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Direct Synthesis of Amides from Carboxylic Acids and Amines Using

B(OCH2CF3)3
Rachel M. Lanigan, Pavel Starkov, and Tom D. Sheppard*
Department of Chemistry, University College London, Christopher Ingold Laboratories, 20 Gordon St, London, WC1H 0AJ, U.K.
S Supporting Information
*

ABSTRACT: B(OCH2CF3)3, prepared from readily available

B2O3 and 2,2,2-triuoroethanol, is as an eective reagent for the
direct amidation of a variety of carboxylic acids with a broad
range of amines. In most cases, the amide products can be
puried by a simple ltration procedure using commercially
available resins, with no need for aqueous workup or
chromatography. The amidation of N-protected amino acids
with both primary and secondary amines proceeds eectively,
with very low levels of racemization. B(OCH2CF3)3 can also be
used for the formylation of a range of amines in good to
excellent yield, via transamidation of dimethylformamide.

INTRODUCTION
The amide bond is widely prevalent in both naturally occurring
and synthetic compounds. It is increasingly important in
pharmaceutical chemistry, being present in 25% of available
drugs, with amidation reactions being among the most
commonly used reactions in medicinal chemistry. There is
considerable interest in the development of new approaches to
direct amidation,1,2 and organizations such as the ACS Green
Chemistry Institute Pharmaceutical Roundtable have indicated
that amide bond formation is one of the most important
reactions used in industry for which better reagents are
required.3 Although there are a large range of reagents and
strategies for amide bond formation available,4 few can really be
considered ideal. Currently there is a focus on the development
of novel, atom-economical, benign methods for amidation, and
there have been many recent developments in this eld. An
important consideration here is the ease with which the reagent
or catalyst can be separated from the resulting product. Direct
thermal amide formation from amines and carboxylic acids has
been reported using toluene as the reaction solvent5 or using
radiofrequency heating under neat conditions,6 and this
reagent-free approach is practical in many cases, but the
substrate scope is quite limited. Alternatively, a number of
metal-based catalytic systems have also been reported, with
recent examples including the use of Ti(OiPr)4,7 Cp2ZrCl2,5
and ZrCl45,8 under strictly anhydrous dehydrating conditions.
Boron mediated amidation reactions have attracted considerable attention,912 and boronic acids have been shown to be
eective catalysts for direct amide formation from carboxylic
acids and amines.9 In general, boronic acid catalyzed amidation
reactions require the removal of water from the reaction either
by a dehydrating agent such as molecular sieves or by
azeotropic reux. The reactions also typically require relatively
dilute reaction conditions. Stoichiometric boron reagents for
2013 American Chemical Society

amidation often require anhydrous conditions and/or an excess

of either the acid or the amine, however.1012 While many of
these boron-mediated processes are promising, to date the
substrate scope is limited to relatively activated systems.
We have recently reported that simple borate esters are
eective reagents for the direct synthesis of amides from
carboxylic acids or primary amides.13 Although commercially
available B(OMe)3 was useful for amidation in some cases, the
2,2,2-triuoroethanol-derived ester B(OCH2CF3)3 gave consistently higher conversions and was applicable to a much wider
range of substrates. The use of B(OCH2CF3)3 as an amidation
reagent is operationally simple, as the reaction can be carried
out open to the air with equimolar quantities of acid and amine
in a solvent in which most amines and acids are readily soluble
(MeCN). In all of the examples examined, the thermal
background yield of amide was found to be low in comparison
to that obtained in the presence of the borate ester.
Herein, we report a method for the large-scale preparation of
B(OCH2CF3)3 from readily available B2O3 and a full study of
the scope and limitations of B(OCH2CF3)3 as a direct
amidation reagent. We also describe its application to the
formylation of amines by transamidation of DMF. Importantly,
a solid phase purication procedure has been developed that
enables the amide products to be obtained without aqueous
workup or chromatography.

RESULTS AND DISCUSSION

Preparation of the B(OCH2CF3)3 Reagent. In our initial
work, we prepared B(OCH2CF3)3 by reaction of 2,2,2triuoroethanol with BBr3 at low temperature (Scheme 1).
This gave B(OCH2CF3)3 in excellent yield after purication by
Received: March 9, 2013
Published: April 16, 2013
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involving treatment of the crude reaction mixture with three

commercially available resins (Amberlyst acidic, basic and
Amberlite boron scavenger resins), followed by MgSO4, and
then ltration/evaporation (Figure 1). This provided the amide

Scheme 1. Synthesis of B(OCH2CF3)3 from (a) BBr3 and (b)

B2O3

distillation. However, BBr3 is somewhat expensive and can be

dicult to handle because of the fact that it readily hydrolyzes
on contact with moisture. We therefore sought an alternative
method for preparing the amidation reagent. The synthesis of
B(OCH2CF3)3 has been previously reported from boric acid14
and from B2O3.15 We found the latter procedure to be
particularly straightforward on multigram scale. Simply heating
a suspension of B2O3 in 2,2,2-triuoroethanol for 24 h, followed
by distillation, gave the borate ester in 3348% yield on 2550
g scale, and up to 28% of the triuoroethanol could be
recovered and recycled. Although this procedure is lower
yielding in comparison to our original approach, B2O3 is
considerably cheaper than BBr3 and the reaction is not
particularly moisture-sensitive. The B(OCH2CF3)3 reagent
can be stored at room temperature under inert atmosphere
for at least four months without any observable deterioration.
Development of a Solid Phase Workup Procedure
and Evaluation of Other Borates. In order to explore
dierent workup procedures and reagents, the amidation of
phenylacetic acid with benzylamine was selected as a test
reaction (Table 1). After the amidation reaction, the reaction

Figure 1. Solid phase workup of amidation reactions.

product in a comparable yield and purity to the aqueous

workup (entry 3). This procedure is more convenient for
general use and could potentially be used to enable automation
of the reaction.
We subsequently compared dierent boron reagents under
these conditions. Trimethyl borate was eective for amidation
(entries 4 and 5), but a longer reaction time was required in
order to obtain a good yield. B2O3 itself showed low reactivity
in the amidation reaction with only 15% yield after a 5 h
reaction time (entry 6). Commercially available trimethoxyboroxine 1 is reported to be a stronger Lewis acid than both
B(OMe)3 and B(OCH2CF3)3 but did not oer any signicant
advantage in the amidation reaction (entry 7).14 Interestingly,
the reaction with 1 did not lead to comparable conversions
even after a 15 h reaction time (entry 8). This may be due to
the fact that 1 can more readily form oligomeric species such as
B2O3 upon heating, and such species are much less active in the
amidation reaction. It should be noted that the thermal reaction
in the absence of any reagent gave only an 18% yield of the
amide. In our preliminary communicaton13 we determined the
thermal reaction yield for the 15 other amidation reactions
studied to be <9%. This clearly demonstrates the importance of
the borate ester in mediating the amidation reaction.
Scope of the Amidation Reactions. The full scope of the
amidation reactions was explored with a wide range of amines
and carboxylic acids. To evaluate the amine scope, the
preparation of phenylactetamides (Figure 2, 2a2x) from
phenylacetic acid was explored using our standard reaction
conditions (2 equiv of B(OCH2CF3)3, MeCN, 80 C). Primary
amines including benzylamines (2a2d), simple aliphatic
amines (2e) and even functionalized examples (2f2h) could
be coupled in good yield. A range of cyclic secondary amines
also underwent amidation eciently, including several medicinally relevant examples (2i2m). The hydrochloride salt of
dimethylamine underwent amidation in good yield when two
or more equivalents of the hydrochloride salt were employed
(2n) in combination with 2 equiv of Hunigs base. The acyclic
secondary amine dibenzylamine showed poor reactivity,
however (2o), and a signicant quantity of the secondary Nbenzyl amide 2a was obtained, indicating that partial cleavage of
one of the benzyl units had occurred. Less nucleophilic systems
such as anilines (2p2u) and tert-butylamine (2v) could also
be coupled, but higher reaction temperatures were needed in
some cases in order to obtain reasonable yields. Extremely
unreactive systems such as 2-pyridylamine (2u) gave only very
low yields of the coupling product and adamantylamine (2w)
and 2-mercaptoaniline (2x) did not undergo amidation at all.

Table 1. Comparison of Boron Reagents and Workup

Procedures

entry

reagent

time [h]

yield [%]a

1
2
3
4
5
6
7
8
9

B(OCH2CF3)3
B(OCH2CF3)3
B(OCH2CF3)3
B(OMe)3
B(OMe)3
B2O3
1
1
none

15
5
5
5
15
5
5
15
15

91b
88b
87c
69c
92b
15b
72c
81c
18b

Isolated yield. bAqueous workup procedure. cSolid phase workup

procedure.

mixture contains the amide product, borate-ester derived

byproducts, and potentially some unreacted amine and/or
carboxylic acid. In our preliminary report, the amidation
reactions were puried by acid and base washes to remove
these impurities.13 Under our original conditions (2 equiv of
borate, 15 h, 80 C), the amide was obtained in 91% yield
(entry 1). The reaction time could be reduced from 15 to 5 h
with only a small decrease in yield (entry 2). We explored an
alternative solid phase workup for the amidation reactions
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Figure 2. Scope of phenylacetamide synthesis with dierent amines. All reactions were carried out at 80 C for 5 h, and the solid phase workup
procedure was used unless otherwise stated. (a) Aqueous workup procedure; (b) 80 C for 15 h; (c) 100 C for 15 h in a sealed tube; (d) puried by
column chromatography; (e) from 1 equiv of Me2NHHCl, 1 equiv of DIPEA; (f) from 2 equiv of Me2NHHCl, 2 equiv of DIPEA; (g) from 3 equiv
of Me2NHHCl, 3 equiv of DIPEA; (h) 6% of 2a was also isolated; (i) 100 C for 24 h in a sealed tube.

Figure 3. Scope of N-benzylamide synthesis using dierent carboxylic acids. All reactions were carried out at 80 C for 5 h, and the solid phase
workup procedure was used unless otherwise stated. (a) Aqueous workup procedure; (b) 80 C for 15 h; (c) 100 C for 15 h in a sealed tube.

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The preparation of N-benzylamides (Figure 3, 3a3v) was

explored using our standard conditions in order to evaluate the
carboxylic acid scope. A range of N-benzyl-2-arylacetamides
(2a, 3a3i) were obtained in very good yield including substituted (3b) and heteroaromatic acids (3h). A simple
aliphatic acid (3j) and N-Boc sarcosine (3k) also underwent
amidation eectively. Carboxylic acids with conjugated alkyne
(3l) and alkene groups (3m3o) could be coupled eciently,
but more hindered examples required a higher reaction
temperature (3n). More hindered aliphatic systems including
triuoroacetic acid (3p) and pivalic acid (3q) could also be
coupled eectively by using a higher reaction temperature.
Benzoic acids (3r3v) were also relatively unreactive and
required higher reaction temperatures in order for reasonable
conversions to be obtained.
The coupling of a selection of other combinations of acids
and amines (Figure 4, 4a4g) was explored, and yields were

Figure 5. Lactamization reactions. All reactions were carried out at 80

C for 5 h unless otherwise stated and puried by solid phase workup.
(a) Yield without B(OCH2CF3)3; (b) 100 C for 5 h in a sealed tube;
16
20
(c) 80 C for 15 h; (d) []25
D 9.5 (c 1.22, MeOH) [lit. []D 10.6
(c 1.22, MeOH)].

To evaluate the amidation reaction on larger scales, both a

secondary (4c) and a tertiary amide (2k) were prepared using
gram quantities of material (Scheme 2). Although in both cases
Scheme 2. Gram Scale Amidation Reactions

a slight reduction in yield was observed, more than 1 g of each

amide could be synthesized in less than 15 mL of MeCN. In
each case, the product was puried using the solid phase
workup, without the need for aqueous workup or column
chromatography. For comparison, the same reaction to give 1 g
of 4c using a boronic acid catalyst would require ca. 70 mL of
solvent.9i
Coupling of Acids with an Adjacent Chiral Center. The
amidation of carboxylic acids bearing a chiral center at the position is of high importance, and the coupling of -amino
acids is of particular signicance. While there are many
methods for achieving such couplings, the fact that
B(OCH2CF3)3-mediated amidation reactions can be easily
puried by a solid phase workup might oer greater
convenience. The successful amidation of amino acids using
boronic acid catalysts or other boron-based amidation reagents
has not been reported to date. We therefore wished to explore
the application of B(OCH2CF3)3 to the coupling of a selection
of amino acids bearing commonly used nitrogen protecting
groups to determine whether the corresponding amides could
be obtained without racemization (Figure 6).
The coupling of a range of protected amino acids with
benzylamine proceeded in good yield (6a6e) including both
Boc (6a6d) and Cbz (6e) protected examples. In most cases
no signicant racemization was observed (6a, 6b, 6d). Where
small levels of racemization were observed, this could be
reduced signicantly by decreasing the reaction time, albeit at
the expense of product yield (6b, 6c). The synthesis of
prolinamide 6d is notable, as derivatives of this compound have
been used as organocatalysts in a variety of reactions.17
Dipeptides (6f, 6g) could also be obtained in moderate yield,
by coupling of two suitably protected amino acids with no
observable formation of diastereomeric products. Dipeptides 6f
and 6g have previously been synthesized via carbodiimide

Figure 4. Further scope of the amidation reaction. All reactions were

carried out at 80 C for 15 h and puried by solid phase workup unless
otherwise stated. (a) Aqueous workup procedure; (b) 80 C for 5 h;
(c) puried by column chromatography.

generally consistent with our observations of the relative

reactivity of amines/acids outlined above. Thus, aliphatic
amine/acid combinations (4a4d) generally gave reasonable
yields of the amide, even with fairly volatile components (4a,
4b). Less reactive picolinic acid underwent amidation in
relatively good yield with glycine methyl ester (4e). The
reaction of a fairly nucleophilic aniline with an unsaturated acid
also proceeded in good yield (4f). Pleasingly, we were also able
to prepare paracetamol (4g) in moderate yield by coupling
acetic acid with 4-hydroxyaniline. Interestingly, monoamidation
of a dicarboxylic acid could also be achieved in 53% yield (4h).
In the majority of cases, the amides 24 could be puried by
the solid phase workup procedure, with the exception of amides
containing strongly basic (2i, 2j, 2t, 2u, 4e) or acidic (4h)
groups, which generally required chromatographic purication.
Lactam formation could also be achieved eectively (Figure
5, 5a5c). The background reaction for formation of six- (5a)
and seven-membered (5b) lactams from simple thermal
condensation was low in comparison to that observed in the
presence of B(OCH2CF3)3. Lactamization of Boc-L-ornithine
(5c) proceeded in 84% yield.
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occur, it can be reduced signicantly by shortening the reaction

time. Notably, the coupling of amino acids with secondary
amines using conventional coupling reagents is often a
considerable challenge, and an aqueous work up and/or
chromatographic purication is generally required. Our method
therefore oers a potentially valuable approach to tertiary
amino acid amides, as it furnishes pure products in reasonable
yield with high enantiopurity, following a simple solid phase
workup.
Transamidation of DMF using B(OCH2CF3)3. In our
preliminary communication, we reported the transamidation of
a limited selection of primary amides using B(OCH2CF3)3.
Since this report, a number of alternative catalysts and reagents
for transamidation reactions have been reported including
hydroxylamine hydrochloride,31 Cp2ZrCl2,32 Cu(OAc)2,33
PhI(OAc)2,34 boric acid,35 CeO236 and L-proline.37 In many
cases these reagents are cheap and readily available, and the
reactions have a wide substrate scope. On this basis, it therefore
seemed that the potential application of B(OCH2CF3)3 as a
reagent for transamidation of primary amides is somewhat
limited. However, during our initial solvent screen for the direct
amidation of carboxylic acids, we observed that B(OCH2CF3)3
was highly eective for the transamidation of DMF. With this in
mind, we opted to investigate the scope of this reaction. Recent
literature methods for the N-formylation of amines include
HCONH2/NaOMe,38 HCONH2/NH2OHHCl,31 HCONH2/
Cp2ZrCl2,32 HCO2H in the presence of protic ionic liquids,39
and HCO2H/HCO2Na.40 All of these methods require high
temperatures, anhydrous conditions and purication by column
chromatography. The direct transamidation of DMF has
recently been achieved with boric acid,35 PhI(OAc)2,34 Lproline,37 and imidazole,41 but at high temperatures,34,35 with
extended reaction times,34,35,41 and/or with purication by
column chromatography.41 We therefore anticipated that
B(OCH2CF3)3-mediated transamidation of DMF may provide
a useful formylation method, especially if the products could be
readily puried by solid phase workup.
The formylation of benzylamine was used as a model for
optimization (Table 2). First, we conrmed that the background reaction, observed when the amine was heated in DMF

Figure 6. Coupling of acids containing adjacent chiral centers. All

reactions were carried out at 80 C for 15 h unless otherwise stated
and puried by solid phase workup. (a) 80 C for 8 h; (b) 100 C for
24 h in a sealed tube; (c) er measured after conversion to the Nbenzoyl amide derivative; (d) 100 C for 8 h in a sealed tube; (e) 80
C for 5 h.

Table 2. Formylation Optimizationa

coupling,1821 but purication by aqueous workup, recrystallization or chromatography was required.

Pleasingly, amino acids could also be coupled with cyclic
secondary amines (6h6l) in reasonable yield, and these
couplings also proceeded with relatively low levels of
racemization. The synthesis of amides 6h6j has been reported
using a range of dierent coupling reagents,2230 but the
enantiomeric purity of the products was not directly
determined in any of these cases. The preparation of
benzamides 6k and 6l has never been previously reported.
The preparation of N-benzylamide 6m was achieved in
excellent yield with negligible racemization. The coupling of
amino acids with acyclic secondary amines was unsuccessful
(6n, 6o).
The above reactions serve to illustrate the scope of the
B(OCH2CF3)3 reagent for the coupling of acids bearing
adjacent chiral centers. Commonly used nitrogen protecting
groups (Boc, Cbz) are tolerated under the reaction conditions,
and very little racemization is observed in many cases despite
the high temperatures employed. Where racemization does

entry
1
2
3
4
5
6
7
8
9
10e

DMF [equiv]
c

neat
neatd
1
2
3
4
5
10
15
10

yield [%]b
11
41
60
62
66
72
74
98
92
95

Product isolated by solid phase workup followed by column

chromatography unless otherwise stated. bIsolated yield. cDMF (0.5
M) as solvent, no B(OCH2CF3)3. dDMF (0.5 M) as solvent. e80 C,
solid phase workup followed by evaporation of DMF, no column
chromatography required.
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at 100 C in the absence of B(OCH2CF3)3, was negligible
(entry 1). In neat DMF with 2 equiv of B(OCH2CF3)3, a 41%
yield of formamide was obtained (entry 2). Surprisingly, the
reaction was more eective with small quantities of DMF in
acetonitrile as solvent (entries 39). Although reasonable
yields were obtained with as little as 1 equiv of DMF (entry 3),
the use of 10 equiv was found to be optimal (entry 8). The
reaction temperature could be lowered to 80 C without a
detrimental eect on yield, and the pure formamide could be
obtained in good yield after solid phase workup and
evaporation (entry 10). Formylation of benzylamine could
also be achieved with similar eciency using formamide (88%
yield) and N-methylformamide (94%). However, DMF is
considerably cheaper and easier to separate from the
formamide product than these alternative formyl donors.
The scope of this reaction was evaluated on a range of
amines (Table 3). Aromatic and aliphatic amines underwent

CONCLUSION

EXPERIMENTAL SECTION

Article

A convenient synthesis of B(OCH2CF3)3 from readily available

bulk chemicals has been reported, and the full scope of its
application in direct amidation reactions has been explored. A
wide range of acids and amines containing varying functionalities can be successfully used in B(OCH2CF3)3-mediated
amidation reactions, and the pure amide products can be
isolated following an operationally simple solid phase workup
procedure using commercially available resins, avoiding the
need for aqueous workup or chromatographic purication. The
amidation of a series of N-protected amino acids with both
primary and secondary amines has been successfully demonstrated, and the products were obtained with high enantiopurity. The formylation of a series of primary and secondary
amines via transamidation of DMF was also successfully
achieved.

Table 3. Formylation of Amines with DMF

General Methods. All solvents and chemicals were used as

supplied unless otherwise indicated. Reactions in MeCN at 100 C
were performed in a sealed (screw cap) carousel tube. All resins were
washed with CH2Cl2 and dried under a vacuum prior to use. Column
chromatography was carried out using silica gel, and analytical thin
layer chromatography was carried out using aluminum-backed silica
plates. Components were visualized using combinations of UV (254
nm) and potassium permanganate. []D values are given in 101 deg
cm2 g1, concentration (c) in g per 100 mL. 1H NMR spectra were
recorded at 300, 400, 500, or 600 MHz in the stated solvent using
residual protic solvent CDCl3 ( = 7.26 ppm, s), DMSO ( = 2.56
ppm, qn) or MeOD ( = 4.87, s and 3.31, quintet) as the internal
standard. Chemical shifts are quoted in ppm using the following
abbreviations: s, singlet; d, doublet; t, triplet; q, quartet; qn, quintet; m,
multiplet; br, broad or a combination of these. The coupling constants
(J) are measured in Hertz. 13C NMR spectra were recorded at 75, 100,
125, or 150 MHz in the stated solvent using the central reference of
CDCl3 ( = 77.0 ppm, t), DMSO ( = 39.52 ppm, septet) or MeOD
( = 49.15 ppm, septet) as the internal standard. Chemical shifts are
reported to the nearest 0.1 ppm. Mass spectrometry data were
collected on either TOF or magnetic sector analyzers. The ionization
method is reported in the experimental data. The data for amides 2a,
2d, 2e, 2g, 2h, 3j, 3l, 3o, 3q, 3r, 4a, 4b, 4d, 4f and 6b was reported in
our preliminary communication.13
Tris-(2,2,2-triuoroethyl) borate.13 25 g Scale. A suspension of
B2O3 (25.6 g, 0.37 mol) in 2,2,2-triuoroethanol (53 mL, 0.73 mol)
was stirred at 80 C for 8 h. The reaction mixture was then ltered to
remove excess boric anhydride. The ltrate was puried by distillation
to give B(OCH2CF3)3 as a clear liquid (36.0 g, 117 mmol, 48%).
50 g Scale (With CF3CH2OH Recovery). A suspension of B2O3
(48.1 g, 0.69 mol) in 2,2,2-triuoroethanol (100 mL, 1.37 mol) was
stirred at 80 C for 24 h. The reaction mixture was then ltered to
remove excess boric anhydride. The ltrate was puried by distillation
to give B(OCH2CF3)3 as a clear liquid (46.3 g, 150 mmol, 33%). 2,2,2Triuoroethanol (38.4 g, 28%) was recovered during the distillation:
bp 122125 C (760 Torr) [lit.13 120123 C (760 Torr)]; max
(lm/cm1) 3165 (CH), 1441 (CF), 1376 (BO), 1156 (CO);
H (300 MHz, CDCl3) 4.24 (q, J 8.3 6H); C (75 MHz, CDCl3) 61.8
(q, J 36.5), 123.2 (q, J 276); F (282 MHz, CDCl3) 77.06; Found
(CI) [M + H]+ 309.0334 C6H7O3F9B, requires 309.0344.
General Procedure for Amidation of Carboxylic acids. All
reactions were performed on a 1 mmol scale. B(OCH2CF3)3 (2.0
mmol, 2 equiv) was added to a solution of acid (1.0 mmol, 1 equiv)
and amine (1.0 mmol, 1 equiv) in MeCN (2 mL, 0.5 M). The reaction
mixture was stirred at the indicated temperature (80 C, or 100 C in a
sealed tube) for the indicated time (524 h).
Solid Phase Workup. After the indicated time, the reaction mixture
was diluted with CH2Cl2 or EtOAc (3 mL) and water (0.5 mL).
Amberlyst A-26(OH) (150 mg), Amberlyst 15 (150 mg) and

Isolated yield. bYield measured using mesitylene as an internal

standard. c100 C for 5 h in a sealed tube.

formylation in moderate to excellent yield (7a7f). Amines

with -substituents such as -methylbenzylamine gave the
corresponding formamide in excellent yield (7d). The volatile
N-butylformamide (7g) could be obtained in good yield as
calculated by 1H NMR, but a signicant loss of the product was
observed during isolation. Less nucleophilic systems such as
aniline and related derivatives (7h, 7i) were formylated in
relatively low yield. Secondary amines (7i, 7j) could also be
formylated, although higher temperatures were required to
obtain better yields.
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N-Phenylacetylmorpholine (2k).45 White solid (182 mg, 89%): mp

6567 C (CH2Cl2) [lit.45 6264 C]; max (solid/cm1) 3064, 3033,
2961, 2917, 2893, 2851 (CH), 1640 (CO); H (400 MHz,
CDCl3) 3.403.44 (m, 2H), 3.443.48 (m, 2H), 3.63 (s, 4H), 3.72 (s,
2H), 7.217.27 (m, 3H), 7.297.34 (m, 2H); C (100 MHz, CDCl3)
40.8, 42.1, 46.5, 66.4, 66.8, 126.9, 128.5, 128.8, 134.8, 169.6.
2-Phenyl-1-(pyrrolidin-1-yl)ethanone (2l). Clear oil (185 mg,
97%): max (lm/cm1) 3061, 3030, 2971, 2874 (CH), 1623 (C
O); H (500 MHz, CDCl3) 1.80 (quintet, J 6.7, 2H), 1.88 (quintet, J
6.7, 2H), 3.39 (t, J 6.7, 2H), 3.46 (t, J 6.7, 2H), 3.63 (s, 2H), 7.19
7.23 (m, 1H), 7.247.31 (m, 4H); C (125 MHz, CDCl3) 24.4, 26.2,
42.3, 46.0, 47.0, 126.7, 128.6, 129.0, 135.0, 169.6; Found (ES+) [M +
H]+ 190.1226 C12H16ON, requires 190.1232.
N-Phenylacetylthiomorpholine (2m).46 Yellow solid (194 mg,
89%): mp 7374 C (CH2Cl2) [lit.46 7375 C]; max (solid/cm1)
3024, 2960, 2911 (CH), 1639 (CO); H (400 MHz, CDCl3)
2.262.30 (m, 2H), 2.522.59 (m, 2H), 3.653.70 (m, 2H), 3.72 (s,
2H), 3.853.90 (m, 2H), 7.207.26 (m, 3H), 7.297.34 (m, 2H); C
(100 MHz, CDCl3) 27.2, 27.4, 41.3, 44.4, 48.8, 126.9, 128.5, 128.9,
134.8, 169.4.
N,N-Dimethyl-2-phenylacetamide (2n).47 White solid (134 mg, 82
mg): mp 3739 C (CH2Cl2) [lit.47 3840 C]; max (solid/cm1)
3062, 3029, 2931 (CH), 1634 (CO); H (600 MHz, CDCl3) 2.91
(s, 3H), 2.93 (s, 3H), 3.66 (s, 2H), 7.177.23 (m, 3H), 7.257.28 (m,
2H); C (150 MHz, CDCl3) 35.7, 37.8, 41.1, 126.8, 128.7, 128.9,
135.2, 171.1.
N,N-Dibenzyl-2-phenylacetamide (2o).48 Puried by column
chromatography (Et2O:PE 3:1). Colorless oil (37 mg, 12%): max
(lm/cm1) 3062, 3029, 2925 (CH), 1639 (CO); H (500 MHz,
CDCl3, 35 C) 3.83 (s, 2H), 4.47 (s, 2H), 4.66 (s, 2H), 7.117.17 (m,
2H), 7.197.25 (m, 2H), 7.257.42 (m, 12H); C (125 MHz, CDCl3,
35 C) 41.0, 48.3, 50.3, 126.5, 126.9, 127.4, 127.6, 128.3, 128.5, 128.7,
128.8, 128.9, 135.0, 136.5, 137.3, 171.6.
N,2-Diphenylacetamide (2p).49 O white solid (125 mg, 60%): mp
116118 C (CH2Cl2) [lit.49 116117 C]; max (solid/cm1) 3254
(NH), 3135, 3061, 3025 (CH), 1655 (CO); H (600 MHz,
CDCl3) 3.69 (s, 2H), 7.09 (t, J 7.4, 1H), 7.27 (t, J 7.8, 2H), 7.337.34
(m, 3H), 7.367.39 (m, 2H), 7.45 (d, J 8.0, 2H), 7.61 (br s, 1H); C
(150 MHz, CDCl3) 44.8, 120.1, 124.6, 127.7, 129.1, 129.3, 129.6,
134.7, 137.9, 169.6.
N-(2-Methoxyphenyl)-2-phenylacetamide (2q).50 Yellow solid
(143 mg, 61%): mp 8283 C (CH2Cl2) [lit.50 8081 C]; max
(solid/cm1) 3284 (NH), 3028, 3011, 2959, 2939, 2918, 2837 (C
H), 1648 (CO), H (500 MHz, CDCl3) 3.72 (s, 3H), 3.76 (s, 2H),
6.80 (dd, J 8.1, 1.1, 1H), 6.93 (td, J 7.8, 1.1, 1H), 7.01 (td, J 7.8, 1.5,
1H), 7.317.37 (m, 3H), 7.377.42 (m, 2H), 7.79 (br s, 1H), 8.35
(dd, J 8.0, 1.4, 1H); C (125 MHz, CDCl3) 45.3, 55.7, 110.0, 119.6,
121.2, 123.8, 127.5, 127.7, 129.1, 129.7, 134.7, 147.9, 168.9.
2-Phenyl-N-p-tolylacetamide (2r).49 White solid (105 mg, 53%):
mp 132133 C (CH2Cl2) [lit.49 131132 C]; max (solid/cm1)
3289 (NH), 3063, 3031, 2922 (CH), 1650 (CO); H (500
MHz, CDCl3) 2.29 (s, 3H), 3.73 (s, 2H), 7.01 (br s, 1H), 7.08 (d, J
8.4, 2H), 7.28 (d, J 8.4, 2H), 7.317.36 (m, 3H), 7.387.42 (m, 2H);
C (125 MHz, CDCl3) 23.6, 47.4, 122.9, 130.2, 131.8, 132.2, 133.3,
136.8, 137.5, 138.0, 172.1.
N-(4-Methoxyphenyl)-2-phenylacetamide (2s).49 White solid (164
mg, 68%): mp 122123 C (CH2Cl2) [lit.49 124125 C]; max
(solid/cm1) 3315 (NH), 3084, 3026, 3009, 2943 (CH), 1650
(CO); H (500 MHz, CDCl3) 3.73 (s, 2H), 3.77 (s, 3H), 6.806.83
(m, 2H), 6.97 (br s, 1H), 7.297.36 (m, 5H), 7.387.42 (m, 2H); C
(125 MHz, CDCl3) 44.8, 55.5, 114.1, 121.9, 127.7, 129.3, 129.6, 130.7,
134.6, 156.6, 169.0.
N-(Pyridin-3-yl)-2-phenylacetamide (2t). Puried by column
chromatography (4% MeOH in EtOAc). White solid (114 mg,
53%): mp 107108 C (CH2Cl2); max (solid/cm1) 3170 (NH),
3032, 2971 (CH), 1686 (CO); H (500 MHz, CDCl3) 3.68 (s,
2H), 7.20 (dd, J 8.3, 4.7, 1H), 7.237.33 (m, 5H), 8.068.10 (m, 1H),
8.27 (dd, J 4.7, 1.2, 1H), 8.57 (d, J 2.4, 1H), 9.05 (br s, 1H); C (125
MHz, CDCl3) 44.3, 123.9, 127.5, 127.6, 129.0, 129.3, 134.4, 135.4,

Amberlite IRA743 (150 mg) were added to the reaction mixture, and
it was stirred for 30 min. MgSO4 was added to the reaction mixture,
which was then ltered, the solids were washed three times with
CH2Cl2 or EtOAc, and the ltrate was concentrated in vacuo to yield
the amide product.
For amides 2i, 2j, 2t, 2u and 4e, Amberlyst 15 was not used. In
these cases, the product was separated from any excess amine by
column chromatography.
Aqueous Workup Procedure. After the reaction was complete, the
solvent was removed under reduced pressure. The residue was
redissolved in CH2Cl2 (15 mL) and washed with aqueous solutions of
NaHCO3 (15 mL, 1 M) and HCl (15 mL, 1 M), dried over MgSO4,
ltered and concentrated under reduced pressure to give the amide
product.
General Procedure for the Formylation of Amines with
DMF. All reactions were performed on a 1 mmol scale. B(OCH2CF3)3
(2.0 mmol, 2 equiv) was added to a solution of amine (1.0 mmol, 1
equiv) and DMF (10.0 mmol, 10 equiv) in MeCN (2 mL, 0.5 M). The
reaction mixture was stirred at 80 C for 5 h. After 5 h, the reaction
mixture was diluted with CH2Cl2 or EtOAc (3 mL) and water (0.5
mL). Amberlyst 15 (150 mg) and Amberlite IRA743 (150 mg) were
added to the reaction mixture, and it was stirred for 30 min. The
reaction mixture was dried over MgSO4 and then ltered, the solids
were washed three times with CH2Cl2 or EtOAc, and the ltrate was
diluted with toluene (10 mL) and then concentrated in vacuo
repeatedly (5 times) to yield the clean product.
N-(2-Methoxybenzyl)-2-phenylacetamide (2b). Yellow solid (256
mg, 99%): mp 9495 C (CH2Cl2); max (solid/cm1) 3284 (NH),
3066, 3030, 2939, 2837 (CH), 1646 (CO); H (600 MHz,
CDCl3) 3.58 (s, 2H), 3.66 (s, 3H), 4.39 (d, J 5.8, 2H), 6.01 (br s, 1H),
6.80 (d, J 8.1, 1H), 6.87 (td, J 7.4, 0.9, 1H), 7.17 (dd, J 7.4, 1.6, 1H),
7.227.25 (m, 3H), 7.277.30 (m, 1H), 7.337.36 (m, 2H); C (150
MHz, CDCl3) 40.0, 44.0, 55.1, 110.2, 120.7, 126.1, 127.4, 128.9, 129.0,
129.6, 129.7, 135.1, 157.6, 170.7; Found (EI) [M]+ 255.1251
C16H17O2N, requires 255.1254.
N-(4-Methoxybenzyl)-2-phenylacetamide (2c).42 Yellow solid
(252 mg, 99%): mp 139141 C (CH2Cl2) [lit.42 138139 C];
max (solid/cm1) 3235 (NH), 3063, 3032, 2969, 2936 (CH), 1623
(CO); H (600 MHz, CDCl3) 3.62 (s, 2H), 3.78 (s, 3H), 4.34 (d, J
5.8, 2H), 5.60 (br s, 1H), 6.816.83 (m, 2H), 7.097.12 (m, 2H),
7.257.26 (m, 1H), 7.267.30 (m, 2H), 7.327.36 (m, 2H); C (150
MHz, CDCl3) 43.2, 44.0, 55.4, 114.1, 127.5, 129.0, 129.2, 129.6, 130.3,
134.9, 159.1, 170.9; Found (EI) [M]+ 255.1257 C16H17O2N, requires
255.1254.
N-(2-(1H-Indol-3-yl)ethyl)-2-phenylacetamide (2f).43 Yellow solid
(158 mg, 57%): mp 145146 C (CH2Cl2) [lit.43 151153 C]; max
(solid/cm1) 3391 (NH), 3249 (NH), 3062, 3033, 2920, 2850
(CH), 1634 (CO); H (500 MHz, CDCl3) 2.90 (t, J 6.7, 2H),
3.503.56 (m, 4H), 5.44 (br s, 1H), 6.77 (s, 1H), 7.087.15 (m, 3H),
7.187.22 (m, 1H), 7.237.28 (m, 1H), 7.267.30 (m, 2H), 7.35 (d, J
8.1, 1H), 7.54 (d, J 7.8, 1H), 8.00 (br s, 1H); C (125 MHz, CDCl3)
25.1, 39.8, 44.0, 111.3, 112.8, 118.7, 119.6, 122.0, 122.3, 127.3, 129.0
(2C), 129.5, 135.0, 136.4, 171.0; Found (ES) [M + Na]+ 301.1305
C18H18ON2Na, requires 301.1317.
N-Methyl-N-phenylacetylpiperazine (2i).44 Puried by column
chromatography (Et2O:MeOH:NEt3 [Link]). Yellow oil (170 mg,
96%): max (lm/cm1) 3029, 2940, 2853, 2795 (CH), 1627 (C
O); H (500 MHz, CDCl3) 2.20 (t, J 5.1, 2H), 2.25 (s, 3H), 2.34 (t, J
5.1, 2H), 3.45 (t, J 5.1, 2H), 3.66 (t, J 5.1, 2H), 3.72 (s, 2H), 7.21
7.25 (m, 3H), 7.297.33 (m, 2H); C (125 MHz, CDCl3) 41.0, 41.7,
46.0 (2C), 54.7, 55.0, 126.9, 128.7, 128.8, 135.1, 169.5.
N-Phenyl-N-phenylacetylpiperazine (2j). Puried by column
chromatography (Et2O). Brown solid (209 mg, 76%): mp 9193
C (CH2Cl2); max (solid/cm1) 2919, 2827 (CH), 1632 (CO);
H (600 MHz, CDCl3) 2.952.98 (m, 2H), 3.103.13 (m, 2H), 3.56
3.59 (m, 2H), 3.783.82 (m, 4H), 6.876.93 (m, 3H), 7.257.31 (m,
5H), 7.337.37 (m, 2H); C (150 MHz, CDCl3) 41.2, 41.8, 46.1, 49.3,
49.6, 116.7, 120.6, 127.1, 128.8, 129.0, 129.4, 135.2, 151.0, 169.6;
Found (ES) [M + H]+ 281.1656 C18H21ON2, requires 281.1654.
4518

[Link]/10.1021/jo400509n | J. Org. Chem. 2013, 78, 45124523

The Journal of Organic Chemistry

Article

141.3, 144.9, 170.4; Found (EI) [M]+ 212.0947 C13H12ON2, requires

212.0944.
N-(Pyridin-2-yl)-2-phenylacetamide (2u).49 Puried by column
chromatography (EtOAc:PE 3:1, 10% NEt3). White solid (25 mg,
12%): mp 121122 C (CH2Cl2) [lit.49 122124 C]; max (solid/
cm1) 3230 (NH), 3046, 2959, 2921 (CH), 1656 (CO); H
(500 MHz, CDCl3) 3.74 (s, 2H), 6.987.03 (m, 1H), 7.277.33 (m,
3H), 7.337.38 (m, 2H), 7.667.71 (m, 1H), 8.198.27 (m, 2H),
8.52 (br s, 1H); C (125 MHz, CDCl3) 45.1, 114.1, 120.0, 127.8,
129.3, 129.6, 134.0, 138.5, 147.7, 151.3, 169.6; Found (ES) [M + H]+
213.1035 C13H13ON2, requires 213.1028.
N-tert-Butyl-2-phenylacetamide (2v).51 White solid (116 mg,
60%): mp 104106 C (CH2Cl2) [lit.51 103 C]; max (solid/cm1)
3303 (NH), 3063, 2962, 2872 (CH), 1638 (CO); H (600
MHz, CDCl3) 1.28 (s, 9H), 3.48 (s, 2H), 5.17 (br s, 1H), 7.24 (d, J
7.2, 2H), 7.267.30 (m, 1H), 7.35 (t, J 7.4, 2H); C (150 MHz,
CDCl3) 28.8, 45.0, 51.4, 127.3, 129.1, 129.4, 135.6, 170.4.
N-Benzyl-2-(naphthalen-2-yl)acetamide (3a).52 Yellow solid (225
mg, 81%): mp 168169 C (CH2Cl2) [lit.52 170174 C]; max
(solid/cm1) 3225 (NH), 3053, 3030, 2976, 2936 (CH), 1628
(CO); H (500 MHz, CDCl3) 3.79 (s, 2H), 4.41 (d, J 5.8, 2H), 5.81
(br s, 1H), 7.18 (d, J 7.0, 2H), 7.217.30 (m, 3H), 7.39 (dd, J 8.3, 1.7,
1H), 7.467.52 (m, 2H), 7.72 (br s, 1H), 7.787.82 (m, 1H), 7.82
7.85 (m, 2H); C (125 MHz, CDCl3) 43.7, 44.1, 126.2, 126.5, 127.4,
127.5, 127.6, 127.7, 127.8, 128.4, 128.7, 129.0, 132.3, 132.6, 133.6,
138.2, 170.8.
N-Benzyl-2,2-diphenylacetamide (3b).53 Yellow solid (247 mg,
81%): mp 127128 C (CH2Cl2) [lit.53 126128 C]; max (solid/
cm1) 3311 (NH), 3060, 3030, 2930 (CH), 1634 (CO); H
(500 MHz, CDCl3) 4.48 (d, J 5.7, 2H), 4.96 (s, 1H), 5.94 (br s, 1H),
7.197.22 (m, 2H), 7.247.30 (m, 8H), 7.307.35 (m, 5H); C (125
MHz, CDCl3) 43.9, 59.3, 127.4, 127.6, 127.7, 128.8, 128.9, 129.0,
138.2, 139.4, 171.8.
N-Benzyl-2-(4-methoxyphenyl)acetamide (3c).54 Yellow solid
(232 mg, 90%): mp 134135 C (CH2Cl2) [lit.54 136 C]; max
(solid/cm1) 3286 (NH), 3082, 3063, 3033, 2968, 2838 (CH),
1635 (CO); H (600 MHz, CDCl3) 3.57 (s, 2H), 3.79 (s, 3H), 4.40
(d, J 5.8, 2H), 5.75 (br s, 1H), 6.866.89 (m, 2H), 7.167.19 (m,
4H), 7.237.26 (m, 1H), 7.287.31 (m, 2H); C (150 MHz, CDCl3)
43.0, 43.7, 55.4, 114.6, 126.8, 127.5, 127.6, 128.8, 130.7, 138.3, 159.0,
171.5.
N-Benzyl-2-(2-bromophenyl)acetamide (3d).55 Yellow solid (276
mg, 90%): mp 143144 C (CH2Cl2) [lit.55 144145 C]; max
(solid/cm1) 3272 (NH), 3055, 3030, 2920, 2871 (CH), 1642
(CO); H (600 MHz, CDCl3) 3.77 (s, 2H), 4.44 (d, J 5.7, 2H), 5.75
(br s, 1H), 7.16 (td, J 7.7, 1.7, 1H), 7.217.27 (m, 3H), 7.30 (app t, J
7.6, 3H), 7.37 (dd, J 7.5, 1.6, 1H), 7.58 (dd, J 8.0, 1.0, 1H); C (150
MHz, CDCl3) 43.8, 44.2, 125.0, 127.6, 127.7, 128.2, 128.8, 129.4,
131.9, 133.3, 134.8, 138.1, 169.5.
N-Benzyl-2-(4-bromophenyl)acetamide (3e). Yellow solid (289
mg, 94%): mp 165166 C (CH2Cl2); max (solid/cm1) 3280 (N
H), 3056, 3026, 2917, 2872 (CH), 1642 (CO); H (600 MHz,
CDCl3) 3.55 (s, 2H), 4.41 (d, J 5.6, 2H), 5.72 (br s, 1H), 7.15 (d, J 8.4,
2H), 7.19 (d, J 7.0, 2H), 7.257.28 (m, 1H), 7.297.33 (m, 2H),
7.457.48 (m, 2H); C (150 MHz, CDCl3) 43.2, 43.8, 121.6, 127.7,
127.8, 128.9, 131.2, 132.2, 133.8, 138.0, 170.2; Found (EI) [M]+
303.0256 C15H14ONBr, requires 303.0253.
N-Benzyl-2-(3,4-dimethoxyphenyl)acetamide (3f). Brown solid
(235 mg, 81%): mp 100101 C (CH2Cl2) [lit.56 98100 C]; max
(solid/cm1) 3297 (NH), 3065, 3033, 3000, 2936, 2835 (CH),
1634 (CO); H (600 MHz, CDCl3) 3.58 (s, 2H), 3.85 (s, 3H), 3.86
(s, 3H), 4.41 (d, J 5.6, 2H), 5.74 (br s, 1H), 6.766.80 (m, 2H), 6.83
(d, J 8.0, 1H), 7.18 (d, J 7.0, 2H), 7.237.26 (m, 1H), 7.287.31 (m,
2H); C (150 MHz, CDCl3) 43.6, 43.7, 55.98, 56.02, 111.6, 112.4,
121.8, 127.2, 127.58, 127.61, 128.8, 138.3, 148.4, 149.4, 171.3; Found
(EI) [M]+ 285.1353 C17H19O3N, requires 285.1359.
N-Benzyl-2-(4-chlorophenyl)acetamide (3g).57 Yellow solid (244
mg, 93%): mp 157158 C (CH2Cl2) [lit.57 151153 C]; max
(solid/cm1) 3277 (NH), 3056, 3027, 2918, 2874 (CH), 1642
(CO), 690 (CCl); H (600 MHz, CDCl3) 3.56 (s, 2H), 4.41 (d, J

5.8, 2H), 5.76 (br s, 1H), 7.187.22 (m, 4H), 7.247.28 (m, 1H),
7.297.32 (m, 4H); C (150 MHz, CDCl3) 43.1, 43.8, 127.69, 127.74,
128.9, 129.2, 130.9, 133.3, 133.5, 138.1, 170.4.
N-Benzyl-2-(thiophen-3-yl)acetamide (3h). Yellow solid (212 mg,
91%): mp 9698 C (CH2Cl2); max (solid/cm1) 3279 (NH),
3086, 3062, 3032, 2925 (CH), 1635 (CO); H (600 MHz,
CDCl3) 3.65 (s, 2H), 4.42 (d, J 5.8, 2H), 5.85 (br s, 1H), 7.01 (d, J 4.8,
1H), 7.147.15 (m, 1H), 7.19 (d, J 7.5, 2H), 7.237.34 (m, 4H); C
(150 MHz, CDCl3) 38.3, 43.7, 123.7, 127.0, 127.61, 127.62, 128.6,
128.8, 134.8, 138.2, 170.5; Found (ES) [M + H]+ 232.0789
C13H14ONS, requires 232.0796.
N-Benzyl-2-(4-phenoxyphenyl)acetamide (3i). Yellow solid (298
mg, 95%): mp 125126 C (CH2Cl2); max (solid/cm1) 3285 (N
H), 3085, 3064, 3033, 2921 (CH), 1636 (CO); H (600 MHz,
CDCl3) 3.60 (s, 2H), 4.43 (d, J 5.9, 2H), 5.71 (br s, 1H), 6.967.01
(m, 4H), 7.107.13 (m, 1H), 7.187.21 (m, 2H), 7.217.24 (m, 2H),
7.257.28 (m, 1H), 7.297.36 (m, 4H); C (150 MHz, CDCl3) 43.2,
43.8, 119.2, 119.3, 123.6, 127.6, 127.7, 128.8, 129.5, 129.9, 130.9,
138.2, 156.8, 157.0, 171.0; Found (EI) [M]+ 317.1416 C21H19O2N,
requires 317.1410.
Boc-Sarcosine-benzamide (3k).58 Yellow solid (265 mg, 95%): mp
8284 C (CH2Cl2) [lit.58 8385 C]; max (solid/cm1) 3310 (N
H), 3067, 2978, 2931 (CH), 1664 (CO), 1685 (CO); H (400
MHz, CDCl3, 58 C) 1.40 (s, 9H), 2.90 (s, 3H), 3.83 (s, 2H), 4.41 (d,
J 5.9, 2H), 6.52 (br s, 1H), 7.197.24 (m, 3H), 7.257.31 (m, 2H); C
(100 MHz, CDCl3, 58 C) 28.2, 35.7, 43.3, 53.4, 80.6, 127.3, 127.5,
128.6, 138.2, 155.9, 169.1; Found (EI) [M]+ 278.1629 C15H22O3N2,
requires 278.1625.
(E)-N-Benzyl-3-(thiophen-3-yl)acrylamide (3m). Yellow solid (217
mg, 88%): mp 107110 C (CH2Cl2); max (solid/cm1) 3275 (N
H), 3029, 2971 (CH), 1739 (CO); H (600 MHz, CDCl3) 4.55
(d, J 5.7, 2H), 6.05 (br s, 1H), 6.26 (d, J 15.5, 1H), 7.227.24 (m,
1H), 7.267.36 (m, 6H), 7.42 (d, J 2.1, 1H), 7.65 (d, J 15.5, 1H); C
(150 MHz, CDCl3) 44.0, 120.2, 125.1, 126.9, 127.4, 127.7, 128.0,
128.9, 135.2, 137.8, 138.3, 166.1; Found (ES+) [M + H]+ 244.0800
C14H14NOS, requires 244.0796.
(E)-N-Benzyl-2-methyl-3-phenylacrylamide (3n). White solid (229
mg, 90%): mp 120121 C (CH2Cl2); max (solid/cm1) 3332 (N
H), 3079, 3059, 2921, 2852 (CH), 1531 (CO); H (600 MHz,
CDCl3) 2.11 (s, 3H), 4.56 (d, J 5.7, 2H), 6.69 (br s, 1H), 7.277.40
(m, 11H); C (150 MHz, CDCl3) 14.5, 44.2, 127.7, 127.98, 128.04,
128.5, 128.9, 129.5, 131.9, 134.3, 136.2, 138.5, 169.6; Found (ES) [M
+ H]+ 252.1394 C17H18ON, requires 252.1388.
N-Benzyl-2,2,2-triuoroacetamide (3p).59 Yellow solid (183 mg,
89%): mp 7274 C (CH2Cl2) [lit.59 7071 C]; max (solid/cm1)
3300 (NH), 3110, 3035, 2923 (CH), 1702 (CO); H (500
MHz, CDCl3) 4.54 (d, J 5.8, 2H), 6.52 (br s, 1H), 7.287.32 (m, 2H),
7.327.41 (m, 3H); C (125 MHz, CDCl3) 43.9, 116.0 (q, J 285.4),
128.0, 128.2, 129.0, 136.1, 157.5 (q, J 36.9); F (282 MHz, CDCl3)
76.2.
N-Benzyl-4-methoxybenzamide (3s).60 Yellow solid (172 mg,
71%): mp 129130 C (CH2Cl2) [lit.60 129130 C]; max (solid/
cm1) 3256 (NH), 3058, 2957, 2930, 2834 (CH), 1631 (CO);
H (500 MHz, CDCl3) 3.85 (s, 3H), 4.64 (d, J 5.7, 2H), 6.28 (br s,
1H), 6.906.94 (m, 2H), 7.287.32 (m, 1H), 7.36 (m, 4H), 7.74
7.77 (m, 2H); C (125 MHz, CDCl3) 44.1, 55.5, 113.8, 126.7, 127.6,
128.0, 128.8, 128.9, 138.5, 162.3, 167.0.
N-Benzyl-4-(triuoromethyl)benzamide (3t).61 Yellow solid (212
mg, 76%): mp 168170 C (CH2Cl2) [lit.61 149151 C]; max
(solid/cm1) 3326 (NH), 3091, 3071, 3036 (CH), 1643 (CO);
H (600 MHz, CDCl3) 4.65 (d, J 5.6, 2H), 6.53 (br s, 1H), 7.297.33
(m, 1H), 7.337.38 (m, 4H), 7.68 (d, J 8.2, 2H), 7.89 (d, J 8.2, 2H);
C (150 MHz, CDCl3) 44.5, 123.7 (q, J 272.5), 125.8 (q, J 3.8), 127.6,
128.0, 128.1, 129.0, 133.4 (q, J 32.7), 137.7, 137.8, 166.2; F (282
MHz, CDCl3) 63.4.
N,2-Dibenzylbenzamide (3u). Yellow solid (184 mg, 61%): mp
119120 C (CH2Cl2); max (solid/cm1) 3296 (NH), 3057, 3025,
3008, 2921, 2873 (CH), 1633 (CO), H (600 MHz, CDCl3) 4.22
(s, 2H), 4.49 (d, J 5.6, 2H), 5.86 (br s, 1H), 7.13 (d, J 7.1, 2H), 7.16
7.19 (m, 3H), 7.217.25 (m, 4H), 7.267.32 (m, 3H), 7.337.37 (m,
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1H), 7.397.42 (m, 1H); C (150 MHz, CDCl3) 39.0, 44.1, 126.2,
126.5, 127.3, 127.7, 128.0, 128.6, 128.9, 129.0, 130.3, 131.3, 136.5,
137.9, 139.0, 140.9, 169.9; Found (ES) [M + H]+ 302.1532
C21H20ON, requires 302.1545.
N-Benzyl-4-iodobenzamide (3v).62 White solid (124 mg, 37%):
mp 167168 C (CH2Cl2) [lit.62 166167 C]; max (solid/cm1)
3311 (NH), 3083, 3060, 3028 (CH), 1640 (CO); H (600
MHz, DMSO) 4.47 (d, J 6.0, 2H), 7.227.26 (m, 1H), 7.297.35 (m,
4H), 7.667.69 (m, 2H), 7.847.88 (m, 2H), 9.10 (br t, J 6.0, 1H); C
(150 MHz, DMSO) 42.7, 98.9, 126.8, 127.3, 128.3, 129.3, 133.8,
137.2, 139.5, 165.6; Found (EI) [M + H]+ 337.9962 C14H13ONI,
requires 337.9958.
N-Butyl-2-p-tolylacetamide (4c).63 White solid (188 mg, 92%): mp
8283 C (CH2Cl2) [lit.63 7374 C]; max (solid/cm1) 3301 (N
H), 2959, 2931, 2866 (CH), 1649 (CO); H (500 MHz, CDCl3)
0.86 (t, J 7.3, 3H), 1.24 (sextet, J 7.3, 2H), 1.39 (quintet, J 7.3, 2H),
2.34 (s, 3H), 3.18 (dt, J 7.3, 6.0, 2H), 3.52 (s, 2H), 5.43 (br s, 1H),
7.117.17 (m, 4H); C (125 MHz, CDCl3) 13.8, 20.0, 21.2, 31.6, 39.5,
43.6, 129.5, 129.8, 132.0, 137.1, 171.2; Found (EI) [M]+ 205.1464
C13H19ON, requires 205.1461.
Methyl 2-(picolinamido)acetate (4e).64 Puried by column
chromatography (PE:EtOAc 1:1). White solid (132 mg, 72%): mp
8284 C (CH2Cl2) [lit.64 8182 C]; max (lm/cm1) 3375 (N
H), 3059, 2954, 2852 (CH), 1746 (CO), 1668 (CO); H (600
MHz, CDCl3) 3.74 (s, 3H), 4.23 (d, J 5.7, 2H), 7.387.42 (m, 1H),
7.80 (t, J 7.6, 1H), 8.13 (d, J 7.6, 1H), 8.49 (br s, 1H), 8.53 (br d, J
4.5); C (150 MHz, CDCl3) 41.3, 52.5, 122.4, 126.6, 137.4, 148.4,
149.3, 164.7, 170.3.
N-(4-Hydroxyphenyl)acetamide (4g).65 White solid (97 mg, 69%):
mp 169170 C (CH2Cl2) [lit.65 167168 C]; max (solid/cm1)
3242 (NH/OH), 1632 (CO); H (600 MHz, MeOD) 2.07 (s,
3H), 6.716.74 (m, 2H), 7.287.32 (m, 2H); C (150 MHz, MeOD)
23.5, 116.2, 123.4, 131.7, 155.4, 171.4.
2-(4-(2-(Benzylamino)-2-oxoethyl)phenyl)acetic acid (4h). B(OCH2CF3)3 (621.8 mg, 2.02 mmol, 2 equiv) was added to a
solution of phenylene diacetic acid (192 mg, 0.99 mmol, 1 equiv) and
benzylamine (0.11 mL, 1.01 mmol, 1 equiv) in MeCN (2 mL, 0.5 M).
The reaction mixture was stirred at 80 C for 5 h. After 5 h the solvent
was removed in vacuo, and the residue was diluted in Et2O (20 mL),
washed with NaHCO3 (20 mL, 1 M), and extracted with Et2O (3 20
mL). The aqueous layer was acidifed with HCl (1 M) and extracted
with CH2Cl2 (3 20 mL). The organic layer was dried over MgSO4
and concentrated in vacuo to yield the product as a white solid (146
mg, 0.52 mmol, 52%): mp 163166 C (CH2Cl2); max (solid/cm1)
3284 (NH/OH), 3030, 3060 (CH), 1699 (CO), 1632 (C
O); H (600 MHz, DMSO-d6) 3.45 (s, 2H), 3.53 (s, 2H), 4.26 (d, J
6.0, 2H), 7.167.19 (m, 2H), 7.207.25 (m, 5H), 7.297.32 (m, 2H),
8.55 (br t, J 5.6, 1H), 12.31 (br s, 1H); C (150 MHz, DMSO-d6) 40.3,
42.0, 42,2, 126.8, 127.3, 128.3, 128.9, 129.3, 133.1, 134.7, 139.5, 170.2,
172.8; Found (EI) [M + H]+ 284.1279 C17H18O3N, requires 284.1287.
Piperidin-2-one (5a).66 Colorless oil (95 mg, 99%): max (lm/
cm1) 3245 (NH), 2945, 2870 (CH), 1637 (CO); H (500
MHz, CDCl3) 1.691.82 (m, 4H), 2.30 (t, J 6.5, 2H), 3.263.32 (m,
2H), 7.03 (br s, 1H); C (125 MHz, CDCl3) 20.8, 22.2, 31.5, 42.1,
172.9.
Azepan-2-one (5b).57 White solid (100 mg, 86%): mp 6768 C
(CH2Cl2) [lit.57 6668 C]; max (solid/cm1) 3202 (NH), 2927,
2855 (CH), 1648 (CO); H (500 MHz, CDCl3) 1.601.71 (m,
4H), 1.721.78 (m, 2H), 2.422.47 (m, 2H), 3.173.22 (m, 2H),
6.42 (br s, 1H); C (125 MHz, CDCl3) 23.3, 29.8, 30.6, 36.8, 42.8,
179.5; Found (EI) [M]+ 113.0828 C6H11ON, requires 113.0835.
(S)-tert-Butyl 2-oxopiperidin-3-ylcarbamate (5c).16 White solid
(180 mg, 84%): mp 100101 C (CH2Cl2) [lit.16 101103 C]; []25
D
9.5 (c 1.22, MeOH) [lit.16 []20
D 10.6 (c 1.22, MeOH)]; max
(solid/cm1) 3264 (NH), 2968 (CH), 1715 (CO), 1652 (C
O); H (400 MHz, CDCl3, 58 C) 1.45 (s, 9H), 1.541.67 (m, 1H),
1.821.93 (m, 2H), 2.412.50 (m, 1H), 3.273.33 (m, 2H), 4.01 (dt,
J 11.3, 5.6, 1H), 5.45 (br s, 1H), 6.33 (br s, 1H); C (100 MHz,
CDCl3, 58 C) 21.1, 27.9, 28.3, 41.7, 51.6, 79.5, 155.8, 171.6.

Boc-L-Methionine-benzamide (6a).67 Yellow solid (266 mg, 79%):

67
24
mp 98100 C (CH2Cl2); []25
D 9.1 (c 1.1, CH2Cl2) [lit. []D 9.2
(c 1.1, CH2Cl2)]; max (solid/cm1) 3335 (NH), 3314 (NH), 3061,
3027, 2968, 2936 (CH), 1679 (CO), 1655 (CO); H (400
MHz, CDCl3, 58 C) 1.41 (s, 9H), 1.881.97 (m, 1H), 2.05 (s, 3H),
2.062.15 (m, 1H), 2.462.59 (m, 2H), 4.28 (app q, J 7.1, 1H), 4.36
(dd, J 14.8, 5.8, 1H), 4.43 (dd, J 14.8, 5.9, 1H), 5.42 (br d, J 8.1, 1H),
7.197.25 (m, 3H), 7.267.30 (m, 2H), 6.86 (br s, 1H); C (100
MHz, CDCl3, 58 C) 15.2, 28.3, 30.4, 32.0, 43.4, 54.1, 80.1, 127.3,
127.5, 128.5, 138.2, 155.7, 171.6; Found (ES) [M + Na]+ 361.1567
C17H26O3N2SNa, requires 361.1562; HPLC (hexane/i-PrOH 92:8, 0.5
mL/min, Chiralcel Daicel OD) tR (D) = 9.28 min (<1%), tR (L) =
12.48 min (>99%).
Boc-L-Phenylalanine-benzamide (6c).68 Yellow solid (287 mg,
81%): mp 128129 C (CH2Cl2) [lit.68 128 C]; []25
D +5.2 (c 1.1,
1
CH2Cl2) [lit.67 []22
D +4.9 (c 0.20, CH2Cl2)]; max (solid/cm ) 3343
(NH), 3312 (NH), 3024, 2927 (CH), 1678 (CO), 1659 (C
O); H (400 MHz, CDCl3, 58 C) 1.43 (s, 9H), 3.09 (dd, J 13.8, 7.2,
1H), 3.13 (dd, J 13.8, 6.7, 1H), 4.324.40 (m, 3H), 5.00 (br s, 1H),
6.03 (br s, 1H), 7.127.16 (m, 2H), 7.207.25 (m, 3H), 7.257.32
(m, 5H); C (100 MHz, CDCl3, 58 C) 28.2, 38.6, 43.5, 56.4, 80.2,
126.8, 127.4, 127.6, 128.5, 128.6, 129.3, 136.8, 137.8, 155.3, 171.0;
HPLC (hexane/i-PrOH 90:10, 0.5 mL/min, Chiralcel Daicel OD) tR
(D) = 10.62 min (<1%), tR (L) = 13.24 min (>99%).
Boc-L-Proline-benzamide (6d).69 Yellow solid (186 mg, 61%): mp
124125 C (CH2Cl2) [lit.69 125126 C]; []25
D 77.0 (c 1.0,
1
CH2Cl2) [lit.66 []24
D 76.2 (c 1.0, CH2Cl2)]; max (solid/cm ) 3303
(NH), 2978, 2933, 2909, 2874 (CH), 1682 (CO), 1653 (C
O); H (400 MHz, CDCl3, 58 C) 1.40 (s, 9H), 1.782.07 (m, 3H),
2.25 (br s, 1H), 3.373.42 (m, 2H), 4.244.30 (m, 1H), 4.37 (dd, J
14.8, 5.6, 1H), 4.46 (dd, J 14.8, 5.7, 1H), 6.82 (br s, 1H), 7.187.30
(m, 5H); C (100 MHz, CDCl3, 58 C) 24.1, 28.3 (2C), 43.3, 47.0,
60.6, 80.3, 127.2, 127.5, 128.5, 138.5, 155.2, 172.1; HPLC (hexane/iPrOH 90:10, 0.5 mL/min, Chiralcel Daicel OD) tR (D) = 13.08 min
(1%), tR (L) = 15.79 min (99%).
Cbz-L-Alanine-benzamide (6e).22 Yellow solid (245 mg, 78%): mp
138139 C (CH2Cl2) [lit.22 140141 C]; []25
D 8.0 (c 1.02,
1
CHCl3) [lit.22 []22
D 8.1 (c 1.3, CHCl3)]; max (solid/cm ) 3286
(NH), 3059, 3035, 2975, 2930 (CH), 1682 (CO), 1641 (C
O); H (500 MHz, CDCl3) 1.37 (d, J 6.9, 3H), 4.284.32 (m, 1H),
4.34 (dd, J 15.0, 5.7, 1H), 4.41 (dd, J 15.0, 5.6, 1H), 4.98 (d, J 12.1,
1H), 5.01 (d, J 12.1, 1H), 5.68 (br d, J 6.5, 1H), 6.88 (br s, 1H), 7.18
7.35 (m, 10H); C (125 MHz, CDCl3) 18.9, 43.5, 50.7, 67.0, 127.5,
127.7, 128.1, 128.3, 128.6, 128.7, 136.2, 138.1, 156.1, 172.5; HPLC
(hexane/i-PrOH 90:10, 0.5 mL/min, Chiralcel Daicel AD) tR (L) =
5.13 min (95%), tR (D) = 7.88 min (5%).
Boc-L-Ala-D-Phe-OMe (6f). Yellow solid (136 mg, 42%): mp 9395
1
C (CH2Cl2); []25
D 58.9 (c 0.99, CHCl3); max (solid/cm ) 3283
(NH), 3254 (NH), 3134, 3060, 3024 (CH), 1655 (CO), 1599
(CO), 1544 (CO); H (600 MHz, CDCl3) 1.27 (d, J 7.1, 3H),
1.42 (s, 9H), 3.06 (dd, J 13.8, 6.3, 1H), 3.13 (dd, J 13.8, 5.7, 1H), 3.70
(s, 3H), 4.18 (br t, J 7.1, 1H), 4.85 (m, 1H), 5.04 (br d, J 5.5, 1H),
6.70 (br s, 1H), 7.10 (d, J 7.1, 2H), 7.207.24 (m, 1H), 7.257.29 (m,
2H); C (150 MHz, CDCl3) 18.6, 28.4, 38.0, 50.0, 52.5, 53.2, 80.2,
127.2, 128.7, 129.4, 135.9, 155.5, 171.9, 172.4; Found (ES) [M + Na]+
373.1720 C18H26O5N2Na, requires 373.1739.
Boc-L-Ala-L-Phe-OMe (6g).70 Yellow solid (208 mg, 64%): mp 82
71
84 C (CH2Cl2) [lit.70 8586 C]; []25
D +23.2 (c 1.01, CHCl3) [lit.
[]D +23.0 (c 0.61, CHCl3)]; max (solid/cm1) 3285 (NH), 3061,
3030, 2926 (CH), 1636 (CO), 1547 (CO); H (400 MHz,
CDCl3, 58 C) 1.27 (d, J 7.0, 3H), 1.41 (s, 9H), 3.04 (dd, J 13.9, 6.6,
1H), 3.12 (dd, J 13.9, 6.1, 1H), 3.64 (s, 3H), 4.13 (quintet, J 7.0, 1H),
4.81 (dt, J 7.6, 6.3, 1H), 5.16 (br d, J 7.6, 1H), 6.71 (br d, J 7.3, 1H),
7.087.12 (m, 2H), 7.157.26 (m, 3H); C (100 MHz, CDCl3, 58
C) 18.1, 28.2, 38.0, 50.4, 51.9, 53.3, 79.9, 126.9, 128.4, 129.2, 136.0,
155.3, 171.7, 172.4.
Boc-L-Alanine pyrrolidine amide (6h).22 Colorless oil (135 mg,
22
24
59%): []25
D 6.4 (c 1.1, CHCl3) [lit. []D 6.8 (c 1.1, CHCl3)]; max
(lm/cm1) 3300 (NH), 2976, 2936, 2879 (CH), 1705 (CO),
1636 (CO); H (400 MHz, CDCl3) 1.24 (d, J 6.8, 3H), 1.36 (s,
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cm1) 3273 (NH), 3061, 3028, 2934, 2866 (CH), 1656 (CO);
H (400 MHz, CDCl3, 58 C) 2.84 (t, J 7.1, 2H), 3.55 (app q, J 6.7,
2H), 5.96 (br s, 1H), 7.147.26 (m, 3H), 7.277.34 (m, 2H), 8.09 (s,
1H); C (100 MHz, CDCl3, 58 C) 35.5, 39.2, 126.5, 128.59, 128.63,
138.6, 161.1.
N-(4-Methoxybenzyl)formamide (7c).73 Mixture of rotamers
(1:0.17). Data for major rotamer reported. Yellow solid (101 mg,
61%): mp 8183 C (CH2Cl2) [lit.73 7980 C]; max (solid/cm1)
3283 (NH), 3010, 2933, 2891 (CH), 1642 (CO); H (600
MHz, CDCl3) 3.77 (s, 3H), 4.37 (d, J 5.9, 2H), 6.11 (br s, 1H), 6.83
6.86 (m, 2H), 7.177.20 (m, 2H), 8.18 (s, 1H); C (150 MHz,
CDCl3) 41.7, 55.4, 114.2, 129.2, 129.9, 159.1, 161.3.
(R)-N-(1-Phenylethyl)formamide (7d).74 Mixture of rotamers
(1:0.19). Data for major rotamer reported. Pale yellow oil (129 mg,
74
[]20
85%): []25
D +160.9 (c 0.52, CHCl3) [lit.
D +161.4 (c 0.50,
CHCl3)]; max (lm/cm1) 3270 (NH), 3032, 2977, 2931, 2829
(CH), 1653 (CO); H (500 MHz, CDCl3) 1.45 (d, J 6.9, 3H),
5.13 (app quintet, J 7.2, 1H), 6.71 (br s, 1H), 7.217.35 (m, 5H), 8.04
(s, 1H); C (125 MHz, CDCl3) 22.0, 47.7, 126.2, 127.4, 128.7, 143.0,
160.7; Found (EI) [M]+ 149.0833 C9H11ON, requires 149.0835.
N-(Cyclohexylmethyl)formamide (7e). Mixture of rotamers
(1:0.25). Data for major rotamer reported. Colorless oil (135 mg,
96%): max (lm/cm1) 3280 (NH), 3060, 2922, 2851 (CH), 1657
(CO); H (600 MHz, CDCl3) 0.770.88 (m, 2H), 1.001.18 (m,
3H), 1.341.42 (m, 1H), 1.531.68 (m, 5H) 3.01 (t, J 6.6, 2H), 6.71
(br s, 1H), 8.06 (s, 1H); C (150 MHz, CDCl3) 25.8, 26.4, 30.8, 37.8,
44.4, 161.8; Found (EI) [M + H]+ 142.1227 C8H16NO, requires
142.1226.
N-Cyclohexylformamide (7f).35 Mixture of rotamers (1:0.30). Data
for major rotamer reported. Brown oil (95 mg, 78%): max (lm/cm1)
3268 (NH), 3050, 2929, 2854 (CH), 1652 (CO); H (500
MHz, CDCl3) 1.091.39 (m, 5H), 1.531.63 (m, 1H), 1.641.76 (m,
2H), 1.821.95 (m, 2H), 3.783.86 (m, 1H), 5.78 (br s, 1H), 8.07 (s,
1H); C (125 MHz, CDCl3) 24.8, 25.5, 33.1, 47.1, 160.5.
N-Butylformamide (7g). Mixture of rotamers (1:0.23). Data for
major rotamer reported. Yellow oil (31 mg, 30%): max (lm/cm1)
3280 (NH), 3058, 2959, 2933, 2868 (CH), 1655 (CO); H (500
MHz, CDCl3) 0.90 (t, J 7.2, 3H), 1.33 (sext, J 7.2, 2H), 1.48 (quintet, J
7.2, 2H), 3.26 (q, J 6.7, 2H), 5.95 (br s, 1H), 8.12 (s, 1H); C (125
MHz, CDCl3) 13.7, 20.0, 31.5, 37.9, 161.5; Found (EI) [M]+ 101.0827
C5H11ON, requires 101.0835.
N-Phenylformamide (7h).75 Mixture of rotamers (1:0.93). Data for
major rotamer reported. Yellow oil (25 mg, 21%): max (lm/cm1)
3273 (NH), 3066, 2923, 2854 (CH), 1682 (CO); H (600
MHz, CDCl3) 7.087.11 (m, 1H), 7.19 (t, J 7.5, 1H), 7.317.38 (m,
2H), 7.537.56 (m, 1H), 8.41 (br s, 1H), 8.71 (d, J 11.3, 1H); C (150
MHz, CDCl3) 118.9, 125.4, 129.9, 136.8, 162.8.
1-Indolinecarbaldehyde (7i).76 Mixture of rotamers (1:0.22). Data
for major rotamer reported. Brown solid (55 mg, 38%): mp 5658 C
(CH2Cl2) [lit.76 5861 C]; max (solid/cm1) 3053, 2960, 2921, 2854
(CH), 1656 (CO); H (600 MHz, CDCl3) 3.14 (2H, t, J 8.6), 4.05
(2H, app td, J 8.5, 0.9), 7.04 (1H, td, J 7.2, 1.5), 7.147.22 (2H, m),
7.24 (1H, d, J 7.2) 8.92 (1H, s); C (150 MHz, CDCl3) 27.3, 44.8,
109.5, 124.4, 126.2, 127.7, 132.1, 141.2, 157.7.
3,4-Dihydro-2(1H)-isoquinolinecarbaldehyde (7j).77 Mixture of
rotamers (1:0.60). Data for major rotamer reported. Pale yellow oil
(119 mg, 71%): max (lm/cm1) 3056, 3026, 2929, 2886 (CH),
1646 (CO); H (500 MHz, CDCl3) 2.87 (t, J 5.9, 2H), 3.60 (t, J 5.9,
2H), 4.65 (s, 2H), 7.057.19 (m, 4H), 8.16 (s, 1H); C (125 MHz,
CDCl3) 29.8, 42.4, 43.3, 126.70, 126.71, 126.8, 129.0, 131.8, 133.7,
161.8.

9H), 1.761.84 (m, 2H), 1.91 (app qn, J 6.8, 2H), 3.313.39 (m, 2H),
3.413.49 (m, 1H), 3.513.58 (m, 1H), 4.37 (app qn, J 6.8, 1H), 5.50
(br d, J 7.8, 1H); C (100 MHz, CDCl3) 18.6, 24.1, 26.0, 28.3, 45.9,
46.2, 47.8, 79.3, 155.1, 171.2; Found (EI) [M + H]+ 243.1713
C12H23O3N2, requires 243.1709; HPLC measured after conversion to
the benzoyl derivative 6k (hexane/i-PrOH 90:10, 0.5 mL/min,
Chiralcel Daicel OD) tR (D) = 15.79 min (<1%), tR (L) = 23.58
min (>99%).
Boc-L-Alanine thiomorpholine amide (6i). Yellow solid (113 mg,
41%): mp 6568 C (CH2Cl2); []25
D 3.8 (c 1.03, CHCl3); max
(solid/cm1) 3317 (NH), 2980, 2927 (CH), 1699 (CO), 1638
(CO); H (400 MHz, CDCl3) 1.29 (d, J 6.8, 3H), 1.43 (s, 9H),
2.532.61 (m, 2H), 2.632.76 (m, 2H), 3.653.75 (m, 2H), 3.80
3.89 (m, 1H), 3.994.08 (m, 1H), 4.59 (app qn, J 7.2, 1H), 5.52 (br d,
J 8.0, 1H); C (100 MHz, CDCl3) 19.3, 27.3, 27.9, 28.4, 44.8, 46.1,
48.1, 79.6, 155.0, 171.3; Found (EI) [M]+ 274.1352 C12H22O3N2S,
requires 274.1346; HPLC measured after conversion to the benzoyl
derivative 6l (hexane/i-PrOH 90:10, 0.5 mL/min, Chiralcel Daicel
OD) tR (D) = 22.20 min (8%), tR (L) = 31.86 min (92%).
Boc-L-Phenylalanine pyrrolidine amide (6j).22 Colorless oil (115
22
[]20
mg, 37%): []25
D +37.2 (c 1.0, CHCl3) [lit.
D +37.5 (c 1.0,
CHCl3)]; max (lm/cm1) 3432 (NH), 2979, 2880 (CH), 1702
(CO), 1631 (CO); H (400 MHz, CDCl3) 1.40 (s, 9H), 1.47
1.77 (m, 4H), 2.522.59 (m, 1H), 2.903.01 (m, 2H), 3.253.46 (m,
3H), 4.534.61 (m, 1H), 5.49 (br d, J 8.6, 1H), 7.167.28 (m, 5H);
C (100 MHz, CDCl3) 24.0, 25.7, 28.3, 40.2, 45.7, 46.2, 53.6, 79.5,
126.8, 128.3, 129.4, 136.6, 155.1, 170.0; HPLC (hexane/i-PrOH
90:10, 0.5 mL/min, Chiralcel Daicel OD) tR (D) = 10.09 min (4%), tR
(L) = 13.21 (96%).
Benz-L-Alanine-pyrrolidine amide (6k). White solid (118 mg,
49%): mp 8991 C (PE/EtOAc); max (solid/cm1) 3301 (NH),
3061, 2975, 2877 (CH), 1724 (CO), 1629 (CO); H (400
MHz, CDCl3) 1.42(d, J 6.8, 3H), 1.811.89 (m, 2H), 1.96 (quintet, J
6.7, 2H), 3.393.54 (m, 3H), 3.65 (dt, J 10.1, 6.7, 1H), 4.90 (quintet, J
7.0, 1H), 7.347.40 (m, 2H), 7.417.47 (m, 2H), 7.777.81 (m, 2H);
C (100 MHz, CDCl3) 18.3, 24.1, 26.0, 46.1, 46.4, 47.3, 127.1, 128.4,
131.5, 134.1, 166.4, 171.0; Found (ES) [M H]+ 245.1290
C14H17N2O2, requires 245.1291; HPLC (hexane/i-PrOH 90:10, 0.5
mL/min, Chiralcel Daicel OD) tR (D) = 17.08 min (2%), tR (L) =
28.56 min (98%).
Benz-L-Alanine-thiomorpholine amide (6l). White solid (120 mg,
45%): mp 137138 C (PE/EtOAc); max (solid/cm1) 3310 (NH),
3059, 2981, 2918 (CH), 1631 (CO); H (400 MHz, CDCl3) 1.42
(d, J 6.8, 3H), 2.522.77 (m, 4H), 3.693.80 (m, 2H), 3.89 (ddd, J
2.8, 6.6, 14.0, 1H), 4.04 (ddd, J 2.8, 6.6, 13.3, 1H), 5.07 (quintet, J 7.0,
1H), 7.377.51 (m, 4H), 7.787.83 (m, 2H); C (100 MHz,
CDCl3)19.1, 27.4, 27.9, 44.9, 45.6, 48.2, 127.1, 128.5, 131.6, 134.0,
166.4, 171.1; Found (ES) [M H]+ 277.1011 C14H17N2O2S, requires
277.1011; HPLC (hexane/i-PrOH 90:10, 0.5 mL/min, Chiralcel
Daicel OD) tR (D) = 24.26 min (4%), tR (L) = 34.28 min (96%).
(S)-N-Benzyl-2-(4-isobutylphenyl)propanamide (6m).9i Yellow
solid (294 mg, 98%): mp 7778 C (CH2Cl2); []25
D +7.2 (c 0.88,
1
CH2Cl2) [lit.9i []20
D +7.1 (c 0.88, CH2Cl2)]; max (solid/cm ) 3304
(NH), 2949, 2866 (CH), 1638 (CO); H (600 MHz, CDCl3)
0.90 (d, J 6.6, 6H), 1.55 (d, J 7.2, 3H), 1.85 (app nonet, J 6.8, 1H),
2.45 (d, J 7.0, 2H), 3.58 (q, J 7.2, 1H), 4.37 (dd, J 15.1, 5.7, 1H), 4.41
(dd, J 15.1, 5.8, 1H), 5.66 (br s, 1H), 7.107.14 (m, 4H), 7.197.29
(m, 5H); C (150 MHz, CDCl3) 18.6, 22.5, 30.3, 43.5, 45.1, 46.6,
127.3, 127.41, 127.43, 128.6, 129.6, 138.7, 138.8, 140.6, 174.7; HPLC
(hexane/i-PrOH 100:0, 0.5 mL/min, Chiralcel Daicel AD) tR (S) =
5.01 min (>99%), tR (R) = 7.41 min (<1%).
N-Benzylformamide (7a).72 Mixture of rotamers (1:0.16). Data for
major rotamer reported. White solid (139 mg, 98%): mp 6364 C
(CH2Cl2) [lit.72 6062 C]; max (solid/cm1) 3269 (NH), 3089,
3056, 2925, 2886 (CH), 1637 (CO); H (500 MHz, CDCl3) 4.41
(d, J 6.0, 2H), 6.41 (br s, 1H), 7.207.28 (m, 3H) 7.297.37 (m, 2H),
8.17 (s, 1H); C (125 MHz, CDCl3) 42.3, 127.8, 127.9, 128.9, 137.6,
161.1.
N-Phenethylformamide (7b).35 Mixture of rotamers (1:0.22). Data
for major rotamer reported. Colorless oil (152 mg, 99%): max (lm/

ASSOCIATED CONTENT

S Supporting Information
*

Copies of 1H, 13C NMR and HPLC spectra are provided. This
material is available free of charge via the Internet at http://
[Link].
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The Journal of Organic Chemistry

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [Link]@[Link]. Fax: +(44)-(0)20-76797463. Phone: +(44)-(0)20-7679-2467.

Notes

The authors declare no competing nancial interest.

ACKNOWLEDGMENTS
We would like to thank the EPSRC (Advanced Research
Fellowship EP/E052789/1 to T.D.S. and Ph.D. studentship to
P.S.) and University College London (Impact Studentship to
R.M.L.) for supporting this work. We would also like to
acknowledge GlaxoSmithKline for providing samples of some
of the carboxylic acids and amines used in this research.

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