrap) m/z: [M + H] Calcd for C13
H20NO
4
254.1387; Found 254.1386.
4.8. 2ꢀ(Dimethylamino)ꢀ3ꢀ(4ꢀnitrophenyl)propanoic Acid (7h)
Analogous to the preparation of 7b, 2ꢀaminoꢀ3ꢀ(4ꢀnitrophenyl)propanoic acid (pꢀnitroꢀDL
ꢀ
phenylalanine, 946 mg, 4.50 mmol) was reacted with formaldehyde (37% aq. soln., 5.0
3 2
mL, 67 mmol) and Na(CN)BH (1544 mg, 24.57 mmol) in H O (100 mL) and MeCN (100
mL) for 1 h at 22 ºC to deliver, after ion exchange chromatography, 7h (1056 mg, 4.43
mmol, 98%) as a slightly orange amorphous solid.
m.p. (decomp.): ≥223 ºC (after ion exchange chromatography upon evaporation of the
1
solvents). IR: 1622, 1509, 1344. HꢀNMR (CD
3
2
OD + 1 drop DCl (37% in D O)): 8.21,
7.64 (2 dꢀlike m, “J” = 8.7, AA’XX’, 2 × 2 H); 4.48 (dd, X of ABX, J = 10.1, 4.8, 1 H); 3.63,
13
3
.37 (AB of ABX, JAB = 13.8, JAX = 10.1, JBX = 4.8, 2 × 1 H); 3.06 (s, 6 H). CꢀNMR
(TFAꢀd): 172.2 (s); 149.7, 143.4 (2 s); 132.4, 126.7 (2 d, 2 × 2 C); 70.6 (d); 44.9, 43.6 (2
+
+
q); 34.6 (t). HRMS (ESI/Orbitrap) m/z: [M + H] Calcd for C11
15 2 4
H N O 239.1026; Found
239.1027.
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.9. 2ꢀ(Dimethylamino)ꢀ3ꢀ(2ꢀnaphthyl)propanoic Acid (7i)
Analogous to the preparation of 7b, 2ꢀaminoꢀ3ꢀ(2ꢀnaphthyl)propanoic acid (3ꢀ(2ꢀ
naphthyl)ꢀDLꢀalanine, 1023 mg, 4.75 mmol) was reacted with formaldehyde (37% aq.
1
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1
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1
2
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2
2
2
2
2
2
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0
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9
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7
8
9
0
1
2
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5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3 2
soln., 5.0 mL, 67 mmol) and Na(CN)BH (1547 mg, 24.62 mmol) in H O (100 mL) and
MeCN (100 mL) for 1 h at 22 ºC to deliver, after ion exchange chromatography, a
product (1110 mg). MeOH was added until no more of the solid was dissolved. After
filtration of the suspension, the solv. of the filtrate was evaporated to deliver 7i (820 mg,
3.37 mmol, 71%) as a colorless, amorphous solid.
1
m.p. (decomp.): ≥223 ºC (upon evaporation of MeOH). IR: 1600. HꢀNMR (CD
3
OD):
7.86–7.80 (m, 4 H); 7.52–7.42 (m, 3 H); 3.95 (t, X of ABX, J = 6.9, 1 H); 3.51–3.36
13
(
symm. m, 8 distinctive lines, AB of ABX, 2 H); 2.87 (s, 6 H). CꢀNMR (100 MHz,
DMSOꢀd + 5 drops DCl (37% in D O)): 169.2 (s); 133.7, 133.4, 132.9 (3 s); 129.0,
128.7, 128.4, 128.3, 128.2, 127.3, 127.0 (7 d); 68.0 (d); 42.0 (q, 2 C); 34.0 (t). HRMS
6
2
+
+
(ESI/Orbitrap) m/z: [M + H] Calcd for C15
H
18NO
2
244.1332; Found 244.1332.
4.10. (S)ꢀ2ꢀDimethylaminoꢀ3ꢀ(1ꢀnaphthyl)propanoic Acid (7j)
Analogous to the preparation of 7b, (S)ꢀ2ꢀaminoꢀ3ꢀ(1ꢀnaphthyl)propanoic acid (3ꢀ(1ꢀ
naphthyl)ꢀ ꢀalanine, 1018 mg, 4.73 mmol) was reacted with formaldehyde (37% aq.
soln., 5.0 mL, 67 mmol) and Na(CN)BH (1532 mg, 24.38 mmol) in H O (100 mL) and
L
3
2
MeCN (100 mL) for 1 h at 22 ºC to deliver, after ion exchange chromatography, 7j (1082
mg, 4.45 mmol, 94%) as a colorless, amorphous solid.
2
D
6
m.p. (decomp.): ≥211 ºC (upon evaporation of MeOH). [
α
]
= 78.0 (c = 1.00, MeOH).
1
IR: 1615. HꢀNMR (CD
3
OD): 8.19 (d, J = 8.4, 1 H); 7.88 (dꢀlike m, “J” = 8.0, 1 H), 7.80
(d, J = 8.2, 1 H); 7.60–7.39 (m, 4 H); 3.99 (t, J = 7.4, 1 H); 3.70 (d, J = 7.4, 2 H); 2.87 (s,
13
6
H). CꢀNMR (CD
3
OD): 172.2 (s); 135.7, 133.7, 133.2 (3 s); 130.2, 129.3, 129.1,
127.7, 127.0, 126.7, 124.6 (7 d); 72.7 (d); 42.2 (q, 2 C); 32.8 (t). HRMS (ESI/Orbitrap)
+
+
2
m/z: [M + H] Calcd for C15H18NO 244.1332; Found 244.1332.
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.11. 2ꢀ(Dimethylamino)ꢀ3ꢀ(2ꢀfuryl)propanoic Acid (7k)
Analogous to the preparation of 7b, 2ꢀaminoꢀ3ꢀ(2ꢀfuryl)propanoic acid (3ꢀ(2ꢀfuryl)ꢀDL
alanine, 737 mg, 4.75 mmol) was reacted with formaldehyde (37% aq. soln., 5.0 mL, 67
mmol) and Na(CN)BH (1569 mg, 24.97 mmol) in H O (100 mL) and MeCN (100 mL)
for 1 h at 22 ºC to deliver, after ion exchange chromatography, 7k (837 mg, 4.57 mmol,
6%) as a slightly brownish amorphous solid.
ꢀ
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
2
9
1
m.p. (decomp.): ≥170 ºC (upon evaporation of MeOH). IR: 1626. HꢀNMR (CD
3
OD):
.47 (ddꢀlike m, “J” = 1.8, 0.7, 1 H); 6.37 (dd, J = 3.2, 1.9, 1 H); 6.31 (brd. dꢀlike m, “J” =
.2, 1 H); 3.89 (dd, X of ABX, J = 6.9, 5.2, 1 H); 3.44, 3.33 (AB of ABX, JAB = 16.3, JAX
7
3
6
1
=
13
3
.9, JBX = 5.3, 2 × 1 H); 2.83 (s, 6 H). CꢀNMR (CD OD): 171.6 (s); 151.3 (s); 143.5,
+
11.9, 109.5 (3 d); 70.6 (d); 42.4 (q, 2 C); 27.6 (t). HRMS (ESI/Orbitrap) m/z: [M + H]
+
3
Calcd for C
9
H
14NO
184.0968; Found 184.0969.
4.12. 2ꢀ(Dimethylamino)ꢀ3ꢀ(3ꢀfuryl)propanoic Acid (7l)
NaH (60% in mineral oil, 2.40 g, 60.0 mmol) was washed with hexane (3 x 10 mL),
suspended in Et
2
O (45 mL), and MeOH (244 ꢀl, 6.0 mmol) was added. It was cooled to
0–5 °C, and furaneꢀ3ꢀcarboxaldehyde (2.88 g, 30.0 mmol) followed by methyl 2ꢀ(N,Nꢀ
dimethylamino)acetate (methyl N,N,ꢀdimethylglycinate, 10.5 g, 90.0 mmol) were added
dropwise. It was allowed to warm to 22 °C and stirred for 16 h. The mixture was cooled
again to 0–5 °C, iceꢀH
2
O (45 mL) was added, and it was extracted with CH
2 2
Cl (4 x 45
mL) to afford, after drying over Na
2
SO and removal of the solvents in vacuo, crude
4
methyl 2ꢀ(dimethylamino)ꢀ3ꢀ(3ꢀfuryl)propenoate (intermediate 1, 6.02 g) as a reddishꢀ
brown, oily liquid, which was used without further purification in the next step.
A soln. of intermediate 1 (979 mg, corr. to 4.88 mmol of the original starting material) in
dry THF (10 mL, containing some bromocresol green) was adjusted to a pH of approx.
4
(yellow color) by the addition of an HCl soln. (1.25 M in MeOH). A soln. of Na(CN)BH
3
(793 mg, 12.60 mmol) in MeOH (15 mL) was added slowly at 22 °C, upon which the
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color of the soln. turned blue. HCl soln. (1.25
M
in MeOH) was added again until the
color of the mixture changed to yellow, and it was stirred at 22 °C for 1 h. The solvents
3
were removed in vacuo, and the residue was taken up into a sat. aq. soln. of KHCO . It
was extracted with Et
solvent was removed in vacuo. The residue was dissolved in an aq. soln. of HCl (1
10 mL) and washed with AcOEt (3 x 10 mL). The aq. phase was basified by the addition
of an aq. soln. of NH (25%), extracted with AcOEt (3 x 10 mL), and the extracts were
2 2 4
O (3 x 50 mL), the extracts were dried with Na SO , and the
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8
9
0
1
2
3
4
5
6
7
8
9
0
M
,
3
2 4
dried with Na SO to deliver after evaporation of the solvent in vacuo a crude amino
ester (679 mg, intermediate 2).
Intermediate 2 (593 mg, corr. to 4.26 mmol of the original starting material) was
dissolved in THF (3 mL), a soln. of LiOH—H
2
O (139 mg, 3.31 mmol) in H
2
O (15 mL) was
Cl
added slowly at 22 °C, and it was stirred for 3 h. The mixture was washed with CH
2
2
(3 x 15 mL) and with MeCN (3 x 5 mL) before the aq. soln. was concentrated in vacuo
to deliver the Li salt of 7l, which upon ion exchange column chromatography on
+
DOWEX 50WX8 (H form, 50–100 mesh, 15 mL), evaporation of the solvents and
drying at high vacuum afforded 7l (540 mg, 2.95 mmol, 69% over three steps) as a
slightly yellowish, amorphous solid.
m.p. (decomp.): ≥186 °C (after ion exchange chromatography upon evaporation of the
1
solvents). IR: 1615. HꢀNMR (CD
3
OD): 7.51 (brd. sꢀlike m, 1 H); 7.46 (tꢀlike m, "J" = 1.7,
1 H); 6.48 (dꢀlike m, "J" = 0.9, 1 H); 3.73 (t, J = 5.9, 1 H); 3.14 (d, J = 5.9, 2 H); 2.86 (s,
13
3
6 H). CꢀNMR (CD OD): 172.2 (s); 144.7, 142.3 (2 d); 120.5 (s); 112.5 (d); 71.8 (d);
+
+
42.6 (q, 2 C); 25.0 (t). HRMS (ESI/Orbitrap) m/z: [M + H] Calcd for C
9 3
H14NO
184.0968; Found 184.0970.
4.13. 2ꢀ(Dimethylamino)ꢀ3ꢀ(2ꢀthienyl)propanoic Acid (7m)
Analogous to the preparation of 7b, 2ꢀaminoꢀ3ꢀ(2ꢀthienyl)propanoic acid (3ꢀ(2ꢀthienyl)ꢀ
DLꢀalanine, 773 mg, 4.51 mmol) was reacted with formaldehyde (37% aq. soln., 5.0 mL,
3 2
67 mmol) and Na(CN)BH (1508 mg, 24.00 mmol) in H O (100 mL) and MeCN (100
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2
2
2
2
2
2
2
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5
6
mL) for 1 h at 21 ºC to deliver, after ion exchange chromatography, 7m (839 mg, 4.21
mmol, 93%) as a yellowish amorphous solid.
1
m.p. (decomp.): ≥202 ºC (upon evaporation of MeOH). IR: 1606. HꢀNMR (CD
3
OD):
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
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5
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9
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1
2
3
4
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3
4
5
6
7
8
9
0
7.30 (dd, J = 5.1, 1.3, 1 H); 7.06 (dd, J = 3.4, 0.9, 1 H); 6.96 (dd, J = 5.1, 3.5, 1 H); 3.83
(t, X of ABX, J = 6.4, 1 H); 3.61–3.46 (symm. m, 7 distinctive lines, AB of ABX, 2 H);
13
2
.86 (s, 6 H). CꢀNMR (CD
3
OD): 171.6 (s); 139.3 (s); 128.4, 128.3, 126.2 (3 d); 72.8
+
+
(
d); 42.5 (q, 2 C); 29.4 (t). HRMS (ESI/Orbitrap) m/z: [M + H] Calcd for C H14NO S
9 2
200.0740; Found 200.0739.
4.14. (S)ꢀ2ꢀ(Dimethylamino)ꢀ3ꢀ(3ꢀthienyl)propanoic Acid (7n)
Analogous to the preparation of 7b, (S)ꢀ2ꢀaminoꢀ3ꢀ(3ꢀthienyl)propanoic acid (3ꢀ(3ꢀ
thienyl)ꢀ ꢀalanine, 813 mg, 4.75 mmol) was reacted with formaldehyde (37% aq. soln.,
5.0 mL, 67 mmol) and Na(CN)BH (1548 mg, 24.63 mmol) in H O (100 mL) and MeCN
(100 mL) for 1 h at 22 ºC to deliver, after ion exchange chromatography, 7n (909 mg,
.56 mmol, 96%) as a slightly orange amorphous solid.
L
3
2
4
2
D
6
m.p. (decomp.): ≥189 ºC (upon evaporation of MeOH). [
α]
= 9.6 (c = 1.00, MeOH).
1
IR: 1623. HꢀNMR (CD
3
OD): 7.40 (dd, J = 4.9, 2.9, 1 H); 7.33 (brd. sꢀlike m, 1 H); 7.13
(dd, J = 4.9, 1.2, 1 H); 3.84 (t, X of ABX, J = 6.3, 1 H); 3.41–3.27 (symm. m, 7 distinctive
13
3
lines, AB of ABX, 2 H); 2.83 (s, 6 H). CꢀNMR (CD OD): 172.3 (s); 137.6 (s); 129.6,
+
127.4, 124.3 (3 d); 72.3 (d); 42.5 (q, 2 C); 29.8 (t). HRMS (ESI/Orbitrap) m/z: [M + H]
+
Calcd for C
9
H
14NO
2
S 200.0740; Found 200.0742.
4.15. (S)ꢀ2ꢀ(Dimethylamino)ꢀ3ꢀ(1Hꢀ4ꢀimidazolyl)propanoic Acid (7o)
Analogous to the preparation of 7b, (S)ꢀ2ꢀaminoꢀ3ꢀ(1Hꢀ4ꢀimidazolyl)propanoic acid (
histidine, 698 mg, 4.50 mmol) was reacted with formaldehyde (37% aq. soln., 8.0 mL,
07 mmol) and Na(CN)BH (2005 mg, 31.91 mmol) in H O (100 mL) and MeCN (100
Lꢀ
1
3
2
mL) for 1 h at 21 ºC to deliver, after ion exchange chromatography and drying in vacuo
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in a desiccator 7o (709 mg, 3.87 mmol, 86%) as a colorless, amorphous, and
hygroscopic solid.
2
D
6
m.p. (decomp.): ≥176 ºC (upon evaporation of MeOH). [
α]
= 10.7 (c = 1.00, MeOH).
1
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
IR: 3589–2119, 1618. HꢀNMR (CD
3
OD): 7.69 (dꢀlike m, J = 1.1, 1 H); 7.04 (brd. dꢀlike
m, J = 0.9, 1 H); 3.84 (t, X of ABX, J = 6.1, 1 H); 3.36–3.20 (m, AB of ABX, 2 H); 2.87 (s,
13
6
H). CꢀNMR (CD
3
OD): 172.1 (s); 136.5 (d); 134.5 (s); 117.7 (d); 71.6 (d); 42.4 (q, 2
+
+
C); 27.1 (t). HRMS (ESI/Orbitrap) m/z: [M + H] Calcd for C
8
14 3 2
H N O 184.1081; Found
184.1083.
4.16. (S)ꢀ2ꢀ(Dimethylamino)ꢀ4ꢀmethylpentanoic Acid (7p)
Analogous to the preparation of 7b, (S)ꢀ2ꢀaminoꢀ4ꢀmethylpentanoic acid (
mg, 4.52 mmol) was reacted with formaldehyde (37% aq. soln., 5.0 mL, 67 mmol) and
Na(CN)BH (1516 mg, 24.12 mmol) in H O (100 mL) and MeCN (100 mL) for 1 h at 22
Lꢀleucine, 593
3
2
ºC to deliver, after ion exchange chromatography, a solid (746 mg) that was
recrystallized from MeOH and dried in a desiccator to afford 7p (720 mg, 4.52 mmol,
100%) as colorless, cubic crystals.
26
D
1
m.p.: 203.9–204.5 ºC (MeOH). [
CD OD): 3.48 (dd, J = 10.0, 4.4, 1 H); 2.86 (s, 6 H); 1.90–1.73 (m, 2 H); 1.64–1.54 (m,
H); 1.01, 1.00 (2 d, J = 6.5, 2 × 3 H). CꢀNMR (CD
α
]
= 35.1 (c = 1.00, MeOH). IR: 1601. HꢀNMR
(
3
13
1
3
OD): 173.3 (s); 71.3 (d); 41.9 (q, 2
+
C); 38.3 (t); 26.9 (d); 24.1, 22.0 (2 d). HRMS (ESI/Orbitrap) m/z: [M + H] Calcd for
+
C
8
H
18NO
2
160.1332; Found 160.1333.
4.17. 3ꢀChloroꢀ5ꢀmethoxyꢀ1ꢀmethylꢀ4ꢀphenylꢀ1,5ꢀdihydroꢀ2Hꢀpyrrolꢀ2ꢀone (8a)
Method A: From (S)ꢀ2ꢀ(dimethylamino)ꢀ3ꢀphenylpropanoic acid (N,Nꢀdimethylꢀ
Lꢀ
phenylalanine, 7a): (COCl) (0.14 mL, 1.63 mmol) was added dropwise to a suspension
2
2 2
of 7a (100 mg, 0.52 mmol) in CH Cl (2.0 mL). A vigorous evolution of gas was
observed. The yellow soln. was stirred for 24 h at 21 ºC. Evaporation of the solvent
delivered crude 3,5ꢀdichloroꢀ1ꢀmethylꢀ4ꢀphenylꢀ1,5ꢀdihydroꢀ2Hꢀpyrrolꢀ2ꢀone (11a'). The
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orange solid was cooled in an ice/H
2
O bath, dissolved in MeOH (2.0 mL), and it was
stirred for 2 h while the cooling was continued. Evaporation of the solvent delivered a
2
crude product (133 mg) which was chromatographed (20 mL SiO , hexane/AcOEt,
gradient from 6:1 to 1:1) to afford 8a (116 mg, 0.49 mmol, 94%) as yellowish rhombic
0
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2
3
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8
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0
crystals.
Method B: From N,Nꢀdimethylꢀ2ꢀphenylethenamine (10a): To a soln. of 10a (102 mg,
0
.69 mmol) in CH
2 °C, and the mixture was stirred for 3.5 h. Evaporation of the solvent and the excess
in vacuo delivered a residue, which was cooled with an ice bath. MeOH (2.0
mL) was added, and it was stirred for 10 min. Evaporation of the solvent delivered a
crude material which was dissolved in a mixture of AcOEt (5 mL), H O (5 mL), and brine
2 2 2
Cl (2.0 mL), (COCl) (0.13 mL, 1.52 mmol) was added dropwise at
2
of (COCl)
2
2
(2 mL). The organic phase was separated, and the aqueous phase was extracted with
AcOEt (4 × 5 mL). The combined organic phases were washed with brine (3 × 5 mL),
4
dried with MgSO , and chromatographed (hexane/AcOEt, 4:1) to deliver 8a (60 mg,
0.25 mmol, 36%) as yellowish rhombic crystals.
1
3
m.p.: 106.0–106.9 ºC (AcOEt). IR: 1711. HꢀNMR (CDCl ): 7.97–7.90 (m, 2 H); 7.53–
13
7
1
2
.43 (m, 3 H); 5.76 (s, 1 H); 3.05 (s, 3 H), 2.95 (s, 3 H). CꢀNMR (CDCl
3
): 164.7 (s);
43.0 (s); 130.3 (d); 129.5 (s); 128.8, 127.8 (2 d, 2 × 2 C); 125.6 (s); 87.8 (d); 48.8 (q);
+
+
2
7.0 (q). HRMS (ESI/Orbitrap) m/z: [M + H] Calcd for C12H13ClNO 238.0629; Found
238.0629. (For single crystal xꢀray analysis, see supporting information).
4.18. 3ꢀChloroꢀ4ꢀ(4ꢀfluorophenyl)ꢀ5ꢀmethoxyꢀ1ꢀmethylꢀ1,5ꢀdihydroꢀ2Hꢀpyrrolꢀ2ꢀone (8b).
Analogous to the preparation of 8a (method A), (COCl)
reacted with 7b (110 mg, 0.52 mmol) in CH Cl (2.0 mL) for 24 h at 20 ºC and for 2 h
with MeOH (2.0 mL) to deliver, after chromatography (SiO , hexane/AcOEt 3:1), 8b
2
(0.14 mL, 1.63 mmol) was
2
2
2
(116 mg, 0.45 mmol, 87%) as colorless, rhombic crystals.
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9
1
m.p.: 108.0–108.6 ºC (AcOEt). IR: 1711. HꢀNMR (CDCl
3
): 7.99 (ddꢀlike m, “J” = 9.0, 5.3,
13
2
H); 7.19 (tꢀlike m, “J” = 8.7, 2 H); 5.76 (s, 1 H); 3.06 (s, 3 H); 2.95 (s, 3 H). CꢀNMR
(
3
CDCl ): 165.2 (s); 163.2 (sD, JCF = 217.6); 141.8 (s); 130.0 (dD, JCF = 8.6); 125.6 (sD,
19
J
CF = 3.9); 125.1 (sD, JCF = 1.9); 116.0 (dD, JCF = 21.8); 87.7 (d); 48.7 (q); 27.0 (q). Fꢀ
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
NMR (282 MHz, CDCl
3
,
δ
rel. to CFCl
3
(0.0)): –108.7 (tt, J = 8.5, 5.4). HRMS
+
+
(ESI/Orbitrap) m/z: [M + H] Calcd for C12
H
12ClFNO
2
256.0535; Found 256.0534.
4
.19. 4ꢀ(4ꢀBromophenyl)ꢀ3ꢀchloroꢀ5ꢀmethoxyꢀ1ꢀmethylꢀ1,5ꢀdihydroꢀ2Hꢀpyrrolꢀ2ꢀone (8c)
Analogous to the preparation of 8a (method A), (COCl) (0.14 mL, 1.63 mmol) was
reacted with 7c (140 mg, 0.51 mmol) in CH Cl (2.0 mL) for 24 h at 22 ºC and for 1.5 h
with MeOH (2.0 mL) to deliver, after chromatography (SiO , hexane/AcOEt, gradient
2
2
2
2
from 7:1 to 3:1), 8c (153 mg, 0.48 mmol, 94%) as colorless, rhombic crystals.
1
m.p.: 119.8–121.3 ºC (AcOEt). IR: 1713. HꢀNMR (CDCl
3
): 7.84, 7.62 (2 dꢀlike m,
13
AA’BB’, “J” = 8.8, 2 × 2 arom. H); 5.74 (s, CHOMe); 3.06 (s, NMe); 2.94 (s, OMe). Cꢀ
NMR (CDCl ): 164.5 (s, CON); 141.8 (s, ArylC); 132.1, 129.2 (2 d, 2 × 2 arom. C); 128.3
s, arom. C); 126.2 (s, CCl); 124.9 (s, arom. CBr); 87.6 (d, CHOMe); 48.8 (q, OMe);
3
(
+
+
2
7.1 (q, NMe). HRMS (ESI/Orbitrap) m/z: [M + H] Calcd for C12
2
H12BrClNO 315.9735;
Found 315.9735.
4
.20. 3ꢀChloroꢀ4ꢀ(4ꢀhydroxyphenyl)ꢀ5ꢀmethoxyꢀ1ꢀmethylꢀ1,5ꢀdihydroꢀ2Hꢀpyrrolꢀ2ꢀone
(8d)
2
Analogous to the preparation of 8a (method A), (COCl) (1.00 mL, 11.66 mmol) was
2 2
reacted with 7d (100 mg, 0.48 mmol) in CH Cl (5.0 mL) for 24 h at 23 ºC and for 20 h
with MeOH (2.0 mL) to deliver, after chromatography, 8d (80 mg, 0.38 mmol, 79%) as a
yellowish, amorphous solid.
1
m.p. (decomp.): ≥156 ºC (MeOH). IR: 3230, 1690. HꢀNMR (500 MHz, CD
3
CN): 7.82,
13
6
.94 (2 dꢀlike m, AA’XX’, “J” = 8.8, 2 × 2 H); 5.79 (s, 1 H); 2.94, 2.89 (2 s, 2 × 3 H). Cꢀ
NMR (125 MHz, CD
3
CN): 165.8 (s); 159.9 (s); 144.8 (s); 131.0 (d, 2 C); 123.3, 122.6 (2
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8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
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4
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5
5
5
5
5
5
5
5
5
6
+
s); 116.6 (d, 2 C); 88.9 (d); 49.4 (q); 27.4 (q). HRMS (ESI/QꢀTOF) m/z: [M + Na] Calcd
+
for C12
H
12ClNO
3
Na 276.0398; Found 276.0403.
4
.21. 3ꢀChloroꢀ5ꢀmethoxyꢀ4ꢀ(4ꢀmethoxyphenyl)ꢀ1ꢀmethylꢀ1,5ꢀdihydroꢀ2Hꢀpyrrolꢀ2ꢀone
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(8e)
Analogous to the preparation of 8a (method A), (COCl)
reacted with 7e (115 mg, 0.52 mmol) in CH Cl (2.0 mL) for 24 h at 22 ºC and for 2 h
with MeOH (2.0 mL) to deliver, after chromatography (SiO , hexane/AcOEt, gradient
2
(0.14 mL, 1.63 mmol) was
2
2
2
from 9:1 to 1:1), 8e (121 mg, 0.45 mmol, 87%) as colorless, rhombic crystals.
1
m.p.: 86.7–88.1 ºC (AcOEt). IR: 1710. HꢀNMR (CDCl
3
): 7.96, 7.00 (2 dꢀlike m, AA’XX’,
13
“
J” = 9.0, 2 × 2 H); 5.73 (s, 1 H); 3.87 (s, 3 H); 3.05 (s, 3 H); 2.93 (s, 3 H). CꢀNMR
(CDCl
3
): 165.1 (s); 161.0 (s); 142.4 (s); 129.5 (d, 2 C); 122.9, 122.0 (2 s); 114.1 (d, 2 C);
+
87.6 (d); 55.3 (q); 48.5 (q); 26.9 (q). HRMS (ESI/Orbitrap) m/z: [M + H] Calcd for
+
C
13
H15ClNO
3
268.0735; Found 268.0735.
4
.22. 4ꢀ(4ꢀBenzyloxyphenyl)ꢀ3ꢀchloroꢀ5ꢀmethoxyꢀ1ꢀmethylꢀ1,5ꢀdihydroꢀ2Hꢀpyrrolꢀ2ꢀone
(8f)
Analogous to the preparation of 8a (method A), (COCl)
reacted with 7f (156 mg, 0.52 mmol) in CH Cl (2.0 mL) for 24 h at 22 ºC and for 2 h
with MeOH (2.0 mL) to deliver, after chromatography (SiO , hexane/AcOEt, gradient
2
(0.14 mL, 1.63 mmol) was
2
2
2
from 9:1 to 1:1), 8f (134 mg, 0.39 mmol, 75%) as yellowish, rhombic crystals.
1
m.p.: 106.2–107.2 ºC (CDCl
3
). IR: 1710. HꢀNMR (CDCl
3
): 7.96 (dꢀlike m, AA’ of AA’XX’,
“
J” = 9.1, 2 H); 7.47–7.35 (m, 5 H); 7.06 (dꢀlike m, XX’ of AA’XX’, “J” = 9.1, 2 H); 5.72 (s,
13
1
1
1
3
H); 5.13 (s, 2 H); 3.04 (s, 3 H); 2.93 (s, 3 H). CꢀNMR (CDCl ): 165.2 (s); 160.2 (s);
42.4 (s); 136.2 (s); 129.6, 128.7 (2 d, 2 × 2 C); 128.2 (d); 127.5 (d); 123.2, 122.3 (2 s);
+
15.0 (d, 2 C); 87.8 (d); 70.0 (t); 48.6 (q); 27.0 (q). HRMS (ESI/Orbitrap) m/z: [M + H]
+
Calcd for C19
H
19ClNO
3
344.1048; Found 344.1054.
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.23. 3ꢀChloroꢀ4ꢀ(3,4ꢀdimethoxyphenyl)ꢀ5ꢀmethoxyꢀ1ꢀmethylꢀ1,5ꢀdihydroꢀ2Hꢀpyrrolꢀ2ꢀ
one (8g)
2
Analogous to the preparation of 8a (method A), (COCl) (0.14 mL, 1.63 mmol) was
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
reacted with 7g (129 mg, 0.51 mmol) in CH
Cl
(2.0 mL) for 24 h at 21 ºC and for 2.5 h
, hexane/AcOEt, gradient
2
2
with MeOH (2.0 mL) to deliver, after chromatography (SiO
2
from 7:1 to 1:1), 8g (106 mg, 0.36 mmol, 71%) as an orange, amorphous solid.
m.p.: 107.2–107.9 ºC (after chromatography upon evaporation of the solvents). IR: 1711.
1
HꢀNMR (CDCl
3
): 7.63 (d, J = 2.1, 1 H); 7.58 (dd, J = 8.5, 2.1, 1 H); 6.96 (d, J = 8.6, 1
13
H); 5.75 (s, 1 H); 3.954, 3.947 (2 s, 2 × 3 H); 3.05 (s, 3 H); 2.96 (s, 3 H). CꢀNMR
(CDCl
3
): 165.0 (s); 150.7, 148.7 (2 s); 142.4 (s); 123.1, 122.2 (2 s); 121.6, 110.8, 110.3
+
(3 d); 87.7 (d); 55.8 (q, 2 C); 48.6 (q); 26.9 (q). HRMS (ESI/Orbitrap) m/z: [M + H]
+
Calcd for C14
H
17ClNO
4
298.0841; Found 298.0840.
4.24. 3ꢀChloroꢀ5ꢀmethoxyꢀ1ꢀmethylꢀ4ꢀ(4ꢀnitrophenyl)ꢀ1,5ꢀdihydroꢀ2Hꢀpyrrolꢀ2ꢀone (8h)
Analogous to the preparation of 8a (method A), (COCl) (0.18 mL, 2.10 mmol) was
2
reacted with 7h (123 mg, 0.52 mmol) in CH
with MeOH (3.0 mL). Evaporation of the solvent delivered a crude product which was
dissolved in a mixture of H O (50 mL), AcOEt (30 mL), and a sat. aq. soln. of Na CO
20 mL). The aqueous layer was extracted with AcOEt (2 × 15 mL) and the combined
2 2
Cl (3.0 mL) for 48 h at 21 ºC and for 2.5 h
2
2
3
(
organic layers were washed with H
2
O/brine (3:2, 50 mL), brine (50 mL), and H
2
O (50
mL). After evaporation of the solvent, the residue was chromatographed (SiO
2
,
hexane/AcOEt 2:1) to afford 8h (119 mg, 0.42 mmol, 81%) as yellowish, cubic crystals.
m.p.: 177.7–179.1 ºC (after chromatography upon evaporation of the solvents). IR: 1719,
1
1518, 1346. HꢀNMR (CDCl
3
): 8.34, 8.15 (2 dꢀlike m, AA’BB’, “J” = 9.1, 2 × 2 H); 5.84 (s,
13
1
3
H); 3.09 (s, 3 H); 2.98 (s, 3 H). CꢀNMR (CDCl ): 163.8 (s); 148.1 (s); 140.7 (s); 135.4
(s); 129.4 (s); 128.7, 123.9 (2 d, 2 × 2 C); 87.7 (d); 49.0 (q); 27.1 (q). HRMS
+
+
2 4
(ESI/Orbitrap) m/z: [M + H] Calcd for C12H12ClN O 283.0480; Found 283.0479.
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2
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2
2
2
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3
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4
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.25. 3ꢀChloroꢀ5ꢀmethoxyꢀ1ꢀmethylꢀ4ꢀ(2ꢀnaphthyl)ꢀ1,5ꢀdihydroꢀ2Hꢀpyrrolꢀ2ꢀone (8i)
Analogous to the preparation of 8a (method A), (COCl)
2
(0.14 mL, 1.63 mmol) was
reacted with 7i (126 mg, 0.52 mmol) in CH Cl (2.0 mL) for 24 h at 21 ºC and for 2.5 h
2
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
with MeOH (2.0 mL) to deliver, after chromatography (SiO
mg, 0.40 mmol, 77%) as slightly orange, rhombic crystals.
, hexane/AcOEt 3:1), 8i (115
2
1
m.p.: 108.7–109.8 ºC (AcOEt). IR: 1712. HꢀNMR (600 MHz, CDCl
3
): 8.42 (brd. dꢀlike m,
"J" = 1.1, arom. H); 8.06 (dd, J = 8.7, 1.8, arom. H); 7.92 (dꢀlike m, "J" = 8.2, 2 arom. H);
7.87 (dꢀlike m, "J" = 8.5, arom. H); 7.59–7.53 (symm. m, 11 distinctive lines, 2 arom. H);
13
3
5.88 (s, CHOMe); 3.09 (s, NMe); 2.96 (s, OMe). CꢀNMR (150 MHz, CDCl ): 164.9 (s,
CON); 143.0 (s, ArylC); 133.8, 132.9 (2 s, 2 arom. C); 128.9, 128.5, 128.4, 127.72,
27.68 (5 d, 5 arom. C); 126.9 (s, arom. C); 126.8 (d, arom. C); 125.8 (s, CCl); 124.3 (d,
arom. C); 87.9 (d, CHOMe); 48.8 (q, OMe); 27.1 (q, NMe). HRMS (ESI/Orbitrap) m/z:
1
+
+
[M + H] Calcd for C16
.26. 3ꢀChloroꢀ5ꢀmethoxyꢀ1ꢀmethylꢀ4ꢀ(1ꢀnaphthyl)ꢀ1,5ꢀdihydroꢀ2Hꢀpyrrolꢀ2ꢀone (8j)
Analogous to the preparation of 8a (method A), (COCl) (0.14 mL, 1.63 mmol) was
reacted with 7j (125 mg, 0.51 mmol) in CH Cl (2.0 mL) for 24 h at 22 ºC and for 2 h
with MeOH (2.0 mL) to deliver, after chromatography (SiO , hexane/AcOEt, gradient
2
H15ClNO 288.0786; Found 288.0786.
4
2
2
2
2
from 5:1 to 1:1), 8j (134 mg, 0.47 mmol, 92%) as colorless, rhombic crystals.
1
m.p.: 137.3–138.2 ºC (AcOEt). IR: 1714. HꢀNMR (CDCl
3
): 7.97–7.91 (m, 2 arom. H);
7.79–7.74 (m, arom. H); 7.59–7.53 (m, 3 arom. H); 7.45 (dd, J = 7.1, 1.1, arom. H); 5.77
13
(s, CHOMe); 3.11 (s, NMe); 3.05 (s, OMe). CꢀNMR (150 MHz, CDCl
3
): 164.4 (s,
CON); 146.5 (s, ArylC); 133.8 (s, arom. C); 130.4 (d, arom. C); 129.64 (s, arom. C);
1
29.56 (s, CCl); 129.0 (d, arom. C); 127.5 (s, arom. C); 126.9, 126.7, 126.4, 125.2,
25.1 (5 d, 5 arom. C); 89.7 (d, CHOMe); 50.9 (q, OMe); 27.4 (q, NMe). HRMS
1
+
+
2
(ESI/Orbitrap) m/z: [M + H] Calcd for C16H15ClNO 288.0786; Found 288.0784.
4.27. 3ꢀChloroꢀ4ꢀ(2ꢀfuryl)ꢀ5ꢀmethoxyꢀ1ꢀmethylꢀ1,5ꢀdihydroꢀ2Hꢀpyrrolꢀ2ꢀone (8k)
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Analogous to the preparation of 8a (method A), (COCl)
reacted with 7k (95 mg, 0.52 mmol) in CH Cl (2.0 mL) for 24 h at 21 ºC and for 2 h with
, hexane/AcOEt 3:1), 8k (30 mg,
2
(0.15 mL, 1.75 mmol) was
2
2
MeOH (2.0 mL) to deliver, after chromatography (SiO
2
0.45 mmol, 25%) as a colorless, amorphous solid.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
m.p.: 106.8–107.8 ºC (after chromatography upon evaporation of the solvents). IR: 1713.
1
3
HꢀNMR (600 MHz, CDCl ): 7.64 (dd, J = 1.8, 0.7, arom. H); 7.14 (dd, J = 3.5, 0.7, arom.
H); 6.60 (dd, J = 3.6, 1.9, arom. H); 5.67 (s, CHOMe); 3.04 (s, OMe); 3.03 (s, NMe).
13
CꢀNMR (150 MHz, CDCl
3
): 164.8 (s, CON); 145.7 (s, ArylC); 145.0 (d, arom. C); 134.3
(s, arom. C); 121.8 (s, CCl); 114.6, 112.3 (2 d, 2 arom. C); 86.9 (d, CHOMe); 49.4 (q,
+
+
OMe); 27.0 (q, NMe). HRMS (ESI/Orbitrap) m/z: [M + H] Calcd for C10
H11ClNO
3
228.0422; Found 228.0422.
4.28. 3ꢀChloroꢀ4ꢀ(3ꢀfuryl)ꢀ5ꢀmethoxyꢀ1ꢀmethylꢀ1,5ꢀdihydroꢀ2Hꢀpyrrolꢀ2ꢀone (8l)
Analogous to the preparation of 8a (method A), (COCl) (0.14 mL, 1.63 mmol) was
reacted with 7l (96 mg, 0.52 mmol) in CH Cl (2.0 mL) for 24 h at 21 ºC and for 2 h with
2
2
2
2
MeOH (2.0 mL) to deliver, after chromatography (SiO , hexane/AcOEt 3:1), 8l (38 mg,
0.17 mmol, 33%) as a slightly orange, amorphous solid.
m.p.: 76.5–78.8 ºC (after chromatography upon evaporation of the solvents). IR: 1715.
1
3
HꢀNMR (CDCl ): 8.14 (s, 1 H); 7.54 (sꢀlike m, 1 H); 7.04 (sꢀlike m, 1 H); 5.53 (s, 1 H);
13
3.02, 3.00 (2 s, 2 × 3 H). CꢀNMR (CDCl
3
): 164.9 (s); 143.8, 143.7 (2 d); 137.3 (s);
123.5 (s); 116.3 (s); 108.3 (d); 87.6 (d); 48.8 (q); 26.9 (q). HRMS (ESI/Orbitrap) m/z: [M
+
+
+
H] Calcd for C10
.29. 3ꢀChloroꢀ5ꢀmethoxyꢀ1ꢀmethylꢀ4ꢀ(2ꢀthienyl)ꢀ1,5ꢀdihydroꢀ2Hꢀpyrrolꢀ2ꢀone (8m)
Analogous to the preparation of 8a (method A), (COCl) (0.15 mL, 1.75 mmol) was
reacted with 7m (104 mg, 0.52 mmol) in CH Cl (2.0 mL) for 24 h at 21 ºC and for 2 h
3
H11ClNO 228.0422; Found 228.0423.
4
2
2
2
2
with MeOH (2.0 mL) to deliver, after chromatography (SiO , hexane/AcOEt 7:1), 8m (67
mg, 0.27 mmol, 52%) as brownish, rhombic crystals.
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m.p.: 131.2–132.2 ºC (upon evaporation of CDCl
3
added to the solid obtained after
1
chromatography). IR: 1708. HꢀNMR (CDCl
3
): 7.79 (dd, J = 3.8, 1.0, 1 H); 7.62 (dd, J =
13
5.1, 1.0, 1 H); 7.19 (dd, J = 5.0, 3.9, 1 H); 5.68 (s, 1 H); 3.05, 3.01 (2 s, 2 × 3 H). Cꢀ
3
NMR (CDCl ): 164.8 (s); 138.3 (s); 131.9 (s); 130.2, 129.6, 127.6 (3 d); 122.3 (s); 87.9
0
1
2
3
4
5
6
7
8
9
0
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2
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8
9
0
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0
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8
9
0
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4
5
6
7
8
9
0
+
+
2
(d); 48.8 (q); 27.0 (q). HRMS (ESI/Orbitrap) m/z: [M + H] Calcd for C10H11ClNO S
244.0194; Found 244.0194. (For single crystal xꢀray analysis, see supporting
information).
4
.30. 3ꢀChloroꢀ5ꢀmethoxyꢀ1ꢀmethylꢀ4ꢀ(3ꢀthienyl)ꢀ1,5ꢀdihydroꢀ2Hꢀpyrrolꢀ2ꢀone (8n).
Analogous to the preparation of 8a (method A), (COCl) (0.14 mL, 1.63 mmol) was
reacted with 7n (104 mg, 0.52 mmol) in CH Cl (2.0 mL) for 24 h at 22 ºC and for 2 h
2
2
2
with MeOH (2.0 mL) to deliver, after chromatography (SiO
2
, hexane/AcOEt, gradient
from 5:1 to 1:1), 8n (94 mg, 0.39 mmol, 75%) as brownish, rhombic crystals.
3
m.p.: 120.0–120.3 ºC (upon evaporation of CDCl added to the solid obtained after
1
chromatography). IR: 1707. HꢀNMR (CDCl
3
): 8.13 (dd, J = 3.0, 1.3, arom. H); 7.80 (dd,
J = 5.2, 1.3, arom. H); 7.45 (dd, J = 5.1, 3.0, arom. H); 5.65 (s, CHOMe); 3.04 (s, NMe);
13
2
1
2
3
.98 (s, OMe). CꢀNMR (CDCl ): 165.0 (s, CON); 138.7 (s, ArylC); 130.7 (s, arom. C);
27.7, 126.3, 126.2 (3 d, 3 × arom. C); 123.2 (s, CCl); 87.9 (d, CHOMe); 48.7 (q, OMe);
+
+
2
6.9 (q, NMe). HRMS (ESI/Orbitrap) m/z: [M + H] Calcd for C10H11ClNO S 244.0194;
Found 244.0195.
4.31. 3ꢀChloroꢀ4ꢀisopropylꢀ5ꢀmethoxyꢀ1ꢀmethylꢀ1,5ꢀdihydroꢀ2Hꢀpyrrolꢀ2ꢀone (8p).
Analogous to the preparation of 8a (method A), (COCl) (0.67 mL, 7.81 mmol) was
reacted with 7p (397 mg, 2.49 mmol) in CH Cl (10 mL) for 24 h at 21 ºC and for 2 h
2
2
2
with MeOH (10 mL) to deliver, after column chromatography (SiO
followed by preparative TLC (Merck TLC plates silica gel 60 F254, hexane/AcOEt 4:1),
p (8 mg, 0.04 mmol, 2%) as a colorless oil.
2
, hexane/AcOEt, 4:1)
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IR: 1725. HꢀNMR (400 MHz, CDCl
3
): 5.22 (s, 1 H); 3.05 (s, 3 H); 2.98–2.87 (symm. m,
13
1
3
H); 2.95 (s, 3 H); 1.29, 1.24 (2 d, J = 7.1, 2 × 3 H). CꢀNMR (125 MHz, CDCl ): 165.0
(
s); 153.2 (s); 126.1 (s); 87.7 (d); 49.7 (q); 27.2 (d); 26.9 (q); 19.84, 19.80 (2 q). HRMS
+
+
(
9 2
ESI/Orbitrap) m/z: [M + H] Calcd for C H15ClNO 204.0786; Found 204.0789.
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4.30. 5ꢀBenzylꢀ4ꢀmethylmorpholineꢀ2,3,6ꢀtrione (9a').
(
COCl)
phenylalanine (12a, 295 mg, 1.65 mmol) in CH
1 h at 25 ºC. Evaporation of the solvent delivered crude 9a' (424 mg) as a brown,
2
(3.0 mL, 35.0 mmol) was added dropwise to a suspension of NꢀmethylꢀLꢀ
2
2
Cl (6.0 mL). The mixture was stirred for
2
amorphous solid. The sample was characterized without further purification, since it
decomposed gradually upon storage and purification.
1
3
HꢀNMR (CD CN): 7.33–7.31 (m, 3 H); 7.10–7.05 (m, 2 H); 4.89–4.86 (m, X of ABX, 1
13
H); 3.40–3.22 (m, AB of ABX, 2 H); 3.13 (s, 3 H). CꢀNMR (CD
3
CN): 163.7, 151.7,
151.3 (3 s); 133.9 (s); 130.9, 130.1 (2 d, 2 × 2 C); 129.3 (d); 64.0 (d); 38.7 (t); 33.5 (q).
4
.31. (E)ꢀN,NꢀDimethylꢀ2ꢀphenylethenamine (10a)
Phenylacetaldehyde (3.2 mL, 27.4 mmol) was added to Me
It was stirred at 22 ºC for 3 min, Et O (5 mL) was added, and it was stirred for an
additional 4 min. Et N (3.8 mL, 27.4 mmol) was added dropwise over a period of 40 min,
and it was stirred at 22 ºC for an additional 1 h. The mixture was filtered, and the filtrate
was dried with MgSO . Evaporation of the solvent delivered virtually pure 10a (3.63 g,
2
NH—HCl (2.06 g, 25.3 mmol).
2
3
4
24.7 mmol, 98%) as an orangeꢀyellowish oil.
1
IR: 1636, 1595. HꢀNMR (CDCl
3
): 7.26–7.14 (m, 4 H); 6.99–6.93 (m, 1 H); 6.74 (d, J =
13
1
3.9, 1 H); 5.16 (d, J = 13.9, 1 H); 2.78 (s, 6 H). CꢀNMR (CDCl
3
): 140.1 (d); 139.7 (s);
1
28.5, 123.6 (2 d, 2 × 2 C); 123.3 (d); 98.3 (d); 40.7 (q, 2 C). HRMS (ESI/QꢀTOF) m/z:
+
+
[
M + H] Calcd for C10H14N 148.1121; Found 148.1122.
4
.32. 3,5ꢀDichloroꢀ1ꢀmethylꢀ4ꢀphenylꢀ1,5ꢀdihydroꢀ2Hꢀpyrrolꢀ2ꢀone (11a')
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