A multigram-scale lower E-factor procedure for MIBA-catalyzed direct amidation and its application to the coupling of alpha and beta aminoacids

Article abstract of DOI:10.1039/c5gc00659g

The development of direct and atom-economical amidation methods is of high priority because of the importance of amides and peptides as components of pharmaceuticals and commodity chemicals. This article describes the identification of more economical and more practical conditions for direct amidation of carboxylic acids and amines using the MIBA catalyst (5-methoxy-2-iodophenylboronic acid, 6) and its application to the coupling of α- and β-amino acid derivatives. It is now possible to use half of the quantity of molecular sieves prescribed in the original procedure, at a higher concentration leading to a reduction of waste and a substantially improved E-factor. This procedure was validated in the multigram scale preparation of prototypical amides, including aminoacids, using toluene as the solvent. Because of substrate inhibition of the catalyst with monoprotected α-aminoacids, the use of doubly-protected N-phthaloyl α-aminoacids or α-azidoacids is required in order to produce dipeptide products in moderate yields. β-Aminoacids do not suffer from this problem, and Boc-β-aminoacids can be coupled successfully. Unlike other boronic acid catalysts, 6 is active under ambient and low-heat conditions, which helps prevent any epimerization of chiral α-aminoacid derivatives.

Full text of DOI:10.1039/c5gc00659g

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ARTICLE
A MultigramꢀScale Lower EꢀFactor Procedure for
MIBAꢀCatalyzed Direct Amidation and Its
Application to the Coupling of alpha and beta
Aminoacids
Z`Cite this: DOI:
10.1039/x0xx00000x
*
Received 00th January 2012,
Accepted 00th January 2012
Solmaz Fatemi, Nicolas Gernigon and Dennis G. Hall
DOI: 10.1039/x0xx00000x
The development of direct and atomꢀeconomical amidation methods is of high priority because
of the importance of amides and peptides as components of pharmaceuticals and commodity
chemicals. This article describes the identification of more economical and more practical
conditions for direct amidation of carboxylic acids and amines using the MIBA catalyst (5ꢀ
www.rsc.org/
methoxyꢀ2ꢀiodophenylboronic acid, 6) and its application to the coupling of αꢀ and βꢀamino
acid derivatives. It is now possible to use half of the quantity of molecular sieves prescribed in
the original procedure, at a higher concentration leading to a reduction of waste and a
substantially improved Eꢀfactor. This procedure was validated in the multigram scale
preparation of prototypical amides, including aminoacids, using toluene as the solvent.
Because of substrate inhibition of the catalyst with monoprotected
doublyꢀprotected Nꢀphthaloyl ꢀaminoacids or ꢀazidoacids is required in order to produce
dipeptide products in moderate yields. ꢀAminoacids do not suffer from this problem, and
Bocꢀ ꢀaminoacids can be coupled successfully. Unlike other boronic acid catalysts, is active
αꢀaminoacids, the use of
α
α
β
β
6
under ambient and lowꢀheat conditions, which helps prevent any epimerization of chiral
aminoacid derivatives.
αꢀ
boronic acids constitute an attractive
class of catalysts for direct amidation
Introduction
8
,9
reactions.
acid catalysts 1,
at elevated temperatures. In contrast, we
The first reported boronic
Because of the great importance of amide
units as components of pharmaceuticals,
agrochemicals, and commodity chemicals,
there is significant interest in the
development of simple methods to prepare
amide products directly from carboxylic
10,11 12 13
2,
and 3
function
1
,2
recently
reported
that
orthoꢀ
iodophenylboronic acid (5) is
a
very
efficient catalyst for direct amidation
reactions under ambient conditions (Figure
3
,4
acids and amines.
In the past decades, a
1
4
1
5
6
). Following this discovery, we designed
large number of sophisticated methods
employing dehydratingꢀactivating reagents
have been developed for direct (“in situ”)
coupling of carboxylic acids and amines.
Common
ꢀmethoxyꢀ2ꢀiodophenylboronic acid (MIBA,
)
as
an
improved,
The MIBA catalyst was found to
give higher yields within shorter reaction
times for wide range of aliphatic and
carboxylic acids and
To the best of our
catalyst (oꢀ
secondꢀgeneration
1
5
5ꢀ7
catalyst.
coupling
reagents
or
like
uronium
a
carbodiimides,
phosphonium
heteroaromatic
salts tend to be expensive and provide
poor atomꢀeconomy. Several common reagents
are known to be toxic and they are often
1
5
aliphatic amines.
knowledge,
only
4
nitrophenylboronic acid, Figure 1) has
been applied to the direct amidation of
required
in
excess.
Moreover,
they
generate large amounts of wasteful byꢀ
products that complicate the isolation of
aminoacid
inherent
peptide synthesis.
derivatives
difficulties
to
address
the
with
associated
the
desired
amide
product.
An
ideal
16
This method, however,
amidation process between carboxylic acids
and amines would be wasteꢀfree, catalytic,
operationally simple, and occur at or near
the ambient temperature. In this regard,
requires an elevated temperature and
stoichiometric amount of boronic acid
a
4
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when
dipeptides.
applied
to
the
preparation
of concentration and reaction time. Thus,
with view to improve 7the reaction’s
Environmental (E) Factor,
decrease the required amount of molecular
a
1
we aimed to
sieves
and
solvent
and
achieve
more
practical
and economical
reaction
conditions. To this end, we chose to
conduct a model amidation reaction between
phenylacetic acid (7) and pyrrolidine (8)
at an exploratory scale of 0.5 mmol at
room temperature (Table 1). Pyrrolidine
was utilized as a model substrate because
it
is
a
challenging
secondary
amine
suitable for a comparison study.
Table 1. Optimization of reactant concentration and amount of molecular
sieves in a model amidation reaction catalyzed by 6.
a
b
c
Entry
conc. (M)
0.2
0.5
0.2
0.5
1.0
1.0
0.2
0.5
mol. sieves (g)
1
1
time (h)
18
18
18
18
18
18
48
48
yield (%)
Figure 1. Known Boronic Acid Catalysts for Direct Amidation Reactions.
1
2
3
4
5
6
7
8
9
68
52
58
49
29
25
65
52
42
11
0.6
0.6
0.6
0.5
0.5
0.5
0.5
0.25
Drawbacks
procedure using boronic acids
include low reactant concentration and
the requirement for large quantity of
heatꢀactivated molecular sieves to remove
water and drive the reaction. These
impediments limit the synthetic utility of
this amidation methodology in larger scale
applications. In this Article, we address
these concerns with an optimization of the
of
our
current
catalytic
5
and
6
a
a
1.0
1.0
48
18
1
0
a
b
Relative to the amine. Powdered 4A molecular
c
sieves dried at 300 °C for 12 hours. Isolated
yields after aqueous acid-base extractions.
reaction
conditions
such
as
solvent,
The results of Table
decrease in the amount of molecular sieves
leads to a reduced yield of amide product
1
confirm that
a
reactant concentration, and the amount of
molecular sieves. An optimized procedure
for the multigram scale preparation of
(
entries
previous work,
lower at higher substrate concentration
compare entries vs 2, 3ꢀ5, 7ꢀ9).
1
vs 3). As observed in our
amides
was
evaluated,
along
with
a
15
the yield of product 9 is
feasibility study for the coupling of
aminoacid derivatives to assemble short
alphaꢀ (α) and betaꢀ (β) peptides.
(
1
Increasing the reaction time can partially
make up for the lower yield of amide
Results and discussion
product observed at 1.0
compare entries 6 vs 9). Thus, based on
the results of Table 1, reasonable
compromise consists in using 1 g of sieves
per mmol of substrate at concentration
M
concentration
(
a
Evaluation of reaction parameters to improve the E-factor.
a
Optimization of amount of molecular sieves and solvent.
of 0.5 or 1.0 M for an extended reaction
time (entries 8ꢀ9). Although the product
yield is slightly inferior compared to the
original procedure of entry 1, these new
Previous
optimization
work
in
our
a
laboratory indicated that to obtain
nearꢀquantitative yield of product within
a
short reaction time,
1
a
g
of molecular
conditions are more advantageous on
green chemistry” standpoint because
a
a
sieves was required in
reaction (in typical reactions using 50ꢀ
0.5 mmol scale
“
smaller quantity of molecular sieves is
necessary and less solvent waste is being
generated. In effect, considering solvent
1
5
100 mgs of substrates).
However, at that
comprehensive
time we did not perform
optimization of multiple variables such as
the effect of the amount of molecular
a
savings,
the
Eꢀfactor
of
these
new
conditions is almost 10 times lower.
sieves
in
combination
with
substrate
2
| J. Name., 2012, 00, 1-3
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recovered from these experiments using
acidꢀbase extractions.
Optimization of reaction solvent and temperature.
In previous studies, amidation reactions
catalyzed by arylboronic acids were found
to perform best in CH Cl2 and toluene as
2
15
solvents. Because toluene is considered a
greener reaction solvent,
1
8
we decided to
compare these two solvents again under the
conditions identified above (c.f. Table 1,
entry 9), using a reduced amount of 1 g of
molecular sieves per mmol of substrate at
a
concentration of
short reaction time of 18 hours. As shown
in Table 2, toluene was found to be
1 M for a relatively
a
better solvent under both ambient and
elevated (50 °C) temperature.
Scheme 1. Scale up of model catalytic direct amidation reactions using 5 g of
carboxylic acid. Note. Indicated temperature is oil bath temperature (CH
reflux temperature: 40 °C).
2 2
Cl
Application to the synthesis of alphaꢀpeptides.
Table 2. Optimization of the reaction solvent in a model amidation reaction
catalyzed by 6.
Evaluation of different arylboronic acid catalysts in direct amide
formation with NꢀtꢀBoc proline.
a
b
Entry
solvent
temperature (°C)
yield (%)
1
2
3
4
CH
CH
toluene
toluene
2
Cl
Cl
2
25
50
25
50
25
33
38
45
Recently, Whiting and coworkers reported
the use of catalytic amounts of 3,4,5ꢀ
trifluorophenylboronic, TFPBA, (1) and o-
nitrophenylboronic acid, oꢀNPBA, (4) in
the model direct amidation of N-tert-
c
2
2
c
a
Dry solvent. Molecular sieves: powdered 4A type
butyloxycarbonyl(Boc)ꢀproline
(12)
with
b
dried at 300 °C for 12 hours. Isolated yields
C
after aqueous acid-base extractions. Oil bath
temperature (CHCl reflux temperature: 40 °C).
16
benzylamine (Scheme 2).
2
2
Examination of the reaction’s scalability.
As described above, toluene as
a
nonꢀ
halogenated
temperature of 50 °C were identified as
the optimal conditions for achieving
solvent
and
a
reaction
a
reasonable
product
with
yield
under
of
the
model
amide
9
a higher concentration
a
decreased amount of molecular
sieves. With these optimized conditions in
hand, the reaction was then performed on a
multigram scale (5
g
(36 mmol) of 7),
which is significantly higher than the
previous largest scale of 5 mmol (~0.7 g
of 7) at which this catalytic amidation Scheme 2. Comparison of different catalysts in the amidation of Boc-proline as
1
5
16
reported by Whiting and co-workers.
was performed.
As presented in Scheme 1,
the amidation reaction of phenylacetic
acid (7) proceeded successfully giving 89%
and 46% product yields (with benzylamine Under these conditions, catalysts 1 and 4
(
10) and pyrrolidine (8) respectively). Up displayed the highest catalytic reactivity
to 60ꢀ80% of catalyst
6
was partially and were both superior to our firstꢀ
generation IBA catalyst (5) under the same
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reaction
conditions
in
refluxing both 3A and 4A molecular sieves (entries
role,
3 was obtained without any racemization. these results support the idea that the
Considering the results from the Whiting choice of solvent and molecular sieves is
fluorobenzene (85 °C). The desired product 3ꢀ4). Although temperature plays
1
a
16
group with oꢀnitrophenylboronic acid (4),
crucial
we set out to activity. We conclude that MIBA catalyst 6
reꢀevaluate the MIBA catalyst (6) in
is a superior catalyst when used in CH Cl
in
optimizing
the
catalytic
1
5
and our previous studies,
a
2
2
range of different reaction conditions as a solvent with 4A molecular sieves as
with the objective of achieving optimal the dehydrating agent (Table 3, entry 12).
conditions in the formation of peptide
bonds.
Thus,
the
comparison
between
catalysts 4 and 5 was expanded to include Stereochemical integrity in the coupling of αꢀaminoacids.
14
our improved secondꢀgeneration catalyst,
MIBA (6), in CH Cl2 or fluorobenzene as
2
Regardless
employed,
possible
optically
derivatives.
assessed catalysts
optimal conditions (fluorobenzene, 85 °C)
for their ability to preserve the optical
of
epimerization
threat in the
αꢀamino
the
amidation
method
a
solvents,
with
both
3A
and
4A
and
is
always
molecular sieves as drying agent. It was
also important to compare these catalysts
under different temperatures because of
the likelihood that they operate under
different mechanisms. The results are
presented in Table 3.
coupling
of
acid
enriched
Whiting
and
and
coꢀworkers
1
4
under their
purity of both
a
carboxyl and amine
partner in the direct formation of amides
1
6
1
3 and 14 (Table 4). We employed the same
substrates to evaluate boronic acid 6 in
the optimal conditions for this catalyst
(
CH Cl , 50 °C). The combined results shown
2
2
in
Table
4
by
highlight the
catalyst 6 in
advantage
avoiding
provided
racemization. On the contrary, although
catalyst 1 was effective for the coupling
of NꢀBoc proline (entry 7), both catalysts
1
and 4 led to partial racemization in the
Table 3. Comparison of product yields for different molecular sieves and
catalysts 4ꢀ6 in a direct amidation reaction between (Boc)ꢀproline and
benzylamine.
formation of amide 14 using phenylalanine
methyl ester (entries 5ꢀ6). It is unclear
whether the lack of epimerization with
MIBA catalyst (6) is due to its use at a
a
b
c
d
Entry catalyst
mol. sieves
3A
solvent
temp. (°C)
yield (%)
74
1
2
3
4
5
6
7
8
9
1
1
1
a
4
4
4
4
5
5
5
5
6
6
6
6
C
6
H
5
F
85
85
50
50
85
85
50
50
85
85
50
50
lower
temperature
or
to
a
different
4A
C
6
H
5
F
67
activation mechanism. Regardless, it is
the most advantageous catalyst both in
terms of activity (higher yields) (c.f.,
Table 3), and lack of epimerization.
3A
4A
CH
CH
2
Cl
Cl
2
51
42
2
2
3A
4A
C
C
6
H
H
5
F
F
48
54
6
5
3A
4A
CH
CH
2
Cl
Cl
2
60
69
2
2
3A
4A
C
C
6
H
H
5
F
F
64
74
0
1
2
6
5
3A
4A
CH
CH
2
Cl
2
82
91
2
Cl
2
Powdered 4A molecular sieves dried at 300 °C for
2 hours. Dry solvent. Oil bath temperature
b
C
1
d
Reflux temp.: CHCl 40 °C; CHF: 85 °C). Isolated
(
yields after aqueous acid-base extractions.
2
2
6
5
Compared to catalysts
activity of the electronꢀrich 5ꢀmethoxyꢀ2ꢀ
iodophenylboronic acid was enhanced in
CH Cl as a solvent and 4A molecular sieves
4
and
5,
the
6
2
2
as a dehydrating agent (entry 4 vs 8 and
1
2). However, as observed by Whiting and
16
coꢀworkers,
the reactivity of 5 (and 6)
was reduced in refluxing fluorobenzene,
and catalyst was superior in these
4
conditions (entries 1, 5, 9). In contrast,
the activity of oꢀnitrophenylboronic acid
(
4) is inferior in CH Cl , at 50 °C, with
2 2
4
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Table 4. Study of possible racemization in the direct formation of amides
from chiral amino acids.
a
c
d
Entry
product
13
13
13
14
temp. (°C)
catalyst
ee (%)
99
79
99
64
1
2
3
4
5
6
85
85
50
85
85
50
1
4
6
1
4
6
14
14
67
99
a
Reaction conditions: for entries 1, 2, 4, 5: see
reference 16. For entries 3 and 6: N-Boc proline
13) or phenylacetic acid (14) (0.55 mmol, 1.1
equiv), boronic acid (20 mol%), and benzyl amine
10) or phenylalanine methyl ester hydrochloride
0.50 mmol, 1.0 equiv) pre-neutralized with i-
Figure 2. Complexation between
boronic acids.
α-hydroxy and α-amino carboxylic acids with
(
(
(
The same failure was observed with a Bocꢀ
PrNEt(1.0 equiv) were stirred at 50 °C for 18 h in
dry CHCl containing the drying agent (1 g per
protected
(22,
primary
4).
αꢀaminoacid, glycine
In contrast, the
2
2
2
Scheme
C
mmol). Oil bath temperature (Reflux temp.: CHCl
2
2
d
0 °C; CHF: 85 °C). Measured by chiral HPLC.
corresponding βꢀaminoacid βꢀalanine (24)
was successfully coupled with benzylamine,
indicating that inhibition by boronic acid
4
6 5
Design of suitable alphaꢀaminoacid substrates.
complexation is not
a
major issue with
monoprotected βꢀaminoacids
because of the lesser stability of the
resulting 6ꢀmembered complexes.
probably
Our preliminary results for the coupling
of monoprotected αꢀamino acids containing
a
free and relatively acidic NH (i.e.,
aminoacids
unsuccessful. For example, the reaction of
Fmocꢀleucine (15) with benzylamine
other
than
proline)
were
catalyzed by MIBA (6) failed to provide
the desired amide product 16, whereas,
FmocꢀNꢀmethyl leucine (16) gave a moderate
yield of amide product 18 (Scheme 3).
Scheme 4. Coupling of Boc-glycine and Boc-
catalyzed by
β-alanine with benzylamine
6.
For
applicable
this
direct
to the
amidation
to
become
of αꢀ
preparation
peptides, the inhibitory complexation of
the catalyst must be prevented. Initially,
the use of additives such as diols that
could break the undesired complex (cf, 21)
and provide
was attempted, however in vain. We then
turned our efforts towards engineering
a way to cycle the catalyst
Scheme 3. Coupling of Fmoc leucine (15) and Fmoc N-methyl leucine (16) with
benzylamine catalyzed by 6.
suitable αꢀaminoacid substrates to avoid
the monoprotected derivatives that provide
a
free NH unit responsible for covalent
It is well documented that boronic acids
have facility to form 5ꢀmembered
complexes with bidentate substrates such
complexation of the catalyst. Thus, we
considered the use of doubly protected αꢀ
a
amino
aminoacids and amine surrogates like αꢀ
azidoacids (Figure 3). Being devoid of
free NH, complexation of the boronic acid
should be prevented, thus allowing the
catalytic amidation to proceed through the
expected acylborate intermediate.
acids
such
as
Nꢀphthaloyl
αꢀ
as αꢀhydroxy carboxylic acids and αꢀ
aminoacid derivatives (e.g., 19ꢀ20, Figure
1
9,20
a
2).
Notably, this sort of condensation
process has been employed in the design of
chiral oxazaborolidinone catalysts (20).
Thus, it is not surprising that in the
reaction of Fmocꢀalanine (15),
a
complex
could form
Figure 2). This complexation leads to
of the catalyst by the
21 between 15 and catalyst 6
(
inhibition
substrate and can explain the failure of
monoprotected, primary aminoacids such as
15 to undergo the boronic acid catalyzed
direct amidation.
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a clear preference for CH Cl as the most
2
2
effective solvent (Scheme 6).
Scheme 6. Optimization of solvent for amidation of doubly protected N-
phthaloyl α-amino acids. Note. Indicated temperature is oil bath temperature
(
2 2
CH Cl reflux temperature: 40 °C).
The corresponding three aminoesters (Gly,
Figure 3. Substrate modifications to avoid inhibitory complexation of the boronic Ala, Val) were selected as the amine
acid catalyst.
fragment,
because
with
of
tertꢀbutoxy
the orthogonality
protection
of
deprotection methods (TFA for the tꢀbutoxy
ester and hydrazine for the Nꢀphthaloyl).
Then,
different
combinations
of
both
aminoacid fragments were subjected to the
optimized reaction conditions to prepare
Synthesis of αꢀdipeptides from Nꢀphthaloyl αꢀaminoacids.
the corresponding αꢀdipeptides. Because it
is
a
study of substrate scope, the
original
reaction
conditions
at
low
To test the viability of Nꢀphthaloyl αꢀ
concentration were employed. To ensure
reaction completion in the case of slower
aminoacids, we planned to prepare
a few
simple model residues like Gly, Ala, and
amino
acid
substrates,
an
arbitrary
Val, and attempt their coupling with αꢀ
reaction time of 48
h
was chosen. The
aminoesters.
The
requisite
Nꢀphthaloyl
results are summarized in Figure 4. It was
shown possible to couple N-terminal to C-
terminal protected amino acids in good to
amino acids were easily prepared from
phthallic anhydride as shown in Scheme 5.
moderate yields at
a
reflux temperature
(
40 °C) in CH Cl . Even highly hindered
2
2
residues, exemplified by valine (28 and
1), were successfully employed to make
amide products using this simple and atomꢀ
3
economical
steric bulk
process.
in
However,
the
increased
Nꢀphthaloyl
both
aminoacid or the aminoester had
a major
negative impact on the yield. The yields
decreased continually from 60% for the
GlyꢀGly dipeptide 32 to 28% to the most
hindered ValꢀVal dipeptide 39.
Scheme 5. Synthesis of double N-protected α-amino acid.
Synthesis of αꢀdipeptides from α-azido carboxylic acids.
As discussed above, the optimal reaction
solvent in the boronic acid catalyzed
As described above, in addition to Nꢀ
phthaloyl αꢀaminoacids, αꢀazidoacids were
also considered as a viable masked form of
amidation
particular
employed.
varies
combination
Therefore, it was necessary to
depending
on
the
of
substrates
15
first
identify
the
preferred
solvent αꢀaminoacids. As with the Nꢀphthaloyl αꢀ
typically, CH Cl2 and toluene) for the aminoacids, we planned to prepare just
(
a
2
coupling of newly prepared Nꢀphthaloyl few simple residues for
aminoacids. In the event, the
a
preliminary
MIBAꢀ study of boronic acid catalyzed coupling
catalyzed amidation between Nꢀphthaloyl with αꢀaminoesters. The requisite αꢀazido
glycine (26) and benzylamine (10) revealed acids 40 and 41 were easily prepared
6
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according to literature procedures as
shown in Scheme 7.
Before embarking into a study of substrate
scope, we briefly compared the most common
solvents for the boronic acid catalyzed
amidation by using αꢀazidoalanine and
glycine tꢀbutyl ester as model substrates
(Scheme 8). This comparison revealed that
toluene would be the favored solvent for
the coupling of αꢀazido acids.
Scheme 7. Synthesis of α-azido acids.
o
at 50 C.
Figure 4. Direct amidations between doubly N-protected
α
-phthaloyl amino acids and C-protected
α
-amino acids (as free amines) catalyzed by boronic acid
6
peptides. All amide products 42ꢀ46 were
isolated in pure form and moderate yields
after
Although
simple
acidꢀbase
with
extractions.
functionalized
residues
sideꢀchains were not tested as yet, the
isolation of 46 demonstrates that αꢀ
substituted residues can be utilized.
Scheme 8. Solvent optimization for the coupling of
temperature is oil bath temperature (CH Cl reflux temperature: 40 °C).
α-azidoacids. Note. Indicated
2
2
Along with the successful example of
Scheme 8, the examples compiled in Figure
5
provide
a
promising glimpse of the
potential of αꢀazido acids towards
a
direct boronic acid catalyzed synthesis of
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Gre/Cen5GChem59istry
Scheme 9. Solvent optimization for the amidation of a monoprotected N-Boc
amino acid. Note. Indicated temperature is oil bath temperature (CH
temperature: 40 °C).
β
-
2 2
Cl reflux
As performed in the case of αꢀpeptides,
the steric tolerance of this direct
amidation method was examined using
a
small panel of βꢀamino acids and βꢀ
aminoesters. The outcome, shown in Figure
6,
is similar to the coupling of αꢀ
aminoacids. For the same reaction time,
the yield of amide products decreases
slightly with an increase of branching in
the coupling partners.
Figure
aminoesters (as free amines) catalyzed by boronic acid
5. Direct amidations between α-azido acids and C-protected α-
o
at 50 C.
6
Application to the synthesis of betaꢀdipeptides.
Evaluation of substrate scope.
As discussed above (cf., Scheme 4), βꢀ
aminoacids
protection.
do
A
not
quick
require
double
Nꢀ
of
examination
solvents for the coupling of Bocꢀβꢀalanine
with βꢀalanine ethyl ester, under a short
reaction time of
indicated that toluene is an appropriate
2
hours at 50 °C,
Figure 6. Direct amidations between N-Boc protected β-amino acid and C-
o
at 50 C.
protected β-amino acid (as free amines) catalyzed by boronic acid
6
solvent for the preparation of βꢀpeptides
(Scheme 9).
Multigram preparation of a β−peptide.
The successful multigram scale results of
Scheme
unfunctionalized
1
were
obtained
substrates.
with
To
demonstrate the suitability of our largerꢀ
scale procedure on functionalized
substrates, we targeted the preparation of
ꢀdipeptide between NꢀBoc ꢀalanine 24 as
the carboxylic acid partner, and ꢀamino
ethyl ester 50 as the amine partner
a
β
β
β
(
Scheme 10). Although
a
a
slightly higher
longer reaction
catalyst loading and
8
| J. Name., 2012, 00, 1-3
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time was required at this scale, dipeptide successfully validated in the multigram
1 was obtained from 5 grams (26.4 mmol) scale preparation of prototypical amides
toluene as relatively green
5
of Bocꢀβꢀalanine (24) in a yield that is using
actually higher than the exploratory scale
of Figure 6. This example, which was
a
solvent. The feasibility of the MIBAꢀ
catalyzed direct amidation was evaluated
achieved
featuring
with
a
the
decreased
optimal
procedure in the coupling of αꢀ and βꢀaminoacids.
quantity
of Because of substrate inhibition of the
molecular sieves (1 vs 2 g/mmol) at a high
concentration of in toluene,
demonstrates the scalability of the direct
amidation methodology catalyzed by MIBA
catalyst with monoprotected αꢀaminoacids,
1
M
the use of doublyꢀprotected Nꢀphthaloyl αꢀ
aminoacids or αꢀazidoacids is required in
order to produce αꢀdipeptide products in
(
6). From βꢀdipeptide 51, the possibility
moderate
yields.
βꢀAminoacids
do
not
for preparing longer peptides was tested
with a doubleꢀelongation affording tetraꢀ
βꢀpeptide 55 in yields similar to that
suffer from this problem, and Bocꢀβꢀ
aminoacids could be coupled successfully.
As observed previously, each substrate
obtained
for
the
first
coupling
of
class often require
solvent (e.g.,
a
different optimal
aminoester 50.
toluene
or
an
is
dicholoromethane)
environmentally
but
toluene,
acceptable
solvent,
usually the most suitable one. Of note,
unlike other boronic acid catalysts, the
remarkable ability of boronic acid
act as a catalyst under ambient and lowꢀ
heating conditions most likely played
6
to
a
key role in preventing any epimerization
of αꢀaminoacid derivatives. Furthermore,
this procedure generates only water as
a
byꢀproduct, and affords pure dipeptide
products after simple filtration and
a
acid–base
unreacted
recyclable
although
extractions
substrates
catalyst.
to
and
In
catalysts
remove
recover
conclusion,
and an
any
the
improved
alternate waterꢀremoval strategy may be
desirable in order to provide general,
a
practical, and higherꢀyielding methodology
for the direct synthesis of αꢀ and βꢀ
peptides, this study makes
a significant
step towards this important objective.
Experimental section
General information.
Scheme 10. Scale up synthesis of β-dipeptide 51 using 5.0 g (26.4 mmol) of Boc-
Unless otherwise stated, all reactions
were performed under a nitrogen atmosphere
using flameꢀdried glassware. Dry toluene,
THF and dichloromethane were obtained from
β-Ala-OH (24) by a direct amidation catalyzed by 6, followed by elongation to
tetrapeptide 55.
β-
a
double cartridge solvent purification
Conclusions
system. The indicated reaction temperature
is that of the oil bath. Analytical thin
layer chromatography was performed on
Merck Silica Gel 60 F254 plates and was
visualized with UV light and KMnO4 stain.
NMR spectra were recorded on 400, or 500
MHz instruments. The residual solvent
This article described the identification
of more economical, practical conditions
for a direct amidation using 5ꢀmethoxyꢀ2ꢀ
iodophenylboronic acid (MIBA, 6) as the
catalyst. It is now possible to use half
1
13
of
prescribed in the original procedure, at a
higher concentration leading to
reduction of waste and substantially
improved Eꢀfactor. This
operationally simple procedure
the
quantity
of
molecular
sieves
protons ( H) or the solvent carbon ( C)
1
were used as internal standards.
data are presented as follows: chemical
shift in ppm downfield from
tetramethylsilane (multiplicity, coupling
constant (J), integration). The following
HꢀNMR
a
a
(δ)
mild
and
was
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Gre/Cen5GChem59istry
abbreviations are used in reporting NMR and the mixture was stirred for 10 min.
data: singlet, doublet, dd
Then, pyrrolidine (8) (41 L, 0.50 mmol,
doublet of 1.0
equiv) was added.
doublet of mixture was stirred for 18
s
=
d
=
=
ꢁ
The
doublet of doublets, ddd
doublet of doublets, dt
triplets,
doublets, m = multiplet, q = quartet, qd = was filtered through a pad of Celite® 545,
quartet of doublets, qdt
doublet of triplets, qt
triplets, app
singlet. Estimated accuracy of J: (+/ ) solution (15 ml) and brine (15 ml). The
.5 Hz. Highꢀresolution mass spectra (TOF organic layer was collected, dried over
analyzer)
electron
=
=
=
resulting
h at room
o
t
=
triplet, td
triplet of temperature or 50 C. The reaction mixture
=
=
quartet of which was rinsed with CH Cl (15 ml). The
quartet of filtrate was then washed with 1M aqueous
2
2
= apparent, br. s = broad acidic solution (15 ml), 1M aqueous basic
_
0
were
impact
(ESI)
recorded
(EI) or
techniques.
using
electrospray to yield the pure amide product 9.
Infrared
either anhydrous Na SO , filtered and evaporated
2 4
ionization
spectra were obtained with frequencies
expressed in cm . Infrared spectra were Organocatalytic Direct Amidation (Scheme
General
Procedure
for
Multigram
−
1
obtained on
frequencies
a
Nicolet MagnaꢀIR 750 with 1). Into
a
250 mL round bottom flask

1
expressed
in
cm .
The equipped with
a
stir
(7)
bar was
(36 mmol,
added
1.1
enantiomeric excesses for chiral compounds phenylacetic
acid
were determined using
instrument using
ChiralpakꢀAS columns under UV detection mmol of amine substrate) of activated 4A
in comparison to racemic products). molecular sieves. Toluene was added to
Powdered 4A molecular sieves (< 5 micron, maintain
concentration at and the
Aldrich) were dried overnight in an oven mixture was stirred. After 10 minutes, the
a
HPLC Agilent equiv), 5ꢀmethoxyꢀ2ꢀiodophenylboronic acid
ChiralcelꢀOD
or (6) (3.3 mmol, 10 mol%) and 33 g (1 g per
(
a
1 M
o
(
300 C) for >12 h prior to use. All the amine (33 mmol, 1.0 equiv) was added. The
different catalysts were stored in
fridge, under inert atmosphere.
a
resulting mixture was stirred for 18 h at
o
50 C. The reaction mixture was filtered
through
a
pad of Celite 545, which was
General
Optimization
Procedure
for
of
and
Table
1
rinsed with CH Cl (50 ml). The filtrate
2
2
(
of
Amount
Molecular was washed with
a
1M aqueous acidic
Sieves
and
Solvent)
Tables
2
solution (4
x
x
50 ml), 1M aqueous basic
50 ml) and brine (50 ml).
(
Optimization of Reaction Solvent and solution (4
Temperature). Into
a 25 ml round bottom The combined aqueous solutions were back
flask equipped with a stir bar was added extracted with CH Cl (4 x 50 mL), then the
2
2
phenyl acetic acid (7) (75.0 mg, 0.55 combined organic layers were dried over
mmol, 1.1 equiv),
5ꢀmethoxyꢀ2ꢀ anhydrous Na SO , filtered and evaporated
2
4
iodophenylboronic acid (6) (13.9 mg, 0.05 to dryness to yield the title amide
mmol, 10 mol%) and the indicated amount of product.
activated 4A molecular sieves. Solvent (in
the indicated concentration) was added and
the mixture was stirred for 10 min. Then, Phenyl-1-pyrrolidin-1-yl-ethanone (9). The
pyrrolidine (8) (41 L, 0.50 mmol, 1.0 title compound was prepared using the
equiv) was added. The resulting mixture general
was stirred for 18ꢀ48 at room organocatalytic
Preparation and Characterization Data of
ꢁ
procedure
for
the
multigram
affording
h
amidations,
temperature. The reaction mixture was 2.893 g of product 9 in a 46% yield, 1.83
filtered through pad of Celite® 545, in 29% yield, in toluene and CH Cl
which was rinsed with CH Cl (15 ml). The respectively. Characterization data of the
a
g
2
2
2
2
filtrate was then washed with 1M aqueous product
acidic solution (15 ml), 1M aqueous basic literature.
solution (15 ml) and brine (15 ml). The
matched
that
found
in
the
2
1
organic layer was collected, dried over
Preparation and Characterization Data of
(11). The
title compound was prepared using the
anhydrous Na SO , filtered and evaporated N-Benzyl-2-phenyl-acetamide
2
4
to yield pure amide product 9.
general
organocatalytic
procedure
for
the
multigram
affording
General Procedure for
Table
2
amidations,
(Optimization of the reaction solvent and 6.693 g of 11 and 89% yield, 5.415 g of 11
temperature in a model amidation reaction and 72% yield, in toluene and CH Cl
2
2
catalyzed by 6). Into a 25 ml round bottom respectively. Characterization data of the
flask equipped with a stir bar was added product
phenyl acetic acid (7) (75.0 mg, 0.55 literature.
matched
that
found
in
the
2
2
mmol,
1.1
equiv),
5ꢀmethoxyꢀ2ꢀ
iodophenylboronic acid (6) (13.9 mg, 0.05
General
Procedure
for
Table
3:
mmol, 10 mol%) and 0.5 g of activated 4A Comparison of product yields for catalysts
molecular sieves. Solvent [1 M] was added 4-6 in a direct amidation reaction between
1
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DOI: 10.1039/C5GC00659G
(
Boc)-proline and benzylamine. Into
ml round bottom flask equipped with a stir vigorously for 10 min. Then, benzylamine
bar was added N-tert- (10) (55
L, 0.50 mmol, 1.0 equiv) was
butyloxycarbonyl(Boc)ꢀproline (12) (108 added to the reaction mixture using
mg, 0.50 mmol, 1.0 equiv), catalysts 4ꢀ6
a 25 was added, and the mixture was stirred
ꢁ
a
gastight 100ꢀ
ꢁ
L
syringe. The resulting
(
0.1 mmol, 20 mol%) and 1 g of activated
or 3A molecular sieves. Solvent [0.07
solution was stirred for 12
temperature. The reaction mixture was
filtered through pad of Celite 545,
which was rinsed with CH Cl (15 ml). The
h
at room
4A
M] was added to the mixture and was
stirred for 10 min. Then, benzylamine (10)
a
2
2
(
55
ꢁ
L, 0.5 mmol, 1.0 equiv) was added. filtrate was washed sequentially with a 1M
acidic solution (15 ml), 1M
at 50 or 85 C. The reaction mixture was aqueous basic solution (15 ml) and brine
filtered through pad of Celite 545, (15 ml). The organic layer was collected,
The resulting mixture was stirred for 18 h aqueous
o
a
®
which was rinsed with CH Cl2 (50 ml). The dried over anhydrous Na SO , filtered and
filtrate was washed with
2
2
4
a
1M aqueous evaporated to yield product 18 (0.196 g,
acidic solution (15 ml), 1M aqueous basic 86% yield).
solution (15 ml) and brine (15 ml). The
organic
layer
collected,
dried
over
General
Procedure
and
Product
anhydrous Na SO , filtered and evaporated Characterization for Scheme 4 (Coupling of
to yield the title compound 13 as a pure
product. Characterization data of the
product
2
4
Boc-glycine
benzylamine catalyzed by 6). Into a 25 mL
roundꢀbottom flask equipped with
magnetic stir bar was added Bocꢀ ꢀAlanine
104 mg, 0.55 mmol, 1.1 equiv), 5ꢀmethoxyꢀ
ꢀiodophenylboronic acid (14 mg, 0.05
of activated 4A
and
Boc-
β
-alanine
with
matched
that
found
in
the
a
16
literature.
β
(
2
General
Procedure
for
Study
of
6
Stereochemical Integrity (Table 4). Into a
mmol, 10 mol%) and
1 g
25 ml round bottom flask equipped with a
molecular sieves. Dichloromethane (7 mL)
was added and the mixture was stirred
vigorously for 10 min. Then, benzylamine
stir bar was added NꢀBoc proline (13) or
phenylacetic acid (14) (0.55 mmol, 1.1
equiv), 5ꢀmethoxyꢀ2ꢀiodophenylboronic acid
(
55
the reaction mixture using
00ꢀ L syringe. The resulting solution was
stirred for 2 h at room temperature. The
reaction mixture was filtered through
ꢁ
L, 0.50 mmol, 1.0 equiv) was added to
(
(
6) (0.10 mmol, 20 mol%), and benzyl amine
10) or phenylalanine methyl ester
a
Gastight®
1
ꢁ
hydrochloride (0.50 mmol, 1.0 equiv) preꢀ
neutralized with iꢀPr NEt (0.50 mmol, 1.0
equiv) were stirred at 50 °C for 18 h in
2
a
pad of Celite 545, which was rinsed with
CH Cl (50 ml). The filtrate was washed
dry CH Cl containing 1 g of activated 4A
2
2
2
2
molecular sieves. The reaction mixture was
filtered through pad of Celite 545,
which was rinsed with CH Cl2 (15 ml). The
sequentially with
solution (15 ml),
a
1M aqueous acidic
1M aqueous basic
a
®
2
solution (15 ml) and brine (15 ml). The
organic layer was collected, dried over
anhydrous Na SO , filtered and evaporated
to yield pure product 25. tꢀButyl (3ꢀ
Benzylamino)ꢀ3ꢀoxopropyl)carbamate 25.
This compound was prepared using the
coupling of Bocꢀ ꢀalanine with benzylamine
catalyzed by 6. Yield: 86%. H NMR (CDCl
00 MHz): = 7.32 (m, 5 H), 6.02 (br. s, 1
filtrate was washed with
a
1M aqueous
acidic solution (15 ml), 1M aqueous basic
solution (15 ml) and brine (15 ml). The
organic layer was collected, dried over
anhydrous Na SO , filtered and evaporated
2
4
(
2
4
to yield the pure amide products 13 and
β
14. Characterization data of the products
1
16
,
3
matched that found in the literature.
HPLC analysis for 13: Chiralcel IB, 50:50
4
δ
H), 5.21 (br. s, 1 H), 4.42 (d, J = 5.7
Hz, 2H), 3.42 (dt, J = 6.2, 6.0 Hz, 2H),
.41 (t, J = 6.0 Hz, 2 H), 1.43 (s, 9H);
H O/CH CN, 0.5 mL/minute,
λ
= 250 nm, Tmajor
2
3
=
20.8 min, Tminor = 20.1 min, ee = 95%.
HPLC analysis for 14: Chiralcel IC, 50:50
iꢀPrOH/Hexanes, 0.5 mL/minute, = 210 nm,
Tmajor 17.9 min, Tminor 9.2 min, ee
00%.
2
13
C
NMR (100.6 MHz, CDCl ):
δ
=
171.2,
56.1, 138.1, 128.8, 127.9, 127.6, 79.4,
3.6, 36.7, 36.3, 28.4 (3 C); IR
3
λ
1
4
(
1
1
2
=
=
=
1

1
Microscope, cm ) 3289, 3087, 2949, 2921,
776, 1728, 1660, 1561; HRMS (ESI) for
General
Characterization for Scheme 3 (Coupling of
Fmoc -aminoacids with benzylamine
catalyzed by 6). Into a 25 mL roundꢀbottom
flask equipped with magnetic stir bar
was added FmocꢀNꢀMeꢀLꢀLeuꢀOH (202 mg, 0.55
mmol,
iodophenylboronic acid
mmol, 10 mol%) and
Procedure
and
Product
+
C H N O (M+H) : calcd. 279.1703; found,
5 23 2 3
79.1700.
α
General Procedure for Preparation of L-
N-Phthaloyl Amino Acids 26-28 (Scheme 5).
a
These
described
Characterization
substrates
were
reference
of the
prepared
as
23.
1.1
equiv),
5ꢀmethoxyꢀ2ꢀ
(14 mg, 0.05
of activated 4A
in
6
data
product
1
g
23
matched that found in the literature.
molecular sieves. Dichloromethane (7 mL)
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General Procedure for Preparation of L- 2 H), 1.76 (s, 9 H), 1.42 (d, J = 7.0 Hz,
1
3
α
-Azido Acids Acids 40 and 41 (Scheme 7). 3H); C NMR (100.6 MHz, CDCl ):
δ
= 169.0,
as 168.9, 167.8, 134.3, 131.9, 123.6, 82.5,
24. 49.3, 42.4, 28.0 (3 C), 15.3; IR
product (Microscope, cm ) 3306, 3067, 2980, 2936,
3
These
described
Characterization
matched that found in the literature.
CAUTION: These low C+O/N ratio compounds C H N O (M+H) : calcd. 333.1445; found,
substrates
were
reference
of the
prepared
in

1
data
24
1776, 1725, 1650, 1540; HRMS (ESI) for
+
1
7 21 2 5
are potentially explosive.
They were 333.1445.
prepared according to recommended safety
precautions for preparing and handling
small organic azides, in a small scale (< yl)acetyl)-L-leucinate
t-Butyl
(2-(1,3-Dioxoisoindolin-2-
34. The title
g), and they were employed immediately compound was prepared using the general
1
after isolation.
procedure for dipeptide synthesis, 6 as a
catalyst (25 mol%) and CH Cl as a solvent.
2
2
1
General
Synthesis Using Catalyst 6 (Figures 4-6). 7.89 (m, 2 H), 7.78 (m, 2 H), 6.20 (br. d,
Into 25 mL roundꢀbottom flask equipped J = 8.2 Hz 1 H), 4.54 (ddd, J = 8.2, 8.1,
with a magnetic stir bar was added the Lꢀ 5.7 Hz, 1 H), 4.40 (m, 2 H), 1.50ꢀ1.70 (m,
αꢀazido/Nꢀphthaloyl amino acid or
ꢀN-Boc 3 H), 1.42 (s, 9 H), 0.96 (d, J = 6.5 Hz,
amino acid (0.55 mmol, 1.1 equiv), 2ꢀiodoꢀ 6 H); C NMR (100.6 MHz, CDCl ):
Procedure
for
Dipeptide Yield: 34%. H NMR (CDCl , 400 MHz):
δ =
3
a
β
13
δ
= 171.9,
ꢀmethoxyphenylboronic acid 6 (0.10 mmol, 167.7, 165.4, 134.2, 132.1, 123.6, 82.3,
0 mol%) and 1 g of activated 4A molecular 51.7, 42.2, 40.7, 28.0 (3 C), 24.9, 22.7,
3
5
2

1
sieves. Dichloromethane or toluene (7 mL) 22.3; IR (Microscope, cm ) 3333, 3067,
was added (see the respective figures), 2959, 2871, 1776, 1725, 1543, 1468; HRMS
and the mixture was stirred vigorously for (ESI) for C H N O (M+H) : calcd. 375.1914;
+
2
0
27
2
5
1
(
0
min. Then,
0.50 mmol, 1.0 equiv) was added to the
gastight 100ꢀ
solution was
stirred for 48 h in a sealed flask at 50
temperature. The reaction mixture was
filtered through pad of Celite 545,
which was rinsed with CH Cl2 (50 ml). The (CDCl
α
or
β
ꢀamino alkyl ester found, 375.1914.
reaction mixture using
syringe. The resulting
a
ꢁ
L
t-Butyl
yl)propanoyl)glycinate
(S)-(2-(1,3-Dioxoisoindolin-2-
35.
The
title
compound was prepared using the general
procedure for dipeptide synthesis and
°C
1
CH Cl as
a
solvent. Yield: 52%.
, 400 MHz):
filtrate was washed sequentially with a 1M (m, 2 H), 6.58 (br. s, 1 H), 5.00 (q, J =
H
NMR
a
2
2
δ = 7.89 (m, 2 H), 7.78
2
3
aqueous acidic solution (2
aqueous basic solution (2
brine (2 x 15 ml). The organic layer was
x
x
15 ml), 1M 7.2 Hz, 1 H), 3.90 (d, J = 4.8 Hz, 2 H),
15 ml) and 1.80 (d, J = 7.3 Hz, 3 H), 1.42 (s, 9 H);
13
C
NMR (100.6 MHz, CDCl ):
δ
=
169.0,
3
collected, dried over anhydrous Na SO , 168.7, 167.8, 134.3, 131.9, 123.6, 82.6,
2
4
filtered and evaporated to yield dipeptide 49.3,
42.4,
28.0
(3
C),
15.3;
IR

1
products
purity.
in
a
satisfactory
level
of (Microscope, cm ) 2967, 1596, 1458, 1377,
1265, 1232, 998; HRMS (ESI) for C H N O
1
7 21 2 5
+
(M+H) : calcd. 333.1445; found, 333.1445.
t-Butyl
(2-(1,3-Dioxoisoindolin-2-
yl)acetyl)glycinate 32. The title compound
was prepared using the general procedure yl)propanoyl)-L-alaninate 36. The title
t-Butyl
((S)-2-(1,3-Dioxoisoindolin-2-
for dipeptide synthesis and CH Cl as
solvent. Yield: 60%. M.p. 165ꢀ166 C;
a
H
compound was prepared using the general
2
2
o
1
procedure for dipeptide synthesis and
1
NMR (CDCl , 400 MHz):
δ
= 7.89 (m, 2 H), CH
2
Cl
2
as
a
solvent. Yield: 46%.
H
NMR
3
7
2
9
1
4
.78 (m, 2 H), 6.40 (br. s, 1 H), 4.40 (s, (CDCl , 400 MHz):
δ
= 7.89 (m, 2 H), 7.78
3
H), 3.98 (d, J = 4.8 Hz, 2 H), 1.42 (s, (m, 2 H), 6.62 (br. s, 1 H), 4.90 (q, J =
1
3
H); C NMR (100.6 MHz, CDCl ):
δ
= 168.6, 7.3 Hz, 1 H), 4.40 (m, 1 H), 1.78 (d, J =
67.8, 165.9, 134.2, 132.0, 123.6, 82.6, 7.3 Hz, 3 H), 1.42 (s, 9 H), 1.40 (d, J =
3
1
3
2.4, 40.6, 28.0 (3 C); IR (Microscope, 7.0 Hz, 3 H); C NMR (100.6 MHz, CDCl ):
δ
3

1
cm ) 3306, 3087, 2976, 2931, 1776, 1728,
=
172.0, 168.3, 167.8, 134.2, 131.9,
+
1
660, 1561; HRMS (ESI) for C H N O (M+H) : 123.6, 82.2, 49.3, 49.0, 28.5 (3 C), 18.6,
16 19 2 5
1
calcd. 319.1288; found, 319.1290.
15.3; IR (Microscope, cm ) 3347, 3063,
980, 2936, 1715, 1682, 1531, 1457; HRMS
2
+
t-Butyl
(2-(1,3-Dioxoisoindolin-2- (ESI) for C H N O (M+H) : calcd. 347.1601;
1
8
23
2
5
yl)acetyl)-L-alaninate
33.
The
title found, 347.1602.
compound was prepared using the general
procedure for dipeptide synthesis and
t-Butyl
((S)-2-(1,3-Dioxoisoindolin-2-
1
CH Cl as
a
solvent. Yield: 52%.
H
NMR yl)propanoyl)-L-leucinate 37. The title
2
2
(
(
4
CDCl , 400 MHz):
δ
= 7.89 (m, 2 H), 7.78 compound was prepared using the general
3
m, 2 H), 6.60 (br. d, J = 6.9 Hz, 1 H), procedure for dipeptide synthesis,
.48 (app pent, J = 7.0 Hz, 1 H), 4.38 (m, the catalyst (25 mol%) and CH Cl
6
as
a
as
2
2
1
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 2012

Page 13 of 16
Journal Name
Green Chemistry
View Article Online
ARTICLE
DOI: 10.1039/C5GC00659G
1
+
solvent. Yield: 31%.
MHz):
= 7.89 (m, 2 H), 7.78 (m, 2 H), 251.1115; found, 251.1117.
.42 (br. S, 1 H), 4.96 (q, J = 7.5 Hz, 1
H), 4.45 (m, 1 H), 1.75 (d, J = 7.3 Hz, 3
H), 1.43ꢀ1.68 (m, H), 1.42 (s,
H), The title compound was prepared using the
.94 (d, J = 6.3 Hz, 6 H);
C NMR (100.6 general procedure for dipeptide synthesis
MHz, CDCl ): 171.8, 168.6, 167.7,
34.2, 131.9, 123.5, 82.0, 53.8, 51.7, NMR (CDCl
2.0, 28.0 (3 C), 24.9, 22.7, 22.3, 15.3; H), 4.00 (s, 2 H), 3.98 (d, J = 5.3 Hz, 2
H
NMR (CDCl3, 400 HRMS (ESI) for C H N NaO (M+Na) : calcd.
9 16 4 3
δ
6
t-Butyl
(2-Azidoacetyl)glycinate
43.
3
9
13
0
1
and toluene as the solvent. Yield: 62%.
H
δ
=
3
1
4
3
, 400 MHz): = 6.80 (br. s, 1
δ

1
13
IR (Microscope, cm ) 3356, 3066, 2960, H), 1.51 (s,
9
H);
C
NMR (100.6 MHz,
2
872, 1780, 1718, 1684,+ 1531, 1469; HRMS CDCl ):
δ = 168.0, 166.2, 82.2, 52.1, 41.3,
3
1
(
ESI) for C H N O (M+H) : calcd. 389.2071; 27.6 (3 C); IR (Microscope, cm ) 3323,
2
1 29 2 5
found, 389.2064.
3082, 2979, 2935, 1735, 1716, 1653, 1527,
+
1
449; HRMS (ESI) for
(S)-(2-(1,3-Dioxoisoindolin-2- calcd. 237.0958; found, 237.0956.
yl)-4-methylpentanoyl)glycinate 38. The
title compound was prepared using the
C
H
N
NaO
(M+Na) :
8
14
4
3
t-Butyl
t-Butyl (2-Azidoacetyl)-L-alaninate 44.
general procedure for dipeptide synthesis The title compound was prepared using the
1
and CH Cl as a solvent. Yield: 44%. H NMR general procedure for dipeptide synthesis
2
2
1
(
(
1
CDCl , 400 MHz):
δ
= 7.89 (m, 2 H), 7.78 and toluene as the solvent. Yield: 58%.
m, 2 H), 6.65 (br. s, 1 H), 4.49 (dd, J = NMR (CDCl , 400 MHz): = 6.90 (br. s, 1
1.4, 4.8 Hz, 1 H), 3.90 (d, J = 4.8 Hz, 2 H), 4.51 (app. pent, J = 7.2, 1 H), 4.00
H
3
δ
3
H), 2.42 (ddd, J = 13.9, 11.4, 4.4 Hz, 1 (s, 2 H), 1.51 (s, 9 H), 1.41 (d, J = 7.2
1
3
H), 1.83 (ddd, J = 14.0, 9.6, 4.8 Hz, 1 Hz, 3 H);
H), 1.44ꢀ1.49 (m, H), 1.42 (s, H), 171.7, 166.0, 82.4, 52.6, 48.6, 28.0 (3
.95 (d, J = 6.6 Hz, 3 H), 0.94 (d, J = C), 18.6; IR (Microscope, cm ) 3311, 3072,
C NMR (100.6 MHz, CDCl ): δ =
3
1
9

1
0
6
=
1
2
3
1
1
3
.6 Hz, 3 H); C NMR (100.6 MHz, CDCl ):
δ
2981, 2934, 2108, 1735, 1664, 1535, 1479;
169.2, 168.7, 168.2, 134.2, 131.7, HRMS (ESI) for
23.6, 82.4, 53.0, 42.3, 37.4, 28.0 (3 C), 251.1115; found, 251.1113.
3
+
C
H
N
NaO
(M+Na) : calcd.
9
16
4
3

1
5.3, 23.1, 21.2; IR (Microscope, cm )
342, 3067, 2962, 2873, 1716, 1681, 1537,
t-Butyl (2-Azidoacetyl)-L-leucinate 45.
(M+H) : The title compound was prepared using the
+
469; HRMS (ESI) for C H N O
2
0 27 2 5
calcd. 375.1914; found, 375.1916.
general procedure for dipeptide synthesis
1
and toluene as the solvent. Yield: 50%.
((S)-2-(1,3-Dioxoisoindolin-2- NMR (CDCl , 400 MHz):
H
t-Butyl
yl)-4-methylpentanoyl)-L-leucinate 39. The 8.4 Hz, 1 H), 4.50 (ddd, J = 8.5, 8.5, 5.2
title compound was prepared using the Hz, 1H), 4.00 (s,
H), 1.51ꢀ1.72 (m,
δ
= 6.70 (br. d, J =
3
2
3
general procedure for dipeptide synthesis, H), 1.46 (s, 9 H), 0.95 (d, J = 6.0 Hz, 3
13
6
as the catalyst (25 mol%) and CH Cl as H), 0.94 (d,
J
=
6.2 Hz,
3
H);
C NMR
2
2
1
solvent. Yield: 28%.
H
NMR (CDCl3, 400
(100.6 MHz, CDCl ):
δ
= 171.7, 166.2, 82.2,
3
MHz):
δ = 7.89 (m, 2 H), 7.78 (m, 2 H), 52.5, 52.1, 41.7, 27.6 (3 C), 24.9, 22.8,
1
6
=
7
1
.60 (br. d, J = 8.0 Hz, 1 H), 4.94 (dd, J 22.0; IR (Microscope, cm ) 3317, 3070,
11.3, 5.0 Hz, 1 H), 4.50 (ddd, J = 13.5, 2961, 2935, 2107, 1736, 1665, 1537, 1471;
+
.5, 5.3 Hz,
.42 (s, H), 0.94 (m, 12 H);
100.6 MHz, CDCl ):
1
H), 1.43ꢀ1.70 (m,1
6
C
H), HRMS (ESI) for C H N NaO (M+Na) : calcd.
12 22 4 3
NMR 293.1584; found, 293.1585.
3
9
(
1
5
2
δ
=
171.3, 168.3,
3
67.7, 133.8, 131.2, 123.1, 81.5, 52.7,
1.2, 41.5, 37.0, 27.5 (3 C), 24.8, 24.5, leucinate 46. The title compound was
2.6, 22.4, 21.7, 20.8; IR (Microscope, prepared using the general procedure for
t-Butyl
((S)-2-Azidopropanoyl)-L-

1
cm ) 3348, 3062, 2959, 2872, 1717, 1683, dipeptide synthesis and toluene as the
+
1
1
529, 1469; HRMS (ESI) for C H N O (M+H) : solvent. Yield: 41%.
H
NMR (CDCl3, 400
= 6.70 (br. s, 1 H), 4.47 (ddd, J =
.4, 8.4, 5.3 Hz, 1 H), 4.08 (q, J = 7.0
2
4 35 2 5
calcd. 431.2540; found, 431.2539.
MHz): δ
8
t-Butyl (S)-(2-Azidopropanoyl)glycinate Hz, 1 H), 1.60ꢀ1.70 (m, 3 H), 1.54 (d, J =
2. The title compound was prepared using 7.0 Hz, 3 H), 1.46 (s, 9 H), 0.95 (d, J =
4
the
synthesis an1d toluene as the solvent.
Yield: 70%. H NMR (CDCl , 400 MHz):
general
procedure
for
dipeptide 6.5 Hz, 3 H), 0.94 (d, J = 6.0 Hz, 3 H);
1
3
C
NMR (100.6 MHz, CDCl ):
δ
=
171.7,
169.4, 82.2, 59.2, 51.3, 41.7, 28.0 (3 C),
.80 (br. s, 1 H), 4.15 (q, J = 7.0 Hz, 1 25.0, 22.7, 22.1, 17.1; IR (Microscope,
3
δ
=
3
6

1
H), 3.95 (d, J = 5.1 Hz, 1 H), 3.94 (d, J cm ) 3311, 3082, 2960, 2873, 2115, 1737,
=
1
=
5.2 Hz, 1 H), 1.58 (d, J = 7.0 Hz, 3 H), 1660,
1536,
3
1470;
HRMS
(ESI)
for
1
3
+
.45 (s, 9 H); C NMR (100.6 MHz, CDCl ):
δ
C H N NaO (M+Na) : calcd. 307.1741; found,
3
13 24
4
169.9, 168.5, 82.6, 59.0, 41.9, 28.0 (3 307.1741.

1
C), 17.0; IR (Microscope, cm ) 3306, 3094,
981, 2935, 2110, 1743, 1665, 1540, 1478;
2
This journal is © The Royal Society of Chemistry 2012
J. Name., 2012, 00, 1-3 | 13

Green Chemistry
Page 14 of 16
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ARTICLE
DOI: 10.10
G
3
r
9
e
/Cen5G
C
C
h
0
e
06
m
59is
G
try
Ethyl
3-(3-((t- 400 MHz):
δ = 6.40 (br. s, 1 H), 5.30 (br.
Butoxycarbonyl)amino)propanamido)propanoat
s, 1 H), 4.18 (m, 1 H), 4.11 (q, J = 7.2
48. The title compound was prepared Hz, 2 H), 3.96 (m, 1 H), 2.58 (m, 2 H),
using the general procedure for dipeptide 2.38 (m, 2 H), 1.40 (s, 9 H), 1.22 (t, J =
e
1
3
synthesis and toluene as the solvent. 7.1 Hz, 3 H), 1.15ꢀ1.20 (m, 6 H);
C NMR
171.6, 169.5,
= 6.40 (br. s, 1 H), 5.20 (br. 154.9, 78.7, 60.6, 43.6, 42.3, 41.5, 39.5,
s, 1 H), 4.14 (q, J = 7.2 Hz, 2 H), 3.50 27.9
(3 C),  20.5, 19.5, 13.7; IR
td, J = 6.2, 6.2 Hz, 2 H), 3.36 (td, J = (Microscope, cm ) 3305, 3071, 2978, 2934,
.2, 6.2 Hz, 2 H), 2.52 (t, J = 6.2 Hz, 2 1737, 1715, 1689, 1649, 1525, 1454; HRMS
o
1
Yield: 60%. M.p. 59ꢀ61 C;
00 MHz):
H NMR (CDCl3,
(100.6
MHz, CDCl ):
δ
=
3
4
δ
1
(
6
+
H), 2.36 (t, J = 6.2 Hz, 2 H), 1.42 (s, 9 (ESI) for C H N O (M+H) : calcd. 317.2071;
15
29
2
5
1
3
H), 1.22 (t, 7.2 Hz, 3 H);
MHz, CDCl ): = 172.5, 171.4, 156.1, 79.2,
0.7, 36.7, 36.2, 34.8, 34.0, 28.4 (3 C), Multigram
C NMR (100.6 found, 317.2070.
δ
3
6
1
2
Scale
Preparation
and

1
4.1; IR (Microscope, cm ) 3323, 3082, Characterization Data of Dipeptide 51
979, 2935, 1735, 1716, 1653, 1527, 1449; (Scheme 10). The title compound was
(25 mol%) and
the general procedure for the multigram
organocatalytic amidations, 5.0 (26.4
+
HRMS (ESI) for C H N O (M+H) : calcd. prepared using catalyst
6
1
3 25 2 5
289.1758; found, 289.1760.
g
Ethyl
3-(3-((t- mmol) of BocꢀβꢀAlaꢀOH (24) and 3.25 mL
Butoxycarbonyl)amino)propanamido)butanoate
1. The title compound was prepared using
the general procedure for
synthesis and toluene as the solvent.
(24.0 mmol) of 3ꢀaminobutanoic acid ethyl
5
ester (50), in toluene at 55 °C, affording
dipeptide 4.629
yield.
g
of 51 in high purity and 58%
o
1
Yield: 52%. M.p. 64ꢀ66 C; H NMR (CDCl3,
4
00 MHz): = 6.20 (br. s, 1 H), 5.20 (br. General Procedure for the Boc-Deprotection
δ
s, 1 H), 4.38 (m, 1 H), 4.22 (q, J = 6.1 of Scheme 10, step i. To the Bocꢀprotected
o
Hz, 2 H), 3.38 (dt, J = 6.2, 6.2 Hz, 2 H), compounds 51 or 54 (3.00 mmol) at 0 C was
2
6
6
.44 (d, J = 5.4 Hz, 2 H), 2.31 (t, J = added a TFA:DCM solution (1:2 ratio, 0.3
.2 Hz, 2 H), 1.40 (s, 9 H), 1.25 (t, J = M) and the mixture was stirred for
.6 Hz, 3 H), 1.20 (d, J = 6.7 Hz, 3 H); hours.
The reaction mixture
171.5, concentrated under reduced
8
was
pressure;
1
3
C
NMR (100.6 MHz, CDCl ):
δ
=
3
2
5
1
3
(
1
70.4, 155.6, 78.7, 60.1, 41.5, 40.0, affording products in 80%ꢀ87% yield.
6.1, 35.8, 27.9 (3C), 19.5, 13.6; IR
Microscope, cm ) 3311, 3078, 2979, 2935, General
736, 1716, 1648, 1529, 1454; HRMS (ESI) Characterization for the Synthesis of tri-

1
Procedure
and
Product
+
for
C H N O
14 27 2 5
(M+H) :
calcd.
303.1914; and tetrapeptides 54 and 55 (Scheme 10,
step ii). Into a 25 mL roundꢀbottom flask
equipped with a magnetic stirbar was added
found, 303.1915.
Ethyl
3-(3-((t- the
equiv), 2ꢀiodoꢀ5ꢀmethoxyphenylboronic acid
(0.25 mmol) and of activated 4A
dipeptide molecular sieves. Toluene (7 mL) was added
synthesis and toluene as the solvent. and the mixture was stirred vigorously for
βꢀN-Boc amino acid 24 (0.55 mmol, 1.1
Butoxycarbonyl)amino)butanamido)propanoate
2. The title compound was prepared using
the general procedure for
5
6
1
g
o
1
Yield: 48%. M.p. 65ꢀ67 C; H NMR (CDCl3,
00 MHz):
= 6.40 (br. s, 1 H), 5.30 (br. (0.50 mmol, 1.0 equiv) neutralized with
s, 1 H), 4.25 (q, J = 7.3 Hz, 2 H), 3.94 DIPEA (1.50 mmol, 1.5 equiv), was
m, 1 H), 3.50 (td, J = 6.2, 6.2 Hz, 2 H), cannulated to the reaction mixture. The
.54 (t, J = 6.2 Hz, 2 H), 2.38 (d, J = resulting solution was stirred for 48 h in
.7 Hz, 2 H), 1.40 (s, 9 H), 1.25 (t, J =
sealed flask at 60 °C. The reaction
.2 Hz, 3 H), 1.20 (d, J = 6.8 Hz, 3 H); mixture was allowed to cool down to room
1 hour. Then, the substrate from step i
4
δ
(
2
5
7
a
1
3
C
NMR (100.6 MHz, CDCl ):
δ
=
172.5, temperature and it was filtered through a
70.9, 155.4, 79.2, 60.7, 44.1, 42.6, pad of Celite 545, which was rinsed with
4.8, 34.0, 28.4 (3 C), 20.5, 14.2; IR CH Cl (50 ml). The filtrate was washed
1M aqueous acidic
15 ml), 1M aqueous basic
15 ml) and brine (2 15
3
1
3
(
1
(
2
2

1
Microscope, cm ) 3317, 3084, 2979, 2934, sequentially with
a
737, 1714, 1690, 1649,+ 1526, 1453; HRMS solution (2
x
x
ESI) for C H N O (M+H) : calcd. 303.1914; solution (2
x
1
4 27 2 5
found, 303.1912.
ml). The organic layer was collected,
dried over anhydrous Na SO filtered and
,
4
2
Ethyl
3-(3-((t- evaporated to yield dipeptide products in
Butoxycarbonyl)amino)butanamido)butanoate
3. The title compound was prepared using
the general procedure for dipeptide
a satisfactory level of purity.
5
Ethyl 2,2,14-trimethyl-4,8,12-trioxo-3-
synthesis and toluene as the solvent. oxa-5,9,13-triazahexadecan-16-oate 54. The
o
1
Yield: 48%. M.p. 69ꢀ71 C; H NMR (CDCl3, title compound was prepared using the
1
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 2012

Page 15 of 16
Journal Name
Green Chemistry
View Article Online
ARTICLE
DOI: 10.1039/C5GC00659G
above general procedure for tripeptide
2
3
4
5
6
S. D. Roughley and A. M. Jordan, J. Med. Chem., 2011, 54, 3451ꢀ
479.
o
1
synthesis. Yield: 51%. M.p. 86ꢀ88 C;
NMR (CDCl , 400 MHz): = 6.70 (br. s, 1
H), 6.50 (br. s, 1 H), 5.20 (br. s, 1 H),
H
3
δ
3
H. Charville, D. A. Jackson, G. Hodges and A. Whiting, Chem.
Commun., 2010, 46, 1813ꢀ1823.
4
3
1
1
.30 (m, 1 H), 4.22 (q, J = 7.2 Hz, 2 H),
.30ꢀ3.60 (m, H), 2.40ꢀ2.50 (m, H),
.40 (s, 9 H), 1.22 (t, J = 7.2 Hz, 3 H),
4
6
H. Lundberg, F. Tinnis, N. Selander and H. Adolfsson, Chem. Soc.
Rev., 2014, 43, 2714ꢀ2742.
13
.21 (d, J = 6.8 Hz, 3 H);
171.4, 171.0, 170.3,
55.6, 78.8, 60.3, 41.8, 39.9, 36.4, 35.9,
5.5, 35.1, 27.9 (3C), 19.7, 13.6; IR
C NMR (100.6
C. A. G. N. Montalbetti and V. Falque, Tetrahedron, 2005, 61
,
MHz, CDCl ):
δ
=
3
10827ꢀ10852.
1
3
(
2
(
J. S. Carey, D. Laffan, C. Thomson and M. T. Williams, Org.
Biomol. Chem., 2006, , 2337ꢀ2347.

1
4
Microscope, cm ) 3323, 3275, 3075, 2978,
931, 1737, 1691, 1642,+ 1549, 1451; HRMS
ESI) for C H N O (M+H) : calcd. 374.2286;
7
8
E. Valeur and M. Bradley, Chem. Soc. Rev., 2009, 38, 606ꢀ631.
I. Georgiou, G. Ilyashenko and A. Whiting, Acc. Chem. Res., 2009,
17 32 3 6
found, 374.2286.
42, 756ꢀ768.
9
1
H. Zheng and D. G. Hall, Aldrichimica Acta, 2014, 47, 41ꢀ51.
Ethyl 2,2,18-trimethyl-4,8,12,16-tetraoxo-
-oxa-5,9,13,17-tetraazaicosan-20-oate 55.
The title compound was prepared using the
above general procedure for tetrapeptide 11 T. Maki, K. Ishihara and H. Yamamoto, Tetrahedron, 2007, 63
0 K. Ishihara, S. Ohara and H. Yamamoto, J. Org. Chem., 1996, 61
,
,
.
3
4
196ꢀ4197.
o
1
synthesis. Yield: 48%. M.p. 135ꢀ137 C;
NMR (CDCl , 400 MHz): = 6.76 (br. s, 1
H), 6.58 (br. s, 1 H), 6.42 (br. s, 1 H),
H
8645ꢀ8657.
δ
3
12 K. Arnold, A. S. Batsanov, B. Davies and A. Whiting, Green Chem
2
008, 10, 124ꢀ134.
5
J
2
(
3
1
4
2
(
1
.38 (br. s, 1 H), 4.38 (m, 1 H), 4.05 (q,
7.2 Hz, H), 3.30ꢀ3.60 (m, H),
.40ꢀ2.50 (m, H), 1.40 (s, H), 1.22
t, J = 7.2 Hz, 3 H), 1.20 (d, J = 6.8 Hz,
1
1
3 R. Latta, G. Springsteen and B. Wang, Synthesis, 2001, 1611ꢀ1613.
=
2
8
6
4 R. AlꢀZoubi, O. Marion and D. G. Hall, Angew Chem. Int. Ed., 2008,
47, 2876ꢀ2879.
9
13
H); C NMR (100.6 MHz, CDCl ):
δ
= 172.1, 15 Gernigon, N.; AlꢀZoubi, R. M.; Hall, D. G. J. Org. Chem. 2012, 77,
3
71.6, 170.9, 156.1, 79.2, 60.8, 42.4,
0.4, 36.9, 36.4, 36.1, 36.0, 35.8, 29.7,
8386.
1
6 S. Liu, Y. Yang, X. Liu, F. K. Ferdousi, A. S. Batsanov and A
8.4
(3C),
20.2,
14.2,
14.1;
IR

1
Whiting, Eur. J. Org. Chem., 2013, 5692
Microscope, cm ) 3293, 3076, 2925, 2854,
1
1
7 R. A. Sheldon, Green Chem., 2007, 9, 1273ꢀ1283.
715, 1687, 1638, 1544, 1454; HRMS (ESI)
+
8 C. Capello, U. Fisher and K. Hungerbühler, Green Chem., 2007, 9,
for
C H N O
(M+H) :
calcd.
445.2657;
2
0 37 4 7
found, 445.2658.
927ꢀ934.
1
9 C. W. Gray, Jr., and T. A. Houston, J. Org. Chem., 2002, 67, 5426ꢀ
428.
5
2
2
0 T. Harada and T. Kusukawa, Synlett, 2007, 1823ꢀ1835.
1 J. H. Smitrovich, L. DiMichele, C. Qu, G. N. Boice, T. D. Nelson, M.
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J. Name., 2012, 00, 1-3 | 15

Green Chemistry
Page 16 of 16
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DOI: 10.1039/C5GC00659G
More economical conditions for direct amidation between amines and carboxylic acids, including
α- and β-amino acids, have been optimized using the MIBA catalyst (5-methoxy-2-
iodophenylboronic acid, 6).