Silver-Catalyzed Enantioselective Mannich Reaction of Diazoacetate Esters with N-Boc Aldimines

Article abstract of DOI:10.1021/acs.joc.9b03177

The highly enantioselective Mannich reaction of diazoacetate esters with N-Boc aldimines catalyzed by silver(I) triflate in the presence of (R)-DM-SEGPHOS is reported. The reaction is broad in scope with respect to the (hetero)aromatic aldehyde-derived al

Full text of DOI:10.1021/acs.joc.9b03177

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Note
Silver-Catalysed Enantioselective Mannich Reaction
of Diazoacetate Esters with N-Boc Aldimines
Gerard P. Robertson, Alistair J. M. Farley, and Darren J. Dixon
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b03177 • Publication Date (Web): 23 Dec 2019
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The Journal of Organic Chemistry
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Silver-Catalysed Enantioselective Mannich Reaction of
Diazoacetate Esters with N-Boc Aldimines
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Gerard P. Robertson, Alistair J.M. Farley and Darren J. Dixon*
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1
3TA, UK. E-mail: Darren.dixon@chem.ox.ac.uk.
O
Boc
R
O
O
O
PAr2
PAr2
NH O
N2
NBoc
Ag
+
OR'
OR'
R
N2
Chiral Bisphosphine
Ligand
O
Ar = 3,5-(Me)2C6H3
17 examples
up to 88% yield
and up to 98% ee
ABSTRACT: The highly enantioselective Mannich reaction of diazoacetate esters with N-Boc aldimines catalysed by silver (I)
triflate in the presence of (R)-DM-SEGPHOS is reported. The reaction is broad in scope with respect to the (hetero)aromatic
aldehyde-derived aldimine and tolerates significant variability of the diazoacetate ester component. Yields and enantioselectivities
are good to excellent and the reaction can be performed on gram scale with catalyst loadings as low as 1 mol%.
The Mannich reaction is a fundamental two-
component coupling reaction in organic chemistry,
enabling the ready construction of chiral amine
building blocks of significance to the pharmaceutical,
agrochemical and fine chemical industries.1 The
reaction, which unites an imine electrophile and a
nucleophilic carbonyl component (via an enol, enol
derivative or an enolate ion), can be rendered
catalytic and with the appropriate catalyst or catalytic
system, highly enantioselective. To date a range of
enantioselective Mannich-type reactions using a
reactions ranging from CH activation to diversity
oriented library generation.5
Figure 1. Previous approaches to β-amino acids bearing α-
diazo substitution and this work.
a. Maruoka's dicarboxylic acid catalysed Mannich reaction
R
NHBoc
CO2tBu
NBoc
5 mol% cat.
CO2tBu
CO2H
CO2H
Ar
CH2Cl2
0 °C, 5 - 72 h
Ar
N2
N2
10 examples
53 - 89% yield, 85 - 96% ee
R
R = 2,6-Me2-4-tBu-C6H2
plethora
of
nucleophilic
and
electrophilic
components have been reported.2 Despite these
advances, considerable opportunities still exist to
improve catalyst loading, efficiency, selectivity and
most importantly scope of the enantioselective
Mannich reaction.
b. Terada's phosphoric acid calysed Mannich reaction
R
NR'
O
O
CO2tBu
N2
R'
2 mol% cat.
CO2tBu
N
P
Ar
OH
O
toluene, rt, 24 h
Ar
N2
R
18 examples
59 - 89% yield, 86 - 97% ee
One class of reagent that has received considerable
attention within the synthetic community due to its
R = 9-anthryl
c. This work
versatility
and
potential
for
downstream
O
Boc
NH
O
CO2R'
N2
NBoc
R
1-5 mol%, Ag(I), L*
10 mol% NEt3
functionalization reactions is the α-diazo carbonyl
compound,3 of which the chemistry of α-diazoacetate
derivatives predominates.4 The diazo unit enables
facile carbene/carbenoid generation under a variety
of conditions that can be widely exploited in
O
O
PAr2
PAr2
R
OR'
CHCl3
N2
17 examples
64 - 88% yield, 88 - 98% ee
R = aryl, heteroaryl
R' = Et, All, Bn, Ph
O
Ar = 3,5-(Me)2C6H3
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Table 1. Optimization of the silver-catalysed addition
Maruoka and Terada independently reported the
organocatalytic enantioselective addition of
of ethyl diazoacetate to N-Boc aldimine 2a.a
1
2
3
4
5
6
7
diazoacetate derivatives to aldimines under
carboxylic acid6a and phosphoric acid catalysis6b
(Figure 1). Very recently, Wang disclosed the ethyl
diazoacetate (EDA) Mannich reaction of cyclic
ketimines.6d
Boc
Ph
5 mol% Ag(I)
O
NH
O
NBoc
1
10 mol% ligand
Et
Et
+
O
O
Ph
0.08 M solvent, T
N2
N2
4a
2a
3a
8
9
Figure 2. Ligands used in the optimization studies.
Ag(I)
1
Solvent
T
(°C)
Time
(h)
Yield
eec
O
(%)b
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N
NH
PPh2
PPh2
MeO
MeO
PPh2
PPh2
1
2
Ag2O
Ag2O
a
b
b
b
b
b
b
b
c
d
e
f
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
Et2O
rt
rt
15
5
81
87
74
71
52
28
38
50
68
52
58
58
65
48
32
68
77
68
40
9d
24d
37d
39d
35d
21d
49d
49d
51
PPh2
N
O
1a
1b
1c
3
AgOTfe
AgOTf
AgOTff
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
rt
5
O
O
O
O
O
O
O
4
rt
5
O
O
PAr2
PAr2
PAr2
PAr2
PPh2
PPh2
5
rt
5
1d
1e
1f
O
O
O
Ar = 3,5-(Me)2C6H3
Ar = 3,5-(tBu)2,4-(OMe)C6H2
6
rt
6
7
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
PhCl
rt
6
8g
rt
4
We envisaged that the development of a new catalyst
system for this reaction which imparted high
enantioselectivity whilst tolerating a broad scope with
respect to both the aldimine electrophile and the
diazoacetate ester would bring synthetic value and
potentially advance the field (Figure 1c).6 As part of our
research programme into the development of challenging
enantioselective Mannich and Aldol reactions of
isocyanoacetate pronucleophiles,7 aminophosphine 1a
ligated silver(I) salts were identified as a privileged
catalytic system for related transformations. Our hope
was that such silver(I) complexes could provide the
necessary reactivity and selectivity for the first silver
catalyzed enantioselective diazoacetate addition to N-Boc
aldimines and herein we wish to report our findings.
9g
rt
2
10g
11g
12g
13g
14g
15g
16g,h
17g,h
18g,h
19g,i
rt
5
59
rt
5
81
rt
7
71
e
e
e
e
e
e
e
rt
6
75
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
rt
6
85
-20
-20
-40
-50
-40
24
16
24
24
24
91
88
97
97
The reaction of benzaldehyde derived N-Boc imine 2a
with ethyl diazoacetate (3a) was chosen as a model
system. Proof of concept was rapidly established when a
catalyst system comprising Ag2O and aminophosphine
ligand 1a (figure 2) was employed in the reaction at room
temperature (table 1, entry 1 and Supporting Information).
We were delighted to observe product formation and
after 15 hours β-amino ester 4a was isolated in 81% yield
and 9% ee. In a search to identify alternative ligands, a
bidentate phosphine, BINAP (1b), was screened and
found to offer improvement to both the reaction time and
enantioselectivity in the formation of 4a (entry 2). The
enantioselectivity was further improved by switching to
AgOTf (entries 3 & 4) although a slightly diminished
reaction yield was returned. Increasing the loading of
AgOTf to 20 mol% reduced both the ee and yield in the
formation of 4a (entry 5).
95
aReactions performed using 0.10 mmol of 2a with 1.2 eq
3a. Isolated yield. Enantiomeric excess (ee) determined
b
c
by chiral HPLC analysis using a chiral stationary phase.
d(S)-4a obtained. 10 mol% Ag used. 20 mol% Ag used.
g10 mol% NEt3 added. hReaction performed at 0.16 M
concentration wrt 2a. iReaction performed at 0.12 M
concentration wrt 2a.
e
f
A brief screen of solvents at this point, revealed that
dichloromethane gave the highest enantioselectivity
(entries 6 & 7). Interestingly, it was found that the
addition of 10 mol% NEt3 to the reaction increased the
yield (entry 8). At this stage, related atropisomeric
bisphosphine ligands 1c-f were evaluated (entries 9 – 12)
and yielded 4a in up to 81% ee (entry 11). Subsequent
optimisation studies were performed with ligand 1e and a
solvent switch to chlorobenzene and chloroform
improved the enantioselectivity to 75 and 85% ee
respectively (entries 13 & 14).
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The Journal of Organic Chemistry
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Figure 3. Scope of the silver catalysed enantioselective Mannich reaction of diazoacetate esters with N-Boc aldimines.
O
Boc
R1
1e
ligand
(10 mol%)
O
NH
O
O
O
PAr2
PAr2
R2
AgOTf (5 mol%)
NEt3 (10 mol%)
R2
NBoc
O
O
+
R1
N2
N2
4a - q
1e
0.16 M CHCl3
-40 °C, 24 h
O
2a - n
3a - d
Ar = 3,5-(Me)2C6H3
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Boc
Boc
Boc
Boc
NH O
NH
O
NH
O
NH O
O
O
O
O
N2
N2
N2
N2
O
O
4b
4c
4d
4e
, 75% yield
98% ee
, 70% yield
98% ee
, 86% yield
96% ee
, 80% yield
98% ee
Boc
Boc
Boc
Boc
NH O
NH
O
NH
O
NH O
O
O
O
O
N2
N2
N2
N2
Cl
Cl
F
Br
4f
4g
4h
4i
, 60% yield
96% ee
, 80% yield
94% ee
, 76% yield
96% ee
, 72% yield
95% ee
Boc
NH
O
Boc
Boc
Boc
O
NH
O
NH
O
NH O
O
O
O
O
N2
N2
S
N2
N2
4j
4k
4l
4m
, 81% yield
98% ee
, 84% yield
96% ee
, 81% yield
97% ee
, 70% yield
98% ee
Boc
Boc
Boc
Boc
NH
O
NH
O
NH
O
NH O
Ph
O
O
O
Ph
O
N2
N2
N2
N2
N
a
4n
4o
4p
4q
, 88% yield
92% ee
, 79% yield
94% ee
, 72% yield
92% ee
, 64% yield
88% ee
Reactions were carried out with 0.10 mmol 2 and 0.12 mmol 3. Yields are isolated yields and enantiomeric excesses were
determined by HPLC analysis on a chiral stationary phase. aThe reaction was quenched after 66 hours.
Lowering the reaction temperature to –20 °C improved
the enantiomeric excess to 91%, albeit to the detriment of
the yield (entry 15). This was circumvented by increasing
the reaction concentration to 0.16 M and the reaction
time to 24 h which enabled the reaction to be performed
at –40 °C (entries 17 & 18). Decreasing the reaction
temperature further to –50 °C did not improve the
enantioselectivity nor did diluting the reaction to 0.12 M
(entries 18 & 19). β-Amino ester 4a was accordingly
synthesised in 77% yield and 97% ee using the optimal
conditions as identified in entry 17.
para position was well-tolerated and afforded both 4b and
4c in 98% ee. Simarly the addition of a methoxy group or
a chlorine atom in the ortho or para positions of the
aromatic imine gave the desired β-amino esters 4d-g in
good yield and with consistently excellent levels of
enantioselectivity. Fluorine and bromine substituents on
the aromatic ring were also compatible and products 4h
and 4i were afforded in 96% and 95% ee respectively.
Both 1- and 2-naphthaldehyde-derived N-Boc aldimines
successfully underwent the Mannich reaction to give 4j
and 4k in good yields and excellent enantiomeric
excesses. Having demonstrated the compatibility of 10 π-
electron aromatics we next focused on heteroaromatic
aldimines and were delighted to observe that both 2-
With optimised conditions in hand, the scope of the
transformation was investigated (Figure 3). The addition
of methyl groups to the aromatic ring in the meta and
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thiophene and 2-furan substituted imines 4l and 4m
5d bearing a fully substituted α-carbon in 79% yield as a
single diastereomer.9
1
2
3
4
5
6
7
8
afforded the desired products with consistently high
levels of enantioselectivity. Significantly, the reaction
could also be performed with an imine incorporating a
pyridine ring and the product 4n was isolated in 88%
yield and 92% ee. After extensive exploration of the imine
component we then investigated the scope with respect
to the α-diazoacetate ester. Allyl, benzyl and phenolic
esters 3b - d all performed well in the formation of 4o - q;
although the formation of 4q required an extended
reaction time of 66 h to give the product in decent yield.
In conclusion, we have developed a silver(I) catalysed
enantioselective Mannich reaction of diazoacetate esters
with N-Boc protected aldimines. The reaction is broad in
scope with respect to the (hetero)aryl aldehyde-derived
N-Boc aldimine and can tolerate variation to the ester of
the diazoacetate. The β-amino ester products are formed
in typically good yields and with excellent levels of
enantioselectivity and the reaction can be performed on
gram scale with catalyst loadings as low as 1 mol%.
Importantly, the diazo moiety remains intact during the
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To further demonstrate the synthetic utility and general
applicability of this catalysed reaction we next set about
performing the reaction on preparative scale and
successfully lowered the catalyst loading to 1 mol% using
5 mmol of 2a to afford 1.28 g of the addition product 4a
in 81% yield and with 96% ee (scheme 1).
transformation and provides
a handle for further
downstream modification without erosion of the
enantiopurity. Further work focusing on the development
of novel catalytic systems and their application to
synthetically useful products is ongoing in our group and
the results will be disclosed in due course.
Scheme 1. Preparative synthesis of 4a and derivatisation.
EXPERIMENTAL SECTION
a.
Boc
General Information
NH
O
Boc
O
N
OEt
a.
Solvents and Reagents Concentration under reduced
pressure was performed by rotary evaporation at the
appropriate pressure and temperature. Reagents used
were obtained from commercial suppliers or purified
according to standard procedures. Petroleum ether refers
to distilled light petroleum of fraction 30 - 40 °C.
Anhydrous toluene, tetrahydrofuran, dichloromethane
and diethyl ether were dried by filtration through
activated alumina (powder ~150 mesh, pore size 58 Å,
basic, Sigma-Aldrich) columns. Chloroform was bought
from Sigma Aldrich in a 2.5 L Winchester, containing
0.5% - 1.0% ethanol as stabilizer and was extracted with
water, basified over K2CO3, distilled and stored over 4 Å
molecular sieves. Deuterated solvents were used as
supplied. (R)-DM-SEGPHOS was obtained from STREM
chemicals. Ethyl diazoacetate was obtained as a 15% stock
solution in toluene from Sigma Aldrich.
+
O
N2
2a
3a
4a
1.28 g
N2
81% yield
96% ee
b.
Boc
Boc
NH
O
NH
O
OEt
OEt
OH
8:1 d.r.
(anti:syn)
b.
e.
c.
d.
5a
5b
Boc
NH
O
OEt
N2
Boc
N
Boc
NH
O
N
N
Bn
CO2Et
OEt
NH2
N
5d
5c
Conditions: (a) 1 mol% AgOTf, 2 mol% 1e, 4 mol% NEt3,
CHCl3, 4 Å molecular sieves, -40 °C, 48 h. (b) 10 mol%
Pd/C, 1 atm H2, MeOH, 12 h, 75%, 96% ee. (c) i. Oxone®,
NaHCO3, acetone/H2O (1.5/1.0), CH2Cl2, ii. NaBH4,
CH2Cl2, -78 °C to RT, 58% (over 2 steps), 8 : 1 d.r.
Chromatography Reactions were monitored by thin
layer chromatography (TLC) using Merck silica gel 60 F254
plates and visualized by fluorescence quenching under
UV light. In addition, TLC plates were stained with
potassium permanganate solution. Flash column
chromatography (FCC) was performed on VWR 60 silica
gel 40 - 63 μm using technical grade solvents that were
used as supplied.
1
(anti:syn) determined by H-NMR analysis. (d) P(n-Bu)3,
Et2O, rt, 20 min, 88%, 96% ee. (e) 1.2 equiv NaH, 1.2 equiv
BnBr, DMF, 0 °C to rt, 30 min, 79%, 96% ee.
In a brief demonstration of the synthetic utility of the
reaction products, 4a was hydrogenated using hydrogen
(balloon pressure) over Pd/C which afforded the β-amino
ester 5a without loss of enantiopurity. Oxone® oxidation
followed by borohydride reduction of the resulting ketone
afforded the alcohol 5b as an 8: 1, anti : syn mixture of
diastereoisomers.8 The diazo unit was partially reduced to
the hydrazone by treatment with tributylphosphine; 5c
was afforded in 88% yield without loss of enantiopurity
(96% ee). Finally, treatment of 4a with NaH and
subsequently with benzyl bromide afforded the triazoline
Instrumentation Melting points were obtained on a
Leica Galen III Hot-stage melting point apparatus and
microscope and on a Kofler hot block and are reported
uncorrected. NMR spectra were recorded on a Bruker
Spectrospin spectrometer operating at 200, 400 or 500
MHz (1H acquisitions), 100 or 125 MHz (13C acquisitions),
377 MHz (19F acquisitions) and 162 MHz (31P acquisitions).
Chemical shifts (δ) are reported in ppm with the solvent
resonance as the internal standard (e.g. chloroform δ 7.27
1
13
ppm for H and 77.0 ppm for C). Coupling constants (J)
are reported in hertz (Hz), and rounded to the nearest
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0.5 Hz. Data are reported as follows: multiplicity [s = observed on addition of electron-deficient aldimines.
1
2
3
4
5
6
7
8
singlet, d = doublet, t = triplet, q = quartet, dd = doublet
of doublets, ddd = doublet of doublets of doublets, td =
triplet of doublets, m = multiplet, br = broad], coupling
Ethyl diazoacetate (0.10 mL, 0.12 mmol, 1.2 eq, 15% in
toluene), which had been pre-cooled was finally added.
After a 24 h period, the reaction mixture was passed
through a short pad of silica on a glass frit, eluting with
diethyl ether. The filtrate was then concentrated in vacuo
and purified immediately via FCC (15 mL of silica) eluting
with [100% petroleum ether to 10% diethyl ether] to yield
the desired compound as either a yellow oil or yellow
solid.
constants
in
Hz,
integration.
Two-dimensional
spectroscopy (COSY, HSQC and HMBC) was used to
assist in the assignment and the data is not reported.
High-resolution mass spectra (ESI) were recorded on
Bruker μTOF mass spectrometer. Infrared spectra were
recorded on a Bruker Tensor 27 FT-IR spectrometer as a
thin film. Only selected maximum absorbances are
reported. Optical rotations were recorded using a Perkin
Elmer 341 polarimeter; [α]DT values are reported in 10-1 deg
cm2 g-1; concentrations (c) are quoted in g/100 mL; D
refers to the D-line of sodium (589 nm); temperatures (T)
are given in degrees Celsius (°C). (+) and (–) compound
number prefixes indicate the sign of the optical rotation.
The enantiomeric excesses were determined by HPLC
analysis on an Agilent 1200 Series instrument employing a
chiral stationary phase column specified in the individual
experiment and by comparing the samples with the
appropriate racemic mixtures. -40 ˚C conditions were
achieved using an EK90 cryocooler.
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10
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Ethyl (3R)-3-{[(tert-butoxy)carbonyl]amino}-2-diazo-
3-phenylpropanoate 4a Prepared according to General
Procedure A using aldimine 2a (20.5 mg, 0.10 mmol) to
afford the title compound in 77% isolated yield as a
yellow solid (25 mg) and 97% ee [determined by HPLC,
Chiralpak AS-H, hexane/isopropanol = 95/5, 1 mL/min, 
= 220 nm, t (minor) = 12.36 min, t (major) = 16.64 min].
25
1
MPT 78 – 80 C; [α]D = +27.3 (c = 1.0, CHCl3); H NMR
(400 MHz, CDCl3) δ ppm 7.27 - 7.41 (m, 5 H, ArH), 5.66
(d, J = 6.6 Hz, 1 H, CHNH), 5.43 (br. s, 1 H, NHCH), 4.21
(q, J=7.3 Hz, 2 H, CH2CH3), 1.46 (s, 9 H, OC(CH3)3), 1.25 (t,
J=7.2 Hz, 3 H, CH2CH3);13C {1H} NMR (101 MHz, CDCl3), δ
ppm 165.9 (OC=O), 154.9 (NC(=O)OC), 139.1 (ArC), 128.9
(ArCH), 128.0 (ArCH), 126.2 (ArCH), 80.4 (OC(CH3)3), 61.0
(CH2CH3), 51.2 (CHNH), 28.3 (OC(CH3)3), 14.4 (CH2CH3);
IR max/cm-1 3346, 2978, 2095, 1697, 1497, 1167; Data is
consistent with that given in the literature.12
General Procedure for N-Boc Aldimine Synthesis (2a
– 2n). Step 1: According to a literature procedure,10
a
mixture of aldehyde (37.5 mmol, 1.5 equiv), N-Boc-
carbamate (2.93 g, 25 mmol, 1.0 equiv) and benzene
sulfinic acid sodium salt (8.26 g, 50 mmol, 2.0 equiv) was
suspended in MeOH/H2O (2:1, 75 mL). Formic acid (1.9
mL) was then added and the resulting mixture was then
stirred for 72 hours at room temperature whereupon the
reaction mixture filtered, the precipitate was washed with
water and then Et2O and dried to afford the desired
amidosulfone as a colourless solid. Step 2: a RBF was
charged with amidosulfone (10 mmol, 1.0 equiv),
potassium carbonate (15.0 equiv) and sodium sulfate (18.0
equiv). Dry THF was added (0.51 mM) under argon and
the suspension was heated to 70 °C in an oil bath for 16
hours after which the reaction mixture was passed
through a thick pad of Celite© on a glass frit, with
washings of CH2Cl2. The filtrate was concentrated in
vacuo to afford the aldimine.
Ethyl (3R)-3-{[(tert-butoxy)carbonyl]amino}-2-diazo-
3-(3-methylphenyl)propanoate 4b Prepared according
to the general procedure A using aldimine 2b (22 mg,
0.10 mmol) to afford the title compound in 75% isolated
yield as a yellow oil (25 mg) and 98% ee [determined by
HPLC, Chiralpak AD-H, hexane/isopropanol = 95/5, 1
mL/min,  = 220 nm, t (major) = 14.42 min, t (minor) =
25
1
15.84 min]. [α]D = +22.3 (c = 1.0, CHCl3). H-NMR
(400 MHz, CDCl3) δ ppm 7.33-7.46 (m, 1 H, ArH), 7.16-7.31
(m, 3 H, ArH), 5.74 (d, J=7.3 Hz, 1 H, CHNH), 5.47 (br. s., 1
H, NHCH), 4.33 (q, J=7.1 Hz, 2 H, CH3CH2), 2.47 (s, 3 H,
ArCH3), 1.57 (s, 9 H, OC(CH3)3), 1.37 (t, J=7.1 Hz, 3 H,
CH2CH3); 13C {1H} NMR (101 MHz, CDCl3) δ ppm 166.1
(OC=O), 155.0 (NC(=O)OC), 139.2 ArC), 138.8 (ArC), 129.0
(ArCH), 128.9 (ArCH), 127.0 (ArCH), 123.3 (ArCH), 80.5
(OC(CH3)3), 61.1 (CH3CH2), 51.3 (CHNH), 28.5 (OC(CH3)3),
21.6 (ArCH3), 14.5 (CH2CH3); IR max/cm-1 3351, 2979, 2093,
1698, 1491, 1368, 1163; HRMS (ESI-TOF): calcd for
[M+Na]+: calcd for C17H23N3O4Na [M+Na]+ 356.1581, found
356. 1577. Data is consistent with that given in the
literature.12
Diazoesters 3b – d were prepared according to a reported
protocol.11
General Procedure A for the Ag(I) catalyzed Mannich
reaction on 0.10 mmol scale. A reaction tube was
charged with silver triflate (1.3 mgs, 0.005 mmol, 5 mol%,)
and phosphine ligand (7.2 mgs, 0.010 mmol, 10 mol%).
Anhydrous chloroform (0.4 mL, 0.167 mM) was added
under an atmosphere of argon. The resulting mixture was
stirred for 1 hour at room temperature after which
triethylamine (1.4 µL, 0.010 mmol, 10 mol%) was added
and a faint yellow solution was produced after 15 min of
stirring at room temperature. The aldimine was then
added (21 mgs, 0.1 mmol in 0.2 mL of CHCl3) and the
reaction mixture was cooled to -40 °C and stirred at this
temperature for 30 min. Electron-rich aldimines produced
a bright yellow colour on addition, no colour change was
Ethyl (3R)-3-{[(tert-butoxy)carbonyl]amino}-2-diazo-
3-(4-methylphenyl)propanoate 4c Prepared according
to the general procedure A using aldimine 2c (22 mg,
0.10 mmol) to afford the title compound as a yellow solid
in 70% isolated yield (22 mg) and 98% ee [determined by
HPLC, Chiralpak AD-H, hexane/isopropanol = 95/5, 1
mL/min,  = 220 nm, t (major) = 15.67 min, t (minor) =
16.86 min]. MPT 74 – 76 °C; [lit. for the racemate 70.8 –
71.4 °C]12; [α]D25 = +13.1 (c =1.3, CHCl3). 1H NMR (400 MHz,
CDCl3) δ ppm 7.23 (d, J=8.1 Hz, 2 H, ArH), 7.16 (d, J=8.1
5
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C; [lit. for the racemate 102 – 103 C]17; [α]D25 = +32.4 (c =
0.75, CHCl3); H NMR (400 MHz, CDCl3) δ ppm 7.34 (d,
Hz, 2 H, ArH), 5.62 (d, J=7.5 Hz, 1 H, CHNH), 5.35 (br. s., 1
H, NHCH), 4.21 (q, J=7.2 Hz, 2 H, CH2CH3), 2.33 (s, 3 H,
ArCH3), 1.45 (s, 9 H, OC(CH3)3), 1.25 (t, J=7.1 Hz, 3 H,
CH2CH3); 13C {1H} NMR 166.1 (OC=O), 155.0 (NC(=O)OC),
137.9 (ArC), 136.3 (ArC), 129.7 (ArCH), 126.2 (ArCH), 80.3
(OC(CH3)3), 61.1 (CH2CH3), 50.9 (CHNH), 28.5
(OC(CH3)3), 21.2 (ArCH3), 14.6 (CH2CH3); IR max/cm-1
3353, 2978, 2093, 1697, 1512, 1392, 1167. HRMS (ESI-TOF):
calcd for [M+Na]+ C17H23N3O4Na 356.1581 found 356.1581.
Data is consistent with that given in the literature.12
1
1
2
3
4
5
6
7
8
J=8.5 Hz, 2 H, ArH), 7.30 (d, J=8.5 Hz, 2 H, ArH), 5.63 (d,
J=7.7 Hz, 1 H, CHNH), 5.42 (br. s., 1 H, NHCH), 4.13 - 4.33
(m, 2 H, CH2CH3), 1.45 (s, 9 H, OC(CH3)3), 1.25 (t, J=7.1 Hz,
3 H, CH2CH3); 13C {1H} NMR (101 MHz, CDCl3) δ ppm
165.9 (OC=O), 155.0 (NC(=O)OC), 137.9 (ArC), 134.0
(ArC), 129.2 (ArCH), 127.8 (ArCH), 80.7 (OC(CH3)3), 61.3
(CH3CH2), 51.0 (CHNH), 28.4 (OC(CH3)3), 14.5 (CH2CH3);
IR max/cm-1 3343, 2876, 2931, 2095, 1695, 1491, 1392, 1166;
HRMS (ESI-TOF) : calcd for [M+Na]+ C16H20ClN3O4Na
376.1035, found 376.1036. Data is consistent with that
given in the literature.12
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Ethyl (3R)-3-{[(tert-butoxy)carbonyl]amino}-2-diazo-
3-(2-methoxyphenyl)propanoate 4d Prepared according
to the general procedure A using aldimine 2d (23.5 mg,
0.10 mmol) to afford the title compound in 86% isolated
yield as a yellow oil (30 mg) and 96% ee [determined by
HPLC, Chiralpak AD-H, hexane/isopropanol = 95/5,
1 mL/min,  = 220 nm, t (major) = 16.29 min, t (minor) =
Ethyl
(3R)-3-{[(tert-butoxy)carbonyl]amino}-3-(2-
4g Prepared
chlorophenyl)-2-diazopropanoate
according to general procedure A using aldimine 2g (23.9
mg, 0.10 mmol) to afford the title compound in 80%
isolated yield (28 mg) and 94% ee [determined by HPLC,
Chiralpak AD-H, hexane/isopropanol = 95/5, 1 mL/min, 
= 220 nm, t (major) = 16.74 min, t (minor) = 19.41 min].
[α]D25 = +104.9 (c =1.0, CHCl3); 1H NMR (400 MHz, CDCl3)
δ ppm 7.47 (d, J=7.3 Hz, 1 H, ArH), 7.38 (dd, J=7.6, 1.4 Hz, 1
H, ArH), 7.21 - 7.32 (m, 2 H, ArH), 5.94 (d, J=7.7 Hz, 1 H,
CHNH), 5.74 (br. s, 1 H, NHCH), 4.01 - 4.37 (m, 2 H,
CH2CH3), 1.44 (s, 9 H, C(CH3)3), 1.23 (t, J=7.1 Hz, 3 H,
CH2CH3);13C {1H} NMR (101 MHz, CDCl3) δ ppm 166.0
(OC=O), 154.8 (NC(=O)OC), 136.8 (ArC), 132.8 (ArC), 130.1
(ArCH), 129.2 (ArCH), 128.2 (ArCH), 127.1 (ArCH), 80.5
25
19.79 min]. [α]D = +4.5 (c =1.2, CHCl3). 1H-NMR
(400 MHz, CDCl3) δ ppm 7.23 - 7.37 (m, 2 H, ArH), 6.88 -
6.98 (m, 2 H, ArH), 5.83 (br. s., 2 H, CHNH& NHCH), 4.17
(q, J=7.1 Hz, 2 H, CH2CH3), 3.87 (s, 3 H, ArOCH3), 1.46 (s, 9
H, OC(CH3)3), 1.23 (t, J=7.1 Hz, 3 H, CH2CH3); 13C {1H}
NMR (101 MHz, CDCl3) δ 166.3 (OC=O), 156.8 (ArC), 154.8
(NC(=O)OC)), 129.2 (ArCH), 128.4 (ArCH), 127.4 (ArC),
120.8 (ArCH), 110.7 (ArCH), 80.2 (OC(CH3)3), 60.9
(CH3CH2), 55.4 (ArOCH3), 47.8 (CHNH), 28.4 (OC(CH3)3),
14.5 (CH2CH3); IR max/cm-1 3353, 2976, 2093, 1695, 1602,
1491, 1392, 1165. HRMS (ESI-TOF): calcd for [M+Na]+ for
C17H23N3O5Na 372.1530, found 372.1527.
(OC(CH3)3), 61.3 (CH2CH3), 49.34 (CHNH),
28.59
(OC(CH3)3), 14.65 (CH2CH3); IR max/cm-1 3343, 2977, 2360,
2096, 1698, 1476, 1169. HRMS (ESI-TOF): calcd for
[M+Na]+ C16H20ClN3O4Na 376.1035, found 376.1036.
Ethyl (3R)-3-{[(tert-butoxy)carbonyl]amino}-2-diazo-
3-(4-methoxyphenyl)propanoate 4e Prepared according
to the general procedure A using aldimine 2e (23.5 mg,
0.10 mmol) to afford the title compound in 80% isolated
yield as a yellow solid (28 mg) and 98% ee [determined by
HPLC, Chiralpak AD-H, hexane/isopropanol = 95/5, 1
mL/min, λ = 220 nm, t (major) = 25.17, t (minor) = 27.78
min]. MPT 68 – 70 C; [lit. for the racemate 97 – 98 C]12;
Ethyl (3R)-3-{[(tert-butoxy)carbonyl]amino}-2-diazo-
3-(4-fluorophenyl)propanoate 4h Prepared according to
general procedure A, using aldimine 2h (22.3 mg,
0.10 mmol) which afforded the title compound in 76%
isolated yield as a yellow solid (25 mg) and 96% ee.
1
[α]D25 = +12.3 (c = 1.3, CHCl3). H-NMR (400 MHz, CDCl3)
[determined
by
HPLC,
Chiralpak
AD-H,
δ ppm 7.28 (d, J = 8.6 Hz, 2H, ArH), 6.90 (d, J=8.6 Hz, 2H,
ArH), 5.62 (d, J=7.3 Hz, 1H, CHNH), 5.32 (br.s, 1H,
NHCH), 4.25 (q, J = 7.1 Hz, 2H, CH2CH3), 3.80 (s, 3H,
ArOCH3), 1.45 (s, 9H, (OC(CH3)3), 1.27 (t, J=7.1 Hz, 3H,
CH2CH3); 13C {1H} NMR (101 MHz, CDCl3) δ ppm 166.0
(OC=O), 159.3 (ArCOMe), 154.8 (NC(=O)OC), 131.2 (ArC),
127.4 (ArCH), 114.2 (ArCH), 80.3 (OC(CH3)3), 61.0
(CH2CH3), 55.3 (ArOCH3), 50.7 (CHNH), 28.3 (OC(CH3)3),
14.4 (CH2CH3); IR max/cm-1 3352, 2978, 2092, 1692, 1511,
1162; HRMS (ESI-TOF) : calcd for [M+Na]+ C17H23N3O5Na
372.1530, found 372.1532. Data is consistent with that given
in the literature.12
hexane/isopropanol = 95/5, 1 mL/min,  = 220 nm, t
(major) = 15.31 min, t (minor) = 17.15 min]. MPT 82 –
25
1
86 C; [α]D = +29.5 (c =1.1, CHCl3). H NMR (400 MHz,
CDCl3) δ ppm 7.31-7.34 (m, 2 H, ArH), 7.02-7.06 (m, 2 H,
ArH), 5.64 (d, J=7.4 Hz, 1 H, CHNH), 5.41 (br. s, 1 H,
NHCH), 4.22 (q, J=7.1 Hz, 2 H, CH2CH3), 1.45 (s, 9 H,
OC(CH3)3), 1.25 (t, J=7.1 Hz, 3 H, CH2CH3); 13C {1H} NMR
(101 MHz, CDCl3) δ ppm 165.8 (OC=O), 163.6 & 161.1 (d, JCF
= 247.2 Hz, ArCF), 154.9 (NC(=O)OC), 134.9 (ArC), 127.9
(ArCH), 127.9 (ArCH), 115.8 (ArCH), 115.6 (ArCH), 80.5
(OC(CH3)3), 61.1 (CH2CH3), 50.8 (CHNH), 28.3
(OC(CH3)3), 14.4 (CH2CH3); 19F NMR δ -114.3; IR max/cm-1
3346, 2980, 2095, 1694, 1509, 1158. Data is consistent with
that given in the literature.12
Ethyl
(3R)-3-{[(tert-butoxy)carbonyl]amino}-3-(4-
4f Prepared
chlorophenyl)-2-diazopropanoate
according to general procedure A using aldimine 2f
(23.9 mg, 0.10 mmol) to afford the title compound in 60%
isolated yield as a yellow solid (19 mg) and 96% ee.
Ethyl
(3R)-3-(3-bromophenyl)-3-{[(tert-
4i
butoxy)carbonyl]amino}-2-diazopropanoate
Prepared according to the general procedure A using
aldimine 2i (28.4 mg, 0.10 mmol) to afford the title
compound as a yellow oil in 72% isolated yield (28 mg)
and 95% ee [determined by HPLC, Chiralpak AS-H,
[determined
by
HPLC,
Chiralpak
AD-H,
hexane/isopropanol = 95/5, 1 mL/min,  = 220 nm, t
(major) = 15.42 min, t (minor) = 17.49 min]. MPT 88-92
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The Journal of Organic Chemistry
General Procedure
A
using aldimine 2l (21.1 mg,
hexane/isopropanol = 95/5, 1 mL/min,  = 220 nm, t
(minor) = 9.65 min, t (major) = 13.11 min]. [α]D25 = +30.5 (c
1
2
3
4
5
6
0.10 mmol) to afford the title compound in 81% isolated
yield as a yellow oil (27 mg), and 97% ee [determined by
HPLC, Chiralpak AD-H, hexane/isopropanol = 95/5,
1 mL/min,  = 220 nm, t (minor) = 11.57 min, t (major) =
1
=1.3 , CHCl3); H NMR(400 MHz, CDCl3) δ ppm 7.53 (s, 1
H, ArH), 7.46 (d, J=7.8 Hz, 1 H, ArH), 7.18 - 7.36 (m, 2 H,
ArH), 5.67 (d, J=7.6 Hz, 1 H, CHNH), 5.48 (br. s, 1 H,
NHCH), 4.18-4.40 (m, 2H, CH2CH3), 1.49 (s, 9 H,
25
1
16.81 min]. [α]D = +8.6 (c = 1.1, CHCl3); H NMR(400
MHz, CDCl3) δ ppm 7.21-7.28 (m, ArH), 6.94 - 7.01 (m, 2
H, ArH), 5.87 (d, J=7.9 Hz, 1 H, CHNH), 5.49 (br. s., 1 H,
NHCH), 4.25 (q, J=7.1 Hz, 2 H, CH2CH3), 1.47 (s, 9 H,
OC(CH3)3), 1.27 (t, J=7.1 Hz, 3 H, CH2CH3); C {1H} NMR
13
7
8
9
(101 MHz, CDCl3)
δ
ppm 165.8 (OC=O), 155.0
(NC(=O)OC), 141.6 (ArC), 131.3 (ArCH), 130.5 (ArCH),
129.5 (ArCH), 125.0 (ArCH), 123.0 (ArC), 80.8 (OC(CH3)3),
61.3 (CH2CH3), 50.9 (CHNH), 28.4 (OC(CH3)3), 14.5
(CH2CH3); IR max/cm-1 3341, 2980, 2095, 1695, 1571, 1475,
OC(CH3)3), 1.27 (t, J=7.1 Hz, 3 H, CH2CH3); C {1H} NMR
13
(101 MHz, CDCl3),
δ
ppm 165.7 (OC=O), 154.7
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(NC(=O)OC), 143.3 (ArC), 127.2 (ArCH), 125.3 (ArCH),
124.9 (ArCH), 80.7 (OC(CH3)3), 61.2 (CH2CH3), 48.1
(CHNH), 28.4 (OC(CH3)3), 14.5 (CH2CH3); HRMS (ESI-
TOF) : calcd for [M+Na]+ C14H19N3O4SNa 348.0988, found
348.0987. Data is consistent with that given in the
literature.12
1369, 1163; HRMS (ESI-TOF)
C16H20BrN3O4Na 420.0529, found 420.0530.
:
calcd for [M+Na]+
Ethyl (3R)-3-{[(tert-butoxy)carbonyl]amino}-2-diazo-
3-(naphthalen-2-yl)propanoate 4j Prepared according
to general procedure A, using aldimine 2j (25.5 mg,
0.10 mmol) which afforded the desired compound in 81%
isolated yield as an amorphous, yellow solid (29 mg) and
98% ee. [determined by HPLC, Chiralpak AD-H,
hexane/isopropanol = 95/5, 1 mL/min,  = 220 nm, t
(minor) = 14.66 min, t (major) = 18.32 min]. [α]D25 = +22.9
Ethyl (3S)-3-{[(tert-butoxy)carbonyl]amino}-2-diazo-3-
(furan-2-yl)propanoate 4m Prepared according to
general procedure A, using aldimine 2m (19.5 mg, 0.10
mmol) which afforded the desired compound in 70%
isolated yield as a yellow oil (22 mg) and 98% ee.
1
[determined
by
HPLC,
Chiralpak
AD-H,
(c = 1.1, CHCl3); H NMR (400 MHz, CDCl3) δ ppm 7.77-
hexane/isopropanol = 95/5, 1 mL/min,  = 220 nm, t
7.93 (m, 4 H, ArH), 7.41 - 7.55 (m, 3 H, ArH), 5.84 (d, J=7.5
Hz, 1 H, CHNH), 5.50 (br. s, 1 H, NHCH), 4.23 (q, J=7.1 Hz,
2 H, CH2CH3), 1.47 (s, 9 H, OC(CH3)3), 1.25 (t, J=7.1 Hz, 3
(minor) = 9.44 min, t (major) = 13.75 min]. [α]D25 = +12.0 (c
1
= 1.0, CHCl3). H NMR (400 MHz, CDCl3) δ ppm 7.36 (s, 1
13
H, CH2CH3); C {1H} NMR (101 MHz, CDCl3) δ ppm 166.1
H, ArH), 6.31 - 6.37 (m, 1 H, ArH), 6.28 (d, J = 3.1 Hz, 1H,
ArH), 5.70 (d, J=7.6 Hz, 1 H, CHNH), 5.39 (br. s, 1 H,
NHCH), 4.23 (q, J=7.2 Hz, 2 H, CH2CH3), 1.46 (s, 9 H,
(OC=O), 155.1 (NC(=O)OC), 136.6 (ArC), 133.4 (ArC), 133.1
(ArC), 129.0 (ArCH), 128.2 (ArCH), 127.8 (ArCH), 126.6
(ArCH), 126.4 (ArCH), 125.1 (ArCH), 124.3 (ArCH), 80.6
(OC(CH3)3), 61.2 (CH2CH3), 51.6 (CHNH), 28.5
(OC(CH3)3), 14.5 (CH2CH3); IR max/cm-1 3342, 2978, 2093,
1695, 1506, 1392, 1164. Data is consistent with that given in
the literature.12
13
OC(CH3)3), 1.26 (t, J=7.1 Hz, 3 H, CH3CH2); C {1H} NMR
(101 MHz, CDCl3)
δ
ppm 165.7 (OC=O), 154.8
(NC(=O)OC), 151.3 (ArC), 142.6 (ArCH), 110.7 (ArCH),
107.2 (ArCH), 80.7 (OC(CH3)3), 61.2 (CH2CH3), 46.2
(CHNH), 28.4 (OC(CH3)3), 14.6 (CH2CH3); HRMS (ESI-
TOF) : calcd for [M+Na]+ C14H19N3O5Na 332.1217, found
332.1216. Data is consistent with that given in the
literature.12
Ethyl (3R)-3-{[(tert-butoxy)carbonyl]amino}-2-diazo-
3-(naphthalen-1-yl)propanoate 4k Prepared according
to general procedure A using aldimine 2k (25.5 mg,
0.10 mmol) to afford the desired compound in 84%
isolated yield as a yellow oil (31 mg) and 96% ee
Ethyl (3R)-3-{[(tert-butoxy)carbonyl]amino}-2-diazo-
3-(pyridin-3-yl)propanoate 4n Prepared according to
the general procedure A using aldimine 2n (20.6 mg,
0.10 mmol) to afford the title compound as a yellow oil in
88% isolated yield and 92% ee [determined by HPLC,
Chiralpak AD-H, hexane/isopropanol = 95/5, 1 mL/min, 
= 220 nm, t (minor) = 36.21 min, t (major) = 45.04 min].
[determined
by
HPLC,
Chiralpak
AD-H,
hexane/isopropanol = 95/5, 1 mL/min, λ = 220 nm, t
(major) = 21.15 min, t (minor) = 22.85 min]. [α]D25= +46.5
1
(c = 1.4, CHCl3). H NMR (400 MHz, CDCl3) δ ppm 8.02
(d, J=8.3 Hz, 1 H, ArH), 7.88 (d, J=7.9 Hz, 1 H, ArH), 7.82
(d, J=8.2 Hz, 1 H, ArH), 7.49 - 7.60 (m, 3 H, ArH), 7.42 -
7.48 (m, 1 H, ArH), 6.43 (d, J=7.0 Hz, 1 H, CHNH), 5.30
(br. s., 1 H, NHCH), 4.25 (q, J=7.1 Hz, 2 H, CH2CH3), 1.44
(br. s., 9 H, OC(CH3)3), 1.26 (t, J=7.1 Hz, 3 H, CH2CH3);
13C {1H} NMR (101 MHz, CDCl3), δ ppm 165.8 (OC=O),
154.9 (NC(=O)OC), 134.3 (ArC), 134.2 (ArC), 130.4 (ArC),
129.2 (ArCH), 129.1 (ArCH), 127.0 (ArCH), 126.2 (ArCH),
125.3 (ArCH),), 123.8 (ArCH), 122.9 (ArCH), 80.6
((OC(CH3)3), 61.3 (CH2CH3), 48.1 (CHNH), 28.4
(OC(CH3)3), 14.6 (CH3CH2); IR max/cm-1 3341, 2978, 2094,
1694, 1510, 1368, 1165; HRMS (ESI-TOF): calcd for
[M+Na]+ C20H23N3O4Na [M+Na]+ 392.1581, found 392.1577.
25
1
[α]D = +33.8 (c =0.145, CHCl3); H NMR (500 MHz,
CDCl3) δ ppm 8.62 (d, J=1.9 Hz, 1 H, ArH), 8.54 (d,
J=3.8 Hz, 1 H, ArH), 7.65-7.73 (m, 1 H, ArH), 7.29 (dd,
J=7.9, 4.8 Hz, 1 H, ArH), 5.70 (br. s., 1 H, CHNH& NHCH),
4.16 - 4.27 (m, 2 H, CH2CH3), 1.45 (s, 9 H, OC(CH3)3), 1.25
(t, J = 7.1 Hz, 3 H, CH2CH3); 13C {1H} NMR (126 MHz,
CDCl3) δ ppm 165.8 (OC=O), 155.0 (NC(=O)OC), 149.4
(ArCH), 148.2 (ArCH), 135.0 (ArC), 134.1 (ArCH), 123.6
(ArCH), 80.9 (OC(CH3)3), 61.4 (CH2CH3), 49.6 (CHNH),
28.4 (OC(CH3)3), 14.5 (CH2CH3); IR max/cm-1 3338, 2979,
2925, 2094, 1695, 1513, 1392, 1166; HRMS (ESI-TOF) : calcd
for [M+H]+ C15H21N4O4 321.1557, found 321.1559.
Prop-2-en-1-yl (3R)-3-{[(tert-butoxy)carbonyl]amino}-
Ethyl (3S)-3-{[(tert-butoxy)carbonyl]amino}-2-diazo-3-
2-diazo-3-phenylpropanoate 4o Prepared according to
(thiophen-2-yl)propanoate 4l Prepared according to
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modified general procedure A, using diazoester 3b was added under argon and the resulting mixture was
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7
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(30 mg, 0.24 mmol, 1.2 eq) and aldimine 2a (41 mg,
0.20 mmol) to afford the title compound in 79% isolated
yield (52 mg) as a yellow oil and in 94% ee [determined by
HPLC, Chiralpak AS-H, hexane/isopropanol =90/10,
1 mL/min,  = 220 nm, t (minor) = 9.77 min, t (major) =
13.83 min]. [α]D = +30.0 (c = 1.2, CHCl3); H NMR
(500 MHz, CDCl3) δ ppm 7.28 - 7.40 (m, 5 H, ArH), 5.93-
5.85 (m, 1 H, CH2CH=CH2), 5.68 (br. s., 1 H, CHNH), 5.37
(br. s, 1 H, NHCH), 5.18 - 5.31 (m, 2 H, CH2CH=CH2), 4.60
- 4.72 (m, 2 H, CH2CH=CH2), 1.45 (s, 9 H, OC(CH3)3);
13C {1H} NMR (126 MHz, CDCl3) δ ppm 165.7 (OC=O),
155.0 (NC(=O)OC), 139.0 (ArC), 132.1 (CH2CH=CH2), 129.0
(ArCH), 128.2 (ArCH), 126.3 (ArCH), 118.4 (CH2CH=CH2),
80.5 (OC(CH3)3), 65.6 (CH2CH=CH2), 51.30 (CHNH), 28.38
(OC(CH3)3); IR max/cm-1 3323, 2095, 1720, 1495, 1114;
HRMS (ESI-TOF) : calcd for [M+Na]+ C17H21N3O4Na
[M+Na]+ 354.1424, found 354.1426.
stirred for 30 minutes at room temperature.
Triethylamine (28 µL, 0.20 mmol, 0.04 eq) was added to
produce a yellow coloured solution of catalyst. Aldimine
2a (1.0 g, 5.0 mmol) was then added in CHCl3 (4.0 mL) to
produce
a brightly coloured yellow solution. 4 Å
25
1
molecular sieves were added at this point. The resulting
mixture was cooled to -40˚C and kept at this temperature
for 30 minutes after which ethyl diazoacetate (5.2 mL,
6.0 mmol, 1.2 eq) was added. After 48 h, the reaction was
quenched by passing it through a short pad of silica on a
glass frit, eluting with diethyl ether. The volatiles were
removed in vacuo and the resulting yellow crude oil was
purified by FCC [100% petroleum ether to 2% diethyl
ether to 10% diethyl ether] afforded diazo adduct 4a as a
yellow solid (1.28 g) in 81% yield and 96% ee determined
by chiral HPLC. All spectroscopic data was consistent
with that given previously.
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Synthesis of racemates A round bottom flask was
charged with aldimine (1.0 equiv, 0.1 mmol), Ag2O
(3.5 mg, 0.015 mmol) was then added and 4 Å molecular
sieves. Ethyl acetate (1.0 mL) was added under an
atmosphere of argon followed by triethylamine (1.4 μL,
0.01 mmol) and the resulting suspension was stirred for 10
minutes. The diazoester was then added (1.2 equiv) in
0.2 mL of solvent. Stirring was maintained for a 24 h
period after which the reaction mixture was filtered
through a pad of Celite® on a glass frit, eluting with ethyl
acetate. The filtrate was concentrated in vacuo and
purified by FCC.
Benzyl (3R)-3-{[(tert-butoxy)carbonyl]amino}-2-diazo-
3-phenylpropanoate 4p Prepared according to modified
general procedure A, using diazoester 3c (42 mg,
0.24 mmol) and aldimine 2a (41 mg, 0.20 mmol) to afford
the title compound 4p in 72% isolated yield (55 mg) as a
yellow oil and in 92% ee [determined by HPLC, Chiralpak
IA, hexane/isopropanol =95/5, 1 mL/min,  = 220 nm, t
(major) = 25.56 min, t (minor) = 32.25 min]. [α]D25 = +21.9
1
(c = 1.1, CHCl3); H NMR (400MHz, CDCl3) δ ppm 7.27-
7.40 (m, 10 H, ArH), 5.70 (br. s, 1 H, CHNH), 5.42 (br. s, 1
H, NHCH), 5.15-5.27 (m, 2 H, ArCH2), 1.45 (s, 9 H,
(OC(CH3)3); 13C {1H} NMR (126 MHz, CDCl3) δ ppm 165.8
(OC=O), 155.0 (NC(=O)OC), 139.0 (ArC), 135.9 (ArC),
129.0 (ArCH), 128.7 (ArCH), 128.4 (ArCH), 128.2 (ArCH),
128.1 (ArCH), 126.3 (ArCH), 80.5 (OC(CH3)3), 66.7
(ArCH2), 51.3 (CHNH), 28.4 (OC(CH3)3); IR max/cm-1 3349,
2094, 1690, 1453, 1165; HRMS (ESI-TOF) : calcd for
[M+Na]+ C21H23N3O4Na [M+Na]+ 404.1581, found 404.1578.
Ethyl
(3S)-3-{[(tert-butoxy)carbonyl]amino}-3-
literature
phenylpropanoate 5a According to
a
procedure,13 a flask was charged with diazo-adduct 4a (100
mg, 0.30 mmol) and 10% palladium on carbon (32 mg).
Dry methanol (1.25 mL) was added under argon. The flask
was flushed with argon 3 times by alternating vacuum and
argon filling with a balloon. The argon balloon was
replaced with H2 and stirred at room temperature for
12 hours. The palladium catalyst was then removed by
filtration through a pad of Celite® on a glass frit, eluting
with methanol. The filtrate was then concentrated in
vacuo and purified directly by FCC eluting with [100%
petroleum ether and ramping to 10% diethyl ether] to
yield the desired compound 5a as a colourless crystalline
solid (66 mg), 75% isolated yield, 96% ee [determined by
HPLC, Chiralcel OD, hexane/isopropanol = 95/5, 1
mL/min,  = 220 nm, t (minor) = 15.81 min, t (major) =
19.28 min]. By comparison of peak order elution on the
HPLC, the absolute stereochemistry of 5a was determined
(3R)-3-{[(tert-butoxy)carbonyl]amino}-2-diazo-3-
phenylpropanoate 4q Prepared according to modified
general procedure A, using diazoester 3d (39 mg,
0.24 mmol) and aldimine 2a (41 mg, 0.20 mmol) to afford
the title compound 4q after 66 h, in 64% isolated yield
(47 mg) as a pale yellow solid and in 88% ee [determined
by HPLC, Chiralpak AS-H, hexane/isopropanol =95/5,
1 mL/min,  = 220 nm, t (major) = 16.75 min, t (minor) =
25
22.32 min]. MPT 102 – 104 C; [α]D = +29.0 (c = 1.1,
1
CHCl3); H NMR 400 MHz, CDCl3) δ ppm 7.30-7.49 (m, 7
H, ArH), 7.19 - 7.24 (m, 1 H, ArH), 7.11 (d, J=6.2 Hz, 2 H,
ArH), 5.76 (br. s, 1 H, CHNH), 5.48 (br. s, 1 H, NHCH),
1.48 (s, 9 H, (OC(CH3)3); 13C {1H} NMR (126 MHz, CDCl3) δ
ppm 164.2 (OC=O), 155.1 (NC(=O)OC), 150.4 (ArC), 138.9
(ArC), 129.5 (ArCH), 129.1 (ArCH), 128.4 (ArCH), 126.4
(ArCH), 125.9 (ArCH), 121.7 (ArCH), 80.7 (OC(CH3)3), 51.5
(CHNH), 28.4 (OC(CH3)3); IR max/cm-1 3327, 2097, 1718,
25
to be (S).13 MPT 76 - 80C; [α]D = -32.7 (c = 1.1, EtOAc)
20
[lit. [α]D = -31.6 (c = 1.0, EtOAc) for (S)-5a. From the
optical rotation, the absolute configuration was
determined to be (S)14; 1H NMR (400 MHz, CDCl3) δ ppm
7.17 - 7.41 (m, 5 H, ArH), 5.50 (br. s., 1 H, NHCH), 5.10 (br.
s., 1 H, CHNH), 4.06 (q, J=7.3 Hz, 2 H, CH2CH3), 2.70 -
2.99 (m, 2 H, CHCHaHbNH), 1.41 (br. s., 9 H, OC(CH3)3),
1.15 (t, J=7.1 Hz, 3 H, CH2CH3); 13C {1H} NMR (100 MHz,
CDCl3) δ ppm 171.0 (OC=O), 155.1 (NC(=O)OC), 141.2
1453, 1137; HRMS
(ESI-TOF) : calcd for [M+Na]+
C20H21N3O4Na [M+Na]+ 390.1424, found 390.1423.
Preparative synthesis of 4a A reaction tube was charged
with silver triflate (12.8 mg, 0.05 mmol, 0.01 eq) and (R)-
DM-SEGPHOS (72 mg, 0.1 mmol, 0.02 eq). CHCl3 (2.0 mL)
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The Journal of Organic Chemistry
(ArC), 128.6 (ArCH), 127.5 (ArCH), 126.2 (ArCH), 79.7 was stirred at room temperature for 20 minutes upon
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(OC(CH3)3), 60.7 (CH2CH3), 51.3 (CHCHaHbNH), 41.1
which the mixture turned from a yellow solution to clear
and then solid precipitate was observed. The reaction
mixture was diluted with ethyl acetate and washed with
saturated sodium hydrogen carbonate solution and brine.
The organic phase was dried over sodium sulfate and
concentrated in vacuo. Purification by FCC [petroleum
ether to petroleum ether/ethyl acetate 1/1] to afford the
title compound 5c in 88% isolated yield (27 mgs) as a
clear oil and 96% ee [determined by HPLC, Chiralpak AD-
H, hexane/isopropanol =80/20, 1 mL/min,  = 220 nm, t
(major) = 7.48 min, t (minor) = 8.37 min]. [α]D25 = -38.2 (c
(CHCHaHbNH), 28.4 (OC(CH3)3), 14.1(CH2CH3); IR

max/cm-1 3352, 2978, 2930, 2358, 1728, 1497, 1167. All data
reported is in agreement with the literature.13
Ethyl
(2R,3R)-3-{[(tert-butoxy)carbonyl]amino}-2-
hydroxy-3-phenylpropanoate 5b According to
a
literature procedure,15 Oxone® (154 mg, 0.50 mmol, 5.0
equiv) was suspended in acetone/H2O (3.0 mL:1.5 mL).
Sodium hydrogencarbonate was then added (168 mg,
2.0 mmol, 20 equiv) and stirred for 15 min at room
temperature, after which the resulting mixture was cooled
to 0 °C. Diazo adduct 4a (32 mg, 0.10 mmol, 1.0 equiv) was
then added in 3.0 mL of dichloromethane over a period of
5 minutes. The mixture was then allowed to warm to
room temperature and stirred at this temperature for 5
hours. Upon completion, the reaction mixture was diluted
with water (3 mL) and extracted with dichloromethane (3
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= 1.3, CHCl3); H NMR (500 MHz, CDCl3) δ ppm 7.32-7.35
(m, 2 H, ArH), 7.25-7.28 (m, 3 H, ArH), 6.65 (br. s., 2 H,
C=NNH2), 6.07 (d, J=9.5 Hz, 1 H, CHNH), 6.00 (br. s., 1 H,
CHNH), 4.16-4.24 (m, 2 H, CH2CH3), 1.46 (s, 9 H,
OC(CH3)3), 1.24 (t, J = 7.1 Hz, 3 H, CH2CH3); 13C {1H} NMR
(126 MHz, CDCl3) δ ppm 164.2 (OC=O), 156.1(NC(=O)OC),
138.5 (C=N-NH2), 137.8 (ArC), 128.8 (ArCH), 127.6 (ArCH),
125.5 (ArCH), 80.4 (OC(CH3)3), 61.2 (CH2CH3), 47.4
(CHNH), 28.3 (OC(CH3)3), 14.1 (CH2CH3); IR max/cm-1
3410, 3300, 3236, 2979, 2932, 1696, 1495, 1167; HRMS (ESI-
TOF) : calcd for [M+Na]+ C16H23N3O4Na 344.1581, found
344.1582.
×
5 mL). The organic phase was washed with brine and
dried over sodium sulfate and concentrated in vacuo. The
resulting clear oil was re-dissolved in dry
dichloromethane (2.5 mL) under argon which was then
cooled to -78°C. Sodium borohydride (8.7 mg, 0.23 mmol,
2.25 equiv) was then added in one portion. The reaction
mixture was allowed to warm to room temperature
slowly. After 27 hours, the reaction was quenched with
1-tert-Butyl 4-ethyl (4S,5R)-4-benzyl-5-phenyl-4,5-
dihydro-1H-1,2,3-triazole-1,4-dicarboxylate
5d
According to a literature procedure,9 a RBF was charged
with sodium hydride (19.1 mg, 0.48 mmol) and cooled to
0 °C with an ice bath under an atmosphere of argon. Dry
N, N-dimethylformamide was then added (1.0 mL). Diazo
adduct 4a (0.40 mmol, 128 mg) and benzyl bromide
(0.48 mmol, 58 μL) were then added in a dropwise
manner in DMF (0.44 mL) and the mixture was stirred for
15 min. The resulting suspension was allowed to warm to
room temperature and stirred for 30 minutes. A saturated
solution of ammonium chloride (2 mL) was then added to
produce a yellow suspension and the organic phase was
extracted using ethyl acetate, dried over Na2SO4 and
concentrated in vacuo. Purification by FCC [100%
petroleum ether to 20% diethyl ether] afforded the title
compound in 79% isolated yield as a white solid (129 mg)
as a single diastereoisomer, 96% ee [determined by HPLC,
Chiralpak IA, hexane/isopropanol =95/5, 1 mL/min,  =
220 nm, t (major) = 15.79 min, t (minor) = 19.12 min]. MPT
160 - 162 C; [α]D25 = +103.6 (c = 0.9, CHCl3); 1H NMR (500
MHz, CDCl3) δ ppm 7.19 - 7.42 (m, 8 H, ArH) 7.05 (br. s., 2
H, ArH) 4.80 (s, 1 H, CHCN(C=O)) 3.57 - 3.72 (m, 2 H,
CH2CH3) 3.54 (d, J = 14.0 Hz, 1 H, ArCHaHbC) 3.25 (d, J =
14.0 Hz, 1 H, ArCHaHbC) 1.27 (s, 9 H, OC(CH3)3) 0.83 (t,
J=7.2 Hz, 3 H, CH2CH3); 13C {1H} NMR (126 MHz, CDCl3) δ
ppm 167.2 (OC=O), 148.9 (NC(=O)OC), 136.7 (ArC), 133.4
(ArC), 130.6 (ArCH), 128.5 (ArCH), 128.4 (ArCH), 128.3
(ArCH), 127.6 (ArCH), 126.8 (ArCH), 95.0 (ArCHaHbC),
83.4 (OC(CH3)3), 62.9 (CHCN(C=O)), 61.8 (CH2CH3), 43.1
(ArCHaHbC), 27.8 (OC(CH3)3), 13.5 (CH2CH3); IR max/cm-1
2978, 2358, 1738, 1498, 1336, 1149. All data reported is in
agreement with the literature.9
×
sat. NH4Cl and extracted with dichloromethane (3
5
mL). The combined organics were dried over sodium
sulfate and concentrated in vacuo. Purification by FCC
[100% petroleum ether to 50% diethyl ether] afforded the
title compound 5b in 58% isolated yield (18 mgs) as a
white, crystalline solid with a 8:1 d.r. (anti:syn). A round
bottom flask was charged with aldimine (1.0 equiv, 0.1
mmol), Ag2O (3.5 mg, 0.015 mmol) was then added and 4
Å molecular sieves. Ethyl acetate (1.0 mL) was added
under an atmosphere of argon followed bytriethylamine
(1.4μL, 0.01 mmol) and the resulting suspension was
stirred for 10 minutes. The diazoester was then added (1.2
equiv) in 0.2 mL of solvent. Stirring was maintained for a
24 h period after which the reaction mixture was filtered
through a pad of Celite® on a glass frit, eluting with ethyl
acetate. The filtrate was concentrated in vacuo and
1
purified by FCC. Major diastereoisomer: H NMR (400
MHz, CDCl3) δ ppm 7.12 - 7.34 (m, 5 H, ArH), 5.61 (d, J=8.3
Hz, 1 H, NHCH), 5.10 (d, J =6.4 Hz, 1 H, CHNH), 4.57 (br.s.
1H, CHOH), 4.09 - 4.17 (m, 2 H, CH2CH2), 2.90 (d, J=6.4
Hz, 1 H, CHOH), 1.43 (s, 9 H, OC(CH3)3), 1.24 (t, J=7.1 Hz,
3 H, CH2CH3); 13C {1H} NMR (100 MHz, CDCl3) δ ppm
172.0 (OC=O), 155.1 (NC(=O)OC), 136.9 (ArC), 128.5
(ArCH), 128.2 (ArCH), 127.5 (ArCH), 80.0 (OC(CH3)3), 73.3
(CHOH), 62.2 (CH2CH3), 56.7 (CHNH), 28.3 (OC(CH3)3),
14.1 (CH2CH3). All data reported is in agreement with the
literature.12
Ethyl
(2E,3R)-3-{[(tert-butoxy)carbonyl]amino}-2-
hydrazinylidene-3-phenylpropanoate 5c Diazo adduct
4a (32 mg, 0.10 mmol) was dissolved in diethyl ether
(0.30 mL) under argon. Tributylphosphine (75 L, 3
equiv) was added in one portion. The resulting mixture
ASSOCIATED CONTENT
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Biphenanthrol Ligands, J. Am. Chem. Soc. 2007, 129, 7185-7194.
Supporting Information
(d) Bew, S. P.; Liddle, J.; Hughes, D. L.; Pesce, P.; Thurston, S. M.
Chiral Brønsted Acid-Catalyzed Asymmetric Synthesis of
N-Aryl-cis-aziridine Carboxylate Esters, Angew. Chem. Int. Ed.
2017, 56, 5322-5326.
1
2
3
4
5
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: xx.
Further optimization tables, NMR spectra and HPLC
chromatograms (PDF)
5
For a recent review, see. (a) Ford, A.; Miel, H.; Ring, A.;
Slattery, C. N.; Maguire, A. R.; McKervey, M. A. Modern Organic
Synthesis with α -Diazocarbonyl Compounds, Chem. Rev. 2015,
115, 9981-10080. For selected examples, see. (b) Phatake, R. S.;
Patel P.; Ramana, C. V. Ir(III)-Catalyzed Synthesis of
Isoquinoline N-Oxides from Aryloxime and α -Diazocarbonyl
Compounds, Org. Lett., 2016, 18, 292-295. (c) Xia, Y.; Zhang Y.;
Wang, J. Catalytic Cascade Reactions Involving Metal Carbene
Migratory Insertion, ACS Catal., 2013, 3, 2586-2598. (d) Shi, Z.;
Koester, D. C.; Arapinis M. B.; Glorius, F. Rh(III)-Catalyzed
Synthesis of Multisubstituted Isoquinoline and Pyridine N-
Oxides from Oximes and Diazo Compounds, J. Am. Chem. Soc.,
2013, 135, 12204-12207. (e) Liu Z.; Wang, J. Cross-Coupling
Reactions Involving Metal Carbene: From C═C/C–C Bond
Formation to C–H Bond Functionalization, J. Org. Chem., 2013,
78, 10024-10030.
AUTHOR INFORMATION
Corresponding Author
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* darren.dixon@chem.ox.ac.uk
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ORCID:
Alistair J.M. Farley: 0000-0001-5578-6790
Darren J. Dixon: 0000-0003-2456-5236
ACKNOWLEDGMENT
G.P.R. thanks the EPSRC for funding through a studentship.
A.J.M.F. thanks the EPSRC (Studentship and Doctoral
Training Grant [EP/M50659X/1] to A.J.M.F.), AstraZeneca
(Studentship to A.J.M.F.) and the SCI (Postgraduate
Scholarship to A.J.M.F.).
6
(a) Hashimoto, T.; Maruoka, K. Design of Axially
Chiral Dicarboxylic Acid for Asymmetric Mannich Reaction of
Arylaldehyde N-Boc Imines and Diazo Compounds, J. Am. Chem.
Soc. 2007, 129, 10054-10055. (b) Uraguchi, D.; Sorimachi, K.;
Terada, M. Organocatalytic Asymmetric Direct Alkylation of α-
Diazoester via C−H Bond Cleavage, J. Am. Chem. Soc. 2005, 127,
9360-9361. (c) Chen, J.; Wen, X. J.; Wang, Y.; Du, F.; Cai, L.; Peng,
Y. G. Asymmetric Mannich Reaction of Isatin-Based Ketimines
with α -Diazomethylphosphonates Catalyzed by Chiral Silver
Phosphate, Org. Lett. 2016, 18, 4336-4339. (d) Zhou, M. H.; Su,
Q.; Addepalli, Y.; He, Y.; Wang, Z. An asymmetric Mannich
reaction of α -diazocarbonyl compounds and N-sulfonyl cyclic
ketimines catalyzed by complexes generated from chiral and
achiral phosphines with gold(I), Org. Biomol. Chem. 2018, 16,
2923-2931. For an example of the asymmetric EDA Mannich
reaction in total synthesis, see: (e) Kumaraswamy, G.;
Jayaprakash, N. Enantioselective synthesis of (2S,3′R,7′Z)-N-(3′-
hydroxy-7′-tetradecenoyl)-homoserine lactone, Tetrahedron Lett.
2010, 51, 6500-6502.
REFERENCES
1
(a) Trost, B. M.; Fleming, I. Comprehensive Organic
Synthesis; Pergamon Press: Oxford, 1991. (b) Denmark, S.;
Nicaise, O. J.-C. Comprehensive Asymmetric Catalysis; Jacobsen,
E. N., Pfaltz, A., Yamomoto, H., Eds.; Springer: Berlin,
1999;Vol. 2, p 93.
2
(a)
Kobayashi,
S.;
H.
Ishitani,
Catalytic
Enantioselective Addition to Imines, Chem. Rev. 1999, 99, 1069.
(b) Kobayashi, S.; Mori, Y.; Fossey, J. S.; Salter, M. M., Catalytic
Enantioselective Formation of C−C Bonds by Addition to Imines
and Hydrazones: A Ten-Year Update, Chem. Rev. 2011, 111, 2626.
3
For reviews, see (a) Ye, T.; McKervey, M. A. Organic
Synthesis with alpha.-Diazo Carbonyl Compounds, Chem. Rev.
1994, 94, 1091. (b) Padwa, A.; Austin, D. J. Ligand Effects on the
Chemoselectivity of Transition Metal Catalyzed Reactions of α
-Diazo Carbonyl Compounds, Angew. Chem., Int. Ed. 1994, 33,
1797. (c) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic
Methods for Organic Synthesis with Diazo Compounds; Wiley:
New York, 1998. (d) Doyle, M. P.; Forbes, D. C. Recent Advances
in Asymmetric Catalytic Metal Carbene Transformations Chem.
Rev. 1998, 98, 911. (e) Davies, H. M. L.; Antoulinakis, E. G. Recent
Progress in Asymmetric Intermolecular C-H Activation by
Rhodium Carbenoid Intermediates, J. Organomet. Chem. 2001,
617-618, 47. (f) Timmons, D. J.; Doyle, M. P. Catalyst selection for
metal carbene transformations, J. Organomet. Chem. 2001, 617-
618, 98. (g) Xiao, Q.; Zhang, Y.; Wang, J. B. Diazo Compounds
and N-Tosylhydrazones: Novel Cross-Coupling Partners in
Transition-Metal-Catalyzed Reactions, Acc. Chem. Res. 2013, 46,
236-247.
7
(a) Sladojevich, F.; Trabocchi, A.; Guarna, A.; Dixon, D.
J.
A New Family of Cinchona-Derived Amino Phosphine
Precatalysts: Application to the Highly Enantio- and
Diastereoselective Silver-Catalyzed Isocyanoacetate Aldol
Reaction, J. Am. Chem. Soc. 2011, 133, 1710-1713. (b) Ortín, I.;
Dixon, D. J. Direct Catalytic Enantio- and Diastereoselective
Mannich Reaction of Isocyanoacetates and Ketimines, Angew.
Chem. Int. Ed. 2014, 53, 3462-3465. (c) de la Campa, R.; Ortín, I.;
Dixon, D. J. Direct Catalytic Enantio- and Diastereoselective
Ketone Aldol Reactions of Isocyanoacetates, Angew. Chem. Int.
Ed. 2015, 54, 4895-4898. (d) de la Campa, R.; Yamagata, A. D. G.;
Ortin, I.; Franchino, A.; Thompson, A. L.; Odell, B.; Dixon, D. J.
Catalytic enantio- and diastereoselective Mannich reaction of α-
substituted isocyanoacetates and ketimines, Chem. Commun.
2016, 52, 10632-10635. (e) de la Campa, R.; Manzano, R.; Calleja,
P.; Ellis, S. R.; Dixon, D. J. Enantioselective Silver-Catalyzed
Cascade Synthesis of Fused Lactone and Lactam Oxazolines,
Org. Lett. 2018, 20, 6033-6036. (f) Franchino, A.; Chapman, J.;
Funes-Ardoiz, I.; Paton, R. S.; Dixon, D. J. Catalytic Enantio- and
Diastereoselective Mannich Addition of TosMIC to Ketimines,
Chem. Eur. J. 2018, 24, 17660-17664. (g) Wei, T.; Dixon, D. J.
Catalytic stereoselective total synthesis of a spiro-oxindole
alkaloid and the pentacyclic core of tryptoquivalines, Chem.
Commun. 2018, 54, 12860-12862.
4
For examples of the use of ethyl diazoacetate in the
asymmetric aza-Darzens reaction, see (a) Williams, A. L.;
Johnston, J. N. The Brønsted Acid-Catalyzed Direct Aza-Darzens
Synthesis of N-Alkyl cis-Aziridines, J. Am. Chem. Soc. 2004, 126,
1612-1613. (b) Antilla, J. C.; Wulff, W. D. Catalytic Asymmetric
Aziridination with Arylborate Catalysts Derived from VAPOL
and VANOL Ligands, Angew. Chem. Int. Ed. 2000, 39, 4518-4521.
(c) Lu, Z.; Zhang, Y.; Wulff, W. D. Direct Access to N-H-
Aziridines from Asymmetric Catalytic Aziridination with Borate
Catalysts Derived from Vaulted Binaphthol and Vaulted
8
Trost, B. M.; Malhotra, S.; Ellerbrock, P. Exploring the
Unique Reactivity of Diazoesters: An Efficient Approach to
Chiral β-Amino Acids, Org. Lett. 2013, 15, 440–443.
10
ACS Paragon Plus Environment

Page 11 of 11
The Journal of Organic Chemistry
9
Kuznetsov, A.; Gulevich, A. V.; Wink, D. J.; Gevorgyan,
New Reactivity Mode for the Diazo Group:
Diastereoselective 1,3-Aminoalkylation Reaction of β-Amino-
13
Wenzel, A. G.; Jacobsen, E. N. Asymmetric Catalytic
V.
A
Mannich Reactions Catalyzed by Urea Derivatives:ꢀ
Enantioselective Synthesis of β-Aryl-
Chem. Soc. 2002, 124, 12964-12965.
1
2
α
β-Amino Acids, J. Am.
-Diazoesters To Give Triazolines, Angew. Chem. Int. Ed. 2014, 53,
3
4
5
6
7
8
9
9021–9025.
14 18 Zhao, W.; Lu, Z.; Wulff, W. D. β -Amino Esters from the
Reductive Ring Opening of Aziridine-2-carboxylates J. Org.
Chem. 2014, 79, 10068-10080.
10
Kanazawa, A. M.; Denis, J.-N.; Greene, A. E. Highly
Stereocontrolled and Efficient Preparation of the Protected,
Esterification-Ready Docetaxel (Taxotere) Side Chain, J. Org.
Chem. 1994, 59, 1238-1240.
15
Karimi, B.; Jafari, E.; Enders, D. Highly Efficient
Catalytic Enantioselective Mannich Reaction of Malonates with
N-tert-Butoxycarbonyl Imines by Using Yb(OTf)3/Pybox
Catalysts at Room Temperature Chem. Eur. J. 2013, 19, 10142-
10145.
11
Toma, T.; Shimokawa, J.; Fukuyama, T. N,N‘-
Ditosylhydrazine:ꢀ A Convenient Reagent for Facile Synthesis of
Diazoacetates Org. Lett. 2007, 9, 3195-3197.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
12
Goodman, C. G.; Do, D. T.; Johnson, J. S. Asymmetric
Synthesis of anti-β-Amino-α-Hydroxy Esters via Dynamic Kinetic
Resolution of β-Amino- α-Keto Esters Org. Lett. 2013, 15, 2446-
2449.
11
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