Direct amidation of amino acid derivatives catalyzed by arylboronic acids: Applications in dipeptide synthesis

Article abstract of DOI:10.1002/ejoc.201300560

The direct amidation of amino acid derivatives catalyzed by arylboronic acids has been examined. The reaction was generally slow relative to simple amine-carboxylic acid combinations though proceeded at 65-68 °C generally avoiding racemization. 3,4,5-Trifluorophenylboronic and o-nitrophenylboronic acids were found to be the best catalysts, though for slower dipeptide formations, high catalyst loadings were required and an interesting synergistic catalytic effect between two arylboronic acids was discovered. Arylboronic acids can be used to catalyze the direct amide formation of protected amino acid derivatives. For less reactive amino acids, cooperative catalysis can be used involving two arylboronic acids, one electron-rich and one electron-deficient, at high catalyst loadings to give good conversions at moderate temperatures. Copyright

Full text of DOI:10.1002/ejoc.201300560

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FULL PAPER
Direct Amidation
S. Liu,* Y. Yang, X. Liu, F. K. Ferdousi,
A. S. Batsanov, A. Whiting* ........... 1–10
Direct Amidation of Amino Acid Deriva-
tives Catalyzed by Arylboronic Acids: Ap-
plications in Dipeptide Synthesis
Arylboronic acids can be used to catalyze
the direct amide formation of protected
amino acid derivatives. For less reactive
amino acids, cooperative catalysis can be
used involving two arylboronic acids, one
electron-rich and one electron-deficient, at
high catalyst loadings to give good conver-
sions at moderate temperatures.
Keywords: Amides / Amino acids / Pept-
ides / Organocatalysis / Synethic methods
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S. Liu, Y. Yang, A. Whiting et al.
FULL PAPER
DOI: 10.1002/ejoc.201300560
Direct Amidation of Amino Acid Derivatives Catalyzed by Arylboronic Acids:
Applications in Dipeptide Synthesis
Shouxin Liu,*[a,b] Yihua Yang, Xinwei Liu, Farhana K. Ferdousi, Andrei S. Batsanov,
[a]
[a]
[b]
[b]
and Andrew Whiting*[
b]
Keywords: Amides / Amino acids / Peptides / Organocatalysis / Synethic methods
The direct amidation of amino acid derivatives catalyzed by
arylboronic acids has been examined. The reaction was gen-
erally slow relative to simple amine-carboxylic acid combina-
tions though proceeded at 65–68 °C generally avoiding race-
mization. 3,4,5-Trifluorophenylboronic and o-nitrophenyl-
boronic acids were found to be the best catalysts, though for
slower dipeptide formations, high catalyst loadings were re-
quired and an interesting synergistic catalytic effect between
two arylboronic acids was discovered.
Introduction
however, the application of these methods to many carbox-
ylic acid-amine combinations are still limited to relatively
simple substrates and more reactive substrates. Direct
amide formation by boronic acids has not been applied on
amino acid derivatives, and in this paper, we report explora-
tions in this area.
Peptides are important compounds, most being synthe-
sized by the condensation of protected amino acid deriva-
tives by using coupling reagents of various types, such as
The amide function is one of most important functional
groups in organic chemistry, being present in a range of
bioactive compounds, with about 25% of known pharma-
ceuticals containing at least one amide bond.[1] Although
the formation of amide bonds is one of the most common
reactions in organic synthesis,[ the development of ef-
ficient amidation methods continues to be an important sci-
entific pursuit. A lot of methods for the formation of
amides have been reported, including: direct reaction of
2]
carbodiimides, uronium/ammonium and phosphonium
[10]
salts, halo-uronium and halo-phosphonium salts.
These
[3]
carboxylic acids with amines; amination of acid halides
can be applied by using both solid- or solution-phase syn-
thetic strategies, which often require the use of an excess of
these expensive reagents to drive the condensation to com-
pletion. In addition, large amounts of solvent are required
to wash the resin when solid-phase synthetic systems are
used, to obtain clean products and separate excess reagent
waste products. Hence, the development of new, cleaner
[
4]
or anhydrides; and the reaction of carboxylic acids with
[5]
amines in the presence of coupling reagents and related
[
6]
approaches. However, most of these synthetic methods
are quite correctly considered to be poorly atom-eco-
[
7]
nomic. In spite of this, with the exception of direct amide
formation, all of these methods have been studied widely
and employed particularly heavily by industry. More re-
cently, a number of papers have reported direct amidation
synthetic methods for peptide synthesis is an important to-
[3c,11,12]
pic.
There remains a need for new approaches and
[
8]
by using boronic acids and borate derivatives as catalysts,
[13]
thinking. Herein, we describe studies into developing di-
rect amide formation applied to amino acid derivatives and
including its application to dipeptide formation with aryl-
boronic acid catalysts, particularly under conditions that
cause minimal racemization.
and in order to get reaction temperatures down, aryl-
boronic acids have found further application.[ To date,
9]
[
a] State Key Laboratory Breeding Base, Hebei Key Laboratory of
Molecular Chemistry for Drug, College of Chemical and
Pharmaceutical Engineering, Hebei University of Science &
Technology,
Shijiazhuang 050018, People’s Republic of China
E-mail: chlsx@hebust.edu.cn
Results and Discussion
Homepage: http://hgxy.web.hebust.edu.cn/english/
researchcooperation/academicleaders/8264.htm
Arylboronic acids such as o-N,N-diisopropylbenzyl-
[
8b]
[9]
[
b] Centre for Sustainable Chemical Processes, Department of aminoboronic acid,
o-iodophenylboronic acid
and
Chemistry, Durham University, Science Laboratories,
3,4,5-trifluorophenylboronic acid (TFPBA), have been suc-
South Road, Durham DH1 3LE, UK
E-mail: andy.whiting@durham.ac.uk
cessfully applied to catalyze the direct amidation of a
Homepage: https://www.dur.ac.uk/chemistry/staff/profile/
[3c]
number of amine-carboxylic acid combinations.
How-
?
id = 204
ever, direct amidation of amino acids derivatives is limited
despite its importance in drug synthesis. We, therefore, de-
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300560.
2
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Direct Amidation of Amino Acid Derivatives
cided to examine the direct amidation of amino acids as Table 1. The effect of different catalysts and conditions on Equa-
tion (1).
both amine and carboxylic acid donor, reacting either with
a simple carboxylic acid or amine partner in the first in-
stance. If successful, the synthesis of dipeptides by direct
amidation could be considered.
Yield[a]
[%]
Entry
Cat. Solvent Temp. Drying
Time
[h]
[°C]
method
[b]
1–1
1–2
1–3
1–4
1–5
1–6
1–7
2–1
2–2
4
4
C
C
C
6
6
6
H
H
H
5
5
5
F
F
F
85
65
41
41
40
41
41
85
65
41
41
40
41
41
85
41
41
41
85
85
65
41
41
41
41
85
65
41
85
65
65
85
65
65
18
18
18
18
18
18
18
18
18
18
18
18
18
18
18
18
18
18
18
12
12
12
18
18
18
18
18
18
18
18
18
18
18
18
66
[
[
[
[
[
[
b]
b]
b]
b]
b]
b]
[d]
46
4
35
29
21
21
24
75
4
toluene
CH Cl
CHCl
CH CN
Direct Amide Formation on Amino Acid Derivatives
4
2
2
4
3
N-tert-butyloxycarbonyl (Boc)-proline was initially se-
lected as carboxylic acid to react with benzylamine to syn-
thesize corresponding amide 3 [see Equation (1)]. Boronic
acids 4–10 were evaluated as catalysts at different tempera- 2–3
tures, with different drying methods and solvents. The re-
sults are summarized in Table 1.
The preliminary studies shown in Table 1 demonstrate
that TFPBA 7 and o-NPBA 5 had the highest catalytic ac- 3–1
tivities under the same reaction conditions (i.e. in fluoro-
benzene heated to reflux at 85 °C). However, it was also
found that the direct amidation of N-Boc-proline was con-
siderably slower than that of many simpler carboxylic acid-
4
3
[b]
[b]
5
C
6
C
6
C
6
H
5
H
5
H
5
F
F
F
[d]
5
59
37
[
[
[
[
b]
b]
b]
b]
5
2
2
2
2
–4
–5
–6
–7
5
toluene
CH Cl
CHCl
CH CN
33
18
21
5
2
2
5
3
[b]
5
3
23
52(55)
12
[
[
[
[
b]
b]
b]
b]
[d]
6
C H F
6
5
3–2
3–3
3–4
4–1
4–2
6
C
6
H
5
F
3
6
CHCl
CH CN
14
6
3
17
[b]
[c]
[d]
[d]
[d]
7
C
6
C
6
C
6
C
6
H
H
H
H
5
5
5
5
F
F
F
F
87(91)
90(98)
81(89)
43
7
[
[
[
[
b]
b]
b]
b]
amine combinations studied previously under the same con- 4–3
7
4–4
7
ditions, which is why substantially higher catalyst loadings
25 versus 10 mol-%) were required.[
8b,8c]
4–5
7
CH
CHCl
CH CN
2
Cl
2
41
26
31
61
31
22
56
30
34
59
26
28
(
The solvent em-
4
4
–6
–7
7
3
ployed was also an important factor and, as expected from
[b]
[b]
7
3
[
14]
previous work, non-polar solvents were preferable to po- 5–1
8
C H F
6
5
[
[
[
b]
b]
b]
5
5
6
6
6
–2
–3
–1
–2
–3
8
C
6
H
5
F
lar solvents and not merely for azeotropic water removal.
Five solvents, including polar and non-polar, and with
higher and lower boiling points, were examined under the
same catalytic and temperature conditions. Of these, fluoro-
8
CH
3
CN
9
C
C
6
5
F
F
[b]
[b]
9
6
5
9
CH
[
[
[
b]
b]
b]
benzene was the best solvent (see Table 1, Entries 1–1, 2–1, 7–1
10
10
10
C
C
6
H
H
5
F
F
7
7
–2
–3
6
5
4–1, 4–2 and 4–3). In addition, temperature was found to
CH
3
CN
be the third important factor controlling the yield of the
reaction. The isolated yield was highest at reflux tempera-
tures, especially when Soxhlet extraction was used. For ex-
ample, with fluorobenzene and TFPBA as catalyst, the
yield of 3 was 90%, even at 65 °C, this reaction gave a yield
of 81% (Table 1, Entries 4–3). The advantage of the latter
[
a] Isolated yield of pure amide. [b] Powdered molecular sieves (3 Å)
in the reaction. [c] Soxhlet thimble containing powdered molecular
sieves (3 Å). [d] Crude residue was washed with EtOAc (40 mL; see
Supporting Information).
conditions are that reactions can be run with molecular chance of racemization owing to the lower reaction tem-
sieves in the reaction mixture; potentially minimising any perature. It is noteworthy that chiral HPLC analysis of the
(
1)
3
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S. Liu, Y. Yang, A. Whiting et al.
FULL PAPER
(
2)
products from Table 1, Entries 4–2 and 4–3 did not reveal
any racemization (ee values were Ͼ 99%; see Supporting
Information).
In order to confirm the scope of application of the best
conditions determined from Table 1 and Equation (1), di-
rect amidation of N-Boc-phenylalanine (11) was examined,
as outlined in Equation (2). In this case, 3,4,5-trifluoro-
phenylboronic acid (7) was not efficient enough for the
amidation of phenylalanine derivative 11, rather o-nitro-
phenylboronic acid (o-NPBA) 5 was superior, providing
benzylamide 12 in 91–94% yield (Table 2, Entry 1–1) when
Soxhlet extraction was used in fluorobenzene heated to re-
flux. In fact, even at 65 °C, 82–89% yields could be ob-
tained over 24 h (Table 2, Entry 1–2). The superior activity
of o-NPBA 5 is not necessarily surprising because Hall et
al.[ reported its use and that it was not dissimilar to their
preferred o-iodophenylboronic acid, however, because it is
cheaper than TFPBA 7 and commercially available, its use
is perhaps preferable to many other catalysts.
9]
Table 2. The effect of different catalysts and conditions on Equa-
tion (2).
Figure 1. X-ray structures of molecules 3 and 12.
Entry
17
Cat. Temp.
Drying
method
Time
[h]
Yield[a]
[%]
[°C]
From the above results, it appears that N-protected
amino acids react quite efficiently with amines to form the
corresponding amides by using electron deficient aryl-
boronic acids as catalysts. We therefore examined the corre-
sponding C-protected amino acids in the form of methyl
ester HCl salts (conveniently neutralized in situ from the
corresponding HCl salts by using Hünig’s base), in which
the amino group reacted with phenylacetic acid (16). The
reactions are outlined in Equation (4) and Table 3, em-
ploying phenylalanine and valine ammonium chloride de-
rivatives 15.
[
d]
1
2
3
4
5
6
7
8
a
a
a
a
b
5
5
7
7
5
5
7
7
85
65
85
65
85
65
85
65
b
b
b
14
14
14
14
14
14
14
14
67(92)
86
[d]
78(94)[
d]
[
c],[b]
[d]
72(89)
[
b]
[d]
86
[
[
[
b]
b]
b]
[b]
[b]
[d]
78
[d]
[d]
68(90)
65(77)
[c],[b]
[
a] Isolated yield of pure amide. [b] Soxhlet thimble containing
powdered molecular sieves (3 Å). [c] Powdered molecular sieves
3 Å) in the reaction. [d] The crude residue was washed with EtOAc
40 mL; see Supporting Information).
(
(
This time, direct amide formation was reasonably ef-
Single crystal X-ray analysis confirmed retention of the ficient by using either o-NPBA 5 or TFPBA 7 as catalysts,
absolute stereochemistry of compound 12 and the structure though TFPBA exhibited marginally higher activity, for ex-
of 3 (Figure 1). Chiral HPLC also confirmed the complete ample, 67% (or 92) versus 78% (or 94%) yield, respectively,
retention of the enantiopurity in both cases (see Supporting at 85 °C for phenylalanine analogue 17a (Table 3, Entries 1
Information).
and 3). However, even at 65 °C, the corresponding amides
When benzylamine was changed for (R)-(+)-α-methyl- could be isolated in respectable yields of 72 (or 89) and
benzylamine (13) reacting with N-Boc-phenylalanine – see 65% (or 77%) yields for 17a and 17b, respectively (Table 3,
Equation (2) – the impact of the increased steric hindrance Entries 4 and 8). Single crystal X-ray structure analysis of
of the methyl group was quite obvious; see Equation (3). both products showed the absolute stereochemistry to be
The yield dropped from 82 (for 12) to 56% (for 14) at ap- intact (Figure 2). However, chiral HPLC analysis gave a
proximately 65 °C when o-NPBA 5 was used as catalyst. slightly different picture of enantiopurity. Although the
1
13
Importantly, examination of the H and C NMR spectro- yields were quite high, some racemization had occurred
scopic data of product 14 showed that it was obtained as a during the amide formation of 17a. It appears that neither
single diastereoisomer, again showing retention of the abso- temperature nor catalyst play the major role in causing loss
lute stereochemistry during the amide formation reaction.
of enantiopurity (i.e., the ee values are almost the same, see
4
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Direct Amidation of Amino Acid Derivatives
(
3)
(
4)
Table 3. Effect of different catalysts/conditions on Equation (4).
Entry Cat. Temp. Drying Time Cat. loading X Yield[a]
[°C]
method [h]
[mol-%]
[%]
[
b]
1–1
1–2
2–1
2–2
2–3
2–4
5
5
7
7
7
7
85
65
85
85
65
65
18
24
18
18
18
18
25
50
25
25
50
25
91(94)
82(89)
37
40
54
[
c]
c]
b]
[
[
[
c]
[
c]
trace
[
a] Isolated yield of pure amide. [b] Soxhlet thimble containing
powdered molecular sieves (3 Å). [c] Powdered molecular sieves
(
(
3 Å) in the reaction. [d] The crude residue was washed with EtOAc
40 mL; see Supporting Information).
Table 4, Entries 6–8), rather the amino acid structure itself,
such as the presence of a benzyl side-chain in 15a (and
hence 17a), results in greater propensity for racemization
under the reaction conditions. In contrast, the more highly
enantiomerically pure amide products were generally de-
rived from derivative 15b by using catalyst 7 at either 85 or
6
5 °C. However, the enantiopurity was diminished particu- Figure 2. X-ray structures of molecules 17a (omitting the disorder)
larly when catalyst 5 was used under the same reaction con- and 17b.
ditions for amides 3 and 17b, causing some racemization
(e.g., 79 and 71% ee values for Table 4, Entries 1 and 9; see
Supporting Information).
Direct Amide Formation to Access Dipeptide Derivatives
Table 4. Summary of effects of catalyst temperature on the racemi-
zation of amides derived from chiral amino acids.
Because the electron deficient arylboronic acids could be
used to catalyze the direct amidation of either N- or C-
protected amino acids, we considered whether it would be
possible to couple N-terminal to C-terminal protected
amino acids in fluorobenzene under conditions that would
hopefully continue to avoid racemization Equation (5) and
to give the corresponding dipeptide derivatives. Initial stud-
ies showed that different arylboronic acids exhibited con-
siderably different activities, with o-NPBA and TFPBA (5
and 7, respectively) showing considerably higher catalytic
activity among all arylboronic acids (4 to 10) selected. The
results of the use of these two catalysts to access dipeptides
Entry
Amide
Catalyst
Temp. [°C]
ee [%]
1
2
3
4
5
6
7
8
9
3
3
3
12
12
17a
17a
17a
17b
17b
17b
5
7
7
5
5
5
7
7
5
7
7
85
85
65
85
65
85
85
65
85
85
65
79
Ͼ 99
Ͼ 99
Ͼ 99
Ͼ 99
67
64
68
71
Ͼ 99
Ͼ 99
10
1
1
20a–20e are shown in Table 5, Entries 1–10.
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S. Liu, Y. Yang, A. Whiting et al.
FULL PAPER
(
5)
Table 5. Dipeptide synthesis by direct amidation as in Equation (5).
Entry
Carboxylic
acid
Ammonium
salt
Cat.
Cat. loading
X [mol-%]
Temp.
[°C]
Base
Yield[a],[b]
[%]
Product
c]
1
2
3
4
5
6
7
8
9
11
15a
15a
15a
15a
15a
15a
15b
19
15a
15b
15b
15b
15a
15a
7
25
50
25
100
100
100
100
100
100
100
50 + 50
50 + 50
50 + 50
50 + 50
65[
Pr
Pr
2
2
NEt
NEt
13
25
16
31
58
53
Ͻ 2
47
48
20
51
55
62
46
20a
20a
20a
20a
20a
20a
20b
20c
20d
20e
20e
20b
20f
21
[
d]
c]
c]
c]
c]
c]
c]
c]
c]
c]
c]
c]
c]
11
7
85
11
7
65[
K CO
2 3
11
7
65[
Pr
Pr
2
NEt
NEt
[
11
5
65
2
11
5
65[
65[
K CO
2 3
11
5
Pr
Pr
Pr
Pr
Pr
Pr
Pr
Pr
2
2
2
2
2
2
2
2
NEt
[
18a
18a
18a
18a
11
5
65
NEt
NEt
NEt
NEt
NEt
NEt
NEt
5
65[
10
11
12
13
14
5
65[
[
5 + 4
5 + 4
5 + 4
5 + 4
65
65[
65[
65[
18b
2
[
a] Isolated yield of pure amide. [b] All reactions were carried out for 32 h before work up and isolation. [c] Powdered molecular
sieves (3 Å) added to the reaction mixture to remove water. [d] Soxhlet thimble containing powdered molecular sieves (3 Å) used for
removing water.
The reaction of phenylalanine methyl ester (15a) with N- carboxylic acid donor; (b) there is a major impact upon
Boc-phenylalanine (11) was studied under different condi- changing the amino donor from being less to more hin-
tions as a representative dipeptide and to optimize this di- dered. Table 5, Entries 5 and 7 show the effect of merely
rect amide formation reaction. The more active catalysts changing from phenylalanine methyl ester as the amine do-
highlighted from the above studies were initially employed, nor to the corresponding valine analogue, with the same
i.e. TFPBA 7 and o-NPBA 5, at different catalyst ratios phenylalanine carboxylic acid donor; the yield drops from
and temperatures, and with different bases to neutralize the 58% to zero. The same trend is also shown in Table 5, En-
ammonium salt amine-donor. The results of these reactions tries 8–10, which show that for the same N-Ac phenylalan-
are summarized in Table 5, Entries 1–6. All these reactions ine carboxylic acid, reaction with a glycine versus phenyl-
were slow and hence, stoichiometric quantities of either alanine versus valine amine donor results in yields of 47, 48
boronic acid catalyst 5 or 7 was required to achieve even and 20%, respectively. The fact that the latter reaction was
moderate yields of dipeptides 5. However, o-NPBA 5 was so inefficient (Table 5, Entry 7) highlights the need for fur-
superior, especially when employed at 65 °C with Hünig’s ther reaction improvements to tackle these less-efficient di-
base to neutralize the ammonium salt, which resulted in a rect amide couplings. After re-examining the seven aryl-
58% isolated yield of amide 20a (Table 5, Entry 5).
boronic acids for reactions involving a valine amine donor,
Employing these conditions on other amino acid deriva- none were found to be suitable for this reaction. However,
tives was not straightforward either, even after initial opti- upon examining mixed catalyst systems, a surprising syner-
mization. Hence, Table 5, Entry 5 and Entries 7–10 demon- getic, or cooperative, effect was discovered, involving the
strate that: (a) there is little effect upon changing an N-Boc use of two catalysts, i.e. o-methylphenylboronic acid (4) and
group to a less hindered N-Ac (see Entries 5 and 9) on the o-NPBA 5 employed in a 1:1 ratio with 50 mol-% loadings
6
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Direct Amidation of Amino Acid Derivatives
of each being necessary to achieve good conversion. Hence, General Procedure for the Direct Amidation of N-Protected Amino
Acids: To the catalyst (25–50 mol-%), solvent (20 mL), amine
the synthesis of dipeptide Boc-Phe-Val methyl ester 20b was
(
1.4 mmol), N-protected amino acid (1.4 mmol) and activated mo-
transformed from Ͻ 2% yield (Table 5, Entry 7) to 55%
yield (Table 5, Entry 12), and corresponding N-Ac dipept-
ide 20e could be isolated in 51% yield (Table 5, Entry 11)
relative to 20% (Table 5, Entry 10) obtained with a single
catalyst. Although the mechanism by which this coopera-
tive catalytic effect works is not clear, we found that it could
lecular sieves (3 Å) (if the reaction was carried out at reflux tem-
perature or 65 °C, or if a Soxhlet apparatus was used, a thimble
was loaded with the activated molecular sieves (3 Å); see Tables
above) were added. The mixture was heated under Ar (time indi-
cated in the Tables above). After the reaction finished, the solution
was filtered and [in some cases (as indicated, see Tables 1, 2, 3, and
be applied to the synthesis of further dipeptides with similar 4) the residue was washed with EtOAc (40 mL)] concentrated under
results. For example, Cbz-Phe-Phe 20f and Boc-Pro-Phe 21 reduced pressure, diluted with CHCl (40 mL) and the solution was
dipeptide methyl esters could also be accessed (Table 5, En- washed with satd. NaHCO (3ϫ 10 mL), 1 m HCl (2ϫ 5 mL), H
2ϫ 10 mL) and brine (10 mL). After drying (MgSO ), filtration
3
3
2
O
(
4
tries 13 and 14, respectively) giving 62 and 46% yields.
Hence, it appears that this method can be used generally
to synthesize different dipeptides, including aryl-aryl, aryl-
alkyl, and aryl-alicyclic systems. Importantly, the amino
acid configurations were retained upon dipeptide forma-
tion, as demonstrated by both single-crystal X-ray analysis
and concentration, the crude product was re-crystallized from a
mixture of acetone and petroleum ether to give pure product (see
isolated yield in Tables above).
N-Boc-Proline Benzylamide (3): (CAS number: 92235–33–1): The
compound was obtained by using (3,4,5-trifluorophenyl)boronic
acid as catalyst with a Soxhlet apparatus loaded with molecular
sieves (3 Å) and C H F as solvent according to the general pro-
6 5
cedure in 90% yield. A single crystal was cultured in a mixture of
1
of N-Ac-Phe-Phe methyl ester 20d and H NMR and chiral
HPLC spectra of all the dipeptides showed that single dia-
stereoisomeric products were obtained (see Supporting In-
formation).
1
toluene and petroleum ether: H NMR (DMSO, 80 °C, 500 MHz):
δ = 1.35 (s, 9 H), 1.72–1.81 (m, 1 H), 1.82–1.87 (m, 2 H), 2.05–2.16
(
m, 1 H), 3.29–3.37 (m, 1 H), 3.38–3.44 (m, 1 H), 4.09–4.15 (m, 1
H), 4.20–2.26 (m, 1 H), 4.34 (dd, J = 15.1, 6.2 Hz, 1 H), 7.18–
Conclusions
13
7
1
1
.33 (m, 5 H), 8.05–8.08 (br., 1 H) ppm. C NMR (DMSO, 80 °C,
25.6 MHz, CDCl ): δ = 24.1, 28.8, 30.9, 42.8, 47.3, 60.6, 79.2,
27.3, 127.8 (2 C), 128.8 (2 C), 140.3, 154.3, 173.0 ppm. MS (ES):
3
We have shown that arylboronic acids can be used as
catalysts for the direct amidation of amino acid analogues
to form simple amide derivatives with reasonable efficiency
and generally with retention of the amino acid absolute
configuration and enantio- or diastereo-purity in most
cases. o-NPBA, being commercially available and reason-
ably cheap, is perhaps the more attractive catalyst for this
purpose, especially when used in fluorobenzene at around
+
m/z = 305.21 [M + H] .
N-Boc-Phenylalanine Benzylamide (12): (CAS number: 84235–32–
5
): This compound was obtained by using o-nitrophenylboronic
acid with a Soxhlet apparatus loaded with molecular sieves (3 Å)
and C F as solvent according to the general procedure in 91%
yield. A single crystal was grown from a mixture of toluene and
6
H
5
1
petroleum ether: H NMR (DCCl
3
, 400 MHz): δ = 1.29 (s, 9 H),
65 °C. However, dipeptide formation is considerably more
2
1
.98 (d, J = 6.6 Hz, 2 H), 4.24–4.30 (m, 2 H), 5.16 (br., 1 H), 6.31 (s,
H), 7.00 (s, 2 H), 7.05–7.21 (m, 8 H) ppm. C NMR (100.6 MHz,
challenging and it appears as though a binary arylboronic
13
acid catalyst system is preferable, i.e., a 1:1 mixture of both CDCl ): δ = 28.3 (3 C), 38.6, 43.4, 56.1, 80.2, 126.9, 127.4, 127.6
3
o-tolyl- and o-nitrophenyl-boronic acids. This cooperative (2 C), 128.6 (2 C), 128.7 (2 C), 129.4 (2 C), 136.7, 137.7, 155.4,
catalytic system is particularly effective with the least reac- 171.1 ppm.
tive amino acid combinations though the overall catalyst
loading of course remains high. It is clear that there is still
N-Boc-Phenylalanine α-Methylbenzylamide (14): (CAS number:
74174–66–4): This compound was obtained by using o-nitrophen-
1
a way to go before developing highly efficient, general cata- ylboronic acid as catalyst in C H F at 64–68 °C according to the
6
5
1
3
lysts for all direct amide formations, however, the present general procedure in 56% yield: H NMR (CDCl , 400 MHz): δ =
work indicates the applicability of boronic acid catalysis for 1.31 (d, J = 6.4 Hz, 3 H), 1.43 (s, 9 H), 2.97–3.03 (m, 1 H), 3.13
(
5
d, J = 6.2 Hz, 1 H), 4.31–4.25 (br., 1 H), 4.96–5.12 (br., 2 H),
.88 (d, J = 6.2 Hz, 1 H), 7.15–7.38 (m, 10 H) ppm. C NMR
accessing peptide analogues through direct amide forma-
tion approaches and avoiding the need for highly reactive
intermediates and reagents. It also suggests that cooperative
catalyst systems may prove beneficial in the future, and it is
this aspect that we are examining at present. The fact that
some racemization is observed, even under milder condi-
tions, shows that further developments are required.
1
3
(
100.6 MHz, CDCl
3
): δ = 21.7, 28.3 (3 C), 38.7, 48.8, 56.1, 80.1,
1
1
26.1 (2 C), 127.0, 127.3, 128.6 (2 C), 128.7 (2 C), 129.4 (2 C),
55.4, 170.0 ppm.
General Procedure for Direct Amidation of C-Protected Amino Ac-
ids: To the catalyst (25 mol-%), C F (20 mL), phenylacetic acid
1.4 mmol), amino acid methyl ester hydrochloride (1.4 mmol), di-
6
H
5
(
isopropylethylamine (1.4 mmol), and activated molecular sieves (3
Å) (if the reaction was carried out at reflux temperature or 65 °C,
or if a Soxhlet apparatus was used, a thimble was loaded with the
activated molecular sieves (3 Å); see Tables above) were added. The
mixture was heated under argon. After the reaction finished, the
solution was filtered through Celite [in some cases (as indicated,
see Table 1, Table 2, Table 3, and Table 4) the residue was washed
with of EtOAc (40 mL)], and concentrated under reduced pressure.
Experimental Section
General: All H and 13C NMR spectroscopic data were recorded
with a Bruker Avance-400 or Varian Inova-500 spectrometer.
Chemical shifts are expressed relative to internal standard TMS.
Mass spectra were performed with a Micromass Autospec. All rea-
gents were obtained from standard laboratory chemical suppliers.
Molecular sieves were activated by heating to 220 °C.
1
3
Then CHCl (40 mL) was added to the residues and the solution
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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7

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S. Liu, Y. Yang, A. Whiting et al.
FULL PAPER
was washed with satd. NaHCO
3
(3ϫ 10 mL), 1 m HCl (2ϫ 5 mL),
400 MHz): δ = 1.27 (t, J = 7.1 Hz, 3 H), 1.98 (s, 3 H), 3.09 (d, J =
7.1 Hz, 2 H), 3.96 (ABq, J = 18.2, 5.3 Hz, sep. 40.9 Hz, 2 H), 4.19
(q, J = 7.1 Hz, 2 H), 4.75 (q, J = 7.2 Hz, 1 H), 6.31 (br., 1 H), 6.55
H
2
O (2ϫ 10 mL) and brine (10 mL). The solution was dried
(
MgSO ), filtered and concentrated to provide the product, which
4
1
3
was re-crystallized from a mixed solvent of acetone and petroleum
to give pure product.
(br., 1 H), 7.19–7.31 (m, 5 H) ppm. C NMR (100.6 MHz,
CDCl ): δ = 14.1, 23.1, 38.2, 41.3, 54.3, 61.5, 127.0, 128.7 (2 C),
29.2 (2 C), 136.5, 169.3, 170.2, 171.2 ppm.
3
1
N-Phenylacetyl-phenylalanine Methyl Ester (15a): (CAS number:
N-Ac-Phe-Phe Methyl Ester (20d): (CAS number: 2562–48–3): This
compound was obtained by o-nitrophenylboronic acid catalysis ac-
cording to the general procedure in 48% yield. A single crystal
9
0966–33–9): Obtained by 3,4,5-trifluorophenyl-boronic acid catal-
ysis according to the general procedure in 78% yield. A single crys-
tal was grown in a mixed solvent of acetone and petroleum ether:
1
1
was grown in a mixture of acetone and petroleum ether: H NMR
3
H NMR (CDCl , 400 MHz): δ = 2.95 (ddd, J = 31.3, 13.8, 5.8 Hz,
(
3
DCCl
H), 4.54 (dd, J = 10.8, 4.3 Hz, 1 H), 4.65–4.70 (m, 1 H), 5.91 (d,
J = 7.2 Hz, 1 H), 6.05 (d, J = 7.5 HZ Hz, 1 H), 6.94 (dd, J =
3
, 400 MHz): δ = 1.87 (s, 3 H), 2.86–3.03 (m, 4 H), 3.60 (s,
2
5
4
5
1
H), 3.48 (s, 2 H), 3.63 (s, 3 H), 4.77 (dt, J = 7.8, 5.8 Hz, 1 H),
.79 (s, 1 H), 6.75–6.85 (m, 2 H), 7.06–7.17 (m, 4 H), 7.21–7.28 (m,
H) ppm. 13C NMR (100.6 MHz, CDCl
3
): δ = 37.64, 43.65, 52.26,
1
3
4
.5, 2.6 Hz, 2 H), 7.09–7.22 (m, 8 H) ppm. C NMR (100.6 MHz,
CDCl ): δ = 23.1, 37.9, 38.1, 52.3, 53.4, 54.3, 127.0, 127.1, 128.6 (2
C), 128.7 (2 C), 129.2 (2 C), 129.3 (2 C), 135.6, 136.4, 169.83, 170.4,
71.2 ppm.
2.99, 127.02, 127.36, 128.52 (2 C), 128.97 (2 C), 129.13 (2 C),
29.39 (2 C), 134.45, 135.60, 170.38, 171.79 ppm.
3
N-Phenylacetyl-valine Methyl Ester (17b): (CAS number: 827619–
3–8): Obtained by the catalysis of 3,4,5-trifluorophenylboronic
1
2
N-Boc-Phe-Val Methyl Ester (20e): (CAS number: 53842–46–9):
This compound was obtained by the catalysis of 50 mol-% o-nitro-
acid according to the general procedure in 78% yield. A single crys-
tal was grown from a mixture solvent of acetone and petroleum
ether: H NMR (DCCl
0
1
phenylboronic acid and 50 mol-% o-methylphenylboronic acid
3
, 400 MHz): δ = 0.68 (d, J = 6.4 Hz, 3 H),
1
according to the general procedure in 51% yield. H NMR (DCCl
3
,
.77 (d, J = 6.4 Hz, 3 H), 1.96–2.05 (m, 1 H), 3.53 (s, 2 H), 3.60
400 MHz): δ = 0.77 (d, J = 6.9 Hz, 3 H), 0.82 (d, J = 6.9 Hz, 3 H),
(s, 3 H), 4.46 (dd, J = 8.8, 4.9 Hz, 1 H), 5.97–6.05 (d, J = 8.2 Hz,
H), 7.18–7.32 (m, 5 H) ppm. 1 C NMR (100.6 MHz, CDCl
3
1.92 (s, 3 H), 1.97–2.03 (m, 1 H), 2.95–3.03 (m, 2 H), 3.61 (s, 3 H),
1
=
3
): δ
17.6, 17.9, 30.1, 42.6, 51.0, 56.1, 126.3, 127.9 (2 C), 128.3 (2 C),
4
.34 (dd, J = 8.5, 5.0 Hz, 1 H), 4.64–4.56 (m, 1 H), 6.00 (d, J =
7.2 Hz, 1 H), 6.07 (d, J = 17.2 Hz, 1 H), 7.11–7.23 (m, 5 H) ppm.
C NMR (100.6 MHz, CDCl ): δ = 17.7, 18.8, 23.2, 31.1, 38.2,
3
1
133.8, 169.9, 171.3 ppm.
1
3
General Procedure for Dipeptide Synthesis by Direct Amidation: The
amino acid methyl ester hydrochloride (1.4 mmol) was neutralized
with diisopropylethylamine (1.4 mmol, 246 μL) in fluorobenzene
5
1
2.1, 54.6, 57.4, 127.1, 128.7 (2 C), 129.3 (2 C), 136.3, 170.0, 170.7,
71.6 ppm.
N-Boc-Pro-Phe Methyl Ester (21): (CAS number: 52071–64–4):
This compound was obtained by the catalysis of 50 mol-% o-nitro-
phenylboronic acid and 50 mol-% o-methylphenylboronic acid
(
5 mL). After 2 h, the catalyst (100 mol-%), fluorobenzene (20 mL),
N-protected amino acid (1.4 mmol) and activated molecular sieves
3 Å) were added. The mixture was heated under argon at 65 °C
(
1
according to the general procedure in 46% yield. H NMR
for 32 h with stirring. After the reaction finished, the mixture was
filtered. The solution was concentrated and the crude solid was
(
(
DMSO, 80 °C, 500 MHz): δ = 1.34 (s, 9 H), 1.76 (m, 3 H), 2.00
m, 1 H), 2.97–3.14 (m, 2 H), 3.22–3.29 (m, 1 H), 3.30–3.37 (m, 1
dissolved in CHCl
CO (4ϫ 10 mL), 1 m HCl (2ϫ 5 mL), H
brine (10 mL). The solution was dried (MgSO
3
(40 mL). The solution was washed with 0.5 m
O (2ϫ 10 mL) and
), filtered and con-
H), 3.61 (s, 3 H), 4.11–4.14 (m, 1 H), 4.52–4.56 (m, 1 H), 7.20–
K
2
3
2
1
3
7
1
6
1
.31 (m, 5 H), 7.84–7.88 (m, 1 H) ppm. C NMR (DMSO, 80 °C,
4
25.6 MHz, CDCl ): δ = 23.8, 28.8 (3 C), 36.9, 47.1, 52.2, 54.3,
0.3, 79.3, 127.1, 128.8 (2 C), 129.6 (2 C), 137.9, 154.3, 172.4,
73.0 ppm.
3
centrated to get the product, which was re-crystallized from a mix-
ture of acetone and petroleum to give pure product.
N-Boc-Phe-Phe Methyl Ester (20a): (CAS number: 13122–89–9):
This compound was obtained by o-nitrophenylboronic acid cataly-
sis according to the general procedure in 58% yield. H NMR
X-ray Crystallography: Single-crystal diffraction experiments were
carried out for 3 with a Bruker 3-circle diffractometer with
SMART 6000 CCD area detector, with graphite-monochromated
1
(
3
6
CDCl
3
, 400 MHz): δ = 1.33 (s, 9 H), 2.91–3.03 (m, 4 H), 3.59 (s,
H), 4.26 (br., 1 H), 4.71 (br., 1 H), 4.86 (br., 1 H), 6.19 (d, J =
.6 Hz, 1 H), 6.91 (dd, J = 7.2, 2.1 Hz, 2 H), 7.10–7.23 (m, 8
sealed-tube Mo-K
Ultra (Oxford Diffraction) κ-diffractometer with a Sapphire3 CCD
detector, with Cu-K radiation from a sealed tube with Enhance
α
radiation; for 17b and 20e with a Gemini S
α
13
H) ppm. C NMR (100.6 MHz, CDCl
2.3, 53.3, 55.7, 80.21, 127.0, 127.1, 128.6 (2 C), 128.7 (2 C), 129.2
2 C), 129.4 (2 C), 135.6, 136.5, 155.2, 170.8, 171.4 ppm.
3
): δ = 28.2 (3 C), 38.0, 38.3,
Ultra X-ray optics. Owing to the relatively small crystal size, data
for 12 and 17a had to be collected with a Bruker 3-circle dif-
fractometer with Platinum135 CCD detector, with Cu-K radiation
α
5
(
N-Boc-Phe-Val Methyl Ester (20b): (CAS number: 2754–02–1):
This compound was obtained by the catalysis of 50% o-nitrophen-
from a Microstar rotating anode source with cross-coupled Göbel
mirrors.[
15]
ylboronic acid and 50% o-methylphenylboronic acid according to
Crystals were cooled by using Oxford Cryosystems open-flow cryo-
1
the general procedure in 55% yield. H NMR (CDCl
3
, 400 MHz):
stats Cryostream 700 (liquid N
liquid N ) for 12 and 17a. Reflection intensities were integrated by
using SAINT 7.46A (3), SAINT 7.60A (12, 17a) and CrysAlisPro
17b, 20e) software. The structures were solved by direct methods
2
) for 3, 17b and 20e or Cobra (non-
δ = 0.77 (d, J = 6.9 Hz, 3 H), 0.80 (d, J = 6.9 Hz, 3 H), 1.35 (s, 9
H), 2.03 (dd, J = 6.9 Hz, 1 H), 3.00 (d, J = 6.9 Hz, 2 H), 3.62 (s,
2
3
H), 4.28 (br., 1 H), 4.39 (dd, J = 8.6, 5.1 Hz, 1 H), 4.96 (br., 1
(
13
H), 6.31 (d, J = 8.5 Hz,1 H), 7.11–7.24 (m, 5 H) ppm. C NMR
100.6 MHz, CDCl ): δ = 17.8, 18.8, 28.3 (3 C), 31.3, 38.0, 52.1,
5.9, 57.2, 80.2, 126.9, 128.7 (2 C), 129.3 (2 C), 136.6, 155.4, 171.1,
71.8 ppm.
2
and refined by full-matrix least-squares against F of all reflections,
by using SHELXTL or SHELX-2013/2 and OLEX2 software.
Crystal data and other experimental details are listed in Table 6.
(
5
1
3
[16]
[17]
CCDC registration numbers shown in Table 6 contain the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
N-Ac-Phe-Gly Ethyl Ester (20c): (CAS number: 52134–81–3): This
compound was obtained by o-nitrophenylboronic acid catalysis ac-
1
cording to the general procedure in 42% yield. H NMR (DCCl
3
,
8
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

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Direct Amidation of Amino Acid Derivatives
Table 6. Crystal data.
3
12
17a
890397
17b
20e
CCDC numbers
Formula
Formula mass
Crystal system
a /Å
b /Å
c /Å
890395
890396
890398
890399
C
304.38
17
H
24
N
2
O
3
C
354.44
21
H
26
N
2
O
3
C
297.34
18
H
19NO
3
C
249.30
14
H
19NO
3
17 24 2 4
C H N O
320.38
orthorhombic
9.5067(4)
9.5926(4)
17.8503(8)
90
1627.84(12)
120(2)
monoclinic
20.9067(5)
15.1539(3)
18.2138(4)
95.960(7)
5739.3(2)
100(3)
monoclinic
9.7679(2)
15.7664(3)
10.1211(2)
99.732(4)
1536.27(5)
100(3)
orthorhombic
6.5750(4)
9.5472(6)
21.6484(14)
90
1358.93(14)
100(3)
orthorhombic
4.8816(2)
16.4990(6)
21.3710(9)
90
1721.25(12)
120(2)
β /°
V/Å
3
Temperature /K
Space group (no.)
Z
P2
4
1
2
1
2
1
(#19)
C2 (#5)
12
P2
4
1
(#4)
P2
4
1
2
1
2
1
(#19)
1 1 1
P2 2 2 (#19)
4
λ /Å
0.71073
0.085
17204
2866
1662
0.095
0.034
0.065
–
1.54188
0.66
34685
8828
4786
0.040
0.036
0.110
1.54188
0.71
11853
4581
2621
0.028
0.029
0.078
–0.04(16)
0.05(5)
0.05(4)
1.54184
0.69
16530
2032
1.54184
0.72
15929
2591
μ /mm–1
Total reflections
Unique reflections
Excluding Friedels
1212
1552
R
R
int
0.029
0.021
0.056
–0.05(21)
0.00(5)
0.031
0.034
0.088
0.1(3)
–0.02(8)
0.01(7)
1
[IϾ2σ(I)]
2
wR(F ) (all data)
Flack parameter, x
Parsons’ method, x
Hooft parameter, y
–0.04(19)
0.03(7)
0.08(6)
–
–
0.01(5)
The crystal of 12 was a non-merohedral twins with the components
related by a 180° rotation around the reciprocal axis (0.575 0 1) or
the real axis (0.5 0 1). The diffraction pattern was deconvoluted by
20e converted into a modulated phase with a (7a, b, c) supercell
(Figure 3).
The absolute configuration of 3 was assigned S, those of four other
[18]
and F2 were calculated by TWINABS
CELL_NOW program
compounds were determined from anomalous scattering, by calcu-
[
19]
program,
by using well-separated reflections of both compo-
lating the Flack[ (x) and Hooft
20]
[21]
(y) parameters which should
nents, as well as the overlapping reflections.
equal 0 for the correct absolute structure and 1 for the inverted
model; x was calculated both by the conventional “hole-in-one” fit
to all intensities and by Parsons’ method based on selected quo-
tients.[ In each case, both x and y equalled 0 within the standard
uncertainty (s.u.), but for the conventional x the s.u.’s were too
large to regard the absolute structures as unequivocal (see dis-
cussion[ ), whereas Hooft method (either Gaussian or Student’s
t-distribution[ ) and Flack–Parsons method gave statistically reli-
able discrimination.
Structure 12 has a (a, b/3, c) subcell; the asymmetric unit comprises
three independent molecules related through approximate b/3
translations. The reflections with k = 3n have the mean intensity
22]
26 times higher than those with k ϶ 3n. Structure 17a has a (a, b,
c/2) subcell: the asymmetric unit comprises two independent mole-
cules related through an approximate c/2 translation. The reflec-
tions with even l indices have the mean intensity 4.8 times higher
than those with even l. In one independent molecule, the C(1)=O(2)
group is disordered (in a 9:1 ratio) between two orientations dif-
fering by 26°; the minor orientation is identical with that realized
in the other (ordered) independent molecule. In structure 20e,
which has a low packing coefficient (0.61), the phenyl and iso-
propyl groups are disordered between two orientations each (see
ESI) with practically equal probability. On cooling below 120 K,
23]
24]
Supporting Information (see footnote on the first page of this arti-
1
13
cle): X-ray crystallographic data, H NMR and C NMR spectra
for all key intermediates and final products are provided, and
HPLC data for single chiral-centre products.
Acknowledgments
The authors are grateful for financial assistance received from the
National Basic Research Program of China (grant numbers
2011CB512007, 2012CB723501), the National Natural Science
Foundation of China (NSFC) (grant numbers 30472074, 30873139)
and the Key basic research project of Hebei province of China
(
grant number 12966737D). The authors are grateful to Prof. E.
Pohl (Durham University) for access to the Bruker MicroStar rot-
ating anode for X-ray diffraction experiments.
[
[
[
1] A. K. Ghose, V. N. Viswanadhan, J. J. Wendoloski, J. Comb.
Chem. 1999, 1, 55–68.
2] C. A. G. N. Montalbetti, V. Falque, Tetrahedron 2005, 61,
10827–10852.
3] a) E. Cherbuliez, F. Landolt, Helv. Chim. Acta 1946, 29, 1315–
Figure 3. X-ray structure of molecule 20e (omitting the disorder).
1315; b) K. Ishihara, Tetrahedron 2009, 65, 1085–1109; c) H.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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9

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/KAP1
Date: 15-07-13 12:12:33
Pages: 10
S. Liu, Y. Yang, A. Whiting et al.
FULL PAPER
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Received: April 18, 2013
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