α,β-Dehydrogenation of esters with free O–H and N–H functionalities via allyl-palladium catalysis

Article abstract of DOI:10.1016/j.tet.2018.02.028

A direct and selective method for the α,β-dehydrogenation of esters using palladium catalysis in the presence of free O–H and N–H functionalities is reported herein. Allyl-palladium catalysis allows for preservation of readily oxidizable functionalities s

Full text of DOI:10.1016/j.tet.2018.02.028

Accepted Manuscript
α,β-Dehydrogenation of esters with free O-H and N-H functionalities via allyl-
palladium catalysis
Suzanne M. Szewczyk, Yizhou Zhao, Holt Sakai, Pascal Dube, Timothy R. Newhouse
PII:
S0040-4020(18)30162-5
10.1016/j.tet.2018.02.028
TET 29299
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 16 January 2018
Revised Date: 12 February 2018
Accepted Date: 13 February 2018
Please cite this article as: Szewczyk SM, Zhao Y, Sakai H, Dube P, Newhouse TR, α,β-
Dehydrogenation of esters with free O-H and N-H functionalities via allyl-palladium catalysis,
Tetrahedron (2018), doi: 10.1016/j.tet.2018.02.028.
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ACCEPTED MANUSCRIPT
Leave this area blank for abstract info.
α,β-Dehydrogenation of Esters with Free
O-H and N-H Functionalities via
Allyl-Palladium Catalysis
a
a
a
b
a,*
Suzanne M. Szewczyk , Yizhou Zhao , Holt Sakai , Pascal Dube , and Timothy R. Newhouse
a
Department of Chemistry, Yale University, 225 Prospect Street, New Haven, CT 06520-8107, United States
Nalas Engineering, 85 Westbrook Road, Centerbrook, CT 06409, United States
b
LiNR2, ZnCl2
CO2R
CO2R
PdLn
Free O-H and N-H
R
N
NH
OH
H
OH
N
H
R

ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
α,β-Dehydrogenation of Esters with Free O-H and N-H Functionalities via
Allyl-Palladium Catalysis
a
a
a
b
a,*
Suzanne M. Szewczyk , Yizhou Zhao , Holt Sakai , Pascal Dube , and Timothy R. Newhouse
a
Department of Chemistry, Yale University, 225 Prospect Street, New Haven, CT 06520–8107, United States
Nalas Engineering, 85 Westbrook Road, Centerbrook, CT 06409, United States
b
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A direct and selective method for the α,β-dehydrogenation of esters using palladium catalysis in
the presence of free O-H and N-H functionalities is reported herein. Allyl-palladium catalysis
allows for preservation of readily oxidizable functionalities such as amines and alcohols.
Furthermore, an economical protocol using LDA was developed for the dehydrogenation of
β-amino esters.
Available online
Keywords:
2
009 Elsevier Ltd. All rights reserved.
Allyl-Palladium
Dehydrogenation
Esters
β-Amino esters
of methods to dehydrogenate carbonyl compounds has
historically been limited to substrates that do not have other
oxidation-prone functionalities owing to the strong, electrophilic
1
. Introduction
Methodologies with defined chemoselectivity profiles are
important for the practical synthesis of complex organic
materials. In particular, the ability to oxidize a specific
functional group in the presence of another allows for strategic
orchestration of sequential synthetic transformations leading to
efficient multistep syntheses. The functional group compatibility
1
oxidants employed in such methods.
Our group has recently reported that a variety of carbonyl
2a
compounds, including esters , can be transformed to their
unsaturated counterparts via conversion to the zinc enolates and
treatment with catalytic Pd(II) and stoichiometric allyl oxidant
2a
(
Figure 1). Our initial report described the use of this approach
for the dehydrogenation of nitriles and esters, and subsequently
we demonstrated the applicability of this mechanistic paradigm
2b
2c
2d,2e
to amides , carboxylic acids , and ketones . Interestingly, we
found in the case of amide dehydrogenation our method could
tolerate oxidation-prone functionality such as unprotected
alcohols and N-H containing amide substrates, which could
2
b
readily undergo oxidation to the corresponding C=X systems.
The key to obtaining complete conversion and synthetically
useful yields was forming the dianion with lithium
cyclohexyl(2,6-diisopropylphenyl)amide (LiCyan) used as a
hindered amide base.
In this report, we extend our earlier findings to the
dehydrogenation of O-H- and N-H-containing esters and
additionally disclose a more cost-effective protocol using
inexpensive LDA for the specific case of β-amino ester
dehydrogenation. The success of allyl-palladium catalysis for
these selective oxidation reactions is remarkable considering the
known propensity for Pd(II) to coordinate to and even oxidize
Figure 1. Allyl-palladium catalysis for carbonyl α,β-
dehydrogenation
3
4
oxygen - and nitrogen -based nucleophiles.
_
_______
∗
Corresponding author.
E-mail address: timothy.newhouse@yale.edu (T.R. Newhouse).

2
Tetrahedron
ACCEPTED MA2.
2
. Results and Discussion
N
2 S
U
co
S
pe
C
o
R
f t
I
ert-butyl ester dehydrogenation
P
T
In our initial attempts to dehydrogenate ester 1a in the
Figure 2. Scope of tert-butyl ester dehydrogenation
presence of a free alcohol, reaction conditions previously
reported by our group were examined (Table 1). The reaction
proceeds via formation of a zinc enolate, transmetalation to Pd
and subsequent β-hydride elimination. To our delight, the
conditions reported for dehydrogenation of amides (Entry 1) in
the presence of free O-H and N-H functionalities were successful
and provided slightly improved conversion as compared to our
original conditions for ester and nitrile dehydrogenation
(
Entries 2-3). Zn(TMP) (Entries 4-5), which was utilized for the
2
dehydrogenation of carboxylic acids and ketones, proved to be
minimally effective for this transformation.
Table 1. Application of previously reported conditions
With these conditions in hand, we evaluated a variety of tert-
butyl esters with free O-H and N-H functionalities (Figure 2). A
lactam (2b), indole (2c), and aniline (2d) were all tolerated and
led to the generation of the dehydrogenated compound in high
yields. Both secondary (2e) and primary alcohols (2a) remained
intact as did a free phenol (2f).
More challenging methyl esters such as methyl
4-hydroxycyclohexane carboxylate proceeded with lower yields.
This is partially due to lower solubility of the resultant dianion,
as compared to the tert-butyl esters.
2
.1 Optimization
Table 2 shows a further examination of reaction conditions for
the dehydrogenation of 1a. The combination of allyl pivalate and
LDA (Entry 1) led to slightly higher conversion than allyl acetate
and LDA (Entry 2). Additionally, LDA outperformed other
commercial bases such as LHMDS (Entry 3), and LiNCy2
2.3 Intermolecular experiments
In order to further probe the scope of this reaction and
demonstrate its robustness, a variety of commercial compounds
with free O-H and N-H functionalities were introduced as
additives to the standard reaction conditions for the
(
Entry 4).
transformation utilize LiCyan as the lithium anilide base
Entry 5). Examination of the equivalents of base and ZnCl2
Nonetheless, the optimal conditions for this
(
5
dehydrogenation of ester 1g with LiCyan (Figure 3). The change
additive (Entries 6-7) demonstrated that formation of the dianion
with an excess of ZnCl2 was critical to achieving high
conversion.
in yield of the dehydrogenated product (2g) relative to the control
1
experiment without an additive was evaluated by H-NMR
analysis. The yield of 2g without additives is consistently around
9
9%. The additive was introduced directly after the starting
material (1g), and an extra equivalent of the base presumably
deprotonated the additive during the enolate formation stage.
The reaction proceeded with good to excellent conversion in the
presence of a variety of additives. Amines and anilines (Figure
Table 2. Optimization of ester dehydrogenation
3
A) are well tolerated, as are a variety of nitrogen-based
heterocycles (Figure 3B). Amides, carbamates, and lactams also
did not impact the reaction (Figure 3C). Additives with free O-
Hs such as carboxylic acids, oximes, and phenols (Figure 3D)
showed minimal inhibition of the reaction. Alcohols such as
cholesterol and even oxidation-prone benzyl alcohol remained
intact without significantly affecting the dehydrogenation.
Neither oxidation nor dehydrogenation of any these additives was
observed.
The addition of thiophenol led to a decreased yield of 2g to
4
4% however, thioanisole did not significantly inhibit the
catalytic cycle providing 74% of 2g. Water (Figure 3D) notably
decreased the yield of 2g to 59% suggesting that hydroxide
affects the reaction beyond quenching the available base. These

intermolecular studies suggest a wider scope for the selective
dehydrogenation of esters than what is demonstrated in Figure 2.
β-Amino acid derivatives are commonly occurring in
unnatural peptides, natural products, and heterocyclic
compounds. Incorporating β-amino acids into the peptide
backbone of pharmaceutically active compounds has been shown
ACCEPTED MANUSCRIPT
Figure 3. Intermolecular dehydrogenation in the presence of
free O-H and N-H compounds
6
to increase drug potency. Dehydrogenation of these compounds
is therefore a desirable transformation to aid in the synthesis of β-
7
i) LiCyan
equiv additive ii) ZnCl2
amino acid derivatives. In the dehydrogenation of methyl ester
1
3
a, LDA outperformed LiCyan, LiTMP, and Zn(TMP) (Table
3). With 4 equivalents of ZnCl , up to 90% conversion could be
obtained. Moreover, LDA is an economical and process-friendly
base for this transformation.
t
t
2
CO2 Bu
CO2 Bu
2g
Ph
Ph
2
iii) 2.5 mol% [Pd(allyl)Cl]2
allyl pivalate, 60 °C, THF
1
g
Free O-H and N-H Additivesa
A - Amines
B - Heterocycles
N
N
2.5 β-Amino ester dehydrogenation
Ph
Me
Ph
8
N
H
N
H
N
H
86%
NH2
9%
In order to evaluate the scope of this transformation, a variety
of β-amino methyl esters with common protecting groups were
synthesized (Table 4). It was determined that mono-protected
amino esters were more efficiently dehydrogenated than their
99%
76%
N
Ph
Ph
TMS
TMS
N
H
N
H
N
H
N
H
96%
diprotected analogues.
For example, N,N-dibenzylated 3b
9
1%
99%
Me
95%
provided a significantly lower yield than substrate 3a. In
addition, β-amino esters protected with Cbz (3c), Piv (3d), and
Bz (3e) groups underwent dehydrogenation in good to excellent
yields. Substitution at the α- or β-positions led to decomposition
of the starting materials under the reaction conditions.
Me
N
Me
Me
H2N
Me
H
7
5%
9
4%
C - Amides and Lactams
O
O
O
Me
N
H
OMe
N
O
N
H
80%
O
H
Table 4. Scope of β-amino ester dehydrogenation
9
7%
9%
99%
O
Me
Me
O
Bn
N
H
Ph
N
H
93%
Ph
N
H
Me
8
99%
D - O-H groups
Ph
O
Me
N
OH
OH
Ph
Ph
OH
Ph
Ph
Me
OH
H
Ph
74%
9
1%
Me
81%
94%
Me
O
OH
H
H
OH
Me
3%
HO
6
59%
99%
90%
aYields of 2g were determined by 1H-NMR analysis using dibromomethane as
internal standard.
3
. Conclusion
In conclusion, we have demonstrated the scope of ester
dehydrogenation in the presence of free O-H and N-H
functionalities. In addition, we have identified a highly practical
and inexpensive protocol for the dehydrogenation of β-amino
acid derivatives that may find utility in the synthesis of unnatural
amino acids and peptides. The robustness and reliability of this
reaction in the presence of a variety of coordinating groups
provokes questions about the role and identity of the active
palladium catalyst in these transformations. This study has also
highlighted the unique interplay between the selection of amide
base and allyl oxidant for efficient dehydrogenation of different
substrates. These topics, along with further mechanistic studies,
are currently under investigation in our laboratory.
2
.4 β-Amino ester optimization
Table 3. Optimization of β-amino ester dehydrogenation
4
. Experimental
4
.1 General experimental procedure
All reactions were carried out under an inert nitrogen
atmosphere with dry solvents under anhydrous conditions unless
otherwise stated. Reactions were capped with a rubber septum or
Teflon–coated silicon microwave cap unless otherwise stated.

4
Tetrahedron
nt MAN
Stainless steel cannulas or syringes were used
A
to
C
tra
C
ns
E
fe
P
r s
T
o
E
lve
D
T
U
RI
o aSC–4 °CPTsolution of N-cyclohexyl-2,6-diisopropylaniline
0
and air-/moisture-sensitive reagents. Reactions were monitored
by thin-layer chromatography (TLC) and carried out on 0.25 mm
Merck silica gel plates (60F-254) using UV light as the
visualizing agent. Potassium permanganate and an acidic solution
of p-anisaldehyde were used as developing agents. Flash column
(CyanH) (135 mg, 0.52 mmol, 2.6 equiv) in THF (4 mL, 0.05 M)
was added n-butyllithium (0.20 mL, 0.50 mmol, 2.5 M in
hexanes, 2.5 equiv). After 3-5 mins, the reaction mixture became
cloudy and was stirred for 1 hour. A stock solution of the desired
substrate (0.20 mmol, 1.0 equiv) in THF (0.4 mL, 0.5 M) was
added, the reaction quickly became translucent, and was stirred
for 1 hour more at the same temperature. A solution of ZnCl2

chromatography employed SiliaFlash P60 (40-60 µm, 230-400
mesh) silica gel purchased from SiliCycle Inc.
(
1.6 mL, 0.80 mmol, 0.5 M in THF, 4.0 equiv) was added, and
the reaction was stirred for 1 hour. The stock solution of
[Pd(allyl)Cl] (1.8 mg, 0.0050 mmol, 2.5 mol %) and allyl
4
.2 Materials
2
pivalate (38 ꢀL, 0.24 mmol, 1.2 equiv) in THF (0.2 mL, 1.2 M)
was added. The reaction mixture was removed from the –40 °C
bath, placed into a preheated oil bath, and stirred at least 12 hours
until completion (as determined by TLC or H NMR analysis).
The reaction was cooled to room temperature and quenched by
All reaction solvents were purified using a Seca solvent
purification system by Glass Contour.
The molarity of
n-butyllithium solutions were determined by titration with
N-benzylbenzamide. All other reagents were used as received
without further purification, unless otherwise stated.
1
the addition of sat. aq. NH Cl (15 mL). The reaction mixture was
4
diluted with EtOAc (5 mL) and the organic phase was separated.
The aqueous phase was extracted with EtOAc (3 × 5 mL) and the
combined organic layers were washed with brine (10 mL), dried
over anhydrous Na SO , filtered, and concentrated under reduced
4
.3 Instrumentation
All new compounds were characterized by means of R , H
1
2
4
f
13
pressure by rotary evaporation.
NMR,
C NMR, FT-IR (thin film from CH Cl ), and
2 2
1
high-resolution mass spectroscopy (HR-MS). Copies of the H
13
4
.5.2 General dehydrogenation of β-amino esters (3b):
and C NMR spectra can be found in the Supplementary
Material. NMR spectra were recorded using a Varian 400 MHz
NMR spectrometer or a Varian 600 MHz NMR spectrometer.
All H NMR data are reported in δ units, parts per million (ppm),
and were calibrated relative to the signal for residual chloroform
To a –40 °C solution of diisopropylamine (56 µL, 0.40 mmol,
.0 equiv) in THF (2.0 mL, 0.2 M) was added n-butyllithium
2
1
(0.16 mL, 0.4 mmol, 2.5 M in hexanes, 2.0 equiv) and the
reaction was stirred for 1 hour at the same temperature. A stock
solution of desired substrate (0.20 mmol, 1.0 equiv) in THF
13
(7.26 ppm) in deuterochloroform (CDCl ). All C NMR data are
3
(0.4 mL, 0.5 M) was slowly added, and the reaction mixture was
reported in ppm relative to CDCl (77.16 ppm) and were obtained
with
3
1
stirred for 1 hour at –40 °C to form a light-yellow heterogeneous
H
decoupling.
The following abbreviations or
mixture. A solution of ZnCl (0.42 mL, 0.80 mmol, 1.9 M in
combinations thereof were used to explain the multiplicities:
s = singlet, d = doublet, t = triplet, q = quartet, quin = quintet,
br = broad, m = multiplet, and a = apparent. All IR spectra were
taken on an FT-IR/Raman Thermo Nicolet 6700. HR-MS data
was recorded on a Bruker microTOF mass spectrometer using
ESI–TOF (electrospray ionization-time of flight).
2
2
1
-MeTHF, 4.0 equiv) was added, and the reaction was stirred for
hour to give a homogeneous solution. The stock solution of
[
(
Pd(allyl)Cl] (1.8 mg, 0.0050 mmol, 2.5 mol %) and allyl acetate
26.0 ꢀL, 0.24 mmol, 1.2 equiv) in THF (0.2 mL, 1.2 M) was
2
added. The reaction mixture was removed from the –40 °C bath,
placed into a 60 °C preheated oil bath and stirred for 12 hours.
The reaction was cooled to room temperature and quenched with
the addition of sat. aq. NH Cl (15 mL). The reaction mixture was
4
4
.4 Solutions
diluted with EtOAc (5 mL), and the organic phase was separated.
The aqueous phase was extracted with EtOAc (3 × 5 mL) and the
combined organic layers were washed with brine (10 mL), dried
over anhydrous Na SO , filtered, and concentrated under reduced
4
.4.1 Zinc chloride stock solution (0.5 M in THF):
Finely powdered anhydrous ZnCl (0.68 g, 5.0 mmol) was
2
weighed into a 50-mL flame-dried flask in the glove box under
an inert atmosphere. The flask was taken out of a glove box and
placed under vacuum. The flask was heated with a heat gun for
2
4
pressure by rotary evaporation.
2
min under vacuum and then back filled with nitrogen (this
4.5.3 General dehydrogenation of free N-H: β-amino esters (3):
To a –40 °C solution of diisopropylamine (84 µL, 0.60 mmol,
3.0 equiv) in THF (2.5 mL, 0.24 M) was added n–butyllithium
(0.24 mL, 0.60 mmol, 2.5 M in hexanes, 3.0 equiv), and the
reaction was stirred for 1 hour at the same temperature. A stock
solution of desired substrate (0.20 mmol, 1.0 equiv) in THF (0.4
mL, 0.5 M) was slowly added, and the reaction mixture was
stirred for 1 hour at –40 °C to form a light-yellow heterogeneous
process was repeated 3 times). After the flask was cooled to
ambient temperature, the flask was back filled with nitrogen,
THF (10 mL) was added, and the suspension was vigorously
stirred for 1-2 hours before it was used.
Note: Commercial 1.9 M ZnCl2 solution in 2-Me THF and
freshly prepared ZnCl2 stock solution in THF can be used
interchangeably.
mixture. A solution of ZnCl (0.42 mL, 0.80 mmol, 1.9 M in 2-
2
MeTHF, 4.0 equiv) was added and stirred for 1 hour to give a
homogeneous solution. Then the stock solution of [Pd(allyl)Cl]2
(1.8 mg, 0.0050 mmol, 2.5 mol %) and allyl acetate (26.0 ꢀL,
0.24 mmol, 1.2 equiv) in THF (0.2 mL, 1.2 M) was added. The
reaction mixture was removed from the –40 °C bath, placed into
a 60 °C preheated oil bath and stirred for 12 hours. The reaction
was cooled to room temperature and quenched with the addition
4
.4.2 Palladium stock solution:
Pd(allyl)Cl] was weighed into a flame dried vial which was
[
2
evacuated and backfilled with nitrogen. Allyl oxidant and THF
were added sequentially and the solution was stirred for
0
4
4
.5-1 hour.
.5 General Procedures
of sat. aq. NH Cl (15 mL). The reaction mixture was diluted
4
with EtOAc (5 mL), and the organic phase was separated. The
aqueous phase was extracted with EtOAc (3 × 5 mL) and the
combined organic layers were washed with brine (10 mL), dried
.5.1 General dehydrogenation of tert-butyl esters (1):

over anhydrous Na SO , filtered, and concentrated under reduced
pressure by rotary evaporation.
added 4-dimethylaminopyridine (DMAP) (61.1 mg, 0.50 mmol,
2
4
ACCEPTED MANUSCRIPT
0.1 equiv), tert-butanol (2.4 mL, 25 mmol, 5.0 equiv) and N,N'-
dicyclohexylcarbodiimide (DCC) (1.12 g, 5.4 mmol, 1.1 equiv).
After stirring for 5 min at 0 °C, the mixture was stirred for
17 hours at 23 °C. After filtration through Celite, the mixture
was concentrated under reduced pressure by rotary evaporation.
Purification by flash column chromatography on silica gel
4
.6 Substrate Synthesis
8
9
2a
10
11
Esters 1a , 1f , 1g , 3a , and 3b were synthesized according
to previously published procedures.
(
4
hexanes/EtOAc = 6:1) afforded the title compound (0.556 g,
4%) as an off-white solid. R = 0.40 (CH Cl ) H NMR (400
f 2 2
1
MHz, CDCl ): δ 7.99 (br s, 1H), 7.62 (d, J = 7.6 Hz, 1H), 7.35 (d,
J = 8.0 Hz, 1H), 7.20 (t, J = 7.2 Hz, 1H), 7.12 (t, J = 7.4 Hz, 1H),
3
4
.6.1 Allyl pivalate (SI-1)
-Bromopropene (50.0 mL, 0.60 mol, 3.0 equiv) was added to
a flask containing K CO (36.0 g, 0.26 mol, 1.3 equiv) and
3
6
.99 (s, 1H), 2.80 (t, J = 7.4 Hz, 2H), 2.31 (t, J = 7.4 Hz, 2H),
13
2
3
2.05–2.01 (m, 2H), 1.46 (s, 9H) C NMR (151 MHz, CDCl ): δ
3
pivalic acid (20.4 g, 0.20 mol, 1.0 equiv). DMF (500 mL) was
added. The mixture was stirred vigorously at ambient
temperature for 48 hours. The reaction was diluted with water
1.0 L) and EtOAc (500 mL). The organic layer was separated
1
8
1
2
73.3, 136.5, 127.6, 122.0, 121.6, 119.3, 119.1, 116.0, 111.2,
–1
0.2, 35.4, 28.3, 25.7, 24.6 IR (cm ): 3416, 2976, 1708, 1264,
+
+
151 ESI-HRMS (m/z): [M+Na] calc’d for C H NNaO :
16
21
2
(
82.1465; found: 282.1540.
and the aqueous phase was extracted with EtOAc (3 x 500 mL).
The organic layers were combined and washed with water (500
mL) and brine (2 x 500 mL). The organic layer was dried over
anhydrous Na SO , filtered, and concentrated under reduced
pressure by rotary evaporation. The crude oil was distilled by
vacuum distillation to yield allyl pivalate as a colorless oil
4
.6.4 tert-Butyl 3-(4-((tert-
butoxycarbonyl)amino)phenyl)propanoate (1d)
2
4
3-(4-Aminophenyl)propanoic acid (1.0 g, 6.0 mmol,
1
.0 equiv) was dissolved in dry THF (15 mL, 0.4 M). Di-tert-
butyl dicarbonate (1.5 mL, 6.5 mmol, 1.1 equiv) was added and
the reaction was stirred at ambient temperature for 12 hours. The
solvent was removed by reduced pressure rotary evaporation.
The residue was dissolved in CH Cl (4.0 mL, 1.5 M) then
(19.67 g, 69%). This procedure was modified from previous
syntheses and spectral data values match those from the
literature. R = 0.69 (hexanes/EtOAc = 5:1) H NMR (400
MHz, CDCl ): δ 5.96–5.86 (m, 1H), 5.30 (dd, J = 17.2, 1.6 Hz,
1
1
6
12
1
f
2
2
3
DMAP (76 mg, 0.62 mmol, 0.10 equiv) and tert-butanol
0.72 mL, 7.5 mmol, 1.3 equiv) were added. A solution of DCC
(1.57 g, 7.3 mmol, 1.2 equiv) in CH Cl (6.0 mL, 1.0 M) was
H), 5.21 (dd, J = 10.4, 1.2 Hz 1H), 4.56 (dt, J = 5.6, 1.6 Hz, 2H)
(
13
.22 (s, 9H) C NMR (101 MHz, CDCl ): δ 178.3, 132.6, 117.6,
3
2
2
–1
5.0, 38.9, 27.3 IR (cm ): 1730, 1280, 1144, 962, 930 ESI-
added to the solution of starting material. The reaction quickly
became cloudy and was stirred for 2 hours more at ambient
temperature. The reaction was filtered through a Celite plug, and
concentrated under reduced pressure by rotary evaporation.
Purification by flash chromatography on silica gel
+
+
HRMS (m/z): [M+H] calc’d for C H O : 143.1067; found:
1
8
15
2
43.1075.
4
.6.2 tert-butyl 11-((2-oxo-1,2,3,4-tetrahydroquinolin-8-
yl)oxy)undecanoate (1b)
(
hexanes/EtOAc = 10:1 to 8:1) afforded the titled compound as a
1
tert-Butyl 11-bromoundecanoate was prepared according to a
white solid (1.42 g, 73%). R = 0.65 (hexanes/EtOAc = 2:1) H
f
13
previously published procedure. To a solution of tert-Butyl
1-bromoundecanoate (321 mg, 1.0 mmol, 1.0 equiv) in DMF
2.0 mL, 0.50 M) was added 7-hydroxy-3,4-dihydroquinolin-
NMR (600 MHz, CDCl ): δ 7.18 (d, J = 8.4 Hz, 2H), 7.04 (d,
3
1
(
2
1
8
J = 8.4 Hz, 2H), 2.90 (t, J = 7.5 Hz, 2H), 2.53 (t, J = 7.8 Hz, 2H),
1
3
1
.41 (s, 18H) C NMR (151 MHz, CDCl ): δ 172.4, 153.0,
3
–1
(1H)-one (163 mg, 1.0 mmol, 1.0 equiv) and K CO (163 mg,
2 3
136.5, 135.6, 128.9, 80.5, 37.3, 30.6, 28.5, 28.2 IR (cm ): 2977,
+
.2 mmol, 1.2 equiv). The mixture was placed into a preheated
0 °C oil bath and stirred for 26 hours. The resulting mixture was
1
727, 1526, 1367, 1236, 1159 ESI-HRMS (m/z): [M+Na]
+
calc’d for C H NaNO : 344.1832; found: 344.1870.
18
27
4
cooled to room temperature and water (50 mL) was added, the
mixture was diluted with EtOAc (80 mL), and the organic phase
was separated. The aqueous phase was extracted with EtOAc
4
.6.5 Lithocholic tert-butyl ester (1e)
This procedure was modified from a previous literature
14
(3 × 40 mL) and the combined organic layers were washed with
report. To a solution of lithocholic acid (1.01 g, 2.7 mmol,
1.0 equiv) in THF (24 mL, 0.12 M) at 0 °C, was added dropwise
trifluoracetic anhydride (3.0 mL, 21 mmol, 7.8 equiv). After
stirring for 1.5 hours at 0 °C, the mixture was treated with
tert-butanol (7.0 mL, 73 mmol, 28 equiv) and let stir at 0 °C for
water (100 mL), brine (100 mL), dried over anhydrous Na SO ,
2
4
filtered, and concentrated under reduced pressure by rotary
evaporation. Purification by flash column chromatography on
silica gel (hexanes/EtOAc = 3:1 to 2:1) afforded the title
compound (258 mg, 64%) as an off-white solid. R = 0.22
f
12 hours. The reaction was neutralized with sat. aq. NH OH
4
1
(hexanes/EtOAc = 2:1) H NMR (400 MHz, CDCl ): δ 7.91 (ad,
3
(5 mL) and let stir at 23°C for 6 hours. The reaction was diluted
1
H), 7.04 (d, J = 8.4 Hz, 1H), 6.51 (dd, J = 8.4, 2.4 Hz, 1H), 6.31
with Et O (20 mL) and washed with aq. 1M NaOH (40 mL),
2
(
(
br s, 1H), 3.91 (t, J = 6.6 Hz, 2H), 2.89 (t, J = 7.6 Hz, 2H), 2.61
t, J = 7.6 Hz, 2H), 2.20 (t, J = 7.4 Hz, 2H), 1.78–1.72 (m, 2H),
water (40 ml), and brine (40 mL). The organic layer was dried
over anhydrous Na SO , filtered, and concentrated under reduced
2
4
1
1
1
2
1
.62–1.55 (m, 2H), 1.44 (s, 9H), 1.44–1.39 (m, 2H), 1.29 (br s,
pressure by rotary evaporation. Recrystallization from hot water
13
0H) C NMR (151 MHz, CDCl ): δ 173.5, 171.7, 158.9, 138.2,
3
gave lithocholic tert-butyl ester (1.03 g, 81%) as a white powder.
1
28.8, 115.7, 108.8, 102.3, 80.1, 68.3, 35.8, 31.3, 29.6, 29.5,
R = 0.32 (hexanes/EtOAc = 3:1) H NMR (600 MHz, CDCl ): δ
f
3
–1
9.5, 29.4, 29.4, 29.2, 28.3, 26.1, 25.2, 24.7 IR (cm ): 2928,
3
(
.63-3.62 (m, 1H), 3.50 (br s, 1H) 2.28–2.23 (m, 1H), 2.15–2.09
m, 1H), 1.96 (dt, J = 12.6, 3.0 Hz, 1H), 1.89–1.72 (m, 5H),
1.67–1.65 (m, 1H), 1.58–1.50 (m, 2H), 1.44 (s, 9H), 1.42–1.36
+
682, 1368, 1265, 1190, 1169 ESI–HRMS (m/z): [M+H] calc’d
+
for C H NO : 388.2846; found: 388.2826.
24
38
3
(
1
m, 6H), 1.36–1.19 (m, 6H), 1.16–1.08 (m, 5H), 1.00–0.94 (m,
1
3
4
.6.3 tert-Butyl 4-(1H-indol-3-yl)butanoate (1c)
H), 0.92 (s, 3H), 0.90 (d, J = 6.6 Hz, 3H), 0.64 (s, 3H).
C
This procedure was modified from a previous literature
NMR (151 MHz, CDCl ): δ 173.9, 80.0, 72.0, 56.6, 56.2, 42.9,
4
28.4, 28.3, 27.4, 26.6, 24.4, 23.5, 21.0, 18.4, 12.2 IR (cm ):
3
2a
report. To a 0 °C solution of 4-(1H-indol-3-yl)butanoic acid
0.989 g, 4.9 mmol, 1.0 equiv) in CH Cl (20.0 mL, 0.25 M) was
2.2, 40.6, 40.3, 36.6, 36.0, 35.5, 35.5, 34.7, 32.7, 31.2, 30.7,
–1
(
2
2

6
Tetrahedron
+
1
2
928, 1729, 1264, 1150. ESI-HRMS (m/z): [
A
M
C
+H
C
]
E
c
P
al
T
c’d
E
f
D
or MA(h
N
ex
7.77–7.75 (m, 2H), 7.51–7.47 (m, 1H), 7.44–7.41 (m, 2H), 6.85
br s, 1H), 3.73 (q, J = 6.0 Hz, 2H), 3.72 (s, 3H), 2.66 (t, J = 6.0
U
ane
S
s
C
/Et
R
O
I
A
P
c = 1:1) H NMR (400 MHz, CDCl ): δ
T
3
+
C H O : 433.3676; found: 433.3699.
28
49
3
(
13
4
.6.6 β-Cbz amino ester (3c)
Hz, 2H) C NMR (101 MHz, CDCl ): δ 173.5, 167.4, 134.5,
3
15
–1
β-Alanine methyl ester (515 mg, 5.0 mmol, 1.0 equiv) was
131.6, 128.7, 127.1, 52.0, 35.4, 33.9 IR (cm ): 3332, 1735,
+
dissolved in a 1:1 mixture of methanol and water (20 mL, 0.25
M) then cooled to 0 °C. NaHCO (1.1 g, 12.5 mmol, 2.5 equiv)
1640, 1536, 1264, 702 ESI-HRMS (m/z): [M+H] calc’d for
C H NO : 208.0968; found: 208.0969.
11 14
+
3
3
was added to the stirred solution, followed by dropwise addition
of CbzCl (2.2 mL, 15.0 mmol, 3.0 equiv). After stirring for
4
.7 Product Characterization
1
0 min at 0 °C, the reaction mixture was removed from the ice
bath, warmed to ambient temperature, and stirred for 12 hours.
The volatile organics were removed by rotary evaporation, the
4.7.1 tert-Butyl (E)-6-hydroxyhex-2-enoate (2a)
The reaction was stirred at 60 °C for 16 hours. 5 mol% of
residue was diluted with EtOAc (30 mL) and sat. aq. NH Cl (50
[Pd(allyl)Cl]2 was used.
Purification by flash column
4
mL), and the organic phase was separated. The aqueous phase
was extracted with EtOAc (2 × 20 mL), and the combined
organic layers were washed with brine (40 mL), dried over
anhydrous Na SO , filtered, and concentrated under reduced
pressure by rotary evaporation. Purification by flash column
chromatography on silica gel (hexanes/EtOAc = 3:1) afforded β-
chromatography on silica gel (hexanes/EtOAc = 6:1 to 1:3)
afforded 2a as a yellow oil (25.8 mg, 69%). R = 0.10
f
(hexanes/EtOAc = 3:1). The spectral data are consistent with
16 1
2
4
those reported in the literature.
H NMR (400 MHz, CDCl ): δ
3
6.90–6.83 (m, 1H), 5.77 (d, J = 15.2 Hz, 1H), 3.68 (br s, 2H),
1
3
2.31–2.25 (m, 2H), 1.76–1.69 (m, 2H), 1.48 (s, 9H) C NMR
amino ester 3c (749 mg, 64%) as a colorless oil. R = 0.20
(101 MHz, CDCl ): δ 166.1, 147.2, 123.6, 80.3, 62.2, 31.1, 28.5,
f
3
1
–1
(
hexanes/EtOAc = 3:1) H NMR (400 MHz, CDCl ): δ 7.38–
28.3 IR (cm ): 1710, 1368, 1264, 1149. ESI-HRMS (m/z):
3
+
+
7
.29 (m, 5H), 5.29 (br s, 1H), 5.09 (s, 2H), 3.68 (s, 3H), 3.47 (q,
[M+H] calc’d for C H O : 187.1329; found: 187.1251.
10 19 3
13
J = 6.0 Hz, 2H), 2.55 (t, J = 6.0 Hz, 2H) C NMR (101 MHz,
CDCl ): δ 172.9, 156.4, 136.6, 128.6, 128.2, 128.2, 66.8, 51.9,
4.7.2 tert-Butyl (E)-11-((2-oxo-1,2,3,4-tetrahydroquinolin-8-
yl)oxy)undec-2-enoate (2b)
3
–1
3
6.7, 34.4 IR (cm ): 3337, 2954, 1720, 1526, 1247, 698 ESI-
+
+
HRMS (m/z): [M+H] calc’d for C H NO : 238.1074; found:
The reaction was stirred at 60 °C for 5 hours. 3.5 equiv
12
16
4
2
38.1071.
LiCyan base were used.
Purification by flash column
chromatography on silica gel (hexanes/ EtOAc = 10:1 to 2:1)
4
.6.7 β-Piv amino ester (3d)
afforded the title product as a white solid (31 mg, 78%).
15
1
β-Alanine methyl ester (515 mg, 5.0 mmol, 1.0 equiv) was
dissolved in CH Cl (20 mL, 0.25 M) and cooled to 0 °C.
Triethylamine (1.1 mL, 7.5 mmol, 1.5 equiv) was added to the
stirred solution followed by dropwise addition of PivCl
R = 0.22 (hexanes/EtOAc = 2:1). H NMR (400 MHz, CDCl3):
f
2
2
δ 8.82 (s, 1H), 7.02 (d, J = 8.0 Hz, 1H), 6.85 (dt, J = 15.6, 7.2 Hz,
1H), 6.51 (dd, J = 8.4, 2.4 Hz, 1H), 6.38 (d, J = 2.4 Hz, 1H), 5.73
(d, J = 15.6 Hz, 1H), 3.91 (t, J = 6.8 Hz, 2H), 2.88 (t, J = 7.6 Hz,
2H), 2.61 (t, J = 6.8 Hz, 2H), 2.16 (q, J = 6.8 Hz, 2H), 1.74 (quin,
(0.80 mL, 6.5 mmol, 1.3 equiv). After stirring for 10 min at 0
13
°
C, the reaction mixture was removed from the ice bath, warmed
J = 7.6 Hz, 2H), 1.47–1.28 (m, 19H) C NMR (101 MHz,
to room temperature, and stirred for 12 hours. The reaction was
stopped by the addition of sat. aq. NH Cl (50 mL), and the
organic phase was separated. The aqueous phase was extracted
with EtOAc (2 × 20 mL) and the combined organic layers were
washed with sat. aq. NaHCO (40 mL), dried over anhydrous
CDCl ): δ 172.3, 166.3, 158.9, 148.2, 138.3, 128.7, 123.0, 115.7,
3
4
108.8, 102.4, 80.1, 68.2, 32.1, 31.2, 29.4, 29.3, 29.2, 28.3, 28.2,
–1
26.1, 24.7 IR (cm ): 2855, 1681, 1368, 1264, 1162 ESI-HRMS
+
+
(m/z): [M+H] calc’d for C H NO : 386.2690; found:
24
36
3
3
386.2371.
Na SO , filtered, and concentrated under reduced pressure by
2
4
rotary evaporation. Purification by flash column chromatography
on silica gel (hexanes/EtOAc = 1:1) afforded β-amino ester 3d
4.7.3 tert-Butyl (E)-4-(1H-indol-3-yl)but-2-enoate (2c)
The reaction was stirred at 90 °C for 12 hours. 5 mol% of
[Pd(allyl)Cl]2 was used. 3.0 equiv of LiCyan were used.
Purification by flash column chromatography on silica gel
(
1
3
673 mg, 72%) as a white solid. R = 0.30 (hexanes/EtOAc =
f
1
:1) H NMR (400 MHz, CDCl ): δ 6.30 (br s, 1H), 3.70 (s, 3H),
3
13
.50 (q, J = 6.0 Hz, 2H), 2.53 (t, J = 6.0 Hz, 2H), 1.18 (s, 9H) C
(hexanes/Et O = 6:1) afforded the product as a pale-yellow solid
2
1
NMR (101 MHz, CDCl ): δ 178.6, 173.5, 51.9, 38.8, 35.0, 33.9,
(39.8 mg, 77%). R = 0.40 (CH Cl ) H NMR (400 MHz,
3
f
2
2
–1
2
7.6 IR (cm ): 3364, 2956, 1740, 1642, 1528, 1174 ESI-HRMS
CDCl ): δ 8.04 (br s, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.38 (d,
3
+
+
(m/z): [M+H] calc’d for C H NO : 188.1281; found: 188.1279.
J = 8.0 Hz, 1H), 7.21 (t, J = 7.6 Hz, 1H), 7.15–7.05 (m, 2H), 7.03
9
18
3
(
s, 1H), 5.79 (d, J = 15.6 Hz, 1H), 3.63 (d, J = 6.4 Hz, 2H), 1.46
13
4
.6.8 β-Benzoyl amino ester (3e)
β-Alanine methyl ester (515 mg, 5.0 mmol, 1.0 equiv) was
(s, 9H) C NMR (151 MHz, CDCl ): δ 166.3, 146.3, 136.4,
127.3, 122.3, 119.7, 119.0, 112.5, 111.3, 80.3, 28.3, 28.1 IR
(cm ): 3410, 1695, 1392, 1264, 1154 ESI-HRMS (m/z): [M+H]
calc’d for C H NO : 258.1489; found: 258.2284.
3
15
–1
+
dissolved in THF (20 mL, 0.25 M) and cooled to 0 °C.
Triethylamine (1.1 mL, 7.5 mmol, 1.5 equiv) was added to the
stirred solution followed by dropwise addition of BzCl (0.76 mL,
+
16
20
2
6
.5 mmol, 1.3 equiv). After stirring for 10 min at 0 °C, the
4.7.4 tert-Butyl (E)-3-(4-((tert-
reaction mixture was removed from the ice bath, warmed to room
temperature, and stirred for 12 hours. The reaction was stopped
butoxycarbonyl)amino)phenyl)acrylate (2d)
The reaction was stirred at 80 °C for 16 hours. 5 mol% of
[Pd(allyl)Cl]2 was used. Purification by flash column
by the addition of sat. aq. NH Cl (50 mL), diluted with EtOAc
4
(15 mL), and the organic phase was separated. The aqueous
chromatography on silica gel (hexanes/Et O = 9:1) afforded the
2
phase was extracted with EtOAc (2 × 20 mL) and the combined
product as an off white solid (50.0 mg, 78%). R = 0.15
f
1
organic layers were washed with sat. aq. NaHCO (40 mL), dried
(hexanes/Et O = 6:1) H NMR (400 MHz, CDCl ): δ 7.52 (d,
3
2
3
over anhydrous Na SO , filtered, and concentrated under reduced
J = 16.0 Hz, 1H) ,7.44 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 8.4 Hz,
2H), 6.56 (s, 1H), 6.27 (d, J = 15.6 Hz, 1H), 1.52 (s, 18H)
2
4
pressure by rotary evaporation. Purification by flash column
chromatography on silica gel (hexanes/EtOAc = 1:1) afforded
13
C NMR (151 MHz, CDCl ): δ 166.7, 152.5, 143.1, 140.1,
3
–
1
β-amino ester 3e (703 mg, 68%) as a white solid. R = 0.31
129.5, 129.1, 118.6, 118.4, 80.5, 28.4, 28.4 IR (cm ): 2977,
f

+
1
705, 1522, 1319, 1149 ESI-HRMS (m/z): [M+Na] calc’d for
4.7.10 Methyl (E)-3-pivalamidoacrylate (4d)
ACCEPTED MANUSCRIPT
+
C H NNaO : 342.1676; found: 342.1649.
Purification by flash column chromatography on silica gel
18
25
4
(hexanes/EtOAc = 13:1) afforded the title product as a light-
4
.7.5 Lithocholic (E)-tert-butylenoate (2e)
The reaction was stirred at 60 °C for 16 hours. Purification by
yellow oil (30.4 mg, 82%). R = 0.23 (hexanes/EtOAc = 11:1)
f
1
H NMR (400 MHz, CDCl ): δ 10.83 (br s, 1H), 7.52 (dd,
3
flash column chromatography on silica gel (hexanes/Et O 3:1)
J = 10.8, 8.8 Hz, 1H), 5.15 (d, J = 8.8 Hz, 1H), 3.73 (s, 3H), 1.27
2
13
afforded the product as a white foam (64.8 mg, 77%). R = 0.32
(s, 9H) C NMR (101 MHz, CDCl ): δ 177.0, 170.0, 139.2,
f
3
1
–1
(
hexanes/EtOAc = 3:1) H NMR (400 MHz, CDCl ): δ 6.72 (dd,
96.0, 51.4, 39.4, 27.3 IR (cm ): 3340, 2963, 1683, 1622, 1378,
3
+
J = 15.6, 8.8 Hz, 1H), 5.64 (d, J = 15.6 Hz, 1H), 3.66–3.59 (m,
1201, 1154, 805, 703 ESI-HRMS (m/z): [M+H] calc’d for
+
1
1
3
1
3
1
H), 2.27–2.19 (m, 1H), 1.96–1.93 (m, 1H), 1.97–1.65 (m, 6H),
.48 (s, 9H), 1.44–1.18 (m, 15H), 1.07–1.05 (m, 5H), 0.92 (s,
C H NO : 186.1125; found: 186.1126.
9
16
3
13
H), 0.67 (s, 3H) C NMR (101 MHz, CDCl ): δ 166.7, 153.7,
4.7.11 Methyl (E)-3-benzamidoacrylate (4e)
Purification by flash column chromatography on silica gel
(hexanes/EtOAc = 13:1) afforded the title product as a white
3
20.7, 80.1, 72.0, 56.5, 55.3, 43.1, 42.2, 40.6, 40.2, 39.7, 36.6,
6.0, 35.5, 34.7, 30.7, 28.4, 28.3, 27.3, 26.5, 24.4, 23.5, 20.9,
–1
9.4, 12.4 IR (cm ): 2928, 1713, 1366, 1151 ESI-HRMS (m/z):
solid (30.8 mg, 75%). R = 0.20 (hexanes/EtOAc = 11:1). The
f
+
+
20
[
M+H] calc’d for C H O : 431.3520; found: 431.3531.
spectral data are consistent with those reported in the literature.
H NMR (500 MHz, CDCl ): δ 11.47 (br s, 1H), 7.95 (d, J = 7.5
28
47
3
1
3
4
.7.6 tert-Butyl (E)-3-(4-hydroxyphenyl)acrylate) (2f)
The reaction was stirred at 80 °C for 16 hours. Purification by
Hz, 2H), 7.75 (dd, J = 11.0, 8.5 Hz, 1H), 7.58 (t, J = 7.5 Hz, 1H),
7.50 (t, J = 7.5 Hz, 2H), 5.27 (d, J = 8.5 Hz, 1H), 3.77 (s, 3H)
13
flash column chromatography on silica gel (hexanes/ Et O = 5:1)
afforded the product as a pale-yellow oil (33.1 mg, 75%). The
spectral data are consistent with those reported in the literature.
R = 0.31 (hexanes/EtOAc = 3:1) H NMR (400 MHz, CDCl ): δ
C NMR (126 MHz, CDCl ): δ 170.1, 164.6, 139.1, 133.0,
3
–1
2
132.3, 129.0, 127.8, 96.8, 51.5 IR (cm ): 3332, 2950, 1682,
17
+
1619, 1378, 1180, 805, 694 ESI-HRMS (m/z): [M+H] calc’d for
1
+
C H NO : 206.0812; found: 206.0811.
f
3
11 12
3
7
.53 (d, J = 16.0 Hz, 1H), 7.42 (d, J = 8.4 Hz, 2H), 6.82 (d,
J = 8.8 Hz, 2H), 6.23 (d, J = 16.0 Hz, 1H), 5.36 (br s, 1H), 1.53
13
Acknowledgments
(
1
2
s, 9H) C NMR (101 MHz, CDCl ): δ 157.3, 143.3, 129.9,
3
–1
17.9, 115.9, 110.2, 80.5, 31.7, 31.4, 29.9, 28.4, 22.8 , IR (cm ):
977, 1674, 1604, 1514, 1264, 1146, ESI-HRMS (m/z):
Yale University, Nalas Engineering, and the National Science
Foundation (CAREER, 1653793) are acknowledged for financial
support.
+
+
[
M+Na] calc’d for C H NaNO : 243.0992; found: 243.1012.
13 16 3
4
.7.7 Methyl (E)-3-((tert-butoxycarbonyl)amino)acrylate (4a)
Purification by flash column chromatography on silica gel
References and notes
1
.
For reviews on carbonyl dehydrogenation see: (a) Muzart, J. Eur.
J. Org. Chem. 2010, 3779−3790. (b) Stahl, S. S.; Diao, T. Comp.
Org. Synth. 2014, 7, 178−212. (c) Turlik, A.; Chen, Y.;
Newhouse, T. R. Synlett 2016, 27, 331−336. (d) Iosub, A. V.;
Stahl, S. S. ACS Catal. 2016, 6, 8201−8213.
(hexanes/EtOAc = 11:1) afforded the title product as a light-
yellow oil (32.6 mg, 81%). The spectral data are consistent with
those reported in the literature. R = 0.50 (hexanes/EtOAc =
18
f
1
7
1
:1) H NMR (400 MHz, CDCl ): δ 9.58 (br s, 1H), 7.23 (t, J =
3
2
.
For carbonyl dehydrogenations published in our group: (a) Chen,
Y.; Romaire, J.; Newhouse, T. R. J. Am. Chem. Soc. 2015, 137,
0.4 Hz, 1H), 5.00 (d, J = 8.8 Hz, 1H), 3.70 (s, 3H), 1.48 (s, 9H)
13
C NMR (101 MHz, CDCl ): δ 169.6, 152.3, 140.6, 93.6, 82.1,
3
5
875−5878. (b) Chen, Y.; Turlik, A.; Newhouse, T. R. J. Am.
–1
5
1
2
1.2, 28.2 IR (cm ): 3342, 2980, 1740, 1689, 1634, 1380, 1211,
Chem. Soc. 2016, 138, 1166−1169. (c) Zhao, Y.; Chen, Y.;
Newhouse, T. R. Angew. Chem. Int. Ed. 2017, 56, 13122–13125.
(d) Chen, Y.; Huang, D.; Zhao, Y.; Newhouse, T. R. Angew.
Chem. Int. Ed. 2017, 56, 8258–8262. (e) Huang, D.; Zhao, Y.;
Newhouse, T. R. Org. Lett. 2018, 20, 684–687.
+
+
147, 802 ESI-HRMS (m/z): [M+H] calc’d for C H NO :
9
16
4
02.1074; found: 202.1078.
4
.7.8 Methyl (E)-3-(dibenzylamino)acrylate (4b)
3
.
For some examples of Pd-catalyzed alcohol oxidation see: (a)
Ferreira, E. M.; Stoltz, B. M. J. Am. Chem. Soc. 2001, 123,
7725–7726. (b) Stahl, S. S. Angew. Chem. Int. Ed. 2004, 43,
3400–3420. (c) Sigman, M. S.; Jensen, D. R. Acc. Chem. Res.
Purification by flash column chromatography on silica gel
hexanes/EtOAc = 5:1) afforded the title product as a pale-yellow
solid (30.9 mg, 55%). The spectral data are consistent with those
(
19
2
006, 39, 221–229.
reported in the literature.
R = 0.22 (hexanes/EtOAc = 5:1)
f
1
4. For an early report of Pd-catalyzed imine formation: Yoshimura,
N.; Moritani, I.; Shimamura, T.; Murahashi, S. I. J. Am. Chem.
Soc. 1973, 95, 3038–3039.
5. Collins, K. D.; Glorius, F. Nat. Chem. 2013, 5, 597–601.
6. (a) Cole, D. C. Tetrehedron 1994, 50, 9517–9582. (b) Martinek,
T.; Bernáth, G.; Fülöp, F. Synth. Commun. 1998, 28, 219–224.
7. For an example of dehydrogenation of β-amino ketones see:
Murahashi, S.; Mitsue, Y.; Tsumiyama, T. Bull. Chem. Soc. Jpn.,
H NMR (400 MHz, CDCl ): δ 7.81 (d, J = 13.2 Hz, 1H),
3
7
.36–7.28 (m, 6H), 7.18–7.16 (m, 4H), 4.80 (d, J = 13.2 Hz, 1H),
13
4
1
1
.30 (s, 4H), 3.67 (s, 3H) C NMR (101 MHz, CDCl ): δ 170.3,
3
–1
52.9, 136.1, 128.9, 127.9, 127.6, 85.6, 50.7 IR (cm ): 2946,
+
688, 1609, 1350, 1142, 791, 698 ESI-HRMS (m/z): [M+H]
+
calc’d for C H NO : 282.1489; found: 282.1488.
18
20
2
1
987, 60, 3285–3290.
4
.7.9 Methyl (E)-3-(((benzyloxy)carbonyl)amino)acrylate (4c)
8
.
Larock, R. C.; Leach, D. R. J. Org. Chem. 1984, 49, 2144–2148.
Purification by flash column chromatography on silica gel
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(
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f
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3
1
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m, 5H), 7.28 (t, J = 10.0 Hz, 1H), 5.22 (s, 2H), 5.07 (d, J = 8.4
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13
Hz, 1H), 3.71 (s, 3H) C NMR (101 MHz, CDCl ): δ 169.3,
3
1
(
53.4, 140.2, 135.4, 128.7, 128.7, 128.4, 94.9, 68.1, 51.3 IR
–1
cm ): 3326, 2952, 1740, 1686, 1632, 1392, 1174, 697 ESI-
+
+
HRMS (m/z): [M+H] calc’d for C H NO : 236.0917; found:
12
14
4
2
36.0914.
1
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8
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Supplementary material
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