Synthesis of Acrylamides via the Doebner-Knoevenagel Condensation

Article abstract of DOI:10.1021/acs.joc.9b00450

A selective synthesis of acrylamides had been developed using the Doebner-Knoevenagel condensation. The reaction occurs under mild conditions at ambient temperatures, tolerates a wide array of functional groups, and affords the E-isomer with high selectivity. The reported method expands the scope of this classic reaction to a class of industrially important products and as well as to the use of aliphatic aldehydes. An organocatalytic mechanism has been proposed, and the ability to scale the process has been demonstrated.

Full text of DOI:10.1021/acs.joc.9b00450

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Synthesis of Acrylamides via the Doebner-Knoevenagel Condensation
Michael Jason Zacuto
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00450 • Publication Date (Web): 18 Apr 2019
Downloaded from http://pubs.acs.org on April 18, 2019
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Synthesis of Acrylamides via the Doebner-Knoevenagel Condensation
Michael J. Zacuto*
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Drug Substance Development, Celgene Corporation, 556 Morris Avenue, Summit, NJ 07901, USA
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mzacuto@celgene.com
cat. pyrrolidine
O
O
O
O
AcOH
R
+
R
N
R
R'
N
R
OH
DMAc
H
R'
>95:5 E:Z
Abstract: A selective synthesis of acrylamides had been developed using the Doebner-
Knoevenagel condensation. The reaction occurs under mild conditions at ambient temperatures,
tolerates a wide array of functional groups, and affords the E-isomer with high selectivity. The
reported method expands the scope of this classic reaction to a class of industrially important
products, and as well as to the use of aliphatic aldehydes. An organocatalytic mechanism has been
proposed, and the ability to scale the process has been demonstrated.
Acrylamides are important pharmaceutical moieties, present in the active pharmaceutical
ingredient (API) of oncology products Ibrutinib (1) and Osimertinib (2),1 antiallergenic Tranilast
(3)2 and the anticonvulsant Ilepcimide (4).3 Ibrutinib and Osimertinib are thought to covalently
bind cellular targets via conjugate addition of heteroatom-containing amino acids in the active
site.1
N
MeO
Me
N
H2N
N
N
N
N
N
NMe2
H
N
O
N
HN
N
PhO
Me
1
Ibrutinib ( )
O
2
Osimertinib ( )
O
N
O
O
OMe
OMe
N
H
O
HO2C
4
Ilepcimide ( )
3
Tranilast ( )
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Due to their sensitivity towards conjugate addition, acrylamides are often installed late in
a synthesis. This typically involves advanced amine intermediates, and therefore impurities from
side reactions divert valuable material and yield away from the desired product. Impurity control
is critical to meeting the high purity standards required for pharmaceuticals, and opportunities to
reject impurities formed late in a synthesis become scarce. In this context, simple and clean
reactions are highly valuable.
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Accordingly, there has been recent interest in acrylamide synthesis.4 Many of the newer
contributions are transition metal- catalyzed reactions, whereas metal- free processes are favorable
for large- scale pharmaceutical applications due to concerns of cost and the toxicity of heavy metal
residues. The commercial syntheses of Ibrutinib5 and possibly Osimertinib,6 for example, employ
a two- step procedure involving acylation with 3-chloropropionyl chloride, followed by
elimination of HCl in a second step.7 This approach bypasses formation of the acrylamide in the
presence of the reacting amine to suppress double addition impurities from conjugate addition of
the nucleophilic amine to the electrophilic acrylamide product.6b, 8 While 3-chloropropionyl
chloride is readily available, substituted analogs are not easily obtained, limiting the generality of
this approach.9 Furthermore, this sequence generates a potential genotoxic impurity- the -chloro-
propanamide- whose levels need to be tightly controlled in the final API.10
To expand the toolkit for late stage acrylamide formation, we envisioned use of the
Doebner-Knoevenagel reaction to form the C=C bond (Scheme 1). Adaptation of this classic
reaction to the synthesis of acrylamides has received little attention. Most known examples focus
primarily on the formation of secondary cinnamide analogs of tranilast and require high
temperatures (refluxing piperidine or toluene).11 The use of aliphatic aldehydes is rarer still, and
the high temperatures employed lead to nearly equal amounts of -and - unsaturated
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amides.12,13 The preparation of tertiary acrylamides is essentially unexplored,13,14 and use of
formaldehyde to prepare unsubstituted acrylamides is unknown. For our studies, we focused on
mild conditions applicable to challenging aliphatic amine substrates such as that in Ibrutinib, using
both aromatic and aliphatic aldehydes.
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Scheme 1. Approaches to acrylamide synthesis.
Ibrutinib/Osimertinib synthesis:
O
O
Cl
NaHCO3
-HCl
ClOC
R
R
R2NH
N
R
N
R
Cl
This work:
O
O
O
R'CHO
R
R
R2NH
N
R
OH
N
R
R'
CO2+H2O
The practicality of this approach relies on the ability to prepare and cleanly isolate the
required -amido acids. To illustrate this feasibility, we prepared 5 as a surrogate for synthetically
relevant analogs to the Ibrunitib system.15 Dibenzylamine was treated with Meldrum’s acid,
TMSCl and Et3N16 to afford 5, which was isolated as its stable tert-butylamine salt (Scheme 2).
Alternatively, 5 could be prepared under Schotten-Baumann conditions.
Scheme 2
ClOC
CO2Et
TMSCl, Et3N
MeCN;
O
O
MTBE/aq. NaOH; Ph
NH
Ph
NH
Bn2N
OH
EtOH, aq. NaOH
89%
Meldrum's acid
91%
Ph
Ph
5
Screening conditions were inspired by a malonic acid precedent with an aliphatic aldehyde,
catalyzed by pyrrolidine in DMAc.17 Accordingly, we subjected a mixture of 5 and aqueous
formaldehyde with secondary amine catalysts in DMAc (Table 1). The results revealed that aldol
(7) and aldol condensation products (8) were possible, along with the catalyst-product adduct (9).
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We have found that impurities such as 7-9 are readily separated from the desired products, often
5
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via extraction into an aqueous phase.
7
8
9
Table 1. Screen of secondary amines for acrylamide formation with aqueous formaldehydea
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O
OH
O
O
HNR2 (10 mol%)
AcOH (1 equiv.)
5
+
O
NR2
+
+
+
Bn2N
Bn2N
Bn2N
CH2O
Bn2N
DMAc/H2O
R2NH
8
7
9
6
CO2H
9a
CO2H
5a
6a
7a
6b
% yield
8a
%
%
%
%
entry
%
1
2
3
4
5
6
pyrrolidine
dibenzylamine
L-proline
piperidine
morpholine
dimethylamine
0.3
5.3
17.6
25.0
4.4
91.0
32.7
28.4
23.3
23.3
92.5
0.8
0.2
49.3
46.2
7.1
11.6
5.3
15.0
45.6
7.5
86%
37%
28%
28%
47%
84%
25.5
3.4
25.6
a HPLC % area under curve. bAssay yields were determined by quantitative dilution of the crude
reaction and comparison of the area under the curve to that of an analytically pure authentic product
(see Experimental Section)
AcOH (1 equiv.) was included to screening runs to impart robust reactivity, as stalled
reactions without this additive reactivated upon addition of AcOH. Of the secondary amines
screened, we selected pyrrolidine (10) for further development. Application of these conditions to
other aliphatic aldehydes was explored (Table 2). Branching at the - and - positions of the
aldehyde (6-13) was tolerated, with little impact on yield. 11 and 14 required slow addition of the
aldehyde to minimize self aldol-condensation. In each case, the E/Z ratio was determined by HPLC
assay of the crude reaction to be ≥95:5.
Table 2. Acrylamide formation from aliphatic aldehydesa
O
O
O
Bn2N
n-C4H9
,c,e (84%)b
Bn2N
6
Bn2N
i-Bu
(89%)b
90%e (87%)b
11 89%
91%e
12
O
CO2Me
O
O
O
Bn2N
Bn2N
13
Cy
Bn2N
15 88%b
65%b,c
(72%)b
78%d,e
14
a Conditions: 1.0 equiv. of 5 (free acid), 1.5 equiv. aldehyde, 0.15 equiv.
b
c
pyrrolidine, 1.0 equiv. AcOH, DMAc. Isolated yield after chromatography.
Slow addition of aldehyde . d 0.3 equiv. of pyrrolidine was utilized. e Assay yield
from crude reaction (see Experimental Section).
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Aldehydes bearing O- and N- heteroatoms at the - position afforded the desired products18
as part of complex mixtures, though these reactions are not synthetically useful.19 Use of 3-
(benzyloxy)-propanal afforded 60% of benzyl alcohol, resulting from elimination of BnOH via an
iminium species. Chloral, trifluoroacetaldehyde, pivaldehyde and ethyl glyoxate were unreactive,
perhaps due to unfavorable iminium formation.20
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Aromatic aldehydes were excellent substrates, with high conversion and E/Z selectivity
(≥95:5) over a wide range of aldehydes (Table 3). Halogen substituents (16-17, 22), heterocycles
(18, 20-22), and electronically diverse motifs were tolerated. The moderate yield of 20 may reflect
the iminium stability, as this species was water-stable. Impurities analogous to 7-9 were not
observed at significant levels.
Table 3. Acrylamide formation from aromatic aldehydesa
O
F
O
O
O
O
Bn2N
Bn2N
Bn2N
16
93%b (84%c, g, h
17
Cl
Br
18
97%b (93%c, f, i
)
)
80%b, g, h
O
O
O
O
S
Bn2N
Bn2N
Bn2N
Bn2N
CO2Me
Br
22
91%b,
N
21
89%b, e, g, i
NH
71%b (64%e, g, i
20
19
89%b, e, g, i
N
e, g, i
)
a Conditions: 1.0 equiv. of 5 (free acid), 1.2-1.5 equiv. aldehyde, 0.15-0.20 equiv. pyrrolidine,
b
1.0 equiv. AcOH, DMAc. Assay yields were calculated by addition of the isolated yield
(obtained from the unoptimized product crystallization) and the measured losses to the
d
liquors (see Experimental Section) c Crystallization from EtOAc/n-heptane (unoptimized).
Isolated yield after chromatography. e Crystallization from DMAc/H2O during reaction
f
g
h
quench (unoptimized). 1.5 equiv. of aldehyde. 1.2 equiv. of aldehyde. 0.15 equiv.
pyrrolidine. i 0.20 equiv. pyrrolidine.
We investigated complex -amido acids and observed a high degree of functional group
compatibility. 23 represents an advanced substrate (eq. 1), and formation of 26 demonstrates the
compatibility of the reaction conditions with aminopyrimidine moieties found in Osimertinib. The
reaction to form 24 (as a crude 96:4 E:Z mixture) contained only one detectable impurity at 0.45
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HPLC area % - identified as the pyrrolidine adduct (analogous to 9)- that was easily extracted from
24 during the workup.21
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8
9
Me
N
Me
N
CN
O
CN
O
OHC
i-Pr
pyrrolidine (10 mol%)
AcOH (1.0 equiv.)
O
O
O
(1)
Me
Me
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N
OH
N
DMAc, 22 o
C
23
90%
24
iPr
iPr
OHC
i-Pr
pyrrolidine (10 mol%)
AcOH (1.0 equiv.)
NH
N
O
O
NH
N
O
Me
Me
(2)
N
N
OH
N
N
DMAc, 22 o
C
26
25
87%
Attempted formation of secondary acrylamides was unsuccessful. For example, 27 reacted
with 2-bromo-4-formylthiazole to form a 4:1 mixture of aldol condensation products 28 (eq. 3).22
Control experiments confirmed that catalytic pyrrolidine was necessary, implying elimination
from a Mannich-type intermediate without decarboxylation. By contrast, 29 gave the acrylamide
30 in 90% yield (eq. 4).23 These results suggest the N-H moiety in 27 disrupted the decarboxylation
mechanism.
O
pyrrolidine (20 mol%)
OHC
O
O
S
AcOH (1.0 equiv.)
Br
N
(3)
+
S
H
N
H
OH
Cl
N
DMAc
O
O
OH
N
28
Cl
(77%)
27
Br
OHC
+
pyrrolidine (20 mol%)
AcOH (1.0 equiv.)
O
O
S
S
Br
Ph2N
(4)
Ph2N
OH
N
DMAc
(90%)
N
30
Br
29
The proposed mechanism involves iminium formation, Mannich-type addition, and a
decarboxylative-elimination of 31 (Scheme 3).24 An intriguing feature is the proposed connection
between the stereochemistry of 31 and the resulting double bond geometry. The high selectivity
suggests either high diastereoselectivity of 31, or selective elimination of one of two equilibrating
diastereomers.25, 26
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Scheme 3. Proposed mechanism
5
6
7
O
RCHO
+
CO2
N
+ AcOH
R
NBn2
H
8
9
N
R
O
H
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AcO
N
O
R
H
Bn2N
O
31
5
The potential to scale this process was explored through a 100 g demonstration (eq. 5). Salt
break of 5 (125 g) was followed by a solvent- switch into DMAc. Acetic acid and pyrrolidine were
added, followed by nicontinaldehyde. After 16 h, quench with aqueous K2CO3 27 affected product
crystallization. Filtration afforded 21 in 89% isolated yield and 99.2% HPLC purity.28
O
O
O
i. aq. citric acid/EtOAc
H2Nt-Bu
OH
ii. solvent switch to DMAc
Ph
N
(5)
Ph
N
pyrrolidine, AcOH,
iii.
21
Ph
N
5
nicotinaldehyde, 16 h
Ph
(103 g)
iv. aq. K2CO3; filter
89%
(125 g)
In conclusion, we have developed a mild process to prepare acrylamides using the
Doebner-Knoevenagel reaction. The method expands the scope of this classic reaction to
industrially important acrylamides, and the benign conditions are compatible with highly
functionalized substrates, aliphatic aldehydes, and tertiary amides. A decarboxylative elimination
mechanism has been proposed, and the potential to scale the reaction demonstrated. This method
represents an attractive alternative to existing protocols and offers promise for clean reaction
profiles.
Experimental Section:
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General. Reagents and solvents were obtained from commercial sources and were used as
received. Chromatography was performed using silica gel (70−230 mesh), using reagent grade
solvents which were used as received. 1H NMR spectra were recorded using a 300 MHz Bruker
Avance spectrometer, using either the CDCl3 resonance (7.26 ppm) or the d6-dmso resonance (2.50
ppm) as an internal standard. 13C NMR spectra were recorded on a 75 MHz Bruker spectrometer
using either the CDCl3 resonance (77.0 ppm) or the d6-dmso resonance (39.5) ppm as an internal
standard measured. High-resolution mass spectrometry (HRMS) was performed using a HPLC-
TOFMS mass spectrometer in electrospray ionization (ESI) mode. Melting points were recorded
on a TA Instruments Q1000 system which applied a heating ramp of 10 ˚C/min from 30 to 320 ˚C.
Melting points are recorded as peak temperatures.
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All manipulations were carried out under an inert atmosphere of nitrogen using standard
Schlenk techniques unless otherwise noted. All aldehydes and other reagents (dibenzylamine,
Meldrum’s acid, ethyl malonyl chloride, and solvents) were purchased from commercial sources.
HPLC assays were performed using a method with the following conditions: Ascentis Express
C18 column; 4.6 mm × 100 mm, 2.7 μm particle size, 40 °C, flow rate of 1.5 mL/min consisting
of a mobile phase comprised of MeCN and 0.1% by volume aqueous H3PO4; gradient 10% MeCN
ramp to 95% MeCN over 5 min, then isocratic 95% MeCN for 2 min, with integration based on
spectra recorded at the 210 nm wavelength. Assay yields were determined by quantitative dilution
of the crude product stream to a known volume, followed by subjection to HPLC analysis.
Comparison of the area under the curve of the diluted sample to that of a sample of known
concentration prepared from the analytically pure authentic product allowed calculation of the total
amount of the desired product. Alternatively, when the product was isolated via crystallization, the
assay yield was determined by combining the mass of the analytically pure isolate with the desired
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product lost to the combined liquors (filtered supernatant plus washes). The loss was determined
as described above for the assay yield, utilizing a standard prepared from the isolate. An example
of assay yield determination is provided for acrylamide 13 and further discussed in the Supporting
Information.
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2-methylpropan-2-aminium
3-(dibenzylamino)-3-oxopropanoate
(5•t-BuNH2)
via
Meldrum’s acid. A flask equipped with an N2 inlet and a reflux condenser was charged with
dibenzylamine (100.0 mmol, 19.7 g, 19.2 mL) and CH2Cl2 (300 mL). Et3N (140.0 mmol, 14.2 g,
19.5 mL) was added, followed by TMSCl (150.0 mL, 16.3 g, 19.0 mL) and the resulting thin slurry
was heated to reflux for 30 min. The resulting solution was cooled to T = 30-35 °C, and Meldrum's
i
acid (110.0 mmol, 15.8 g) was added in a single portion. After an additional 1 h of stirring at
ambient temperature, HPLC assay showed full conversion to the desired product. The reaction was
quenched with 1N HCl (180 mL) and the contents were transferred to a separatory funnel. The
phases were split and the organic phase was washed with 15% aq. NaCl (100 mL). The phases
were split and the organic phase was dried over MgSO4, filtered, and concentrated to an oil under
reduced pressure. IPAc (100 mL) was added, and the resulting solution was concentrated to an oil
under reduced pressure. The resulting oil was diluted with IPAc (250 mL) and transferred to a
flask equipped with an overhead stirrer and an N2 inlet, with overhead stirring. t-BuNH2 (110
mmol, 11.6 mL) was added via syringe pump over 30 min., maintaining Ti = 20-30 °C. The
resulting slurry was aged 12 h and was filtered. The wetcake was displaced with IPAc (100 mL).
Drying via vacuum suction/N2 tent afforded 32.54 g (91%) of 5•t-BuNH2 as a white solid. Mp =
124.8 ˚C (DSC). 1H NMR (300 MHz, d6-dmso):  7.92 (br s,2H), 7.39-7.16 (m, 10H), 4.54 (s, 2H),
4.44 (s, 2H), 3.12 (s, 2H), 1.22 (s, 9H); 13C{1H} NMR (75 MHz, d6-dmso):  170.2, 169.8, 137.8,
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137.5, 128.7, 128.2, 127.3, 127.2, 126.7, 126.6, 50.4, 50.2, 47.0, 45.7, 27.4; HRMS (ESI/Q-TOF)
m/z: [M + H]+ calc’d for C17H18NO3 (free acid) 284.1281; found 284.1281. The combined liquors
were adjusted to a volume of 400 mL, and using the isolated product as a reference standard the
liquors were assayed to contain 1.25 g of the desired product.
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2-methylpropan-2-aminium 3-(dibenzylamino)-3-oxopropanoate (5•t-BuNH2) under
Schotten-Baumann conditions. A flask was charged with dibenzylamine (25.35 mmol, 5.0 g, 4.9
mL), MTBE (25.0 mL) and 3N NaOH (25.0 mL), and the resulting stirred solution was cooled to
0-5 ˚C with an external ice bath. Ethyl malonyl chloride (technical grade 5.35 g, 4.55 mL) was
added over 1 h via syringe pump. The resulting solution was aged 30 min. at which time HPLC
assay showed full conversion of Bn2NH. The reaction mixture was warmed to ambient temperature
and diluted with EtOH (15 mL) and 5N NaOH (20 mL) and stirred for 5 h. After HPLC confirmed
full conversion of the intermediate ester, 6N HCl (25 mL) was added so as to adjust the reaction
pH to 2.5. The biphasic mixture was transferred to a separatory funnel and the phases were split.
The organic phase was washed with 15% aq. NaCl (10 mL), then dried over MgSO4. The MTBE
stream was filtered and concentrated under reduced pressure. IPAc (50 mL) was added, and the
resulting solution was concentrated under reduced pressure. The resulting oil was diluted with
IPAc (50 mL) and transferred to a 100 mL three neck flask equipped with overhead stirring and
seeded with 5•t-BuNH2 (20 mg). t-BuNH2 (27.5 mmol, 2.9 mL) was added via syringe pump over
1.5 h and the resulting slurry was aged for 16 h. The slurry was filtered, and the cake was displaced
with IPAc (20 mL). Drying via vacuum suction/N2 tent afforded 7.98 g of 5•t-BuNH2 (89%).
Representative procedure for acrylamide formation utilizing slow addition of the aldehyde
(Table 1, entries 2 and 5). The t-BuNH2 salt of 5 (1.07 g, 3.0 mmol) was slurried in EtOAc (10
mL), to which was added 15 wt% aqueous citric acid (8 mL). After stirring for 0.5-1 h, the biphasic
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mixture was transferred to a separatory funnel. The phases were separated, and the aqueous phase
was back extracted with EtOAc (5 mL). The combined organic phases were washed with 15 wt%
aq. NaCl (5 mL), then dried over MgSO4, filtered, and concentrated to an oil. The oil was dissolved
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in DMAc (4 mL), to which was added pyrrolidine (25 L, 0.3 mmol) and AcOH (171 L, 3.0
mmol). The resulting solution was stirred at Ti = 22 ˚C while a solution of the aldehyde (4.5 mmol)
in DMAc (1-2 mL) was added over 6-10 h via syringe pump. Upon completion of the addition, the
solution was aged for 16-18 hours, at which point HPLC assay confirmed >95% conversion of 5.
The reaction was quenched by the addition of H2O (8 mL), and the product was extracted with
EtOAc (8 mL). The mixture was transferred to a separatory funnel and the phases were separated.
The aqueous phase was back extracted with EtOAc (6 mL). The combined organic phases were
washed with 10 wt% aq. LiCl (4 mL), then dried over MgSO4, and subsequently filtered. The
solution was diluted to a specified volume with EtOAc in a volumetric flask for assay yield
determination, and/or was concentrated to an oil and purified by silica gel chromatography.
Representative procedure for acrylamide formation with aldehydes under standard batch
conditions (Table 1, entries 1, 3, 4, and 6). The t-BuNH2 salt of 5 (1.07 g, 3.0 mmol) was slurried
in EtOAc (10 mL), to which was added 15 wt% aqueous citric acid (8 mL). After stirring for 0.5-
1 h, the biphasic mixture was transferred to a separatory funnel. The phases were separated and
the aqueous phase was back extracted with EtOAc (5 mL). The combined organic phases were
washed with 15 wt% aq. NaCl (5 mL), then dried over MgSO4, filtered, and concentrated to an oil.
The oil was dissolved in DMAc (4 mL), to which was added pyrrolidine (38 L, 0.45 mmol),
AcOH (171 L, 3.0 mmol), and the aldehyde (4.5 mmol). The resulting solution was stirred at Ti
= 22 ˚C while a solution of the aldehyde (4.5 mmol) in DMAc (1 mL) was added over 6-10 h via
syringe pump. Upon completion of the addition, the solution was aged for 12-16 hours, at which
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point HPLC assay confirmed >95% conversion of 5. The reaction was quenched by the addition
of H2O (8 mL), and the product was extracted with EtOAc (8 mL). The mixture was transferred to
a separatory funnel and the phases were separated. The aqueous phase was back extracted with
EtOAc (6 mL). The combined organic phases were washed with 10 wt% aq. LiCl (4 mL), then
dried over MgSO4, filtered, and concentrated to an oil. The solution was diluted to a specified
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volume with EtOAc in a volumetric flask for assay yield determination, and/or was concentrated
to an oil and purified by silica gel chromatography.
N,N-dibenzylacrylamide (6). Performed according to the standard batch mode procedure. The
final solution was diluted to 25 mL total in a volumetric flask, and a 100 L aliquot was diluted
to 10 mL total in a volumetric flask and injected onto the HPLC method. The area count
(1903151) was compared to that of a previously prepared standard from material isolated by
silica gel chromatography (1713322 area counts, corresponding to 12.36 mg/50 mL) to show 675
mg of 6 (90% assay yield). The EtOAc solution was concentrated to an oil and purified via silica
gel chromatography (eluting with EtOAc/hexanes, 0 to 20% EtOAc/hexanes gradient) to afford 6
1
as a clear, colorless oil (656 mg). HNMR (300 MHz, d6-dmso):  7.40 (m, 10 H), 6.79 (dd, J1 =
16.6 Hz, J2 = 10.3 Hz, 1 H), 6.26 (dd, J1 = 16.6 Hz, J2 = 2.5 Hz, 1 H), 5.72 (dd, J1 = 10.3 Hz, J2
= 2.5 Hz, 1 H), 4.62 (s, 2H), 4.56 (s, 2H). 13C{1H} NMR (75 MHz, d6-dmso):  165.9, 137.5,
137.5, 128.6, 128.4, 128.4, 128.2, 127.7, 127.3, 127.1, 126.5, 49.8, 48.5. This was consistent
with published data.29
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(E)-N,N-dibenzylhept-2-enamide (11). Performed under the slow aldehyde addition procedure
conditions. A solution of the aldehyde in DMAc (2 mL) was added over 10 h via syringe pump.
The final solution was diluted to 50 mL total in a volumetric flask, and a 200 L aliquot was
diluted to 10 mL total in a volumetric flask and injected onto the HPLC method. The area count
(2198687 for the E isomer, 65807 for the Z isomer) was compared to that of a previously prepared
standard from material isolated by silica gel chromatography (1,979,577 area counts as a 99.8:0.2
HPLC ratio, corresponding to 16.80 mg/50 mL) to show 825 mg of 11 E isomer as part of a 97:3
HPLC ratio of isomers (89% assay yield). The EtOAc solution was concentrated to an oil and
purified via silica gel chromatography (eluting with EtOAc/hexanes, 0 to 15% EtOAc/hexanes
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gradient) to afford 11 as a clear, colorless oil (770 mg). H NMR (300 MHz, d6-dmso):  7.41-
7.13 (m, 10H), 6.81 (dt, J1 = 15.1 Hz, J2 = 7.3 Hz, 1H), 6.44 (dt, J1 = 15.1 Hz, J2 = 1.5 Hz, 1H),
4.60 (2, 2H), 4.54 (s, 2H), 2.15 (dd, J1 = J2 = 7.3 Hz, 2H), 1.41-1.16 (m, 4H), 0.83 (t, J = 7.3 Hz,
3H); 13C{1H} NMR (75 MHz, d6-dmso):  166.5, 146.8, 138.3, 138.2, 129.1, 128.9, 128.2, 127.7,
127.5, 127.0, 121.2, 50.3, 48.9, 31.7, 30.4, 22.1, 14.1; HRMS (ESI/Q-TOF) m/z: [M + H]+ calc’d
for C21H26NO 308.2009; found 308.2020.
(E)-N,N-dibenzyl-5-methylhex-2-enamide (12). Performed on a 2.0 mmol scale according to
the standard batch mode procedure. The final solution was diluted to 25 mL total in a volumetric
flask, and a 150 L aliquot was diluted to 10 mL total in a volumetric flask and injected onto the
HPLC method. The area count (2316148 for the E isomer, 77631 for the Z isomer) was compared
to that of a previously prepared standard from material isolated by silica gel chromatography
(2128251 area counts, corresponding to 15.50 mg/50 mL) to show 562 mg of 12 E isomer as part
of a 97:3 HPLC ratio of isomers (90% assay yield). The EtOAc solution was concentrated to an
oil and purified via silica gel chromatography (eluting with EtOAc/hexanes, 0 to 20%
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EtOAc/hexanes gradient) to afford 12 as a clear, colorless oil (544 mg). H NMR (300 MHz, d6-
dmso):  7.42-7.14 9 (m, 10H), 6.79 (dt, J1 = 14.9 Hz, J2 = 7.5 Hz, 1H), 6.44 (dt, J1 = 14.9 Hz, J2
= 1.4 Hz, 1H), 4.60 (s, 2H), 4.54 (s, 2H), 2.04 (dd, J1 = J2 = 7.4 Hz, 2H), 1.67 (sept., J = 6.7 Hz,
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1H), 0.82 (d, J = 6.7 Hz, 6H); C{1H} NMR (75 MHz, d6-dmso):  166.5, 145.4, 138.3, 138.2,
129.1, 128.9, 128.2, 127.7, 127.5, 127.2, 127.0, 122.3, 50.3, 48.9, 41.3, 27.8, 22.6; HRMS (ESI/Q-
TOF) m/z: [M + H]+ calc’d for C21H26NO 308.2009; found 308.2022.
(E)-N,N-dibenzyl-3-cyclohexylacrylamide (13). 5•t-BuNH2 (2.0 mmol, 713 mg) was slurried
in EtOAc (8 mL), to which was added 15% aq. citric acid (6 mL). After 20 min., the biphasic
mixture was transferred to a separatory funnel and the phases were split and both were retained.
The aqueous was extracted with EtOAc (4 mL) and the aqueous phase was discarded. The
combined organic phases were washed with 15% aq. NaCl (5 mL), then dried over MgSO4, filtered,
and concentrated under reduced pressure to an oil. The oil was dissolved in DMAc (3.5 mL), to
which was added pyrrolidine (0.6 mmol, 50 L) followed by AcOH (2.0 mmol, 114 L) and cyclo-
hexanecarboxaldehyde (3.0 mmol, 364 L). After 36 h, H2O (7 mL) was added, followed by
EtOAc (6 mL). The biphasic mixture was transferred to a separatory funnel and the phases were
split and both were retained. The aqueous phase was extracted with EtOAc (4 mL) and the aqueous
phase was discarded. The combined org phases were washed with 10 wt% aq. LiCl (2 x 4 mL).
The organic phase was dried over MgSO4, filtered, then diluted (with EtOAc) to 25 mL total in a
volumetric flask. A 150 L aliquot was diluted to 10 mL in a volumetric flask and injected onto
the described HPLC assay. Comparison of the area under the curve (1,934,035 area counts as a
97:3 HPLC ratio of olefin isomers) to that of a previously prepared standard from material isolated
by silica gel chromatography (2,145,831 area counts as a 99.8:0.2 HPLC ratio, corresponding to
16.80 mg/50 mL) showed 20.76 mg/mL, or 519 mg total of 13 (78% AY) which, after purification
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was isolated as a white solid (478 mg). Mp = 81.6 ˚C (DSC); H NMR (300 MHz, d6-dmso): 
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2H), 4.54 (s, 2H), 2.20-2.01 (m, 1H), 1.72-1.54 (m, 5H), 1.31-0.98 (m, 5H); C{1H} NMR (75
MHz, d6-dmso):  166.7, 151.7, 138.3, 138.2, 129.1, 128.9, 128.3, 127.7, 127.5, 127.0, 118.9, 50.3,
48.9, 40.3, 32.0, 25.6; HRMS (ESI/Q-TOF) m/z: [M + H]+ calc’d for C23H28NO 334.2165; found
334.2177.
Methyl (E)-6-(dibenzylamino)-6-oxohex-4-enoate (14). Performed under the slow aldehyde
addition procedure conditions. A solution of the aldehyde in DMAc (2 mL) was added over 10 h
via syringe pump. Following silica gel chromatography (eluting with EtOAc/hexanes, 0 to 20%
EtOAc/hexanes gradient), the product was isolated as an oil (650 mg, 65% yield). 1H NMR (300
MHz, d6-dmso):  7.41-7.14 (m, 10H), 6.81 (dt, J1 = 15.2 Hz, J2 = 6.3 Hz, 1H), 6.50 (d, J = 15.2
Hz, 1H), 4.49 (s, 2H), 4.52 (s, 2H), 3.54 (s, 3H), 2.47-2.36 (m, 4H); 13C{1H} NMR (75 MHz, d6-
dmso):  172.4, 165.8, 144.5, 137.7, 137.5, 128.6, 128.4, 127.7, 127.2, 127.0, 126.6, 121.2, 51.3,
49.7, 48.3, 31.9, 26.8; HRMS (ESI/Q-TOF) m/z: [M + H]+ calc’d for C21H24NO3 338.1751; found
338.1759.
(E)-N,N-dibenzyl-4-(tetrahydro-2H-pyran-4-yl)but-2-enamide (15). Performed according to
the standard batch mode procedure. Following silica gel chromatography (eluting with
EtOAc/hexanes, 0 to 20% EtOAc/hexanes gradient), the product was isolated as an oil (926 mg).
1H NMR (300 MHz, d6-dmso):  7.39-7.13 (m, 10H), 6.76 (dt, J1 = 15.0 Hz, J2 = 7.4 Hz, 1H), 6.45
(d, J = 15.0 Hz, 1H), 4.60 (s, 2H), 4.56 (s, 2H), 6.76 (dd, J1 = 11.6 Hz, J2 = 4.3 Hz, 2H, ), 3.21 (dt,
J1 = 11.6 Hz, J2 = 1.9 Hz, 2H), 2.08 (dd, J1 = J2 = 7.1 Hz, 2H), 1.64-1.50 (m, 1H), 1.48-1.38 (m,
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1H), 1.07 (ddd, J1 = , J2 = 7.1 Hz, J3 = 7.1 Hz, 2H); 13C{1H} NMR (75 MHz, d6-dmso):  166.4,
144.4, 138.3, 129.1, 128.9, 128.2, 127.6, 127.6, 127.0, 122.8, 67.3, 50.4, 49.1, 34.4, 32.8 ; HRMS
(ESI/Q-TOF) m/z: [M + H]+ calc’d for C23H28NO2 350.2115; found 350.2125.
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Representative procedure for acrylamide formation with aromatic aldehydes (Table 2). The
same procedure was utilized as that for standard batch mode in Table 1. 5•t-BuNH2 (3.0 mmol,
1.07 g) was slurried in EtOAc (10 mL), to which was added 15% aq. citric acid (8 mL). After 30
min., the biphasic mixture was transferred to a separatory funnel and the phases were split and
both were retained. The aqueous was extracted with EtOAc (2 mL) and the aqueous phase was
discarded. The combined organic phases were washed with 15% aq. NaCl (5 mL), then dried over
MgSO4, filtered, and concentrated under reduced pressure to an oil. The oil was dissolved in
DMAc (5.0 mL), to which was added pyrrolidine (0.45-0.60 mmol) and AcOH (3.0 mmol, 171
μL), followed by the aldehyde (3.6-4.5 mmol). A combination of chromatography and
crystallization was applied for product isolation depending on the substrate, as illustrated below.
(E)-N,N-dibenzyl-3-(4-bromophenyl)acrylamide (16). The standard procedure was
implemented with pyrrolidine (0.45 mmol, 38 μL) and and 4-bromobenzaldehyde (3.6 mmol, 555
mg). After 16 h, H2O (10 mL) was added, followed by MTBE (12 mL). The biphasic mixture was
transferred to a separatory funnel and the phases were split and both were retained. The aqueous
phase was extracted with MTBE (3 mL) and the resulting aqueous phase was discarded. The
combined organic phases were diluted with EtOAc (10 mL) in order to dissolve product solids,
and the resulting organic phase was washed with 10% aq. LiCl (2 x 5 mL), followed by 15% aq.
NaCl (5 mL). The organic phase was dried over MgSO4, filtered, and concentrated under reduced
pressure to a solid. MTBE (2 mL) was added and the resulting slurry was stirred magnetically for
30 min. n-Heptane (10 mL) was then added via syringe pump over 1 h. After an additional 1 h, the
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slurry was filtered. The cake was displaced with 5:1 n-heptane:MTBE (3 mL), then n-heptane (3
mL). Drying via vacuum suction/N2 tent afforded 1.02 g of 17 (83.7%) as a white solid. Mp =
124.7 ˚C (DSC); 1H NMR (300 MHz, d6-dmso):  7.69-7.54 (m, 5H), 7.42-7.18 (m, 11H), 4.77 (s,
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2H), 4.59 (s, 2H); 13C{1H} NMR (75 MHz, d6-dmso):  165.9, 141.1, 137.8, 137.6, 134.3, 131.7,
130.0, 128.7, 128.4, 127.7, 127.3, 127.1, 126.8, 122.9, 119.1, 49.9, 48.5; HRMS (ESI/Q-TOF)
m/z: [M + H]+ calc’d for C23H21BrNO 406.0801; found 406.0797. Using the isolated product as a
standard, the combined liquors were diluted to 25 mL in a volumetric flask and assayed for loss of
4.453 mg/mL (111 mg total, 9.1%). Thus, assay yield was 1.131g (92.8%).
(E)-N,N-dibenzyl-3-(2-chloro-6-fluorophenyl)acrylamide (17). The standard procedure was
implemented with pyrrolidine (0.45 mmol, 38 μL) and AcOH (3.0 mmol, 171 μL) and 2-chloro-
6-fluorobenzaldehyde (3.6 mmol, 571 mg). After 48 h, H2O (10 mL) was added, followed by
EtOAc (8 mL). The biphasic mixture was transferred to a separatory funnel and the phases were
split and both were retained. The aqueous phase was extracted with EtOAc (4 mL) and the resulting
aqueous phase was discarded. The combined organic phases were washed with 10% aq. LiCl (2 x
5 mL), followed by 15% aq. NaCl (5 mL). The organic phase was dried over MgSO4, filtered, and
concentrated under reduced pressure to an oil. The oil was purified via silica gel chromatography
(0 to 15% EtOAc/Hexanes) afforded 915 mg of 17 as an oil (80.3%) that solidified to a white solid
upon standing. Mp = 83.9 ˚C (DSC); 1H NMR (300 MHz, d6-dmso):  7.71 (d, J = 15.8 Hz, 1H),
7.46-7.21 (m, 13H), 7.20 (d, J = 15.8 Hz, 1H), 4.70 (s, 2H), 4.67 (s, 2H); 13C{1H} NMR (75 MHz,
d6-dmso):  165.6, 160.8 (d, JC-F = 254 Hz), 137.5 (d, JC-F = 2.5 Hz), 134.4 (d, JC-F = 5.0 Hz),
131.6, 131.3, 131.1, 128.7, 128.5, 127.9, 127.3, 127.2, 126.5, 126.1 (d, JC-F = 2.6 Hz), 125.4 (d,
JC-F = 12.0 Hz), 121.5 (d, JC-F = 14.3 Hz), 115.3 (d, JC-F = 23.5 Hz), 50.1, 49.2; HRMS (ESI/Q-
TOF) m/z: [M + H]+ calc’d for C23H20ClFNO 380.1212; found 380.1218.
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(E)-3-(benzo[d][1,3]dioxol-5-yl)-N,N-dibenzylacrylamide (18). The standard procedure was
implemented with pyrrolidine (0.60 mmol, 50 μL) and AcOH (3.0 mmol, 171 μL) and piperonal
(4.5 mmol, 676 mg). After 16 h, H2O (10 mL) was added, followed by EtOAc (8 mL). The biphasic
mixture was transferred to a separatory funnel and the phases were split and both were retained.
The aqueous phase was extracted with EtOAc (4 mL) and the resulting aqueous phase was
discarded. The combined organic phases were washed with 10% aq. LiCl (2 x 5 mL), followed by
15% aq. NaCl (5 mL). The organic phase was dried over MgSO4, filtered, and concentrated under
reduced pressure to 3 mL total volume (containing ~ 2 mL EtOAc). The resulting solution was
stirred and n-heptane (2 mL) was added, resulting in the formation of a seed bed. Additional n-
heptane (10 mL) was added via syringe pump over 1 h, followed by an additional 1 h of stirring.
The slurry was filtered, and the cake was displaced with 1:6 EtOAc:n-heptane (3.5 mL), then n-
heptane (3.5 mL). Drying via vacuum suction/N2 tent afforded 1.03 g of 18 (93%). Mp = 123.6 ˚C
(DSC); 1H NMR (300 MHz, d6-dmso):  7.56 (d, J = 15.5 Hz, 1H), 7.42-7.10 (m, 13H), 6.92 (d, J
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= 8.0 Hz, 1H), 6.05 (s, 2H), 4.75 (s, 2H), 4.58 (s, 2H); 13C{1H} NMR (75 MHz, d6-dmso):  166.3,
148.6, 147.9, 142.3, 138.0, 137.8, 129.5, 128.6, 128.4, 127.7, 127.2, 127.0, 126.8, 124.3, 116.0,
108.3, 106.6, 101.4, 49.7, 48.4; HRMS (ESI/Q-TOF) m/z: [M + H]+ calc’d for C24H22NO3
372.1594; found 372.1594. Using the isolated product as a standard, the combined liquors were
diluted to 25 mL in a volumetric flask and assayed for loss of 46 mg total, (4.1%). Thus, assay
yield was 1.076 g (97%).
Methyl (E)-4-(3-(dibenzylamino)-3-oxoprop-1-en-1-yl)benzoate (19). The standard
procedure was implemented with pyrrolidine (0.60 mmol, 50 μL) and AcOH (3.0 mmol, 171 μL)
and methyl-4-formylbenzoate (3.6 mmol, 591 mg). After 16 h, HPLC assay showed full
conversion of 5. H2O (3 mL) was added, resulting in crystallization of the product. After stirring
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for an additional 3.5 h, the slurry was filtered and the cake was displaced with 1:1 DMAc:H2O (3
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Mp = 119.4 ˚C (DSC); 1H NMR (300 MHz, d6-dmso):  7.94 (d, J = 8.4 Hz, 1H), 7.82 (d, J = 8.4
Hz, 1H), 7.68 (d, J = 15.4 Hz, 1H), 7.47-7.20 (m, 11H), 4.79 (s, 2H), 4.59 (s, 2H), 3.85 (s, 3H);
13C{1H} NMR (75 MHz, d6-dmso):  165.8, 141.0, 139.6, 137.8, 137.6, 130.1, 129.5, 128.7, 128.5,
128.3, 127.8, 127.3, 127.1, 126.8, 120.9, 52.2, 49.9, 48.6; HRMS (ESI/Q-TOF) m/z: [M + H]+
calc’d for C25H24NO3 386.1751; found 386.1748. Using the isolated product as a standard, the
combined liquors were diluted to 25 mL in a volumetric flask and assayed for loss of 4.4 mg total,
(0.4%). Thus, assay yield was 1.024 g (89%).
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(E)-N,N-dibenzyl-3-(1H-indol-3-yl)acrylamide (20). The standard procedure was
implemented with pyrrolidine (0.60 mmol, 50 μL) and AcOH (3.0 mmol, 171 μL) and Indole-3-
carboxaldehyde (3.6 mmol, 540 mg of 97% reagent). After 8 days, H2O (10 mL) was added,
followed by EtOAc (8 mL). The biphasic mixture was transferred to a separatory funnel and the
phases were split and both were retained. The aqueous phase was extracted with EtOAc (4 mL)
and the resulting aqueous phase was discarded. The combined organic phases were washed with
10% aq. LiCl (2 x 5 mL), followed by 15% aq. NaCl (5 mL). The organic phase was dried over
MgSO4, filtered, and concentrated under reduced pressure to 2 mL total volume (containing ~ 1
mL EtOAc), which resulted in the formation of a slurry. MTBE (10 mL) was added over several
minutes, and the resulting slurry was stirred for 2 h. The slurry was filtered, and the cake was
displaced with MTBE (3 mL). Drying via vacuum suction/N2 tent afforded 700 mg of 20 (63.7%).
Mp = 202.0 ˚C (DSC); 1H NMR (300 MHz, d6-dmso):  11.61 (s, 1H), 7.85 (d, J = 15.3 Hz, 1H),
7.84 (d, J = 2.8 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.44-7.23 (m, 11H), 7.15 (dd, J1 = J2 = 7.5 Hz,
1H), 7.04 (dd, J1 = J2 = 7.5 Hz, 1H), 6.86 (d, J = 15.3 Hz, 1H), 4.75 (s, 2H), 4.69 (s, 2H); 13C{1H}
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NMR (75 MHz, d6-dmso):  167.2, 138.5, 138.3, 137.3, 136.7, 130.6, 128.7, 128.4, 127.8, 127.2,
127.0, 126.6, 124.9, 122.2, 120.5, 119.8, 112.4, 112.2, 111.6, 50.3, 49.1; HRMS (ESI/Q-TOF)
m/z: [M + H]+ calc’d for C25H23N2O 367.1805; found 367.1801. Using the isolated product as a
standard, the combined liquors were diluted to 25 mL in a volumetric flask and assayed for loss of
81 mg total, (7.4%). Thus, assay yield was 781 mg (71%).
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(E)-N,N-dibenzyl-3-(pyridin-3-yl)acrylamide (21). The standard procedure was implemented
with pyrrolidine (0.60 mmol, 50 μL) and AcOH (3.0 mmol, 171 μL) and Indole-3-carboxaldehyde
(3.6 mmol, 386 mg, 338 μL). After 16 h, a solution of K2CO3 (3.0 mmol, 415 mg) dissolved in
H2O (10 mL) was added via syringe pump over 1 h, resulting in crystallization of the product.
After stirring for an additional 12 h, the slurry was filtered and the cake was displaced with 1:2
DMAc:H2O (3 mL), followed by H2O (2 mL). Drying via vacuum suction/N2 tent afforded 880
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mg of 21 (89.3%). Mp = 167.7 ˚C (DSC); H NMR (300 MHz, CDCl3):  7.83 (d, J = 15.5 Hz,
1H), 7.73 (dt, J1 = 8.0 Hz, J2 = 2.0 Hz, 1H), 7.44-7.17 (m, 11H), 6.95 (d, J = 15.5 Hz, 1H), 4.73
(s, 2H), 4.61 (s, 2H); 13C{1H} NMR (75 MHz, CDCl3):  166.3, 150.2, 149.2, 139.9, 136.9, 136.3,
134.1, 130.7, 128.9, 128.5, 128.2, 127.7, 127.4, 126.3, 123.4, 119.3, 50.0, 48.8; HRMS (ESI/Q-
TOF) m/z: [M + H]+ calc’d for C22H21N2O 329.1648; found 329.1651. No product was detected
in the filtrates.
(E)-N,N-dibenzyl-3-(2-bromothiazol-5-yl)acrylamide (22): The standard procedure was
implemented with pyrrolidine (0.60 mmol, 50 μL) and AcOH (3.0 mmol, 171 μL) and 2-bromo-
4-formylthiazole (3.6 mmol, 691 mg). After 16 h, HPLC assay showed full conversion of 5. H2O
(1 mL) was added, resulting in crystallization of the product. Additional H2O (4 mL) over 30 min.,
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followed by 2 h of stirring. The slurry was filtered and the cake was displaced with 1:1 DMAc:H2O
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(4 mL), followed by H2O (4 mL). Drying via vacuum suction/N2 tent afforded 1.13 g of 22 (91%).
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Mp = 138.6 ˚C (DSC); 1H NMR (300 MHz, d6-dmso):  8.06 (s, 1H), 7.60 (d, J = 15.0 Hz, 1H),
7.42-7.18 (m, 10H), 7.17 (d, J = 15.0 Hz, 1H), 4.70 (s, 2H), 4.6 (s, 2H); 13C{1H} NMR (75 MHz,
d6-dmso):  165.9, 151.9, 137.6, 137.4, 137.2, 133.9, 128.8, 128.5, 127.7, 127.3, 127.1, 126.6,
126.5, 120.1, 49.9, 48.7; HRMS (ESI/Q-TOF) m/z: [M + H]+ calc’d for C20H18BrN2OS 413.0318;
found 413.0315. No product was detected in the filtrates.
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(R)-3-((5-cyano-2-((6-methylpyridin-3-yl)oxy)benzyl)(1,2,3,4-tetrahydronaphthalen-1-
yl)amino)-3-oxopropanoic acid (23). A mixture of 3-formyl-4-((6-methylpyridin-3-
yl)oxy)benzonitrile30 (1.4 mmol, 335 mg) and DMAc (2.0 mL) was treated with (R)-1,2,3,4-
tetrahydronaphthalen-1-amine (1.68 mmol, 255 mg), followed by AcOH (2.80 mmol, 160 L).
After stirring at ambient temperature for 1 h, NaBH(OAc)3 (4.2 mmol, 900 mg) was added as a
solid. The resulting slurry was aged 16 h at ambient temperature. The reaction was quenched with
H2O (4 mL), and the pH of the resulting solution was adjusted from 4.5 to 8.5 with NH4OH. The
product was extracted with CH2Cl2 (2 x 5 mL). The resulting organic solution was washed with
saturated aqueous NaCl (3 mL), then dried over MgSO4, filtered, and concentrated to an oil. Silica
gel chromatography (gradient 0 to 55% EtOAc/Heptane) afforded 373 mg of (R)-4-((6-
methylpyridin-3-yl)oxy)-3-(((1,2,3,4-tetrahydronaphthalen-1-yl)amino)methyl)benzonitrile as an
oil. 1H NMR (300 MHz, CDCl3):  8.31 (d, J = 2.8 Hz, 1H), 7.90 (d, J = 2.0 Hz, 1H), 7.47 (dd, J1
= 8.5 Hz, J2 = 2.1 Hz, 1H), 7.35-7.28 (m, 1H), 7.25-7.06 (m, 5H), 6.76 (d, J = 8.5 Hz, 1H), 4.05
(d, J = 14.6 Hz, 1H), 3.97 (d, J = 14.6 Hz, 1H), 3.84 (dd, J1 = J2 = 4.8 Hz, 1H), 2.89-2.67 (m, 2H),
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155.2, 149.8, 141.6, 138.9, 137.7, 134.1, 132.9, 132.5, 129.3, 128.8, 127.7, 127.0, 126.0, 124.2,
118.9, 116.5, 106.9, 77.6, 77.1, 76.7, 55.4, 45.3, 29.4, 28.4, 23.9, 19.1; HRMS (ESI/Q-TOF) m/z:
[M + H]+ calc’d for C24H23N3O 370.1914; found 370.1901.
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The intermediate amine- (R)-4-((6-methylpyridin-3-yl)oxy)-3-(((1,2,3,4-tetrahydronaphthalen-
1-yl)amino)methyl)benzonitrile- (0.5 mol, 185 mg) was dissolved in CH2Cl2 (3 mL). Et3N (100
L, 0.7 mmol) was added, followed by TMSCl (95 L, 0.75 mmol) and the resulting solution was
heated to reflux for 45 min. The solution was cooled to Ti = 22 °C, and then was charged with
Meldrum's acid (79 mg. 0.55 mmol) in a single portion. After 2 h, an additional charge of
Meldrum's acid (0.25 equiv., 18 mg) was made. After an additional 16 h age, the reaction was
quenched with 15% aq. citric acid (1 mL). The resulting mixture was transferred to a separatory
funnel and the phases were separated. The organic phase was extracted with 15% aq. citric acid (1
mL), followed by saturated brine (1 mL). The resulting organic phase was dried over MgSO4, then
filtered and subjected to a solvent switch into n-heptane which resulted in the formation of a white
slurry. The n-heptane volume was reduced to 4 mL, and EtOAc (1 mL) was added to the resulting
slurry. After stirring for 0.5 h, the slurry was filtered and displacement- washed with n-heptane (1
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mL). Drying afforded 155 mg of 23 as a white solid. Mp = 270 ˚C (decomp., DSC); H NMR
showed desired product as rotamers (~2:1 ratio by 1H NMR). 1H NMR (300 MHz, CDCl3): major
rotamer  8.20 (s, 1H), 7.64 (s, 1H), 7.49-7.42 (m, 1H), 7.31-7.10 (m, 5H), 6.99-6.92 (m, 1H), 6.67
(d, J = 8.7 Hz, 1H), 5.23-5.11 (m, 1H), 4.89 (d, J = 16.5 Hz, 1H), 4.20 (d, J = 16.5 Hz, 1H), 3.69-
3.60 (m, 2H), 2.86-2.72 (m, 2H), 2.57 (s, 3H), 2.26-2.13 (m, 1H), 2.11-1.95 (m, 1H), 1.91-1.56
(m, 2H); minor rotamer  8.29 (s, 1H), 7.56-7.48 (m, 1H), 7.44 (s, 1H), 7.31-7.10 (m, 5H), 7.06-
7.00 (m, 1H), 6.71 (d, J = 8.8 Hz, 1H), 6.20-6.09 (m, 1H), 4.66 (d, J = 18.2 Hz, 1H), 4.26 (d, J =
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18.2 Hz, 1H), 3.54 (d, J = 18.8 Hz, 1H), 3.30 (d, J = 18.8 Hz, 1H), 2.86 (m, 2H), 2.60 (s, 3H),
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combined rotamers ; 171.3, 170.3, 168.6, 168.0, 158.5, 158.0, 155.9, 155.1, 149.5, 148.6, 141.6,
141.2, 138.9, 138.5, 133.7, 133.6, 133.5, 132.7, 131.1, 130.1, 129.8, 129.4, 129.2, 128.6, 128.1,
127.9, 127.7, 127.0, 126.8, 126.7, 126.1, 124.9, 124.6, 118.8, 118.2, 116.1, 115.5, 107.0, 107.0,
58.9, 54.9, 43.8, 42.4, 38.9, 37.9, 29.6, 29.3, 29.2, 28.6, 27.7, 23.4, 22.2, 22.0; HRMS (ESI/Q-
TOF) m/z: [M + H]+ calc’d for C27H26N3O4 456.1918; found 456.1894.
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(R,E)-N-(5-cyano-2-((6-methylpyridin-3-yl)oxy)benzyl)-5-methyl-N-(1,2,3,4-tetrahydro-
naphthalen-1-yl)hex-2-enamide (24). A vial was charged with 23 (39 mg, 0.086 mmol), DMAc
(1.0 mL), pyrrolidine (0.02 mmol, 1.7 μL) and AcOH (0.1 mmol, 60 μL). Isovaleraldehyde (0.15
mmol, 16 μL) was added. After 25 h, HP LC assay showed ~50% conversion. An additional charge
of isovaleraldehyde (0.15 mmol, 16 μL) was performed, and HPLC assay showed full conversion
after an additional 15 h. H2O (2 mL) was added, followed by EtOAc (2 mL). The biphasic mixture
was transferred to a separatory funnel and the phases were separated with retention of each. The
aqueous phase was extracted with EtOAc (1 mL) and the resulting aqueous phase was discarded.
The combined organic phases were washed with 10% aq. LiCl (3 x 1 mL). The organic phase was
separated and dried over MgSO4, then filtered and concentrated under reduced pressure. Silica gel
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chromatography (0 to 100% EtOAc/Hexanes) afforded 37 mg of 24 as a viscous oil (90%). H
NMR (300 MHz, CDCl3): (major rotamer)  8.20 (s, 1H), 7.60 (s, 1H), 7.40 (dd, J1 = 8.5 Hz, J2 =
1.8 Hz, 1H), 7.22-7.00 (m, 7H), 6.64 (d, J = 8.5 Hz, 1H), 6.42 (d, J = 15.0 Hz, 1H), 5.41-5.30 (m,
1H), 4.87 (d, J = 16.9 Hz, 1H), 4.07 (d, J = 16.9 Hz, 1H), 2.85-2.70 (m, 2H), 2.55 (s, 3H), 2.24-
1.43 (m, 7H), 0.95 (d, J = 6.5 Hz, 3H), 0.94 (d, J = 6.5 Hz, 3H) (minor rotamer)  8.20 (s, 1H),
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7.60 (s, 1H), 7.46 (dd, J1 = 8.5 Hz, J2 = 1.8 Hz, 1H),, 7.22-7.00 (m, 7H), 6.69 (d, J = 8.6 Hz, 1H),
6.27-6.17 (m, 1H), 5.98 (d, J = 15.0 Hz, 1H), 4.68 (d, J = 19.1 Hz, 1H), 4.22 (d, J = 19.1 Hz, 1H),
2.85-2.70 (m, 2H), 2.57 (s, 3H), 2.24-1.43 (m, 7H), 0.87 (d, J = 6.8 Hz, 3H), 0.85 (d, J = 6.8 Hz,
3H); : 13C{1H} NMR (75 MHz, CDCl3): (combined rotamers)  168.4, 168.0, 158.0, 157.8, 155.6,
155.0, 149.3, 148.8, 148.1, 147.3, 141.6, 138.7, 138.2, 135.1, 135.0, 132.7, 132.5, 132.0, 132.0,
130.5, 130.2, 129.5, 129.3, 128.1, 128.0, 127.9, 127.5, 127.1, 127.0, 126.6, 126.5, 126.2, 124.1,
124.0, 121.1, 121.0, 118.9, 118.3, 115.9, 115.5, 106.7, 106.6, 58.0, 53.6, 42.9, 42.1, 41.9, 41.9,
30.0, 29.4, 29.2, 28.7, 27.9, 27.8, 23.8, 23.7, 22.4, 22.4, 22.2, 22.0; HRMS (ESI/Q-TOF) m/z: [M
+ H]+ calc’d for C31H34N3O2 480.2646; found 480.2648.
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3-(4-((4-isopropylphenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-3-
oxopropanoic acid (25).
A solution of tert-butyl 4-chloro-5H,6H,7H,8H-pyrido[4,3-
d]pyrimidine-6-carboxylate (2.9 g, 10.0 mmol) and 4-isopropylaniline (1.50 mL, 11.0 mmol) in
isopropanol (8 mL) and H2O (8 mL) was heated to Ti = 75 ˚C, after which HPLC assay showed
full conversion to the N-Boc protected intermediate. The solution was cooled to Ti = 50 ˚C and 3N
HCl (5 mL) was added. After 8 h, the solution was cooled to Ti = 22 ˚C, followed by the addition
of NH4OH (2.0 mL). Isopropanol was removed via distillation under reduced pressure, resulting
in the precipitation of dark solids. Addition of IPAc (20 mL) to a stirring solution of the dark solids
resulted in the formation of a triphasic slurry containing a dark organic phase, a clear aqueous
phase, and lightly colored solids. The solids were filtered and displacement-washed with IPAc.
The solids were dried via vacuum suction under a N2 tent, affording 2.01 g of the desired product
as a pale beige solid (75% yield). Mp = 199.7 ˚C (DSC); 1H NMR (300 MHz, d6-dmso):  8.53 (s,
1H), 8.37 (s, 1H), 7.51 (d, J = 8.5 Hz, 2H), 7.191 (d, J = 8.5 Hz, 2H), 4.01 (s, 2H), 3.28 (t, J = 6.2
Hz, 2H), 2.92-2.77 (m, 3H), 1.20 (d, J = 6.9 Hz, 6H); 13C{1H} NMR (75 MHz, d6-dmso):  159.1,
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156.8, 155.4, 143.4, 137.0, 126.0, 122.5, 109.3, 40.6, 40.4, 32.9, 29.0, 24.0; HRMS (ESI/Q-TOF)
m/z: [M + H]+ calc’d for C16H21N4 269.1761; found 269.1766.
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The intermediate amine N-(4-isopropylphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-
amine (268 mg, 1.0 mmol) was dissolved in a biphasic mixture of MeTHF (3 mL) and saturated
aq. NaHCO3 (3 mL). Ethyl malonyl chloride (191 L, 1.5 mmol) was added via syringe pump over
1 h. After 10 h, an additional charge of saturated aq. NaHCO3 (3 mL) was followed by ethyl
malonyl chloride (600 L) over 1 h. After an additional 12 h, HPLC assay revealed high
conversion. The biphasic mixture was transferred to a separatory funnel and the organic phase was
discarded. The organic phase was washed with 1N glycolic acid (3 mL), followed by saturated aq.
NaCl (3 mL). The resulting organic phase was concentrated under reduced pressure to an oil.
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The resulting oil was dissolved in EtOH, to which was added 1 N NaOH (1 mL). After 1 h,
HPLC assay showed full consumption of the starting ester. 1N glycolic acid (2.5 mL) was added,
forming an initially homogeneous solution that spontaneously began to crystallize a white solid.
After stirring for 3 h, the slurry was filtered. The wetcake was displacement-washed with 1:3.5
EtOH:H2O (1.5 mL), then dried to afford 25 (186 mg of a white solid) as a ~2:1 mixture of
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rotamers. Mp = 153.6 ˚C (DSC); H NMR (300 MHz, CD3OD): major rotamer  8.31 (s, 1H),
7.49-7.40 (m, 2H), 7.29-7.20 (m, 2H), 4.66 (s, 2H), 3.87 (t, J = 5.8 Hz, 2H), 3.66 (s, 1H), 2.97-
2.79 (m, 3H), 1.26 (d, J = 6.9 Hz, 6H): minor rotamer  8.33 (s, 1H), 7.49-7.40 (m, 2H), 7.29-7.20
(m, 2H), 4.61 (s, 2H), 3.94 (t, J = 5.9 Hz, 2H), 3.65 (s, 1H), 2.97-2.79 (m, 3H), 1.26 (d, J = 6.9 Hz,
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6H); C{1H} NMR (75 MHz, CD3OD) combined rotamers  171.5, 171.4, 168.8, 168.6, 160.2,
159.6, 159.2, 158.9, 156.0, 155.8, 146.9, 137.4, 137.4, 127.7, 127.1, 125.0, 124.8, 111.8, 111.6,
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C19H23N4O3 355.1765; found 355.1765.
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(E)-1-(4-((4-isopropylphenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-5-
methylhex-2-en-1-one (26). A solution of 25 (0.282 mmol, 100 mg) in DMAc (2 mL) was treated
with pyrrolidine (0.042 mmol, 3.5 μL) and AcOH (0.282 mmol, 16 μL). Isovaleraldehyde (0.423
mmol, 45 μL). The resulting solution was stirred for 5 h, at which point HPLC assay showed full
conversion of 25. H2O (4 mL) was added, followed by MTBE (4 mL). The biphasic mixture was
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transferred to a separatory funnel and the phases were separated with retention of each. The
aqueous phase was extracted with MTBE (2 mL) and the resulting aqueous phase was discarded.
The combined organic phases were washed with 10% aq. LiCl (3 x 1 mL). The organic phase was
separated and dried over MgSO4, then filtered and concentrated under reduced pressure. Silica gel
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chromatography (50 to 100% EtOAc/Hexanes) afforded 93 mg of 26 as a viscous oil (87%). H
NMR (300 MHz, CDCl3):  8.57 (s, 1H), 7.46 (d, J = 8.5 Hz, 2H), 7.24 (d, J = 8.5 Hz, 2H), 7.01-
6.84 (m, 1H), 6.33 (d, J = 15.0 Hz, 1H), 4.65 (s, 2H), 3.94-3.82 (m, 2H), 3.03-2.83 (m, 3H), 2.13
(dd, J1 = J2 = 7.1 Hz, 2H), 1.84-1.69 (m, 1H), 1.26 (d, J = 6.9 Hz, 3H), 0.94 (d, J = 6.7 Hz, 3H);
13C{1H} NMR (75 MHz, CDCl3):  166.3, 158.3, 157.4, 155.3, 147.2, 145.3, 135.6, 126.8, 122.9,
120.2, 110.2, 42.5, 41.9, 39.6, 33.6, 31.6, 27.8, 24.0, 22.4; HRMS (ESI/Q-TOF) m/z: [M + H]+
calc’d for C23H31N4O 379.2492; found 379.2495.
3-((2-chlorophenyl)amino)-3-oxopropanoic acid (27). A flask was charged with 2-chloroaniline
(10.0 mmol, 1.27 g) and CH2Cl2 (30 mL). Et3N (14.0 mmol, 1.42 g) was added, followed by
TMSCl (15.0 mmol, 1.63 g) and the resulting thin slurry was heated to reflux for 30 min. The
solution was cooled to Ti = 30 °C, then Meldrum's acid (11.0 mmol, 1.58 g) was added in a single
portion. After 4 h, the reaction was quenched with 1N HCl (18 mL), which resulted in a triphasic
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system in which the product had solidified. The slurry was filtered, and the collected product was
washed with water (10 mL), followed by DCM (10 mL). Drying via suction/N2 tent afforded 1.69
g (94%) of 27 as a white solid. Mp = 140.3 ˚C (DSC);: 1H NMR (300 MHz, d6-dmso):  12.73 (s,
1H), 9.83 (s, 1H), 7.85 (d, J = 8.1 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.34 (dd, J1 = J2 = 7.8 Hz,
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1H), 7.18 (dd, J1 = J2 = 7.8 Hz, 1H), 3.49 (s, 2H); C{1H} NMR (75 MHz, d6-dmso):  169.7,
165.1, 134.8, 129.5, 127.5, 126.1, 125.4, 125.1, 43.0; HRMS (ESI/Q-TOF) m/z: [M + H]+ calc’d
for C9H9ClNO3 214.0265; found 214.0252.
3-(2-bromothiazol-5-yl)-2-((2-chlorophenyl)carbamoyl)acrylic acid (28) control experiment
without AcOH. A flask was charged with 27 (1.0 mmol, 214 mg), DMAc (1.0 mL), pyrrolidine
(0.2 mmol, 17 μL) and 2-bromo-4-formylthiazole (1.2 mmol, 230 mg). After 1.5 h, LC showed
full conversion. H2O (2 mL) was added, followed by EtOAc (1 mL) which resulted in the formation
of a triphasic slurry (solid product and a biphasic supernatant). The slurry was filtered, and the
cake was displaced with EtOAc (1 mL). Drying via suction/N2 tent afforded 183 mg of the major
isomer of 28. Mp = 175.5 ˚C (DSC); 1H NMR (300 MHz, d6-dmso):  13.04 (br S, 1H), 9.87 (s,
1H), 8.19 (s, 1H), 7.95 (dd, J1 = 8.1 Hz, J2 = 1.4 Hz, 1H), 7.56 (s, 1H), 7.48 (dd, J1 = 8.0 Hz, J2 =
1.3 Hz, 1H), 7.37 (ddd, J1 = J2 = 7.9 Hz, J3 = 1.4 Hz, 1H), 7.20 (ddd, J1 = J2 = 7.8 Hz, J3 = 1.5 Hz,
1H); 13C{1H} NMR (75 MHz, d6-dmso):  165.8, 164.4, 149.9, 136.9, 134.9, 130.7, 130.3, 129.7,
129.4, 127.1, 126.9, 126.7, 126.3; HRMS (ESI/Q-TOF) m/z: [M + H]+ calc’d for C13H9BrClN2O3S
386.9200; found 386.9203. Using the isolated product as a standard, loss to the EtOAc phase
(diluted to 10 mL) was 82 mg as a mixture of isomers. Therefore, the assay yield was 77%.
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3-(diphenylamino)-3-oxopropanoic acid (29). A flask was charged with Ph2NH (10.0 mmol,
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1.69 g) and DCM (20 mL). Et3N (14 mmol, 1.42 g) was added, followed by TMSCl (15 mmol,
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1.63 g) and the resulting thin slurry was heated to reflux for 30 min. The solution was cooled to T
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= 27 °C, then Meldrum's acid (11.0 mmol, 1.58 g) was added in a single portion. After 1 h, the
heterogeneous reaction was quenched with 15% aq. citric acid (11 mL), and the biphasic mixture
was transferred to a separatory funnel and the layers were separated. The product- containing
organic phase was washed with sat. aq. NaCl (6 mL), and the phases were separated. The organic
phase was solvent-switched into IPAc and diluted to 40 mL total volume, resulting in the formation
of a slurry. IPAc was removed via distillation to form a slurry (~15 mL total volume). The
heterogeneous mixture was filtered and displaced with IPAc (10 mL). Drying via suction/N2 tent
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afforded 1.81 g of a solid that was shown by H NMR to be 29 contaminated with 5 mol% of
Et NHCl.
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A portion of the initially isolated solid (550 mg) was dissolved in CH2Cl2 (10 mL) and stirred, to
which was added 1N HCl (5 mL). After 10 min., the biphasic solution was transferred to a
separatory funnel and the phases were split. The resulting organic phase was washed with 15% aq.
NaCl (5 mL), then dried over MgSO4, filtered, and concentrated to a thin slurry (~2 mL total
volume). IPAc (8 mL) was added over 1 h via syringe pump. The resulting slurry was aged 1 h,
then filtered. The cake was displaced with IPAc (5 mL) and dried via suction/N2 tent to afford
clean 29 as a white solid. Mp = 115.5 ˚C (DSC); 1H NMR (300 MHz, d6-dmso):  12.57 (s, 1H),
7.52-7.12 (m, 10H), 3.25 (s, 2H); 13C{1H} NMR (75 MHz, d6-dmso):  168.8, 166.0, 142.6, 129.9,
129.0, 128.7, 128.2, 126.9, 126.4, 126.4, 42.4; HRMS (ESI/Q-TOF) m/z: [M + H]+ calc’d for
C15H14NO3 256.0968; found 256.0976.
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(E)-3-(2-bromothiazol-5-yl)-N,N-diphenylacrylamide (30). A flask was charged with 29 (1.0
mmol, 255 mg) and DMAc (2.5 mL). Pyrrolidine (0.12 mmol, 10 L) and AcOH (1.0 mmol, 57
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L) were subsequently added to the DMAc solution. A solution of 2-bromo-4-formylthiazole (1.2
mmol, 230 mg) dissolved in DMAc (1.5 mL) was then added over 10 h via syringe pump. After
addition was complete, the reaction was aged an additional 24 h. H2O (2 mL) was charged via
syringe pump over 1 h, followed by 2 h of stirring. The slurry was filtered, and the cake was
displaced with 1:1 DMAc:H2O (0.5 mL), followed by H2O (0.5 mL). Drying via vacuum
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suction/N2 tent afforded 346 mg of 30 (90%) as a white solid. Mp = 187.0 ˚C (DSC); H NMR
(300 MHz, d6-dmso):  8.04 (s, 1H), 7.56 (d, J = 15.0 Hz, 1H), 7.50-7.23 (m, 10H), 6.59 (d, J =
15.0 Hz, 1H); 13C{1H} NMR (75 MHz, d6-dmso):  164.7, 151.6, 142.6, 142.6, 137.5, 133.2, 129.4,
129.4, 129.4, 129.4 127.8, 127.8, 127.3, 121.6; HRMS (ESI/Q-TOF) m/z: [M + H]+ calc’d for
C18H14BrN2OS 385.0005; found 385.0000.
100 g demonstration of the synthesis of (21): 5•t-BuNH2 (125 g, 351 mmol) was charged to a 2
L flask equipped with overhead stirring and a drop valve. EtOAc (700 mL) was added, followed
by 15 wt% aq. citric acid (700 mL). The resulting biphasic mixture was stirred for 30 min., after
which agitation was stopped and the phases were allowed to settle. The lower aqueous phase was
drained and discarded. 15 wt% aq. NaCl (150 mL) was added to the vessel and the resulting
biphasic mixture was stirred for 30 min., after which agitation was stopped and the phases were
allowed to settle. The lower aqueous phase was drained and discarded. The retained organic phase
then concentrated under reduced pressure (40-50 mm Hg partial pressure and 30-35 ˚C) to a final
volume of 300 mL. A solvent switch was performed under the conditions of constant volume
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