Syn/anti switching by specific heteroatom-titanium coordination in the Mannich-like synthesis of 2,3-diaryl-β-amino acid derivatives

Article abstract of DOI:10.1002/ejoc.201400142

A very efficient synthesis of 2,3-diaryl-β-amino acid derivatives is realized by a TiCl₄/triethylamine-catalyzed Mannich-like reaction of arylacetic or arylthioacetic esters with arylimines. The presence on the arylacetic moiety of an ortho-het

Full text of DOI:10.1002/ejoc.201400142

FULL PAPER
DOI: 10.1002/ejoc.201400142
syn/anti Switching by Specific Heteroatom–Titanium Coordination in the
Mannich-Like Synthesis of 2,3-Diaryl-β-amino Acid Derivatives
Andrea Bonetti,[a] Francesca Clerici,[a] Francesca Foschi,[b] Donatella Nava,[a]
Sara Pellegrino,[a] Michele Penso,*[b] Raffaella Soave,[b] and Maria Luisa Gelmi*[a]
Keywords: Synthetic methods / C–C coupling / Amino acids / Diastereoselectivity / Titanium
A very efficient synthesis of 2,3-diaryl-β-amino acid deriva-
tives is realized by a TiCl4/triethylamine-catalyzed Mannich-
like reaction of arylacetic or arylthioacetic esters with aryl-
imines. The presence on the arylacetic moiety of an ortho-
heteroatom group able to coordinate to the titanium center
is of dramatic importance for the outcome of the reaction and
to tune the syn/anti diastereoselection. In particular, with o-
F-, o-Cl-, and o-Br-arylacetates, the syn adduct was isolated
as the largely prevalent isomer. When (–)-8-phenylmenthyl
(2-fluorophenyl)acetate was used, the condensation with
imines resulted in high diastereo- and enantioselectivity. In
agreement with the stereochemical results and NMR studies,
a conceivable reaction mechanism was proposed.
Stimulated by both the literature overview and by our
interest in the preparation of nonproteinogenic amino
acids,[5a,5b,14] we studied the applicability of the Mannich-
like reaction of aryl acetate titanium enolates with N-alk-
ylimines to the synthesis of β2,3-amino acids bearing a 2,3-
diaryl substitution pattern. The success of this reaction is
related to the presence of a coordinating atom at the ortho
position of the starting aryl acetic ester. Interestingly, by
tuning the nature of the heteroatom, the syn/anti chirality
switch can be modulated. On the other hand, the use of the
corresponding thioesters gave exclusively the anti adducts.
To the best of our knowledge, the titanium enolate of an
ortho-aryl-substituted ester and the coordination concept is
innovative in the Mannich-like reaction. Furthermore, the
new ortho-halogenated β2,3-diarylamino acids represent a
very interesting source for ortho-functionalized compounds,
which can be generated by both aromatic nucleophilic sub-
stitution and coupling.
Introduction
The β-amino acid motif[1] is recurrent in biologically
active compounds such as β-lactam antibiotics[1a,1b,2] and
β-peptides;[1,3] therefore, the preparation of new nonprote-
inogenc β-amino acids is particularly interesting. In particu-
lar, β2,3-amino acids, which can enhance the helical content
and the resistance to peptidases of a peptide,[3f] have been
widely studied. The synthesis of these compounds through
the addition of an ester enolate[4] or silyl ketene acetal[5] to
an imine has received special attention because of
the possibility to address the reaction stereoselectivity. By
these Mannich-like reactions, several α-alkyl-, α-unsubsti-
tuted-, and α-phenyl-β-aryl-β-amino acids have been ac-
cessed,[5c,5d,5f,6–9] whereas compounds containing α-aryl
substituents different from phenyl have not yet been pre-
pared,owingtotheeasyradicaldimerizationofthestartingaryl-
acetic esters.[10] With few exceptions,[6a,6b,7a] a syn/anti mix-
ture of β2,3-amino esters forms through this method, and
the syn adduct is the major diastereoisomer. Recently, a
series of 2,3-diaryl-3-amino thioesters have been prepared
by a base-organocatalyzed Mannich reaction of expensive
trifluoroethyl arylthioacetates,[11] an organocatalytic re-
duction of enamines,[12] or a three-component reaction of
aryl organoboranes, diazoacetate, and imines.[13]
Results and Discussion
Preliminary Experiments
Recently, we were interested in the synthesis of 2,3-di-
aryl-β-amino esters 3a/4a derived from the condensation of
methyl (3,4-methylendioxyphenyl)acetate (1a) and piper-
onal N-benzylimine (2a). According to a literature pro-
cedure,[9b] we used a Mannich-like TiCl4/triethylamine
(TiCl4/TEA) promoted reaction, but even with different
stoichiometries and temperatures, the reaction did not pro-
ceed, and only the starting reagents were recovered
(Scheme 1). To verify if this behavior was dependent on the
use of substrates 1a and 2a, we reinvestigated the literature
[a] DISFARM, Sezione di Chimica Generale e Organica “A.
Marchesini”, Università degli Studi Milano,
Via Venezian 21, 20133 Milano, Italy
E-mail: marialuisa.gelmi@unimi.it
www.disfarm.unimi.it
[b] CNR – Istituto di Scienze e Tecnologie Molecolari (ISTM),
Via Golgi 19, 20133 Milano, Italy
E-mail: michele.penso@istm.cnr.it
http://www.istm.cnr.it
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201400142.
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FULL PAPER
reaction between methyl phenylacetate (1b) and benzalde-
hyde N-benzylimine (2b; Scheme 1),[9b] which is reported to
give exclusively the syn/anti adducts 3b/4b (73:27 ratio) in
78% yield. When we reproduced this reaction, in addition
to 3b/4b, we found (TLC and 1H NMR spectroscopic analy-
ses, see Supporting information, Figure S1) the starting
imine 2b, the dimethyl 2,3-diphenylsuccinates S*,S*-5b and
R*,S*-5b, and the Claisen compound 6 [(3b/4b)/2b/5b/6
1:1.33:0.60:0.24 molar ratio)]. After purification, the main
syn adduct 3b was isolated in 23% yield only, together with
minor amounts of 4b (Ͻ10%), impure of Claisen com-
pound 6 and benzylamine, and dimer 5b (10%). Several ex-
periments were performed on the Mannich condensation of
1b with 2b at different temperatures or molar ratios without
any significant improvement. In addition to this divergent
Scheme 2. Mannich-like reaction of 2-bromophenylacetic ester 1c.
Table 1. Evaluation of the reaction parameters for the Mannich-
like condensation between 1c and 2a.
1
result, we also found that the H NMR spectra (Figures
Entry TiCl4 [mol][a] T [°C] TEA [mol]
t [min][b] Yield [%][c]
S2–S4) of the isolated compounds 3b/4b, inexplicably, do
not completely match those reported.[9b] Furthermore, the
formation of 5b and 6 is in agreement with the literature
data[10] concerning the radical dimerization or the Claisen
condensation of phenylacetic ester 1b promoted by TiCl4/
TEA.[15]
1
2
3
4
5
6
7
8
9
2.1
2.1
2.1
2.1
1.7
0
2.1
2.1
2.1
2.1
1.7
2.5
2.1
2.1[e]
2.1
180
180
180
180
180
180
480
480
75
40
60
65
70
50
75
–
–40
–50
–60
–50
–50
–60
–60
–78
2.5
2.1[d]
2.1
–
2.1
98[f]
[a] Reaction conditions: ester 1c (1 mol-equiv.), imine 2a (1 mol-
equiv.) in DCM (0.1 molL–1); TiCl4 was dropped in 15 min and the
mixture was stirred for 15 min before addition of the base. [b] Time
after addition of TEA. [c] Overall yield of isolated compounds 3c/
4c (3:1). [d] The mixture of ester 1c and TiCl4 in DCM was stirred
for 15 min, TEA (5 min) was added then 2a (from –60 to 0 °C). [e]
DIPEA was used as a base instead of TEA (from –60 to 0 °C). The
experiment was repeated twice. [f] Diastereoisomers 3c (74%) and
4c (24%) were separated by flash column chromatography.
TEA (Table 1, Entry 8). Finally, the best conversion was
obtained at a reaction temperature of –78 °C (Table 1, En-
try 9).
Scheme 1. Mannich-like reaction of ortho-unsubstituted esters 1a,b.
To extend the scope of this condensation to the synthesis
of different functionalized 1,2-diaryl-β-amino acid deriva-
tives and to evaluate the efficacy of the ortho group to coor-
Mannich-Like Condensation
Adrian et al.[16] reported that methyl (methoxy)acetate dinate to titanium in connection to its relative hardness, a
titanium enolate reacts with aldimines to afford mainly anti series of ortho-substituted arylacetates 1d–1i were reacted
β-amino-propionic acid derivatives. From these data, we with the imines 2a–2c (Scheme 3, Table 2).
reasoned that a coordinating group positioned close to the
As expected, methyl o-fluorophenylacetate (1d), bearing
enolate could be crucial for the reaction outcome, probably the hardest and more coordinating o-halogen atom, gave
owing to the formation of a stabilized titanium enolate high yields of the syn adduct 3d as the largely predominant
complex. To confirm our hypothesis, the ortho-bromo de- isomer (Table 2, Entry 1) when reacted with 2c. A similar
rivative 1c and the imine 2a (Scheme 2) were subjected to behavior was found for the reaction of o-chlorophenylacet-
the above protocol (Table 1, Entry 1), and a mixture of 3c/ ate (1e) with imine 2c (Table 2, Entry 2), whereas the o-
4c (3:1 ratio) was isolated in 40% yield.
bromophenylacetate (1f) reacted with imine 2a (Table 2, En-
Several reaction conditions were then tested (Table 1), try 3) to afford a syn/anti (6.7:1) mixture 3f/4f, which con-
and the overall results indicate that the same syn/anti ratio firms that the bromine atom, less hard than F and Cl, is
of 3c/4c was always obtained; the lower the reaction tem- also less coordinating. The ester 1g, which contains the
perature, the higher the yields (Table 1, Entries 1–4); lower more polarizable o-iodine atom, reacted with 2b (Table 2,
amounts of TiCl4 and TEA gave lower yields (cf. Table 1, Entry 4) to afford good yields of a quasi-equimolar syn/anti
Entries 5 and 6). The reaction failed when the addition or- mixture 3g/4g. Unexpectedly, a complete diastereoselectiv-
der of the reagents was changed (Table 1, Entry 7) or when ity switch toward the anti adduct 4h was found by using
N,N-diisopropylethylamine (DIPEA) was used instead of the o,oЈ-dichloro ester 1h and 2b (Table 2, Entry 5). Also
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Mannich-Like Synthesis of 2,3-Diaryl-β-amino Acid Derivatives
creased, but they had no influence on the diastereoselec-
tivity of the reaction. In contrast, the reaction did not pro-
ceed when N-benzylimines of ortho-substituted benzalde-
hydes (2-nitro-, 2-bromo-, 2,4-dimethoxy-, and 2,4-di-
chlorobenzaldehyde) were used with both 1g and 1h. These
latter examples indicate that an increased steric crowding
near the reactive functions changes the coordination envi-
ronment of the ester/imine/titanium complex and, thus, pre-
vents the reaction.
Scheme 3. Mannich-like reaction between ortho-substituted aryl-
acetates 1d–1i and imines 2a–2e.
Table 2. Mannich-like reaction between ortho-substituted arylacet-
ates 1d–1i and imines 2a–2c.[a]
Entry Ester Imine t [min] Products Yield [%][b] syn/anti [%][c]
1
2
3
4
5
6
7
8
1d
1e
1f
1g
1h
1i
2c
2c
2a
2b
2b
2c
2b
2b
15
60
75
180
180
75
600
600
3d/4d
3e/4e
3f/4f
3g/4g
3h/4h
3i/4i
–
91
81
88[d]
81
76
73
–
Ͼ97:3
92:8
87:13
55:45
Ͻ3:97
47:53
Figure 1. Graphical representation of the Mannich-like reaction
diastereoselectivity switch by coordinating ortho-group modula-
tion.
[e]
1j
1k
–
[e]
Table 3. Mannich-like reaction of esters 1d, 1g, and 1h with imines
2a and 2c–2e.[a]
–
–
–
[a] Reaction conditions: ester
1 (1 mol equiv.) and imine 2
Entry Ester Imine t [min] Products Yield [%][b] syn/anti [%][c]
(1 mol equiv.) in DCM (0.1 molL–1) at –78 °C, then TiCl4
(2.1 mol equiv.), 15 min; TEA (2.1 mol equiv.). [b] Overall yield of
isolated compounds. [c] Determined by 1H NMR spectroscopic
analysis. [d] A syn/anti mixture (7%) of dimers 5f was isolated. [e]
At 25 °C after the addition of TEA.
1
2
3
4
5
1d
1g
2a
2c
2d
2e
2c
80
30
75
120
150
3j
3k/4k
3l/4l
4m
91
97
76
85
79
Ͼ97:3
55:45
59:41
Ͻ3:97
Ͻ3:97
1g
1h[d]
1h
4n
[a] Reaction conditions: ester
1 (1 mol equiv.) and imine 2
surprising was the absence of diastereoselectivity in the re-
action of o-methoxyphenylacetate (1i) with imine 2c
(Table 2, Entry 6), even if the methoxy group is a good tita-
nium-coordinating group.[16] Finally, the Mannich-like reac-
(1 mol equiv.) in DCM (0.1 molL–1) at –78 °C, then TiCl4
(2.1 mol equiv.), 15 min; TEA (2.1 mol equiv.). [b] Overall yield of
isolated compounds. [c] Determined by 1H NMR spectroscopic
analysis. [d] The reaction temperature was increased to –20 °C after
tion did not proceed when esters 1j and 1k bearing a non- the addition of TEA.
coordinating electron-withdrawing ortho group were em-
To determine the correct configuration of 4h, a catalytic
ployed.
The reactions between the imine 2b and the esters 1g and
hydrogenation (H2, Pd/C, MeOH, 25 °C, 1 atm) was per-
formed to remove both the N-benzyl protection and the
aromatic chlorine atoms and afford the known 2S*,3R*-
methyl 3-amino-2,3-diphenylpropionate (7) (Scheme 4).[18]
1h were selected as model reactions, and the screening of
both the Lewis acid and the reaction solvent was con-
ducted. The reaction failed in DCM in the presence of
SnCl4, InCl3, TiF4, or Ti(OiPr)4. Moreover, the same be-
havior was found for TiCl4 in tetrahydrofuran (THF) or
acetonitrile (MeCN); therefore, the coordinating solvent
probably destabilizes the architecture of the imine/ester/
TiCl4 complex.[17]
Further runs were conducted with arylacetic esters 1d,
1g, and 1h and the arylimines 2a and 2c–2e, characterized
by different para-substitution patterns for a variety of elec-
Scheme 4. Reduction of Mannich adduct 4h.
The attempts to make the condensation of the achiral
tronic effects (Scheme 3, Figure 1, Table 3). All these aryl- imine 2c with the o-fluorophenylacetate 1d enantioselective
imines gave good results, and the yields increased as the by using (–)-sparteine or (–)-quinine as chiral bases was
electron-withdrawing character of the para substituent in- completely unsuccessful, as was the reaction of benzylidene-
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M. Penso, M. L. Gelmi at al.
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N-(S)-α-methylbenzylimine with 1d. On the contrary, com-
Mannich-like reactions of thioesters with benzylimines in
plete enantioselectivity was reached in the reaction of 2c the presence of TiCl4/TEA have also been described in the
with the optically pure (–)-8-phenylmenthyl ester 1j literature.[20] The corresponding β-amino-thioesters were
(Scheme 5), which gave the enantiopure syn adduct obtained as syn/anti mixtures in variable ratios, depending
(1R,2R)-3o (X-ray analysis, Figure 2) as the major dia- on the starting reagents and conditions. Notably, examples
stereoisomer (syn/anti Ͼ93:7) in 77% yield (see Supporting of 2,3-diaryl-3-amino thioesters prepared under these con-
1
Information, H NMR spectrum Figure S6, HPLC trace ditions are unknown.
Figure S7). On the basis of the proposed reaction mecha-
To analyze the reactivity of ortho-substituted aryl-
nism (see below), we can hypothesize that the formation of thioacetic esters in the Mannich-like condensation, com-
this enantiomer can be ascribed to the formation of the pounds 8a and 8b were prepared and reacted under the us-
complex TS-syn-A* (Scheme 5) derived from the approach ual conditions with imine 2c (Scheme 6). Surprisingly, the
of the imine 2c toward the less hindered Si face of the enol- anti adducts 9a and 9b were isolated in good yields and
ate. This stereochemical result indirectly confirms our hy- complete diastereoselectivity in both cases. On the other
pothesis on the stereochemistry of syn-3 and anti-4 formu- hand, methyl 2-(2-iodophenyl)ethanedithioate was com-
1
lated on the basis of H NMR analyses (see Supporting pletely unreactive in the condensation with 2c.[21]
Information).
Scheme 5. Mannich-like reaction of chiral ester 1j.
Scheme 6. Mannich-like reaction of thioesters 8 and their transfor-
mation.
The stereochemistry of thioester 9a was unambiguously
assigned after it was transformed into the corresponding
methyl ester 4k by methanolysis (Scheme 6). The same
strategy failed for 9b, but this compound was quantitatively
cyclized to the corresponding β-lactam 10 by treatment
1
with Hg(OCOCF3)2 (Scheme 6).[22] The H NMR coupling
constant between 2-H and 3-H (J3 = 2.1 Hz) confirmed the
trans disposition of the two aryl groups, in agreement with
the literature data.[23]
Discussion
The overall results indicate that the ortho substituent of
the arylacetate is essential for the outcome of the Mannich-
like condensation of these compounds with N-alkylimines.
The efficacy of the substituent to promote the reaction de-
pends mainly on its ability to coordinate to the titanium
center and seems independent from its electronic effect,
Figure 2. ORTEP plot of 3o at 180 K with atom numbering
scheme; ellipsoids at 50% probability level.[19]
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Mannich-Like Synthesis of 2,3-Diaryl-β-amino Acid Derivatives
which determines only the CH-α acidity. On the contrary,
an ortho group on the arylimine is detrimental to the reac-
tion; this suggests that the architecture of the transition
state is destabilized by the additional steric crowding.
To explain the stereochemical results of the reaction, we
have postulated a general mechanistic rationale, which takes
into account both ortho-coordinated and non-coordinated
transition states (Scheme 7). As shown by NMR studies
(see Supporting Information), in non-coordinating solvents,
the iminium species (I) and the hexacoordinate ester–
titanium complex (II), in which both the ortho-substituent
and the carbonyl function are coordinated to the titanium
center, are first formed. As further evidence, we found that
the reaction did not proceed in a coordinating solvent
(THF, MeCN), which can displace the ortho-substituent
from the titanium coordination sphere.[17] To the best of
our knowledge, the only complexes of titanium with halo-
organic ligands reported in the literature, are those with
aryl fluorides,[24] acetyl chloride, and acetyl bromide
(CH3COClϾ CH3COBr).[25] In agreement with the litera-
ture data and hard and soft acids and bases (HSAB) theory,
we could conclude that the halogen propensity to coordi-
nate to the titanium center follows the hardness of the halo-
gen atom (FϾ ClϾ BrϾ I). After the addition of TEA,[26]
titanium E/Z enolates are formed from the intermediate II.
NMR experiments on 1d (see Supporting Information) con- Scheme 7. Transition states for Mannich-like reaction.
firmed the presence of the E/Z titanium enolate mixture,
which by reaction with I can afford four possible dimetallic
transition states (Scheme 7).[26a,27] With a strongly coordi- Conclusions
nating ortho group (X = F, Cl, Br), most likely both TS-syn-
A very efficient synthesis of β2,3-diarylamino acids was
A and TS-anti-B are initially formed from the E/Z enolate.
realized by using a Mannich-like reaction. The use of ortho-
Complex TS-syn-A, which is probably promoted by both
halogen substituted arylacetic esters allowed a chirality
switch by tuning the syn/anti diastereoselectivity. On the
other hand, independently from the ortho heteroatom, the
use of the corresponding thioesters gave exclusively the anti
titanium/X coordination and π–π stacking,[28] quickly
evolves to the kinetically favored syn adduct, as also indi-
cated by the short reaction times (e.g., Table 2, Entry 1). On
the contrary, the less-reactive non-coordinated TS-anti-B
adducts, which are interesting starting materials for the
probably equilibrates to TS-syn-A via the sterically
preparation of trans-β-lactam derivatives. The presence of a
crowded, unstable intermediate TS-syn-B. According to
halogen atom on the aryl group represents a very interesting
previous reports[17] and to NMR experiments (see Support-
tool for further functionalization of the ortho position.
ing Information), if the ortho substituent is a less coordinat-
ing and/or a more crowding group, the less hindered TS-
anti-B can form directly from the E enolate or indirectly
Experimental Section
from TS-syn-A via TS-syn-B. As a result, a progressive yield
increase of the thermodynamically favored anti adduct was
obtained from o-bromo- (1f), o-iodo- (1g), and o-methoxy-
phenylacetic (1i) esters. The case of the o,oЈ-dichlorophen-
ylacetate (1h) is peculiar as it gave exclusively the anti ad-
General Procedure for the Preparation of 2,3-Diarylpropanoates: In
a three-necked round-bottomed flask equipped with a magnetic
stirrer, thermometer, a nitrogen inlet, and a dropping funnel, ester
1 or thioester 8 (2.56 mmol) and imine 2 (2.56 mmol) were dis-
duct 4h. We hypothesized that even if one chlorine atom solved in dry CH2Cl2 (25 mL), and the solution was cooled to
–78 °C. A solution of TiCl4 (560 μL, 5.12 mmol) in dry CH2Cl2
(5 mL) was added slowly over 15 min. After 5 min, freshly distilled
triethylamine (714 μL, 5.12 mmol) was slowly added to produce a
deep purple solution. The temperature and reaction time indicated
are for a single example. A saturated solution of K2CO3 was added,
and the temperature was increased to 25 °C. The mixture was
stirred for 10 min, after which TiO2 precipitated and was removed
by filtration through a Celite pad. The organic layer was separated,
washed with brine, and dried with Na2SO4. The crude mixture was
purified by column chromatography. As examples, the analytical
and spectroscopic data for 3c and 4c are reported below. The data
strongly coordinates to the titanium center, the second ortho
chlorine atom increases the steric crowding and prevents
the π–π stacking; thus, the formation of the less hindered
TS-anti-A is favored.
Finally, from o-fluoro- (8a) and o-iodophenylthioacetate
(8b), an almost complete anti diastereoselectivity was ob-
served, independently from the coordinating ability of the
ortho substituent. Most likely, TS-anti-BЈ (Scheme 7) is pre-
ferred as the steric hindrance between the thioalkyl and N-
benzyl groups is minimized in this conformation.
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3207

M. Penso, M. L. Gelmi at al.
FULL PAPER
for 3d–3g, 3i–3l, 4d–4i, 4k–4n, 9a, and 9b are reported in the Sup-
porting Information.
2,3-diaryl-β-amino esters 3 and 4. NMR discussion and spectra for
the Mannich-like reaction of ester 1d and 1i with imine 2c. Single-
crystal X-ray crystallography of 3o.
Methyl 3-(N-Benzylamino)-2-(2-bromo-4,5-methylenedioxyphenyl)-
3-(3,4-methylenedioxyphenyl)propanoate (3c/4c): T = –78 °C; t =
75 min. Column chromatography (cyclohexane/Et2O 10:3): 3c
(45%), mixture of isomers 3c/4c (26%), 4c (27%).
Acknowledgments
2S*,3S*-3c: White solid; m.p. 129–133 °C (CH2Cl2/Et2O). 1H
NMR (CDCl3, 300 MHz): δ = 7.26–6.77 (m, 10 H), 6.02 (d, J =
1.5 Hz, 1 H), 5.97 (s, 3 H), 4.46, 4.04 (AX system, J = 10.2 Hz, 2
H), 3.61, 3.32 (AB system, J = 13.9 Hz, 2 H), 3.40 (s, 3 H), 1.6 (br.
s, 1 H, exch.) ppm. 13C NMR (CDCl3, 75 MHz): δ = 30.1, 50.9,
52.2, 57.4, 64.2, 101.3, 102.1, 108.3, 108.5, 108.9, 113.1, 117.1,
122.4, 127.2, 128.3, 128.6, 128.9, 135.1, 140.5, 147.5, 148.2, 172.2
Funding for this work was provided by the Ministero dell’Uni-
versità
e della Ricerca (MIUR) (PRIN 2010–2011 – prot.
20109Z2XRJ).
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ppm. IR (KBr): νmax = 3332, 1448 cm–1. MS (ESI+): m/z: 513.9 [M
˜
+ H]+. C25H22BrNO6 (512.36): calcd. C 58.61, H 4.33, N 2.73;
found C 58.48, H 4.48, N, 2.50.
2S*,3R*-4c: White solid; m.p. 82–84 °C (AcOEt/n-hexane). 1H
NMR (CDCl3, 200 MHz): δ = 7.34–6.53 (m, 10 H), 5.93–5.89 (m,
4 H), 4.45, 4.09 (AM system, J = 10.2 Hz, 2 H), 3.69 (s, 3 H), 3.63,
3.52 (AB system, J = 13.4 Hz, 2 H), 1.70 (br. s, 1 H, exch.) ppm.
13C NMR (CDCl3, 50 MHz): δ = 29.9, 51.3, 52.4, 56.5, 65.1, 101.1,
102.0, 107.9, 108.0, 112.7, 115.9, 121.9, 127.1, 128.2, 128.3, 128.5,
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˜
max
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Methyl 2S*,3R*-3-Amino-2,3-diphenylpropanoate (7): Compound
4h (250 mg, 0.6 mmol) was dissolved in MeOH (5 mL), 10% Pd/C
(191 mg) was added, and the mixture was hydrogenated at 1 atm
and 25 °C for 57 h. The catalyst was removed by filtration through
a Celite pad, the solvent was evaporated, and the mixture was dis-
solved in CH2Cl2 (50 mL). The organic layer was washed with a
saturated solution of NaHCO3 and dried with Na2SO4. After col-
umn chromatography (CH2Cl2/MeOH, from 40:1 to 30:1), pure 7
(94 mg, 61%) was isolated, m.p. 85 °C (n-hexane), 84–87 °C (petro-
leum ether).[18] 1H NMR (CDCl3, 200 MHz): δ = 7.20–7.02 (m, 10
H), 4.48, 3.78 (AB system, J = 10.3 Hz, 2 H), 3.70 (s, 3 H), 1.86
(s, 2 H, exch.) ppm.
N-Benzyl-2-(2-fluorophenyl)-3-(4-bromophenyl)-lactam (10): Under
a nitrogen atmosphere, a mixture of 9b (135 mg, 0.25 mmol) in dry
CH3CN (15 mL) was stirred at 25 °C for 5 min. Hg(OCOCF3)2
(215 mg, 0.50 mmol) was added, and the reaction mixture was
stirred for 5 min. The solvent was removed under vacuum, and the
residue was dissolved in CH2Cl2 (15 mL), washed with HCl
(10 mL, 1 m), and dried with Na2SO4. The crude mixture was puri-
fied by column chromatography (hexane/ethyl acetate 1:1) to afford
10 (83 mg, 80%) as a white solid, m.p. 95 °C (Et2O/cyclohexane).
1H NMR (CDCl3, 200 MHz): δ = 7.55–7.00 (m, 13 H), 4.93, 3.84
(AX system, J = 15.0 Hz, 2 H), 4.32, 4.28 (AB system, J = 2.1 Hz,
2 H) ppm. 13C NMR (CDCl3, 50 MHz): δ = 45.1, 59.9, 61.9, 115.8
(d, J = 21.3 Hz), 121.1 (d, J = 15.6 Hz), 122.9 124.7 (d, J = 3.8 Hz),
128.1, 128.4 (ϫ2), 128.8 (ϫ2), 129.0 (ϫ2), 129.3 (d, J = 4.2 Hz),
129.8 (d, J = 8.0 Hz), 132.4 (ϫ2), 135.2, 136.4, 161.0 (d, J =
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247.2 Hz), 167.3 ppm. IR (NaCl): ν
= 3370, 1760 cm–1. MS
˜
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(ESI): m/z: 410.3 [M]+. C22H17BrFNO (410.29): calcd. C 64.40, H
4.18, N 3.41; found C 64.08, H 4.30, N 3.11.
Supporting Information (see footnote on the first page of this arti-
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scopic data (1H and 13C NMR spectra) for all new compounds.
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Received: January 27, 2014
[15] The reaction was repeated and the literature protocol was fol-
lowed.[10] The presence of dimeric compounds and a Claisen
1
adduct (present in its enol form) was confirmed by H NMR
Published Online: April 8, 2014
Eur. J. Org. Chem. 2014, 3203–3209
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3209