1,1-Diacyloxy-1-phenylmethanes as versatile N-acylating agents for amines

Article abstract of DOI:10.1016/j.tet.2018.05.044

1,1-Diacyloxy-1-phenylmethanes and 1-pivaloxy-1-acyloxy-1-phenylmethanes have been used as bench stable N-acylating reagents for primary and secondary amines and anilines under solvent-free conditions to afford their corresponding amides in good yield.

Full text of DOI:10.1016/j.tet.2018.05.044

Accepted Manuscript
1,1-Diacyloxy-1-phenylmethanes as versatile N-acylating agents for amines
Robert. S.L. Chapman, Joshua. D. Tibbetts, Steven. D. Bull
PII:
S0040-4020(18)30579-9
10.1016/j.tet.2018.05.044
TET 29551
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 19 February 2018
Revised Date: 15 May 2018
Accepted Date: 16 May 2018
Please cite this article as: Chapman RSL, Tibbetts JD, Bull SD, 1,1-Diacyloxy-1-phenylmethanes as
versatile N-acylating agents for amines, Tetrahedron (2018), doi: 10.1016/j.tet.2018.05.044.
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1,1-Diacyloxy-1-Phenylmethanes as Versatile
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N-Acylating Agents for Amines
Robert. S. L. Chapman, Joshua. D. Tibbetts, Steven. D. Bull*

ACCEPTED MANUSCRIPT
1,1-Diacyloxy-1-Phenylmethanes as Versatile N-Acylating Agents for
Amines
Robert. S. L. Chapman, Joshua. D. Tibbetts, Steven. D. Bull*
Department of Chemistry, University of Bath, Bath, BA27AY, UK.
KEYWORDS (Word Style “BG_Keywords”). If you are submitting your paper to a journal that requires
keywords, provide significant keywords to aid the reader in literature retrieval.
ABSTRACT: 1,1-Diacyloxy-1-phenylmethanes and 1-pivaloxy-1-acyloxy-1-phenylmethanes have
been used as bench stable N-acylating reagents for primary and secondary amines and anilines under
solvent-free
conditions
to
afford
their
corresponding
amides
in
good
yield.
N-Acylation reactions of primary and secondary
amines are important transformations in organic
chemistry, because they provide direct access to
the highly versatile amide group.1 The amide
bond occurs widely throughout nature and is pre-
sent in many drug molecules, which means that
N-acylation reactions are some of the most wide-
ly carried out transformations.2 Consequently a
range of synthetic protocols have been developed
that employ different reagents for N-acylation,
many of which are used in the presence of cata-
lysts to increase their rate of reaction.2,3 For ex-
ample, acyl chlorides are commonly employed as
acylating agents for amines, often in conjunction
with acyl transfer catalysts (e.g. DMAP), or Lew-
is acid catalysts.2 However, there are problems
associated with using acid chlorides, because
they are volatile, moisture-sensitive and easily
hydrolyzed, whilst their reactions with amines
are often exothermic and produce HCl as a by-
product that can cause problems in the presence
of acid sensitive functional groups.4 Therefore, a
range of alternative N-acylating reagents and
conditions have been developed to address these
problems,5 most notably the use of stoichiometric
coupling agents (e.g. DCC) for peptide synthe-
sis.6 A range of N-acylating reagents for direct
reaction with amines have also been developed
for amide bond formation, including N-acyl ben-
zotriazoles,4 N-acyl DBN.BPh4 salts,7 and 2-acyl-
pyridazin-3-ones.8 Given this precedent, we now
report herein that 1,1-acylals may be used as
moisture tolerant N-acylating agents for amines
and also demonstrate how mixed 1-pivaloxy-1-
acyloxy-1-phenylmethanes 10a-h can be used as
selective N-acyl transfer agents.
We have recently reported that formyloxyacetox-
yphenylmethane 1 can be used as a versatile N-
formylating reagent for amines under solvent free
conditions, with exclusive transfer of its O-
formyl group occurring over its O-acetyl group
(Scheme 1a).9 We reasoned that 1,1-acylals10
containing identical O-acyl groups might also
function as useful reagents for the N-acylation of
amines. A review of the literature revealed a sin-
gle report where ethylidenene diacetate 2 had
been used to N-acylate aniline under non-optimal
conditions, to afford N-acetyl-acetanilide in 57%
yield (Scheme 1b).11 In this non-optimal proto-
col, aniline was reacted with ethylidene acetate in
ether at rt for 1 h, with acetaldehyde and solvent
then being removed by passing air through the
reaction mixture for 1 h to afford a mixture that
was fractionally distilled to afford acetic acid and
acetanilide.11
Given this precedent, we decided to carry out a
full investigation into the potential of using ben-
zylidene diacetate (BDA) 3 as an acylating agent
for amines.12 BDA 3 was chosen as an N-
acylating agent to avoid potential side reactions
that can arise from competing elimination reac-
tions of acetate groups from 1,1-diacylals such as

ACCEPTED MANUSCRIPT
ethylidene diacetate 2 that would afford unwant-
ed vinyl acetates.
Table 1. Optimization of the N-acetylation reac-
tions of benzylamine using BDA 3 as an acyl
donor.
Scheme 1: (a) Formyloxyacetoxyphenylmethane
1 as an N-formylating agent for amines. (b)
Ethylidene diacetate 2 as an N-acetylating rea-
gent for aniline.11 (c) Synthesis of benzylidene
diacetate (BDA) 3
Time
(h)
Temp
(°C)
Entry Solvent
4a:5
50:50
1
2
EtOAc
2
rt
rt
toluene
2
48:52
51:49
53:47
51:49
52:48
65:35
95:5
3
CH2Cl2
2
rt
4
-
2
rt
5
-
16
16
16
16
16
16
16
rt
6a
-
-
rt
BDA 3 was prepared in 95% yield via treatment
of benzaldehyde and acetic anhydride with a cat-
alytic amount of para-toluene sulfonic acid (p-
TSA) (Scheme 1c).13 Initial treatment of 1 equiv.
of benzylamine with 1.5 equiv. of BDA 3 in
EtOAc, at rt for 2h resulted in formation of a
50:50 mixture of the desired N-benzyl acetamide
4a and N-benzylidenebenzylamine 5 (Table 1,
Entry 1). A solvent screen was then carried out to
identify conditions that would suppress compet-
ing formation of imine 5. Repeating the acetyla-
tion reaction in toluene or CH2Cl2, gave similar
results, affording essentially 50:50 mixtures of
acetamide 4a and imine 5 (Table 1, Entries 2-3).
Reaction of benzylamine with 1.5 or 5 equiv. of
BDA 3 under solvent free conditions for 2 or 16
h also gave equimolar mixtures of acetamide 4a
and imine 5 (Table 1, Entries 4-6). However,
using 1.5 equiv. of BDA 3 under solvent free
conditions at 50 oC gave a 65:35 ratio of acetam-
ide 4a:imine 5 after 16 h (Table 1, Entry 7). Fi-
nally, carrying out the acetylation reaction of
benzylamine at 70 °C for 16 h gave a 95:5 ratio
in favor of the desired acetamide 4a (Table 1,
Entry 8). A solvent screen revealed that EtOAc,
toluene and CHCl3 could also be used as cosol-
vents where necessary, affording >90:10 ratio of
acetamide 4a to imine 5 in each case.
7
50
70
70
70
70
8
-
9
EtOAc
toluene
CHCl3
90:10
94:6
10
11
92:8
Product ratios determined from integrals of diag-
1
nostic resonances for 4a and 5 in H NMR spec-
a
tra of crude reaction products. 5 equiv. of BDA
3 used.
Sampling the solvent free acetylation reactions of
benzylamine using 1.5 equiv. of BDA 3 at 70 °C
over time, revealed that the pH of the reaction
mixture remained neutral around pH 7.0 until the
majority of benzylamine had been consumed.
After this time, the reaction mixture became
more acidic (pH 3.0). This study also revealed
that all the benzylamine was consumed after 1 h
affording a 60:40 ratio of acetamide 4a to imine
5 which gradually increased to a ratio of 95:5 in
favor of amide 4a over the next 15 h. A plausible
mechanism (Figure 1) to explain these observa-
tions, involves irreversible reaction of benzyla-
mine with one of the acetyl groups of BDA 3 to
afford acetamide 4a, with benzaldehyde and ace-
tic acid being formed as by-products. The ben-
zaldehyde produced may then react with benzyl-
amine in a reversible manner to competitively
afford imine 5. The acetic acid by-product may
4

ACCEPTED MANUSCRIPT
also react with benzylamine to afford ben-
62% yield, with no acetylation of its indole nitro-
gen occurring. Sterically hindered benzhydryla-
mine gave its corresponding acetamide 4d in
70% yield, whilst acyclic and cyclic secondary
amines were acetylated to give 88-95% yields of
the acetamides 4e-h, respectively. Pleasingly,
electron-deficient aniline and its secondary N-
methyl analogue gave their corresponding acet-
amides 4i-j in 60-68% yields, with acetylation of
electron deficient methyl para-aminobenzoate
affording acetamide 4k in 65% yield after 24 h.
The selectivity of BDA 3 for N-acetylation over
zylammonium acetate 6, which can act as a buff-
er to maintain neutrality in the initial stages of
the acetylation reaction. Since formation of ben-
zylammonium acetate 6 is reversible, equilibra-
tion may occur to regenerate benzylamine and
acetic acid, which results in all the benzylamine
eventually being consumed to afford a 60:40
mixture of acetamide 4a and imine 5 after 1 h.
This equilibration process results in a gradual
decrease in the amount of benzylammonium ace-
tate 6 present over time, that coincides with a
proportional increase in the amount of acetic acid
present. Overall, this results in a decrease in
buffering capacity (decrease in benzylammonium
acetate 6) and a decrease in pH (increase in acetic
acid) of the reaction mixture as it proceeds be-
yond 1 h. The reversible nature of the acid-
catalysed imine bond forming reaction, results in
gradual regeneration of benzylamine, that can
then react irreversibly with BDA 3 to drive the
equilibria towards acetamide 4a formation. This
results in gradual conversion of imine 5 into ac-
etamide 4a over time, as witnessed by the change
in ratio of acetamide 4a to imine 5 from 60:40 (1
h) to 95:5 (16 h).
O-acetylation was confirmed via treatment of
serine methyl ester with 1.5 equiv. of BDA 3 at
70 °C for 16 h to afford N-acetyl- -serine methyl
L-
L
ester 4l in 83% yield, with no evidence of any
competing O-acetylation, or racemization having
occurred. For example, N-acetylation of (S)-α-
methylbenzylamine
gave
(S)-N-(1-
phenylethyl)acetamide 4m in 89% yield which
gave an [α]D25 of -143 (c 1.0, EtOH), which com-
pared favorably with the value previously report-
ed for (S)-4m (>99% ee) of -145 (c 1.0, EtOH)
thus indicating that no racemisation had oc-
curred.14a Furthermore, N-acetylation of the me-
thyl ester of dipeptide L-Leu-L-Leu proceeded in
65% yield, with only a single diastereomer (S,S)-
4n being present in the H NMR spectra of the
crude reaction product. This means that this N-
acylation reaction proceeds without epimeriza-
tion and that reversible formation of the ben-
Figure 1. Plausible mechanism for N-acetylation
of benzylamine using BDA 3 as an acetyl donor.
1
zylimine of
L-Leu-L-Leu proceeds in a racemiza-
tion free manner.
Our attention then turned to investigating the
potential of using other 1,1-acylals as reagents
for the N-acylation of benzylamine with different
acyl donors. Treatment of benzaldehyde with a
range of acid anhydrides in the presence of a cat-
alytic amount of PTSA for 12 h gave their corre-
sponding 1,1-acylals 7a-f in excellent 90-97%
yield after chromatographic purification (Scheme
3). Synthesis of highly reactive trifluoroacetyl
1,1-diacylal 7f required use of 10 mol% of tri-
fluoroacetic acid as catalyst for 12 h, which was
used immediately without purification, due to its
sensitivity to hydrolysis that led to rapid decom-
position on standing.
With optimized conditions in hand, a range of
primary and secondary amines were reacted with
1.5 equiv. of BDA 3 under solvent free condi-
o
tions at 70 C for 16 h which afforded fourteen
acetamides 4a-n in 60-95% isolated yields
(Scheme 2). Most of these N- formylation reac-
tions were carried out under solvent-free condi-
tions, however, toluene was employed as a sol-
vent where the parent amine was insoluble in
neat BDA 3. Crude amide products could be pu-
rified directly via chromatography, without the
need for any aqueous work up. The primary
amines benzylamine and 4-aminomethyl-pyridine
were N-acetylated to afford acetamides 4a-b in
84% and 86% yields respectively, whilst trypta-
mine was N-acetylated to afford acetamide 4c in
5

ACCEPTED MANUSCRIPT
Scheme 3. Synthesis of a range of 1,1-acylals 7a-
f
Scheme 2: BDA 3 as an N-acetylating agent for
primary and secondary amines.
a
Reaction conditions; 1 equiv. benzaldehyde, 1.5
equiv. acid anhydride, 10mol%, 70 °C, 16 h.
b
pTSA. 1 equiv. benzaldehyde, 1.5 equiv. acid
anhydride, 10mol% TFA, rt, 1 h.
These 1,1-diacylal reagents 7a-e were then used
to N-acylate benzylamine at 70 oC for 16 h with a
range of acyl, benzoyl, and acryloyl groups being
transferred under solvent free conditions to give
five N-acyl benzylamides 8a-e in 79-96% yield
respectively (Scheme 4). The 1,1-trifluoroacylal
reagent 7f proved to be much more reactive, with
trifluoroacetylation of benzylamine proceeding to
completion at rt after only 1 h to afford N-
trifluoroacetyl-benzylamide 8f in 91% yield
(Scheme 4).
We next decided to investigate whether mixed 1-
pivaloxy-1-acyloxy-1-phenylmethanes 10 could
be used as selective N-acyl donors for amines. It
was reasoned that the steric demand of the pivalic
acid group of a mixed 1-pivaloxy-1-acyloxy-1-
phenylmethane 10 would prevent nucleophilic
attack at its proximal carbonyl, thus ensuring that
selective transfer of its donor acyl group would
occur. This would avoid the wastage of one
equivalent of the acylating group that occurs
when symmetric 1,1-acylals 3, 7 are used as N-
acylating reagents. In order to prepare these rea-
gents, benzaldehyde was first treated with 1.5
equiv. of pivaloyl chloride, in the presence of a
catalytic amount of p-TSA to afford chlo-
ro(phenyl)methyl pivalate 9,15 that was then re-
acted immediately with a series of carboxylic
acids and Et3N in acetone at 40 °C to afford eight
mixed 1-pivaloxy-1-acyloxy-1-phenylmethanes
10a-h in 70-89% yield (Scheme 5).16
Reaction conditions: 1 mmol of amine, 1.5 equiv.
a
BDA 3, 16 h, 70 °C. Toluene employed as sol-
vent. b24 h reaction time.
6

ACCEPTED MANUSCRIPT
thyl ester to afford amides 8j-l with retention of
configuration. The ω-amino group of α-N-Fmoc-
-lysine could also be acylated using 10b to af-
ford amide (S)-8l in 70% yield, thus highlighting
the potential of this type of 1,1-acylal for carry-
ing out N-acylation reactions on sensitive sub-
strates under racemization free conditions.
Scheme 4. N-acylation reactions of benzylamine
with 1,1-acylals 7a-f to afford N-acyl benzyla-
mides 8a-f
L
Scheme 6. N-acylation reactions of 1-pivaloxy-1-
acyloxy-1-phenylmethanes 10a-h to afford N-
acyl amides 4a, 8a, 8c, 8e, 8g-l
a
Reaction conditions: 1 mmol of amine, 1.5
b
equiv. 1,1-acylal 7a-e, 16 h, 70 °C. 1 mmol of
amine, 1.5 equiv. acylal 7f, rt, 1 h.
Scheme 5. Synthesis of mixed 1-pivaloxy-1-
acyloxy-1-phenylmethanes 10a-h
These
mixed
1-pivaloxy-1-acyloxy-1-
In conclusion, we have shown that bench stable
1,1-diacylals can be used as moisture-tolerant N-
acylating reagents for primary and secondary
amines and anilines under solvent-free condi-
tions, affording their corresponding acetamides in
good yields. This N-acylation methodology has
been further extended to enable mixed pivaloyl
1,1-acylals to be used as more efficient N-
acylating agents for the selective transfer of do-
nor acyl groups to a wide range of amines.
phenylmethanes 10a-h were then used to N-
acylate a range of primary amines to give ten
amides 4a, 8a, 8c, 8e, 8g-l in 60-86% yield
(Scheme 6). Pleasingly, no evidence of any prod-
ucts arising from pivaloyl transfer were detected
1
in the H NMR spectra of the crude products of
any of these reactions. Mixed pivaloyl acylals
could be used for the N-acylation of (S)-α-
methylbenzylamine and (S)-phenylalanine me-
7

ACCEPTED MANUSCRIPT
General Procedures General Procedure A: N-
acetylation of amines
EXPERIMENTAL SECTION
General conditions
Amine (1.0 mmol) was added to phenyl-
methylene diacetate 3 (0.291 g, 1.5 mmol) and
the reaction stirred at 70 °C for 16 h. The crude
reaction product was then purified by silica gel
chromatography to give the desired acetamide. In
those cases, where the reaction mixture was not
homogeneous, then 2 mL of EtOAc or toluene
were added as cosolvent at the start of the reac-
tion. These reactions were worked-up by remov-
ing the cosolvent in vacuo, followed by purifica-
tion of the crude reaction product by chromatog-
raphy.
Unless preparative details are given, reagents and
solvents were obtained from commercial suppli-
ers. All reactions were performed without air
exclusion, at room temperature and with magnet-
ic stirring unless otherwise stated. Anhydrous
MgSO4 or Na2SO4 were used as drying agents for
organic solutions. Petrol refers to petroleum ether
with a boiling range of 40-60 °C. Thin layer
chromatography (TLC) was carried out on Ma-
cherey-Nagel aluminium-backed plates that were
precoated with silica. Compounds were visual-
ised by quenching of UV fluorescence at 254 nm
or by staining with potassium permanganate,
phosphomolybdic acid (PMA) or vanillin dip
followed by gentle heating. Purification by flash
column chromatography was performed using
high-purity grade 60 Å silica gel (60 Å pore size,
40-75 ꢀm particle size). Capillary melting points
were determined using a Stuart digital SMP10
melting point apparatus and are reported to the
nearest °C. An Optical Activity Ltd AA-10 Se-
ries Automatic Polarimeter with a path length of
1 dm was used to measure optical rotations, with
concentration (c) quoted in g/100 mL. Nuclear
Magnetic Resonance (NMR) spectroscopy exper-
iments were performed in deuterated solvent at
298 K on either a Brüker Avance 250, 300, 400
or 500 MHz spectrometer or an Agilent ProPulse
500 MHz spectrometer, with proton decoupling
General Procedure B: Synthesis of acylals
para-Toluenesulfonic acid (mono hydrate) (0.18
g, 0.94 mmol) was added to a mixture of benzal-
dehyde (1.0 g, 9.4 mmol) and anhydride (18.8
mmol) at rt. The reaction was stirred for 12 h and
then diluted with Et2O (50 mL) and washed with
saturated Na2CO3 (3 x 20 mL). The organics
were dried (MgSO4) and concentrated in vacuo to
give the title compound which was used without
further purification unless stated otherwise.
General Procedure C: N-acylation of amines
Amine (1.0 mmol) was added to the acylating
reagent (1.5 mmol) and the reaction stirred at 70
°C for 16 h. The crude reaction product was then
purified by silica gel chromatography to give the
desired amide.
1
13
used for all 13C NMR spectra. H and C NMR
chemical shifts, δ, are quoted in parts per million
(ppm) and where possible are referenced against
the residual, non-deuterated solvent peak. A
PerkinElmer Spectrum 100 FTIR spectrometer
with Universal ATR FTIR accessory was used to
record infrared (IR) spectra; with samples run
neat and the most relevant, characteristic absorb-
ances quoted as ν in cm-1. High resolution mass
spectrometry (HRMS) results were acquired on
an externally calibrated Bruker Daltonics micrO-
TOFTM time-of-flight mass spectrometer coupled
to an electrospray source (ESI-TOF). Molecular
ions were detected in positive mode as either the
protonated or sodiated form, with Bruker Dalton-
ics software, DataAnalysisTM used to process the
data.
General Procedure D: Synthesis of mixed ac-
ylals
Trimethylacetyl chloride (0.813 mL, 6.60 mmol)
was added dropwise to a mixture of benzalde-
hyde (0.489 g, 4.40 mmol) and para-
toluenesulfonic acid (0.083 g, 0.44 mmol) at rt
and the reaction mixture stirred for 3 h. The reac-
tion was then quenched via addition of saturated
NaHCO3(aq) (10 mL) and diluted with Et2O (50
mL). The reaction was then extracted with satu-
rated NaHCO3(aq) (3 x 20 mL), the organic layer
dried (MgSO4) and concentrated in vacuo to af-
ford chloro(phenyl)methyl pivalate (1.0 g, 4.40
mmol) as a yellow oil that was used without fur-
ther purification. Triethylamine (0.60 mL, 4.40
mmol) was added dropwise to a solution of chlo-
8

ACCEPTED MANUSCRIPT
ro(phenyl)methyl pivalate (4.40 mmol) and car-
raphy [EtOAc] to give the title compound as a
pale brown solid in 62% yield (0.125 g, 0.62
boxylic acid (4.40 mmol) in acetone (10 mL).
The reaction was stirred at 40 °C for 12 h during
which time a white ppt formed. The reaction
product was then filtered through celite® and
concentrated in vacuo to afford a crude reaction
product that was purified by silica gel chroma-
tography (5% EtOAc in pet ether) to give the title
compound.
1
mmol). m.p. 76-78 °C (lit.21 77-78°C) H NMR
(300 MHz, CDCl3) δ 8.16 (s, 1H, NH), 7.61 (ddt,
J = 7.8, 1.5, 0.8 Hz, 1H, ArH), 7.39 (dt, J = 8.1,
1.0 Hz, 1H, ArH), 7.22 (ddd, J = 8.2, 7.0, 1.3 Hz,
1H, ArH), 7.13 (ddd, J = 8.1, 7.1, 1.2 Hz, 1H,
ArH), 7.06 – 7.03 (m, 1H, ArH), 5.54 (s, 1H,
NH), 3.60 (q, J = 6.5 Hz, 2H, CH2CH2NH), 2.98
(td, J = 6.7, 0.9 Hz, 2H, CH2CH2NH), 1.92 (s,
3H, CH3). 13C NMR (75 MHz, CDCl3) δ 170.2,
136.5, 127.5, 122.4, 122.2, 119.7, 118.8, 113.1,
111.4, 77.4, 39.9, 25.4, 23.6.
Phenylmethylene diacetate 315
General procedure B was followed to afford the
title compound as a clear oil in 98% yield (1.92
1
N-Benzhydrylacetamide 4d22
g, 9.21 mmol). H NMR (300 MHz, CDCl3) δ
7.68 (s, 1H, CH(OAc)2), 7.55 – 7.48 (m, 2H,
ArH), 7.46 – 7.37 (m, 3H. ArH), 2.13 (s, 6H, 2 x
CH3). 13C NMR (75 MHz, CDCl3) δ 169.0,
135.6, 129.9, 128.8, 126.8, 89.8, 21.0. I.R (thin-
film) νmax (cm-1): 2981 (ArC-H), 1746 (C=O);
HRMS (ESI): m/z calculated for C11H12O4: re-
quires: 231.0633 for [M+Na]+; found: 231.0683.
General procedure A was followed to afford a
crude product that was purified by chromatog-
raphy [CH2Cl2:EtOAc (80:20] to afford the title
compound as a crystalline white solid in 70%
yield (0.158 g, 0.70 mmol). m.p. 148-150 °C
(lit.23 151 °C) 1H NMR (300 MHz, CDCl3) δ 7.32
(qt, J = 6.2, 1.8 Hz, 5H, ArH), 7.30 – 7.18 (m,
5H, ArH), 6.26 (d, J = 8.0 Hz, 1H, CH), 6.04 (s,
1H, NH), 2.08 (s, 3H, CH3). 13C NMR (75 MHz,
CDCl3) δ 169.2, 141.6, 128.8, 127.6, 127.5, 57.1,
23.6.
N-Benzylacetamide 4a17
General procedure A was followed to afford a
crude product that was purified by chromatog-
raphy [CH2Cl2:EtOAc (70:30)] to afford the title
compound as a cream solid in 86% yield (0.128
g, 0.86 mmol). m.p. 61-62 °C (lit.18 61-62 °C).
1H NMR (300 MHz, CDCl3); δ 7.39 – 7.21 (m,
5H, ArH), 5.89 (s, 1H, NH), 4.42 (d, J = 5.7 Hz,
2H, CH2), 2.01 (s, 3H, CH3). 13C NMR (75 MHz,
CDCl3) δ 170.0, 138.3, 128.8, 128.0, 127.7, 43.9,
23.4.
N,N-Dibutylacetamide 4e24
General procedure A was followed to afford a
crude product that was purified by chromatog-
raphy [CH2Cl2:EtOAc (70:30)] to afford the title
compound as a clear oil in 90% yield (0.154 g,
1
0.90 mmol). H NMR (300 MHz, CDCl3) δ 3.33
– 3.24 (m, 2H, NCH2), 3.23 – 3.15 (m, 2H,
NCH2), 2.06 (s, 3H, CH3), 1.49 (dddd, J = 15.2,
9.2, 7.8, 5.4 Hz, 4H, CH2CH2CH2), 1.30 (hept, J
= 7.4 Hz, 4H, CH2CH2CH3), 0.92 (dt, J = 10.0,
7.3 Hz, 6H, 2x CH2CH3). 13C NMR (75 MHz,
CDCl3) δ 170.2, 48.7, 45.6, 31.1, 30.0, 21.7,
20.4, 20.2, 14.0, 14.0.
N-(Pyridin-4-ylmethyl)acetamide 4b19
General procedure A was followed to afford a
crude product that was purified by chromatog-
raphy [CH2Cl2:EtOAc:Et3N (70:29:1)] to afford
the title compound as an orange oil in 84% yield
1
(0.126 g, 0.84 mmol). H NMR (300 MHz,
N,N-Diallylacetamide 4f24
CDCl3) δ 8.58 – 8.48 (m, 2H, ArH), 7.22 – 7.14
(m, 2H, ArH), 6.07 (s, 1H, NH), 4.44 (d, J = 6.1
Hz, 2H, CH2), 2.07 (s, 3H, CH3). 13C NMR (75
MHz, CDCl3) δ 170.4, 150.1, 147.5, 122.4, 42.6,
23.3.
General procedure A was followed to afford a
crude product that was purified by chromatog-
raphy [CH2Cl2:EtOAc (70:30)] to afford the title
compound as a yellow oil in 88% yield (0.122 g,
N-(2-(1H-Indol-3-yl)ethyl)acetamide 4c20
1
0.88 mmol). H NMR (300 MHz, CDCl3) δ 5.86
– 5.64 (m, 2H, CH=CH2), 5.25 – 5.04 (m, 4H,
CH=CH2), 3.98 (dt, J = 6.1, 1.4 Hz, 2H,
General procedure A was followed to afford a
crude product that was purified by chromatog-
9

ACCEPTED MANUSCRIPT
NCHaHb), 3.86 (dt, J = 4.9, 1.8 Hz, 2H,
1H, ArH), 7.23 – 7.15 (m, 2H, ArH), 3.27 (s, 3H,
NCH3), 1.87 (s, 3H, CH3). 13C NMR (75 MHz,
CDCl3) δ 170.7, 144.7, 129.9, 127.8, 127.2, 37.3,
22.6.
NCHaHb), 2.09 (s, 3H, CH3).13C NMR (75 MHz,
CDCl3) δ 170.8, 133.4, 132.7, 117.4, 116.7, 50.1,
47.9, 21.5.
1-(Piperidin-1-yl)ethanone 4g17
Methyl 4-acetamidobenzoate 4k29
General procedure A was followed to afford a
crude product that was purified by chromatog-
raphy [CH2Cl2:EtOAc (80:20)] to afford the title
compound as a yellow oil in 95% yield (0.121 g,
General procedure A was followed to afford a
crude product that was purified by chromatog-
raphy [CH2Cl2:EtOAc (70:30)] to afford the title
compound as a pale yellow solid in 65% yield
(0.126 g, 0.65 mmol). m.p. 126-128 °C (lit.30 128
1
0.95 mmol). H NMR (300 MHz, CDCl3) δ 3.59
1
– 3.49 (m, 2H, NCHAX), 3.38 (dd, J = 6.2, 4.6
Hz, 2H, NCHEQ), 2.07 (s, 3H, CH3), 1.71 – 1.43
(m, 6H, CH2CH2CH2). 13C NMR (75 MHz,
CDCl3) δ 168.9, 47.6, 42.6, 26.6, 25.6, 24.6,
21.7.
°C). H NMR (300 MHz, CDCl3) δ 8.08 – 7.92
(m, 2H, ArH), 7.59 (d, J = 8.4 Hz, 2H, ArH),
7.42 (s, 1H, NH), 3.90 (s, 3H, CO2CH3), 2.21 (s,
3H, CH3). 13C NMR (75 MHz, CDCl3) δ 168.6,
166.7, 142.2, 131.0, 125.7, 118.8, 52.2, 25.0.
1-(4-Methylpiperazin-1-yl)ethanone 4h25
(S)-Methyl 2-acetamido-3-hydroxypropanoate 4l
General procedure A was followed to afford a
crude product that was purified by chromatog-
raphy [CH2Cl2:EtOAc (70:30)] to afford the title
compound as a yellow oil in 92% yield (0.131 g,
Et3N (0.42 mL, 3.21 mmol) was added in a
dropwise manner to a stirred suspension of serine
methyl ester hydrochloride salt (0.5 g, 3.21
mmol) in acetone (3 mL). The reaction mixture
was stirred for 10 min, filtered through a Celite®
pad, and the filtrate concentrated in vacuo to give
serine methyl ester which was used as a substrate
for N-acylation without further purification.
1
0.92 mmol). H NMR (300 MHz, CDCl3) δ 3.69
– 3.58 (m, 2H, AcNCHAX), 3.51 – 3.42 (m, 2H,
AcNCHEQ), 2.38 (dt, J = 10.0, 5.2 Hz, 4H,
CH2NCH3), 2.30 (s, 3H, CH2NCH3), 2.08 (s, 3H,
(C=O)CH3). 13C NMR (75 MHz, CDCl3) δ 169.1,
55.2, 54.7, 46.3, 46.1, 41.4, 21.5.
General procedure A was followed to afford a
crude product that was purified by chromatog-
raphy [CH2Cl2:MeOH (95:5)] Eluent 5% to af-
ford the title compound as a brown oil in 83%
yield (0.428 g, 2.56 mmol), [α]D20 = -9.5 MeOH;
1H NMR (500 MHz, CDCl3) δ 6.52 (s, 1H, NH),
4.67 (dt, J = 7.3, 3.6 Hz, 1H, CHNH), 3.95 (qd, J
= 11.2, 3.6 Hz, 2H, CH2OH), 3.79 (s, 3H, OCH3),
2.80 (s, 1H, OH), 2.07 (s, 3H, (C=O)CH3), 13C
NMR (126 MHz, CDCl3) δ 171.1, 170.8, 63.6,
N-Phenylacetamide 4i17
General procedure A was followed to afford a
crude product that was purified by chromatog-
raphy [CH2Cl2:EtOAc (80:20)] to afford the title
compound as a pale yellow solid in 68% yield
(0.92 g, 0.68 mmol). m.p. 114-115 °C (lit.26 114-
1
115 °C). H NMR (300 MHz, CDCl3) δ 7.54 –
20
7.45 (m, 2H, ArH), 7.32 (t, J = 7.9 Hz, 2H, ArH),
7.15 – 7.06 (m, 1H, ArH), 2.18 (s, 3H, CH3). 13C
NMR (75 MHz, CDCl3) δ 168.4, 138.0, 129.2,
124.5, 119.9, 24.8.
54.9, 52.9, 23.3. [α]D = -9.5 in MeOH. I.R
(thinfilm) νmax (cm-1): 3291 ((C=O)NH and OH),
1738, 1648 (C=O); HRMS (ESI): m/z calculated
for C6H11NO4: requires: 162.0766 for [M+H]+;
found: 162.0788.
N-Methyl-N-phenylacetamide 4j27
(S)-N-(1-phenylethyl)acetamide 4m
General procedure A was followed to afford a
crude product that was purified by chromatog-
raphy [CH2Cl2:EtOAc (70:30)] to afford the title
compound as a pale green solid in 60% yield
(0.089 g, 0.60 mmol). m.p. 100-102 °C (lit.28
General procedure A was followed to afford a
crude product that was purified by chromatog-
raphy [CH2Cl2:EtOAc (60:40)] to afford the title
compound as a white solid in 89% yield (0.145 g,
1
20
0.89 mmol). [α]D = -143 (c 1.0, EtOH) (lit.14a
101-102 °C). H NMR (300 MHz, CDCl3) δ 7.42
(dd, J = 8.3, 6.5 Hz, 2H, ArH), 7.37 – 7.30 (m,
20
[α]D = -145 (c 1.0, EtOH), >99% ee). m.p. 97-
10

ACCEPTED MANUSCRIPT
1
99 °C (lit.14b 99-100 °C). H NMR (300 MHz,
CDCl3); δ 7.39 – 7.26 (m, 5H, ArH), 5.67 (s, 1H,
NH), 5.23 – 5.03 (m, 1H, CHN), 1.99 (s, 3H.
CH3), 1.49 (d, J = 6.9 Hz, 3H, PhCHCH3). 13C
NMR (75 MHz, CDCl3) δ 169.2, 143.2, 128.8,
127.6, 126.4, 48.94, 23.7, 21.8.
ArH), 2.37 (td, J = 7.4, 2.3 Hz, 4H, 2 x
(C=O)CH2CH2), 1.70 – 1.58 (m, 4H, 2 x
(C=O)CH2CH2), 1.30 (dq, J = 7.2, 3.7, 3.3 Hz,
8H, 2 x (C=O)CH2CH2), 0.94 – 0.82 (m, 6H, 2 x
CH2CH2CH3). 13C NMR (75 MHz, Chloroform-
d) δ 171.8, 135.9, 129.8, 128.7, 126.8, 89.6, 34.2,
31.3, 24.5, 22.4, 14.0. I.R (thinfilm) νmax (cm-1):
2956 (ArC-H), 1752 (C=O); HRMS (ESI): m/z
calculated for C19H28O4: requires: 343.1885 for
[M+Na]+; found: 343.1898.
N-acetyl-L,L-leucyl-leucine methyl ester 4n
General procedure C was followed to afford a
crude product was purified by chromatography
[petroleum ether:EtOAc (90:10)] to give the title
compound as a white solid (0.189g, 0.63 mmol)
in 63% yield. m.p. 99 - 101 °C, [α]D = -52 (c
1.0, CHCl3). H NMR (500 MHz, CDCl3) δ =
6.39 (d, 1H, J = 8.0 Hz, 1H, NH), 5.96 (d, 1H, J
= 8.0 Hz, NH), 4.59 – 4.55 (m, 1H, NCH), 4.50-
4.55 (m, 1H, NCH), 3.73 (s, 3H, OCH3), 2.00 (s,
3H, C(=O)CH3), 1.63 – 1.49 (m, 6H, 2CH2 and
Phenylmethylene bis(2-phenylacetate) 7c
20
General procedure B was followed to afford the
title compound as a clear oil in a 94% yield (3.18
1
1
g, 8.84 mmol). H NMR (250 MHz, CDCl3) δ
7.69 (s, 1H, CHPh), 7.43 – 7.16 (m, 15H, ArH),
3.64 (s, 4H, 2 x CH2Ph). 13C NMR (75 MHz,
CDCl3) δ 169.5, 135.3, 133.2, 129.9, 129.5,
129.4, 128.7, 127.4, 126.7, 90.3, 41.1. I.R (thin-
film) νmax (cm-1): 3032, 2981 (ArC-H), 1759
(C=O); HRMS (ESI): m/z calculated for
C23H20O4: requires: 383.1259 for [M+Na]+;
found: 383.1259.
2CH2CH(CH3)2), 0.95
–
0.91 (m, 12H,
2CH(CH3)2) . 13C NMR (126 MHz, CDCl3) δ =
173.2, 172.0, 170.2, 52.5, 51.7, 50.9, 41.5, 41.3,
25.0, 24.9, 23.3, 23.0, 22.9, 22.4, 22.0. I.R (thin-
film) νmax (cm-1): 3275, 3072, 2957, 1749 (C=O
ester), 1643 (C=O amide), 1547 (C=O amide).
HRMS (ESI): m/z calculated for C15H28N2O4:
requires: 323.1941 for [M+Na]+; found:
323.1941.
Phenylmethylene dibenzoate 7d31
General procedure B was followed to afford the
title compound as a clear oil in 99% yield (3.09
1
Phenylmethylene dipropionate 7a31
g, 9.30 mmol). H NMR (300 MHz, CDCl3) δ
8.25 – 8.06 (m, 5H, CH and ArH), 7.75 – 7.64
(m, 3H, ArH), 7.62 – 7.50 (m, 4H, ArH), 7.49 –
7.40 (m, 4H, ArH). 13C NMR (75 MHz, CDCl3) δ
164.6, 162.5, 134.7, 133.7, 130.7, 130.2, 129.9,
129.2, 129.0, 128.9, 128.6, 126.9, 90.8. I.R (thin-
film) νmax (cm-1): 3064 (ArC-H), 1722 (C=O);
HRMS (ESI): m/z calculated for C21H16O4: re-
quires: 355.0946 for [M+Na]+; found: 355.0929.
General procedure B was followed to afford the
title compound as a clear oil in 97% yield (2.15
g, 9.12 mmol).1H NMR (300 MHz, CDCl3) δ
7.71 (s, 1H, CH(OCOEt)2), 7.51 (qd, J = 3.8, 1.5
Hz, 2H, ArH), 7.41 (ddt, J = 4.3, 3.1, 1.6 Hz, 3H,
ArH), 2.40 (tt, J = 7.4, 3.6 Hz, 4H, 2 x CH2CH3),
13
1.16 (t, J = 7.5 Hz, 6H, 2 x CH2CH3). C NMR
(75 MHz, Chloroform-d) δ 172.47, 135.81,
129.80, 128.72, 126.78, 89.72, 27.55, 8.89. I.R
(thinfilm) νmax (cm-1): 2983 (ArC-H), 1756
(C=O); HRMS (ESI): m/z calculated for
C13H12O4: requires: 259.0946 for [M+Na]+;
found: 259.0995.
Phenylmethylene diacrylate 7e
General procedure B was followed to afford the
title compound as a clear oil in 97% yield (2.12
g, 9.12 mmol). 1H NMR (300 MHz, Chloroform-
d) δ 7.87 (s, 1H, CHPh), 7.65 – 7.48 (m, 2H,
ArH), 7.51 – 7.36 (m, 3H, ArH), 6.52 (dd, J =
17.3, 1.4 Hz, 2H, CHaHb=CH), 6.27 – 6.03 (m,
2H, CHaHb=CH), 5.93 (dd, J = 10.5, 1.3 Hz, 2H,
Phenylmethylene dihexanoate 7b32
General procedure B was followed to afford the
title compound as a clear oil in 96% yield (2.89
g, 9.02 mmol). 1H NMR (300 MHz, Chloroform-
d) δ 7.71 (s, 1H, CHPh), 7.51 (qd, J = 3.7, 1.5
Hz, 2H, ArH), 7.40 (ddt, J = 4.2, 3.1, 1.6 Hz, 3H,
13
CHaHb=CH). C NMR (75 MHz, Chloroform-d)
δ 164.0, 134.8, 132.8, 129.9, 128.8, 127.6, 126.8,
90.1. I.R (thinfilm) νmax (cm-1): 3040 (ArC-H),
1732 (C=O); HRMS (ESI): m/z calculated for
11

ACCEPTED MANUSCRIPT
C13H12O4: requires: 255.0633 for [M+Na]+;
found: 255.0667.
raphy [CH2Cl2:EtOAc (70:30)] to give the title
compound as a pale brown solid in a 79% yield
(0.178 g, 0.79 mmol). m.p. 120-122 °C (lit.37
121-123 °C). 1H NMR (300 MHz, CDCl3) δ 7.26
(s, 8H, ArH), 7.22 – 7.13 (m, 2H, ArH), 5.69 (s,
1H, NH), 4.42 (d, J = 5.8 Hz, 2H, PhCH2NH),
3.64 (s, 2H, PhCH2). 13C NMR (75 MHz, CDCl3)
δ 171.0, 138.2, 134.9, 129.6, 129.2, 128.8, 127.6,
127.6, 44.0, 43.7.
Phenylmethylene bis(2,2,2-trifluoroacetate) 7f
Trifluoroacetic acid (0.035 mL, 0.47 mmol) was
added in a dropwise manner to a solution of ben-
zaldehyde (0.50 g, 4.7 mmol) and trifluoroacetic
anhydride (0.98 mL, 7.08 mmol) at rt. After 2 h,
the reaction was concentrated in vacuo to give
the title compound as a yellow oil in 95% yield
(1.4 g, 4.5 mmol). 1H NMR (300 MHz, CDCl3) δ
7.79 (s, 1H, ArH), 7.62 – 7.45 (m, 5H, ArH). 13C
NMR (75 MHz, CDCl3) δ 155.3 (q, 2JC-F = 44.7
N-Benzylbenzamide 8d33
General procedure C was followed to afford a
crude product that was purified by chromatog-
raphy [CH2Cl2:EtOAc (70:30)] to give the title
compound as a cream solid in 87% yield (0.184
g, 0.87 mmol). m.p. 105-106 °C (lit.38 105.8-
1
Hz), 134.4, 131.8, 129.4, 127.0, 114.1 (q, JC-F
= 285.5 Hz), 93.8. I.R (thinfilm) νmax (cm-1):
1809 (C=O)
1
106.2 °C). H NMR (300 MHz, CDCl3) δ 7.84 –
N-Benzylpropionamide 8a33
7.68 (m, 2H, ArH), 7.56 – 7.28 (m, 8H, ArH),
6.40 (s, 1H, NH), 4.66 (d, J = 5.6 Hz, 2H.
CH2Ph). 13C NMR (75 MHz, CDCl3) δ 167.5,
138.3, 134.5, 131.7, 129.0, 128.8, 128.1, 127.8,
127.1, 44.3.
General procedure C was followed to afford a
crude product that was purified by chromatog-
raphy [CH2Cl2:EtOAc (70:30)] to give the title
compound as a fluffy white solid in 95% yield
(0.155 g, 0.95 mmol). m.p. 49-50 °C (lit.34 49-50
N-Benzylacrylamide 8e39
1
°C). H NMR (300 MHz, CDCl3) δ 7.39 – 7.22
(m, 5H, ArH), 5.80 (s, 1H, NH), 4.43 (d, J = 5.7
Hz, 2H, CH2Ph), 2.24 (q, J = 7.6 Hz, 2H,
CH2CH3), 1.18 (t, J = 7.6 Hz, 3H, CH2CH3). C
NMR (75 MHz, CDCl3) δ 173.7, 138.5, 128.8,
128.0, 127.6, 43.7, 29.8, 10.0.
General procedure C was followed. to afford a
crude product that was purified by chromatog-
raphy [CH2Cl2:EtOAc (70:30)] to give the title
compound as a cream solid in 96% yield (0.154
g, 0.96 mmol). m.p. 58-59 °C (lit.40 58-59 °C).
1H NMR (300 MHz, CDCl3) δ 7.40 – 7.27 (m,
5H, ArH), 6.33 (dd, J = 16.9, 1.5 Hz, 1H,
CH=CHaHb), 6.11 (dd, J = 17.0, 10.2 Hz, 1H,
CH=CHaHb), 5.88 (s, 1H, NH), 5.67 (dd, J =
10.2, 1.5 Hz, 1H, CH=CHaHb), 4.52 (d, J = 5.8
Hz, 2H, CH2Ph). 13C NMR (75 MHz, CDCl3) δ
165.5, 138.1, 130.7, 128.9, 128.7, 128.7, 128.1,
128.0, 127.8, 127.0, 126.8, 43.8.
13
N-Benzylhexanamide 8b35
General procedure C was followed to afford a
crude product that was purified by chromatog-
raphy [CH2Cl2:EtOAc (70:30)] to give the title
compound as a white solid in 91% yield (0.186 g,
1
0.91 mmol). m.p. 53-55 °C (lit.36 54-55 °C). H
NMR (300 MHz, CDCl3) δ 7.39 – 7.26 (m, 5H,
ArH), 5.68 (s, 1H, NH), 4.45 (d, J = 5.7 Hz, 2H,
CH2Ph), 2.21 (dd, J = 8.6, 6.7 Hz, 2H,
(C=O)CH2CH2CH2), 1.73 – 1.60 (m, 2H,
(C=O)CH2CH2CH2), 1.32 (dq, J = 7.2, 3.8, 3.2
Hz, 4H, (C=O)CH2CH2CH2CH2), 0.95 – 0.83 (m,
3H, CH3). 13C NMR (75 MHz, CDCl3) δ 173.1,
138.5, 128.9, 128.0, 127.7, 43.7, 37.0, 31.6, 25.6,
22.6, 14.1.
N-Benzyl-2,2,2-trifluoroacetamide 8f41
Benzylamine (0.107 g, 1.0 mmol) was added to
phenylmethylene-
bis(2,2,2-trifluoroacetate)
(0.474 g, 1.5 mmol) and the reaction mixture
stirred at rt for 1 h. The crude reaction product
was then purified by chromatography
[CH2Cl2:EtOAc (70:30)] to give the title com-
pound as a white solid in 91% yield (0.184 g,
N-Benzyl-2-phenylacetamide 8c35
1
0.91 mmol). m.p. 74-76 °C (lit.42 75-76 °C). H
NMR (300 MHz, CDCl3) δ 7.43 – 7.33 (m, 3H,
ArH), 7.32 – 7.27 (m, 2H, ArH), 6.63 (s, 1H,
General procedure C was followed to afford a
crude product that was purified by chromatog-
12

ACCEPTED MANUSCRIPT
NH), 4.53 (d, J = 5.8 Hz, 2H, CH2). 13C NMR
HRMS (ESI): m/z calculated for C15H20O4: re-
quires: 287.1254 for [M+Na]+; found: 287.1268.
2
(75 MHz, CDCl3) δ 157.3 (q, JC-F = 37.2 Hz),
1
135.9, 129.1, 128.4, 128.1, 116.0 (q, JC-F =
Phenyl(pivaloyloxy)methyl acrylate 10d
287.8 Hz), 44.0.
General procedure D was followed to afford a
crude product that was purified by chromatog-
raphy [Petroleum ether:EtOAc (95:5)] to give the
title compound as a clear oil in 82% yield (0.94
g, 3.61 mmol). 1H NMR (300 MHz, Chloroform-
d) δ 7.8 (s, 1H, OCHO), 7.6 – 7.5 (m, 2H, ArH),
7.5 – 7.4 (m, 3H, ArH), 6.5 (dd, J = 17.3, 1.4 Hz,
1H, CH=CHaHb), 6.2 (dd, J = 17.3, 10.4 Hz, 1H,
CH=CHaHb), 5.9 (dd, J = 10.4, 1.4 Hz, 1H,
CH=CHaHb), 1.2 (s, 9H, C(CH3)3). 13C NMR (75
MHz, Chloroform-d) δ 176.4, 164.1, 135.8,
132.6, 129.8, 128.7, 127.7, 126.7, 90.0, 39.0,
27.0. I.R (thinfilm) νmax (cm-1): 2975, 2875 (ArC-
H), 1744 (C=O); HRMS (ESI): m/z calculated for
C15H18O4: requires: 285.1097 for [M+Na]+;
found: 285.1149.
Acetoxy(phenyl)methyl pivalate 10a
General procedure D was followed to afford a
crude product that was purified by chromatog-
raphy [Petroleum ether:EtOAc (95:5)] to give the
title compound as a clear oil in 89% yield (0.97
1
g, 3.92 mmol). H NMR (300 MHz, CDCl3)) δ
7.7 (s, 1H, OCHO), 7.6 – 7.4 (m, 2H, ArH), 7.5 –
7.3 (m, 3H, ArH), 2.1 (s, 3H, C(O)CH3), 1.2 (s,
13
9H, C(O)C(CH3)3). C NMR (75 MHz, CDCl3))
δ 176.4, 169.1, 135.8, 129.7, 128.7, 126.7, 89.9,
39.0, 27.0, 21.1. I.R (thin film) νmax (cm-1): 1745
(C=O). HRMS (ESI): m/z calculated for
C14H18O4: requires: 273.11027 for [M+Na]+;
found: 273.1103.
Phenyl(2-phenylacetoxy)methyl pivalate 10b
Phenyl(pivaloyloxy)methyl benzoate 10e
General procedure D was followed to afford a
crude product that was purified by chromatog-
raphy [Petroleum ether:EtOAc (95:5)] to give the
title compound as a clear oil in 84% yield (1.20
g, 3.69 mmol). 1H NMR (300 MHz, Chloroform-
d) δ 7.7 (s, 1H, OCHO), 7.5 – 7.4 (m, 2H, ArH),
7.5 – 7.3 (m, 3H, ArH), 7.4 – 7.2 (m, 5H, ArH),
3.7 (s, 2H, CH2Ph), 1.2 (s, 9H, C(CH3)3). 13C
NMR (75 MHz, Chloroform-d) δ 176.3, 169.6,
135.7, 133.4, 129.7, 129.4, 128.7, 128.7, 127.4,
126.6, 90.0, 41.3, 38.9, 27.0. I.R (thinfilm) νmax
(cm-1): 2995, 2983 (ArC-H), 1769, 1756 (C=O);
HRMS (ESI): m/z calculated for C20H22O4: re-
quires: 349.1410 for [M+Na]+; found: 349.1473.
General procedure D was followed to afford a
crude product that was purified by chromatog-
raphy [Petroleum ether:EtOAc (95:5)] to give the
title compound as a colourless oil (0.874 g, 2.80
mmol) in 70% yield. 1H NMR (500 MHz, CDCl3)
δ = 8.08 (d, J = 7.3 Hz, 2H, ArH), 7.94 (s, 1H,
CHPh), 7.61 – 7.42 (m, 8H, ArH), 1.25 (s, 9H,
3xCH3). 13C NMR (125 MHz, CDCl3) δ = 176.4,
164.6, 136.0, 133.6, 130.1, 129.7, 129.4, 128.8,
128.6, 126.7, 90.4, 77.4, 77.2, 76.9, 39.1, 27.0.
I.R (thin film) νmax (cm-1): 1732 (C=O). HRMS
(ESI): m/z calculated for C19H20O4: requires:
335.1254 for [M+Na]+; found: 335.1270.
Phenyl(propionyloxy)methyl pivalate 10c
Phenyl(pivaloyloxy)methyl cinnamate 10f
General procedure D was followed to afford a
crude product that was purified by chromatog-
raphy [Petroleum ether:EtOAc (95:5)] to give the
title compound as a clear oil a 82% yield (0.95 g,
3.62 mmol).1H NMR (300 MHz, Chloroform-d)
δ 7.7 (s, 1H, OCHO), 7.5 – 7.4 (m, 2H, ArH), 7.4
– 7.4 (m, 3H, ArH), 2.4 (qd, J = 7.5, 3.0 Hz, 2H,
CH2CH3), 1.2 (s, 9H, C(CH3)3), 1.2 (t, J = 7.5
Hz, 3H, CH2CH3). 13C NMR (75 MHz, Chloro-
form-d) δ 176.4, 172.5, 135.9, 129.7, 128.7,
126.7, 89.8, 39.0, 27.6, 27.0, 9.0. I.R (thinfilm)
νmax (cm-1): 2978 (ArC-H), 1754, 1750 (C=O);
General procedure D was followed and the crude
product was purified by column chromatography
(petroleum ether : ethyl acetate (95:5), Rf = 0.45)
to give the title compound as a white solid (0.950
g, 2.81 mmol) in 70% yield. 1H NMR (500 MHz,
CDCl3) δ = 7.82 (s, 1H, CHPh), 7.77 (d, J = 16.0
Hz, 1H, CH=CHPh), 7.58 – 7.52 (m, 4H, ArH),
7.45 – 7.38 (m, 6H, ArH), 6.47 (d, J = 16.0 Hz,
1H, CH=CHPh), 1.26 (s, 9H, 3xCH3). 13C NMR
(125 MHz, CDCl3) δ = 176.4, 164.9, 146.6,
136.1, 134.3, 130.8, 129.7, 129.1, 128.7, 128.4,
126.7, 117.2, 90.0, 39.0, 27.1. I.R (thin film) νmax
13

ACCEPTED MANUSCRIPT
(cm-1): 1743 (C=O), 1712 (C=O). HRMS (ESI):
142.2, 140.0, 137.7, 131.3, 128.9, 128.4, 128.3,
m/z calculated for C21H22O4: requires: 361.1410
127.9, 92.6, 44.4.
for [M+Na]+; found: 361.1436.
(S)-N-(1-Phenylethyl)propionamide 8h44
Phenyl(pivaloyloxy)methyl 2-iodobenzoate 10g
General procedure C was followed to afford a
crude product that was purified by chromatog-
raphy [Petroleum ether:EtOAc (60:40)] to give
the title compound as a white solid (0.128 g, 0.73
General procedure D was followed to afford a
crude product that was purified by chromatog-
raphy [Petroleum ether:EtOAc (95:5)] to give the
title compound as a colourless oil (1.276 g, 2.91
mmol) in 73% yield. 1H NMR (500 MHz, CDCl3)
δ = 8.01 (d, J = 8.0 Hz, 1H, ArH), 7.90 (s, 1H,
CHPh), 7.82 (d, J = 8.0 Hz, 1H, ArH), 7.62 –
7.60 (m, 2H, ArH), 7.45 – 7.15 (m, 4H, ArH),
7.16 (t, J = 7.4 Hz, 1H, ArH), 1.27 (s, 9H,
3xCH3). 13C NMR (125 MHz, CDCl3) δ = 176.3,
164.4, 141.7, 135.6, 134.1, 133.2, 131.5, 129.9,
128.8, 128.1, 126.9, 94.5, 90.9, 39.1, 27.1. I.R
(thin film) νmax (cm-1): 1747 (C=O). HRMS
(ESI): m/z calculated for C19H19O4I: requires:
461.0220 for [M+Na]+; found: 461.0250.
20
mmol) in 73% yield. [α]D = -136 (c 1.0,
CHCl3); 1H NMR (500 MHz, CDCl3) δ = 7.35 –
7.25 (m, 5H, ArH), 5.65 (s, 1H, NH), 5.16 (app.
quin., J = 7.0 Hz, 1H, CHN), 2.24 – 2.17 (m, 2H,
CH2), 1.49 (d, J = 6.9 Hz, 3H, PhCHCH3), 1.15
(t, J = 7.6 Hz, 3H, CH2CH3). 13C NMR (125
MHz, CDCl3) δ = 172.9, 143.4, 128.8, 127.5,
126.3, 48.7, 30.0, 21.9, 9.9.
(S)-N-(1-Phenylethyl)hexanamide 8i
General procedure C was followed to afford a
crude product that was purified by chromatog-
raphy [Petroleum ether:EtOAc (60:40)] to give
the title compound as a pale yellow oil (0.136 g,
Phenyl(pivaloyloxy)methyl hexanoate 10h
20
General procedure D was followed to afford a
crude product that was purified by chromatog-
raphy [Petroleum ether:EtOAc (95:5)] to give the
title compound as a colourless oil (0.875 g, 2.86
mmol) in 71% yield. 1H NMR (500 MHz, CDCl3)
δ = 7.68 (s, 1H, CHPh), 7.51 – 7.39 (m, 5H,
ArH), 2.42 – 2.31 (m, 2H, C(=O)CH2), 1.64 (app
quin., J = 7.1, 2H, C(=O)CH2CH2), 1.32 – 1.29
(m, 4H, C(=O)CH2CH2CH2CH2), 1.23 (s, 9H,
3xCH3), 0.88 (t, J = 7.0 Hz, 3H, CH3) . 13C NMR
(125 MHz, CDCl3) δ = 176.4, 171.9, 136.0,
129.7, 128.7, 126.7, 89.7, 39.0, 34.3, 31.3, 27.0,
24.6, 22.4, 14.0. I.R (thin film) νmax (cm-1): 1752
(C=O). HRMS (ESI): m/z calculated for
C18H26O4: requires: 329.1723 for [M+Na]+;
found: 329.1746.
0.62 mmol) in 62% yield. [α]D = -61 (c 1.0,
1
EtOH). H NMR (500 MHz, CDCl3) δ = 7.28 –
7.17 (m, 5H, ArH), 5.63 (s, 1H, NH), 5.07 (app.
quin., J = 7.2 Hz, 1H, CHPh), 2.09 (t, J = 7.4
Hz, 2H, C(=O)CH2), 1.56 (app quin., J = 7.4, 2H,
C(=O)CH2CH2), 1.41 (d, J = 7.0 Hz, 3H,
CHCH3),
1.26
–
1.20
(m,
4H,
C(=O)CH2CH2CH2CH2), 0.81 (t, J = 7.0 Hz, 3H,
CH2CH3) . 13C NMR (125 MHz, CDCl3) δ =
172.3, 143.4, 128.8, 127.5, 126.3, 48.7, 37.0,
31.6, 25.6, 22.5, 21.8, 14.1. I.R (thin film) νmax
(cm-1): 1634 (C=O amide). HRMS (ESI): m/z
calculated for C14H21NO: requires: 242.1515 for
[M+Na]+; found: 242.1523
Methyl cinnamoyl-L-phenylalaninate 8j
N-Benzyl-2-iodobenzamide 8g43
General procedure C was followed to afford a
crude product that was purified by chromatog-
raphy [Petroleum ether:EtOAc (70:30)] to give
the title compound as a brown oil (0.194 g, 0.63
mmol) in 63% yield. [α]D20 = +60 (c 1.0, CHCl3);
1H NMR (500 MHz, CDCl3) δ = 7.64 (d, J = 15.6
Hz, 1H, CH=CHPh), 7.51 – 7.49 (m, 2H, ArH),
7.38 – 7.35 (m, 3H, ArH), 7.31 – 7.25 (m, 3H,
ArH), 7.13 – 7.11 (m, 2H, ArH), 6.39 (d, J =
15.6 Hz, 1H, CH=CHPh), 6.07 (d, J = 7.5 Hz,
1H, NH), 5.04 (m, 1H, CHN), 3.76 (s, 3H, CH3),
General procedure C was followed to afford a
crude product that was purified by chromatog-
raphy [Petroleum ether:EtOAc (70:30)] to give
the title compound as a white solid (0.202g, 0.60
mmol) in 60% yield. 1H NMR (500 MHz, CDCl3)
δ = 7.85 (d, J = 8.0 Hz, 1H, ArH), 7.41 – 7.30
(m, 7H, ArH), 7.09 (td, J = 7.5, 1.8 Hz, 1H,
ArH), 6.07 (s, 1H, NH), 4.63 (d, J = 5.8 Hz, 2H,
CH2). 13C NMR (125 MHz, CDCl3) δ = 169.3,
14

ACCEPTED MANUSCRIPT
3.22 (m, 2H, CH2Ph). 13C NMR (125 MHz,
29.1, 22.5. I.R (thin film) νmax (cm-1): 1738,
1690, 1638 (C=O). HRMS (ESI): m/z calculated
for C30H32N2O5: requires: 501.2384 for [M+H]+;
found: 501.2442.
CDCl3) δ = 172.2, 165.4, 142.0, 136.0, 134.8,
130.0, 129.5, 129.0, 128.8, 128.0, 127.3, 120.1,
53.4, 52.5, 38.1. I.R (thin film) νmax (cm-1): 1739
(C=O ester), 1655 (C=O amide). HRMS (ESI):
m/z calculated for C19H19NO3: requires:
310.1438 for [M+H]+; found: 310.1437.
ASSOCIATED CONTENT
Methyl benzoyl-L
-phenylalaninate 8k45
Complete experimental procedure and relevant
1
spectra (13C and H NMR spectra) for all com-
General procedure C was followed to afford a
crude product that was purified by chromatog-
raphy [Petroleum ether:EtOAc (70:30)] to give
the title compound as a yellow oil (0.181 g, 0.64
mmol) in 64% yield. [α] D20 = +65 (c 1.0, CHCl3);
1H NMR (500 MHz, CDCl3) δ = 7.74 – 7.71 (m,
2H, ArH), 7.51 – 7.41 (m, 3H, ArH), 7.31 – 7.25
(m, 3H, ArH), 7.15 – 7.12 (m, 2H, ArH), 6.57 (d,
J = 6.5 Hz, 1H, NH), 5.10 (m, 1H, CHN), 3.77 (s,
pounds.
AUTHOR INFORMATION
Corresponding Author
*E.mail:s.d.bull@bath.ac.uk
Notes
The authors declare no competing financial inter-
est.
13
3H, CH3), 3.26 (m, 2H, CH2Ph). C NMR (125
ACKNOWLEDGMENT
MHz, CDCl3) δ = 172.2, 167.0, 136.0, 134.0,
131.9, 129.5, 128.8, 127.3, 127.1, 53.7, 52.6,
38.1.
We thank the EPSRC and the Centre for Doctoral
Training in Sustainable Chemical Technologies
(EP/L016354/1) for funding.
(S)-Methyl
2-((((9H-fluoren-9-
yl)methoxy)carbonyl)amino)-6-(2-
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16