Efficient monoacylation of symmetrical secondary alkanediamines and synthesis of unsymmetrical diacylated alkanediamines. A new L-proline-based organocatalyst

Article abstract of DOI:10.24820/ark.5550190.p011.054

A simple procedure was developed for the monoacylation of several unprotected alkanediamines with carboxylic acids by using PyBOP-HOBt as coupling agent in the presence of DIEA at room temperature. Yields were moderate with primary alkanediamines and good to excellent with linear or cyclic secondary ones. To illustrate the utility of these monoacylated products, six unsymmetrical diacylated alkanediamines were synthesized. In addition, one of these compounds was evaluated as organocatalyst in an asymmetric aldol reaction. R' R' NHR O R _N O R _N PyBOP, HOBt PyBOP, HOBt DIEA, DMF DIEA, DMF NHR NHR O N O 10 equiv O R 11 exemples R' R = H, alkyl R'' OH 67-95% yield R'' OH 6 exemples

Full text of DOI:10.24820/ark.5550190.p011.054

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Efficient monoacylation of symmetrical secondary alkanediamines and synthesis
of unsymmetrical diacylated alkanediamines.
A new L-proline-based organocatalyst
Laure Moulat, Jean Martinez, and Xavier J. Salom-Roig*
Institut des Biomolécules Max Mousseron (IBMM), UMR 5247, Université de Montpellier, CNRS, ENSCM,
Place Eugène Bataillon, 34095 Montpellier, France
Email: Xavier.Salom-Roig@umontpellier.fr
Received 09-03-2019
Accepted 11-13-2019
Published on line 01-12-2020
Abstract
A simple procedure was developed for the monoacylation of several unprotected alkanediamines with
carboxylic acids by using PyBOP-HOBt as coupling agent in the presence of DIEA at room temperature. Yields
were moderate with primary alkanediamines and good to excellent with linear or cyclic secondary ones. To
illustrate the utility of these monoacylated products, six unsymmetrical diacylated alkanediamines were
synthesized. In addition, one of these compounds was evaluated as organocatalyst in an asymmetric aldol
reaction.
R'
N
R'
O
O
O
R
R
R
NHR
N
PyBOP, HOBt
PyBOP, HOBt
DIEA, DMF
O
DIEA, DMF
O
NHR
NHR
N
10 equiv
11 exemples
67-95% yield
R'
R''
R''
R = H, alkyl
OH
OH
6 exemples
Keywords: Monoacylated alkanediamines, unsymmetrical diacylated alkanediamines, pseudopeptidic
derivatives, organocatalyst
DOI: https://doi.org/10.24820/ark.5550190.p011.054
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Introduction
Unsymmetrical diacylated alkanediamines (A, Fig. 1) are a widely occurring structural component incorporated
into numerous interesting molecules usually evaluated for biological purposes. Examples can be found in the
field of fluorescent molecular probes1-9 and bioactive compounds.10-17 As shown in Figure 1, the synthetic
strategy leading to unsymmetrical diacylated alkanediamines involves a mono acylated alkanediamine (B) as
precursor. For the synthesis of B, in order to avoid the formation of the parasite diacylated product, the
common strategy normally used by investigators is the sequence consisting in the acylation of a pre-
monoprotected alkanediamine (C) followed by the protecting group cleavage. A myriad of examples using this
tedious and time-consuming strategy exists in the literature.1-18
O
First
Acylation
R'
RHN
N PG
R
N
N PG
R
R
C; PG = Protecting group
O
N
O
O
Second
Acylation
R''
Deprotection
R'
R'
N
NHR
N
R
R
R
B
A
Figure 1. Strategy for the classical synthesis of unsymetrical diacylated alkanediamines A.
In this paper we describe a shorter strategy leading to monoacylated (B) and diacylated alkanediamines
(A), which doesn’t require the use of a pre-monoprotected alkanediamine (C). This strategy is particularly
efficient for secondary alkanediamines.
Monoacylated symmetrical alkanediamines (B) are valuable scaffolds that appear in the chemical
structure of several biologically active compounds in medicinal chemistry. Figure 2 provides representative
examples including the cardiotonic agent vesnarinone19 (1) and the antihypertensive agents doxazosin (2),
prazosin (3) and terazosin (4).20
H
N
O
MeO
MeO
N
N
Vesnarinone (1)
O
O
O
NH2
Doxazosin (2); R=
MeO
MeO
N
O
Prazosin (3); R=
Terazosin (4); R=
N
N
N
R
O
O
Figure 2. Bioactive compounds bearing a monoacylated moiety.
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However, monoacylation of symmetrical diamines remains difficult.21 Thus, treating a symmetrical
alkanediamine with one equivalent of an acylating agent is expected to yield a statistical distribution of
products comprising unreacted starting alkanediamine and the mono- and diacylated products (Fig. 3).
Consequently, the maximum theoretical yield of the monoacylated product reach 50% with the yield of the
diacylated material not exceeding 25%. Unfortunately, the diacylated products are often formed
predominantly or exclusively, even though the alkanediamine is present in large excess over the acylating
agent. Such finding was attributed by Sayre and co-workers22 to a mixing problem due to the rapidity of the
acylation reaction. Thus, the initial monoacylated product formed at the interface between the drop of the
acylated agent and the alkanediamine solutions is acylated a second time at this interface before being
dispersed in the reaction medium.
O
R'
N
NHR
R
+
Acylating
Agent
RHN
R = H, alkyl
NHR
RHN
O
NHR
+
O
N
R'
R'
N
R
R
Figure 3. Acylation of unprotected alkanediamines.
In light of this, monoacylation of symmetrical diamines has attracted considerable interest from the
synthetic community and several methodologies have already been published. Thus, in the case of
alkanediamines with short hydrocarbon chains one can minimize diacylation at a controlled pH.23-24 By
increasing reactant dilution and decreasing reactivity of the acylating agent, Sayre reached a statistical yield
for the mono-acylation of 1,2-ethanediamine and 1,4-butanediamine.22 Furthermore, Chou’s group obtained
monoacylated products in excellent yields by one-pot neat reaction of aliphatic or aromatic carboxylic esters
and alkanediamines.25 Wang’s strategy focused on the reaction of one equivalent of an acylating agent with
the previously prepared alkanediamine Li di-anion.26 The same group also reached monoacylation by using 9-
BBN to protect one of the two amino groups.27 By using ionic immobilization of piperazine and
homopiperazine to sulfonic acid-functionalized silica gel, monoacylation was also realized.28 Lai reported a
convenient method for preparing aryl monoacylated piperazine derivatives by using trimethylacetic
arylcarboxylic anhydrides.29 Fang developed a protocol leading to monoacylated alkanediamines by reacting
phenyl esters with a phenyl carbonate as acylation agents in the presence of water.30 Finally, most recently,
Bandgar obtained a series of monoacylated piperazine derivatives by the reaction of carboxylic acids with 2-
chloro-4,6-dimethoxy-1,3,5-triazine.31 Most of the synthetic methods described above suffer from drawbacks,
notably the use of drastic reaction conditions or aggressive reagents or are limited to aryl acylations.
Therefore, there still exists a need to develop simply and general procedures more efficient than those
currently in existence.
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Results and Discussion
In this context, our interest in acylated alkanediamines arose from a desire to access a convenient
monoacylation procedure for the preparation of secondary and tertiary amides by reaction of carboxylic acids
with linear or cyclic alkylenediamines. Thus, we accomplished the synthesis of monoacylated derivatives
starting from commercially available carboxylic acids, which were coupled to the corresponding inexpensive
alkanediamine in excess utilizing PyBOP-HOBt32-34 as coupling agent in the presence of DIEA and DMF as a
solvent. The desired monoacylated alkanediamines could be obtained after purification by column
chromatography on silica gel in moderated yields for primary amines to excellent yields for secondary ones.
As shown in Table 1, we first examined the monoacylation of two primary alkanediamines (1,2-
ethanediamine and 1,6-hexanediamine) using N-Boc-protected lysine (5, entries 1 and 2), N-Boc-protected
phenylalanine (6, entries 3 and 4) and (S)-naproxen (7, entries 5 and 6) as acylating agents. As expected, the
corresponding monoacylated alkanediamines were obtained in low to moderate yields due to the concomitant
presence of the corresponding diacylated analogues in a range of 20-30%. Thus, while 1,2-ethanediamine led
to 8, 10 and 12 in disappointing yields (30-31%), 1,6-hexanediamine furnished the corresponding
monoacylated products 9, 11 and 13 in yields ranging from 51 to 56%.
Table 1. Monoacylated primary alkanediamines prepared by PyBOP/HOBt coupling
Entry
1
Carboxylic acid
Alkanediamine
Monoacylated amine
Yield (%)
30
O
O
BocHN
NH2
BocHN
NH2
N
H
OH
H2N
H2N
5
5
8
9
(CH2)4NHZ
(CH2)4NHZ
O
O
2
NH2
BocHN
BocHN
NH2
BocHN
N
H
OH
3
56
3
(CH2)4NHZ
(CH2)4NHZ
O
O
3
4
5
NH2
BocHN
NH2
H2N
H2N
OH
N
H
6
10
11
31
51
31
Bn
O
Bn
O
NH2
BocHN
MeO
BocHN
MeO
NH2
O
OH
Bn
N
3
H
3
6
Bn
O
NH2
NH2
H2N
N
OH
H
Me
Me
12
7
7
MeO
MeO
O
6
O
NH2
H2N
NH2
3
N
H
55
OH
3
Me
Me
13
Interestingly, as we carried out the monoacylation of cyclic alkanediamines (piperazine and
homopiperazine, Table 2) using the same conditions described before (vide supra), the reaction crudes were
proved by LC-MS to contain only traces of the contaminant diacylated alkane diamines. The use of an excess of
alkane diamine was necessary to avoid the formation of significant amounts of the corresponding diacylated
alkanediamines. Consequently, the corresponding monoacylated piperazine and homopiperazine derivatives
were obtained, after purification by column chromatography on silica gel, in good to high yields (67-96%). As
shown in Table 2, monoacylated homopiperazine compounds were obtained in somewhat lower yields than
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piperazine analogues (compare entries 1,3 and 5 with entries 2,4 and 6. (S)-Naproxen was reacted with a
linear secondary amine (entry 7) yielding the corresponding tertiary amide 25 in 96% yield and confirming that
the nucleophilic power of cyclic diamines and not their constrained form was responsible for their better
reactivity compared to primary amines. In order to demonstrate the general scope of this procedure, we also
prepared in good yields N-acylpiperazines 26-28 (entries 8-10) as precursors of vesnarinone (1) and the
antihypertensive agents doxazosin (2) and a prazosin 2-thienyl analogue respectively in addition to compound
29 bearing a linear chain.35
Table 2. Monoacylated secondary alkanediamines prepared by PyBOP/HOBt coupling
Entry
1
Carboxylic acid
Alkanediamine
Monoacetylated amine
Yield (%)
70
NH
O
BocHN
N
HN
O
NH
BocHN
OH
ZNH(CH2)4
19
(CH2)4NHZ
5
O
2
NH
HN
BocHN
N
NH
ZNH(CH2)4
20
5
94
O
O
NH
HN
3
4
5
ZHN
N
ZHN
OH
NH
Bn
Bn
14
21
87
95
79
O
O
NH
HN
BocHN
N
ZHN
OH
Bn
NH
N
Bn
6
22
MeO
MeO
NH
HN
MeO
O
O
OH
OH
OH
15
NH 23
Me
Me
7
7
7
MeO
MeO
O
O
6
NH
HN
N
Me
NH
Me
24
93
96
O
7
8
Me
25
O
O
NH
HN
MeO
MeO
MeO
MeO
N
OH
NH
26
88
84
O
O
9
NH
HN
O
O
O
O
OH
N
NH
16
27
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Table 2. Continued
Entry
10
Carboxylic acid
Alkanediamine
Monoacetylated amine
Yield (%)
O
O
NH
HN
N
OH
S
NH
S
17
28
29
67
98
O
O
11
NH
HN
OH
N
18
NH
The synthetic potential of this methodology was further exemplified by using the monoacylated
alkanediamines in hand as intermediates for the construction of unsymmetrical diacylated alkanediamines.
Thus, in a first time, we synthesized a series of six pseudopeptidic derivatives which were studied as
supramolecular receptors for non-steroidal antiinflammatory drugs.36-37 For this meaning, as detailed in
Scheme 1, in compounds 8, 9 and 10, the remaining free amine was coupled to commercially available Boc-
tryp-OH by using the PyBOP/HOBt methodology32-34 in the presence DIEA obtaining the pseudopeptidic
models 30, 31 and 33 in good yields. Analogously, we carried out the coupling of compounds 10 and 22 with
Boc-tyr-OH providing models 32 and 34. Finally, the N-monoacylated compound 10 was reacted with Z-Pro-
OH giving, after cleavage of the proline amine protecting group, the unsymmetrical diacylated piperazine 35.
During the last years, L-proline-based compounds have been successfully employed in asymmetric
organocatalysis enlarging the scope of the natural amino acid.38-41 In this context, we decided to evaluate the
catalytic properties of the proline-based compound 35.
As a benchmark reaction, we examined the aldol reaction between p-nitrobenzaldehyde and acetone. The
results of this study are reported in Table 3.
In our initial experiments, we screened various solvent systems by using 30 mol % catalyst 35 to promote
the reaction (entries 1-4). Thus, in a 1:4 acetone/DMSO mixture,42 after stirring the homogenous reaction
mixture for 8 days at room temperature, chiral-phase HPLC analysis revealed that the expected aldol product
36 was formed in 19% ee. When using DMF instead of DMSO as a co-solvent, the reaction took place in 5 days
improving slightly the enantioselectivity. With the system acetone/AcCN (1:4), after 3 days, the ee was
enhanced to 36% with a 92% of conversion rate. The use of chloroform as a co-solvent induced lower
enantioselectivity and gave a shorter reaction time. We decided then to conduct the reaction with acetone
serving as an only solvent. Thus, aldol 36 was formed in 46% ee (entry 5). By decreasing the catalyst loading to
10%, the reaction rate increased and the ee dropped dramatically (entry 6). By further reduction of the
amount of the catalyst (5%) only 54% of conversion was achieved after 3 days with a comparable enantiomeric
excess (entry 7). The increase of the quantity of catalyst (50%) considerably accelerated the reaction (4h) but
resulted in a lower enantioselectivity (entry 8). Finally, we studied the influence of the reaction temperature in
the enantioselectivity (entries 9-11). Thus, when the reaction was carried out at 0°C, the ee increased to 52%.
The best result was obtained when the reaction proceeded at -20°C giving the hydroxyketone 36 in 69% yield
and 72% ee. Further decrease of the reaction temperature to -30°C reduced somewhat the ee value (66%).
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NH
O
H
N
a
BocHN
8
N
NHBoc
H
67%
O
(CH2)4NHZ
30
NH
O
H
N
3
a
BocHN
9
N
H
NHBoc
80%
O
(CH2)4NHZ
31
OH
O
N
b
BocHN
Ph
22
65%
N
NHBoc
NH
O
32
O
H
BocHN
N
N
NHBoc
H
O
OH
Ph
a, 53%
33
O
H
b, 64%
BocHN
Ph
N
N
NHBoc
10
H
O
34
c,83%
d,81%
O
H
BocHN
Ph
N
N
N
H
H
O
35
Scheme 1. Synthesis of unsymmetrical diacylated alkanediamines. Reagents and conditions: a: Boc-Trp-OH,
PyBOP (1 equiv), HOBt (2 equiv), DIEA (2 equiv) in anhydrous DMF, 24 h; b: Boc-Tyr-OH, PyBOP (1 equiv), HOBt
(2 equiv), DIEA (2 equiv) in anhydrous DMF, 24 h; c: Z-Pro-OH, PyBOP (1 equiv), HOBt (2 equiv), DIEA (2 equiv)
in anhydrous DMF, 24 h; d: H2, Pd(OH)2/C, EtOH.
Interestingly, when the reaction was conducted by using L-proline as a catalyst with acetone serving as a
solvent, no reaction occurred after 3 days stirring of the heterogeneous mixture (entry 12). We attributed this
lack of reactivity to the low solubility of proline in acetone. In order to get the completion of the reaction
promoted by proline, a 1:4 acetone/DMSO solvent system is necessary (entries 13 and 14).42,43 Compared to
the described conditions using proline as catalyst at room temperature or at -20°C (entries 13 and 14), we
observed similar yield and enantioselectivity by using our proline-based organocatalyst 35 at -20°C. However,
it is worth mentioning that in our case the use of DMSO, which is not easy to remove, as a co-solvent was not
necessary.
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Table 3. Aldol Reaction between p-Nitrobenzaldehyde and Acetone Catalyzed by proline derivative 35
O
O
OH
O
35
+
H
solvent
NO2
NO2
36
Entry Catalyst
% mol
Solvent
T(C°)
Time (h)
Conversion
(%)a,b
97
ee
(%)a,c
19
26
36
27
46
29
28
40
52
72d
66
-
1
2
35
35
30
30
30
30
30
10
5
50
30
30
30
30
30
30
Acetone/DMSO (1:4)
Acetone/DMF (1:4)
Acetone/AcCN (1:4)
Acetone/CHCl3 (1:4)
Acetone
rt
rt
rt
rt
rt
rt
rt
rt
0
-20
-30
0
rt
-20
192
120
72
24
24
72
72
4
24
24
24
72
24
24
100
92
96
94
94
3
35
4
35
5
35
6
35
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
7
35
54
8
35
100
100
100
95
0
100
100
9
35
10
11
12
13
14
35
35
L-Pro
L-Pro20
L-Pro21
Acetone/DMSO (1:4)
Acetone/DMSO (1:4)
76
71
aConversion and enantioselectivity of the aldol product were determined by analytical chiral HPLC analysis
b
on a chiralpak AS-H column, detection at 270 nm. No secondary products were observed by analytical
chiral HPLC analysis. cThe absolute configuration of the major enantiomer was assigned by comparison
with literature data. dCompound 36 was isolated with 69 % yield.
Conclusions
In conclusion, a convenient protocol to obtain monoacylated acyclic and cyclic alkanediamines has been
developed. We have demonstrated that this is a general procedure leading to secondary, and more efficiently
to tertiary amides, and illustrated its utility by preparing in good yields three monoacylated piperazine
derivatives as key intermediates in the synthesis of bioactive compounds. This simple procedure provides a
practical and timely method for the synthesis of unsymmetrical diacylated alkanediamines, avoiding the
employment of any pre-protected alkanediamine as we have demonstrated by the synthesis of six
pseudopeptidic derivatives. This protocol is particularly useful for the acylation of inexpensive alkanediamines
with precious carboxylic acids. We strongly believe that this methodology will find broad application in
synthetic organic chemistry. In addition, one of these compounds was tested as organocatalyst in an
asymmetric aldol reaction showing similar results to that described in the literature employing proline. Further
studies focusing on new applications of this promising proline-based catalyst and analogues are now under
investigation.
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Experimental Section
General. All reagents and solvents were purchased from commercial sources. Reactions were conducted in
flame-dried glassware under an argon atmosphere. 1H NMR and 13C NMR spectra were recorded at 300 or 400
MHz and at 75 or 101 MHz in CD3OD or DMSO-d6. Chemical shifts are given in ppm and reported to the
residual solvent peak (CD3OD 3.31 ppm and 49.00 ppm; DMSO-d6 2.50 ppm and 39.52 ppm). Data are
reported as follows: chemical shift (δ), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m =
multiplet), coupling constants, and integration. Analytical TLC were performed on silica gel 60 F254 plates.
Column chromatographies were carried out on silica gel 60 (63-200 μm). High- resolution mass spectra (HRMS)
were measured using electrospray ionization (ESI) and Q-Tof detection. Melting points were measured with a
Büchi apparatus and are reported uncorrected.
General procedure for the synthesis of monoacylated diamines. In a typical procedure, alkanediamine (0.014
mol) was suspended in 20 ml DMF. Diisopropylethylamine (DIEA, 0.48 ml, 2.78 mmol) was added, followed by
the appropriate carboxylic acid (1.39 mmol), 1-Hydroxybenzotriazole (HOBt, 380 mg, 2.78 mmol) and PyBOP
(720 mg, 1.39 mmol). The reaction was allowed to proceed at room temperature 24-30 hours. DMF was then
removed by evaporation under reduced pressure and the resultant residue was suspended in ethyl acetate
and treated with an aqueous saturated solution of NaHCO3. Phases were separated and the aqueous one
extracted with ethyl acetate. The organic layers were dried over magnesium sulfate and rotary evaporated to
produce a crude yellow oil, which was purified by column chromatography (silica, CH2Cl2/MeOH 4:1).
For the description of compounds 8, 10, 30, 31, 32, 33, see reference 18.
tert-Butyl (S)-1-(6-aminohexylcarbamoyl)-5-(benzylami-nopentylcarbamoyl)carbamate (9) was prepared
following the general procedure from 5 (528 mg, 1.39 mmol) yielding compound of 9 as a white solid (372 mg,
56%). mp < 30°C. 1H NMR (300 MHz, CD3OD): δ 7.90 (sl, 1H), 7.35-7.26 (m, 5H), 5.07 (s, 2H), 3.94-3.91 (m, 1H),
3.27-3.09 (m, 2H), 2.93-289 (m, 2H), 1.71-1.29 (m, 14H), 1.44 (s, 9H). 13C NMR (75 MHz, CD3OD): δ 175.3,
159.0, 157.8, 138.4, 129.5, 129.0, 128.7, 80.6, 67.3, 56.3, 41.4, 40.7, 39.9, 33.0, 30.5, 30.1, 28.7, 28.4, 27.1,
26.9, 24.1. HRMS (ESI): m/z calcd for C25H43N4O5: 479.3233 [M+H]+ ; found 479.3228.
tert-Butyl-(S)-1-(6-aminohexylcarbamoyl)-2-phenylethyl-carbamate (11) was prepared following the general
procedure from 6 (369 mg, 1.39 mmol) yielding compound 11 as a white solid (258 mg, 51%). mp 60-62°C. 1H
NMR (400 MHz, DMSO-d6): δ 7.98 (s, 0.25H), 7.83-7.80 (m, 1H), 7.61 (s large, 2H), 7.28-7.16 (m, 5H), 6.83 (d,
0.75H, J = 8.5 Hz), 4.13-4.07 (m, 1H), 3.11-2.88 (m, 4H), 2.76 (t, 2H, J = 7.6 Hz), 1.54-1.46 (m, 2H), 1.40-1.20 (m,
8H), 1.30 (s, 9H). 13C NMR (75 MHz, DMSO-d6): δ 171.4, 160.9, 155.2, 138.1, 129.2, 128.0, 126.2, 78.0, 55.8,
38.8, 38.3, 37.8, 28.9, 28.8, 28.2, 27.0, 26.0, 25.8, 25.5. HRMS (ESI): m/z calcd for C20H34N3O3: 364.2595
[M+H]+ ; found 364.2603.
(R)-N-(2-Aminoethyl)-2-(2-methoxynaphthalen-6-yl)pro-panamide (12) was prepared following the general
procedure from 7 (320 mg, 1.39 mmol) yielding compound 12 as a white solid (117 mg, 31%). mp 121-123°C.
1H NMR (300 MHz, CD3OD): δ 7.74-7.70 (m, 2H), 7.42 (dd, 1H, J 8.5, 1.8 Hz), 7.20 (d, 1H, J 2.4 Hz), 7.11 (dd, 1H,
J 9.0, 2.5 Hz), 3.89 (s, 3H), 7.78 (q, 1H, J 7.1 Hz), 3.53-3.46 (m, 1H), 3.36-3.33 (m, 1H), 3.07-2.96 (m, 2H), 1.53
(d, 3H, J 7.1 Hz). 13C NMR (75 MHz, CD3OD): δ 178.6, 159.2, 137.7, 135.3, 130.4, 130.2, 128.3, 127.0, 126.9,
120.0, 55.7, 47.4, 40.8, 38.5, 18.8. HRMS (ESI): m/z calcd for C16H21N2O2: 273.1598 [M+H]+ ; found 273.1627.
(R)-N-(6-Aminohexyl)-2-(2methoxynaphthalen-6-yl)pro-panamide (13) was prepared following the general
procedure from 7 (320 mg, 1.39 mmol) yielding compound 13 as a white oil (258 mg, 55%). 1H NMR (300 MHz,
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CD3OD): δ 7.82 (sl, 1H), 7.72-7.68 (m, 3H), 7.42 (d, 1H, J 8.6 Hz), 7.19 (sl, 1H), 7.11-7.08 (m, 1H), 3.86 (s, 3H),
3.74 (q, 1H, J 7.1 Hz), 3.21-3.08 (m, 2H), 1.51-1.44 (m, 4H), 1.50 (d, 3H, J 7.1 Hz), 1.35-1.17 (m, 4H). 13C NMR
(75 MHz, CD3OD): δ 177.2, 159.01, 138.1, 135.0, 130.3, 130.2, 128.1, 127.1, 126.7, 119.8, 106.6, 55.7, 47.4,
40.6, 40.1, 30.0, 28.3, 27.0, 26.7, 18.7. HRMS (ESI): m/z calcd for C20H29N2O2: 329.2229 [M+H]+ ; found
329.2217.
tert-Butyl (S)-6-aminobenzylcarbamoyl-1-(1,4-diazepan-1-yl)-1-oxohexan-2-ylcarbamate (19) was prepared
following the general procedure from 5 (528 mg, 1.39 mmol) yielding compound 19 as a white solid (449 mg,
1
70%). mp 88-90°C. H NMR (300 MHz, CD3OD): δ 7.35-7.27 (m, 5H), 5.07 (s, 2H), 4.41-4.33 (m, 1H), 4.17-3.92
(m, 2H), 3.73-3.33 (m, 4H), 3.29-3.07 (m, 4H), 2.29-1.96 (m, 2H), 1.74-1.28 (m, 6H), 1.44 (s, 9H). 13C NMR (75
MHz, CD3OD): δ 175.2, 159.0, 158.4, 158.3, 138.5, 129.5, 128.9, 128.7, 80.8, 67.3, 52.4, 52.3, 47.8, 47.2, 46.7,
45.9, 45.8, 43.7, 41.2, 32.1, 30.5, 28.7, 27.1, 26.0, 24.1, 23.8. HRMS (ESI): m/z calcd for C24H39N4O5: 463.2915
[M+H]+ ; found 436.2922.
tert-Butyl (S)-6-aminobenzylcarbamoyl-1-(piperazin-1-yl)-1-oxohexan-2-ylcarbamate (20) was prepared
following the general procedure from 5 (528 mg, 1.39 mmol) yielding compound 20 as a white solid (585 mg,
94%). mp < 25°C. 1H NMR (400 MHz, CD3OD): δ 7.34-7.25 (m, 5H), 5.06 (s, 2H), 4.47-4.44 (m, 1H), 3.70-3.44 (m,
4H), 3.16-3.05 (m, 2H), 2.95-2.83 (m, 4H), 1.70-1.28 (m, 6H), 1.42 (s, 9H). 13C NMR (75 MHz, CD3OD): δ 173.1,
159.0, 157.9, 138.5, 129.5, 129.0, 128.7, 80.6, 67.3, 51.6, 47.0, 46.4, 46.0, 43.4, 41.3, 32.7, 30.5, 28.7, 23.8.
HRMS (ESI): m/z calcd for C23H37N4O5: 449.2764 [M+H]+ ; found 449.2768.
Benzyl (S)-1-(1,4-diazepan-1-yl)-1-oxo-3-phenylpropan-2-ylcarbamate (21) was prepared following the
general procedure from 14 (416 mg, 1.39 mmol) yielding compound 21 as a white solid (461 mg, 87%). mp 88-
90°C °C. 1H NMR (300 MHz, CD3OD): δ 7.35-7.24 (m, 10H), 5.09-5.01 (m, 2H), 4.78-4.66 (m, 1H), 3.98-3.86 (m,
1H), 3.72-3.60 (m, 1H), 3.48-3.39 (m, 1H), 2.98 (d, 2H, J 7.5 Hz), 2.92-2.83 (m, 5H), 2.12-1.82 (m, 2H). 13C NMR
(75 MHz, CD3OD): δ 174.3, 138.1, 137.8, 137.7, 130.6, 129.6, 129.5, 129.0, 128.7, 128.7, 128.3, 128.2, 67.7,
54.0, 53.8, 47.0, 45.8, 45.1, 43.4, 39.2, 39.1, 26.5, 25.7. HRMS (ESI): m/z calcd for C22H28N3O3: 382.2131
[M+H]+ ; found 382.2130.
tert-Butyl (S)-1-oxo-3-phenyl-1-(piperazin-1-yl)propan-2-ylcarbamate (22) was prepared following the
general procedure from 6 (369 mg, 1.39 mmol) yielding compound 22 as a white solid (440 mg, 95%). mp 124-
126 °C. 1H NMR (300 MHz, DMSO-d6): δ 7.29-7.13 (m, 5H), 4.61-4.47 (m, 1H), 3.81 (s large, 1H), 3.54-3.36 (m,
4H), 2.89-2.56 (m, 6H), 1.31 (s, 9H). 13C NMR (75 MHz, DMSO-d6): δ 169.9, 155.1, 137.7, 129.5, 128.1, 126.4,
78.1, 51.2, 44.3, 44.2, 40.8, 37.4, 28.2, 27.9. HRMS (ESI): m/z calcd for C18H28N3O3: 334.2131 [M+H]+ ; found
334.2137.
(R)-1-(1,4-Diazepan-1-yl)-2-(2-methoxynaph-thalen-6-yl)propan-1-one (23) was prepared following the
general procedure from 7 (320 mg, 1.39 mmol) yielding compound 23 as a white solid (343 mg, 79%). mp >
230 °C (decomp.). 1H NMR (300 MHz, DMSO-d6): δ 7.82 (d, 1H, J 8.7 Hz), 7.81 (d, 1H, J 8.8 Hz), 7.74 (s, 1H), 7.44
(dd, 1H, J 8.4, 1.4 Hz), 7.32 (d, 1H, J 2.0 Hz), 7.19 (dd, 1H, J 8.9, 2.4 Hz), 4.25-4.18 (m, 1H), 3.90 (s, 3H), 3.81-
3.34 (m, 5H), 3.22-2.91 (m, 3H), 2.83-2.68 (m, 1H), 1.96-1.66 (m, 2H), 1.41(d, 1H, J 6.7 Hz). 13C NMR (75 MHz,
DMSO-d6): δ 172.9, 172.8, 157.2, 137.2, 137.1, 133.2, 133.1, 129.1, 128.5, 127.3, 127.2, 126.2, 126.1, 125.5,
125.4, 118.8, 105.8, 55.2, 47.1, 47.0, 45.6, 45.5, 45.4, 45.2, 44.4, 43.8, 42.1, 41.7, 41.6, 25.8, 25.7, 24.9, 20.9,
20.7. HRMS (ESI): m/z calcd for C19H25N2O2: 313.1916 [M+H]+ ; found 313.1926.
(R)-2-(2-Methoxynaphthalen-6-yl)-1-(piperazin-1-yl)pro-pan-1-one (24) was prepared following the general
procedure from 7 (320 mg, 1.39 mmol) yielding compound 24 as a white solid (386 mg, 93%). mp > 220 °C
(decomp.). 1H NMR (300 MHz, DMSO-d6): δ 7.78 (d, 2H, J 8.7 Hz), 7.67 (s, 1H), 7.36 (dd, 1H, J 8.4, 1.6 Hz), 7.28
(d, 1H, J 2.4 Hz), 7.14 (dd, 1H, J 8.9, 2.5 Hz, J Hz), 4.22 (q, 1H, J 6.8 Hz), 3.62-3.56 (m, 3H), 3.35-3.31 (m, 1H),
2.89-2.73 (m, 3H), 2.35-2.30 (m, 1H), 1.35 (d, J 6.8 Hz). 13C NMR (75 MHz, DMSO-d6): δ 171.5, 157.1, 137.1,
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133.0, 129.1, 128.5, 127.3, 126.1, 125.3, 118.8, 105.8, 55.2, 43.9, 41.1, 40.2, 20.5. HRMS (ESI): m/z calcd for
C18H23N2O2: 299.1760 [M+H]+ ; found 299.1758.
(R)-2-(2-Methoxynaphthalen-6-yl)-N-methyl-N-(2-(me-thylamino)ethyl)propanamide (25) was prepared
following the general procedure from 7 (320 mg, 1.39 mmol), yielding compound 25 as a white oil (401 mg,
96%). 1H NMR (400 MHz, CD3OD): δ 7.65 (d, 1H, J 8.5 Hz), 7.61 (d 1H, J 9.0 Hz), 7.54 (sl, 1H), 7.25 (dd, 1H, J 8.5,
1.7 Hz), 7.11 (d, 1H, J 2.3 Hz), 7.02 (dd, 1H, J 9.0, 2.5 Hz), 4.08 (q, 1H, J 6.8 Hz), 3.92-3.85 (m, 1H), 3.80 (s, 3H),
3.14-3.01 (m, 4H), 2.89 (s, 3H), 2.64 (s, 3H), 1.37 (d, 3H, J 6.8 Hz). 13C NMR (75 MHz, CD3OD): δ 178.2, 159.2,
137.5, 135.2, 130.5, 130.1, 128.8, 126.9, 126.8, 120.1, 106.6, 55.7, 51.7, 46.3, 44.3, 36.5, 34.1, 20.8. HRMS
(ESI): m/z calcd for C18H25N2O2: 301.1911 [M+H]+ ; found 301.1914.
(3,4-Dimethoxyphenyl)(piperazin-1-yl)metha-none (26) was prepared following the general procedure from
1
15 (253 mg, 1.39 mmol yielding compound 26 as a white solid (306 mg, 88%). mp > 200 °C (decomp.). H NMR
(300 MHz, CD3OD): δ 7.07-7.04 (m, 3H), 3.87 (s, 3H), 3.86 (s, 3H), 3.79-3.66 (m, 4H), 3.12-3.01 (m, 4H). 13C
NMR (75 MHz, CD3OD): δ 172.6, 152.1, 150.3, 128.3, 121.6,112.4, 112.1, 56.5, 56.4 45.4. HRMS (ESI): m/z calcd
for C13H19N2O3: 251.1396 [M+H]+ ; found 251.1398.
(2,3-Dihydrobenzo[b][1,4]dioxin-2-yl)(pipera-zin-1-yl)-methanone (27) was prepared following the general
procedure from 16 (250 mg, 1.39 mmol) yielding compound 27 as a white solid (291 mg, 84%). mp 57-59 °C. 1H
NMR (300 MHz, CD3OD): δ 6.93-6.81 (m, 4H), 5.07 (dd, 1H, J 7.1, 2.6 Hz) 4.41 (dd, 1H, J 11.8, 2.6 Hz), 4.22 (dd,
1H, J 11.8, 7.1 Hz), 3.80-3.48 (m, 4H), 2.95-2.79 (m, 4H). 13C NMR (75 MHz, CD3OD): δ 167.3, 144.5, 144.0,
123.0, 122.6, 118.2, 118.1, 71.4, 66.1, 47.2, 46.6, 46.0, 43.4. HRMS (ESI): m/z calcd for C13H17N2O3: 249.1239
[M+H]+ ; found 249.1240.
(Piperazin-1-yl)(thiophen-2-yl)methanone (28) was prepared following the general procedure from 17 (178
1
mg, 1.39 mmol yielding compound 28 as a white solid (182 mg, 67%). mp > 230 °C (decomp.). H NMR (300
MHz, CD3OD): δ 7.68 (dd, 1H, J 5.0, 1.1 Hz), 7.48 (dd, 1H, J 3.7, 1.1 Hz), 7.15 (dd, 1H, J 5.0, 3.7 Hz), 3.99-3.96
(m, 4H). 13C NMR (75 MHz, CD3OD): δ 165.9, 136.5, 131.2, 131.1, 128.3, 44.4. HRMS (ESI): m/z calcd for
C9H13N2OS: 197.0749 [M+H]+ ; found 197.0745.
4-Methyl-1-(piperazin-1-yl)pentan-1-one (29) was prepared following the general procedure from 18 (161
1
mg, 1.39 mmol) yielding compound 29 as a white solid (161 mg, 98%). mp °C. H NMR (300 MHz, CD3OD): δ
3.69-3.65 (m, 4H), 3.11-3.01 (m, 4H), 2.40-2.35 (m, 2H), 1.61-1.38 (m, 3H), 0.87 (d, 6H, J 6.5 Hz). 13C NMR (75
MHz, CD3OD): δ 174.7, 49.8, 45.0, 44.8, 44.6, 40.5, 35.0, 31.7, 28.7, 22.5.
tert-Butyl (S)-1-(2-aminoethyl-(2-pyrrolidine carbamoyl)-carbamoyl)-2-phenylethylcarbamate (34). The
mono-acylated diamine 10 (472 mg, 1.5 mmol) was dissolved in 22 ml DMF. To the resultant solution were
added DIEA (0.57 ml, 3.4 mmol) followed by Z-protected proline (421 mg, 1.7 mmol), 1-hydroxybenzotriazole
(HOBt, 456 mg, 3.4 mmol) and PyBOP (879 mg, 1.7 mmol). The reaction was allowed to proceed at room
temperature until judged complete by HPLC, typically 24–30 h. DMF was then removed by evaporation under
reduced pressure and the resulting residue was suspended in ethyl acetate and treated with an aqueous
saturated solution of NaHCO3. Phases were separated and the aqueous one extracted with ethyl acetate. The
organic layers were dried over magnesium sulfate and rotary evaporated to produce a crude yellow oil, which
was purified by column chromatography (silica, CH2Cl2/MeOH 10:1) leading to compound 34 as a white solid
1
(687 mg, 83%). mp 157-158°C. H NMR (400 MHz, CDCl3): δ 7.35-7.19 (m, 10H), 6.64 (s large, 1.5H), 5.38 (s
large, 0.5H), 5.21 (d, 1H, J 12.4 Hz), 5.08 (d, 1H, J 11.8 Hz), 4.36-4.13 (m, 2H), 3.57-2.95 (m, 8H), 2.17-1.82 (m,
4H), 1.37 (s, 9H). 13C NMR (75 MHz, CDCl3): δ 173.2, 172.6, 156.0, 137.4, 136.7, 129.7, 128.9, 128.8, 128.5,
128.2, 127.1, 80.3, 67.7, 61.2, 56.4, 47.4, 39.5, 39.0, 38.9, 29.7, 28.6, 24.9. HRMS (ESI): m/z calcd for
C29H39N4O6: 539.2870 [M+H]+ ; found 539.2863.
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tert-Butyl (S)-1-(2-aminoethyl-[1-benyl-(2-pyrrolidine carbamoyl)carbamoyl)-2-phenylethylcarbamate (35).
A solution of 0.216 g of the Z-protected amine derivative 34 was prepared in 15 mL of ethanol degassed with
argon and two drops of AcOH. Under a positive argon flow, 33 mg of Pd(OH)2 catalyst was slowly added to the
vigorously stirring degassed solution. After 4 h, the suspensionwas filtered through Celite. The Celite pad was
washed with more ethanol and the filtrate was concentrated under vacuum. The resultant white solid was
1
recristallized in DCM/ether. Compound 35 (0.131 g, 81%) was obtained as a white solid. mp 57-58°C. H NMR
(400 MHz, DMSO-d6): δ 7.30-7.19 (m, 5H), 4.25-4.21 (m, 1H), 3.71-3.7 (m, 1H), 3.27-3.21 (m, 4H), 3.10-2.94 (m,
3H), 2.84-2.79 (m, 1H). 13C NMR (75 MHz, DMSO-d6): δ 176.4, 174.7, 138.7, 130.5, 129.4, 127.7, 80.7, 61.6,
57.7, 47.9, 40.0, 39.9, 39.4, 31.8, 28.7, 26.7. HRMS (ESI): m/z calcd for C21H33N4O4: 405.2502 [M+H]+ ; found
405.2509.
Acknowledgements
Thanks are expressed to Mr. Pierre Sánchez for his help in the obtaining mass spectrometry spectra.
Supplementary Material
1
Copies of H and 13C NMR spectra of the new compounds 9, 11-13, 19-29, and 34-35 can be found in the
supplementary material file.
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