Efficient synthesis of heterocyclic neurotensin receptor ligands by microwave-assisted aminocarbonylation

Article abstract of DOI:10.1055/s-0033-1338497

Marking the heterocyclic neurotensin receptor antagonist SR142948A as a lead compound, the development of an efficient and a practical synthetic route to heterocyclic aryl carboxamides is reported. Thus, a highly efficient and flexible access to these carboxamides was elaborated by taking advantage of microwave-assisted aminocarbonylation reaction mediated by Mo(CO)₆, Herrmann's palladacycle, [(t-Bu)₃PH]BF₄, and DBU.

Full text of DOI:10.1055/s-0033-1338497

2474▌
PAPER
paper
Efficient Synthesis of Heterocyclic Neurotensin Receptor Ligands by
Microwave-Assisted Aminocarbonylation
Microwave-Assisted Aminocarbonylation
Christopher Lang, Peter Gmeiner*
Department of Chemistry and Pharmacy, Emil Fischer Center, Friedrich Alexander University Erlangen-Nürnberg, Schuhstr. 19,
91052 Erlangen, Germany
Fax +49(9131)8522585; E-mail: peter.gmeiner@fau.de
Received: 07.05.2013; Accepted after revision: 29.05.2013
Taking advantage of a recently described microwave-
assisted methodology,5 we planned to employ the palladi-
um-catalyzed aminocarbonylation6 reaction as the key
step to simultaneously generate the carboxamide moiety
Abstract: Marking the heterocyclic neurotensin receptor antago-
nist SR142948A as a lead compound, the development of an effi-
cient and
a practical synthetic route to heterocyclic aryl
carboxamides is reported. Thus, a highly efficient and flexible ac-
cess to these carboxamides was elaborated by taking advantage of and attach the basic side chain (Scheme 1). Our short and
microwave-assisted aminocarbonylation reaction mediated by
Mo(CO)6, Herrmann’s palladacycle, [(t-Bu)3PH]BF4, and DBU.
practical approach should allow structural variation of the
N-substituents of both carboxamide moieties during the
Key words: aminocarbonylation, microwave, aryl bromide, palla-
dium catalysis, palladacycles, medicinal chemistry
last reaction steps. Additionally, purification should be
simplified by avoiding the occurrence of amino acid struc-
tures until the end of the sequence.
The diarylpyrazole derivative SR48692 is known as a po-
tent neurotensin NTS1 receptor antagonist that underwent
clinical studies for the therapy of schizophrenia and small-
cell lung cancer (Figure 1).1 Although a clinical evalua-
tion was not successful, a very recent study demonstrated
the ability of SR48692 to sensitize tumor tissue for irradi-
ation, showing the applicability and potential of NTS1
receptor antagonists.2 The N-[3-(dimethylamino)pro-
pyl]carboxamide SR142948A3 represents a further devel-
opment of SR48629 with higher binding affinity for
NTS1, which is presumably due to an interaction of the
tertiary amine of the arylcarboxamide side chain. Because
the previously described synthesis of SR142948A4 re-
quires eight reaction steps, we attempted to elaborate an
efficient and practical small scale approach to the lead
compound allowing also the construction of focused li-
braries to further optimize target binding and selectivity.
[Pd], Mo(CO)6, HNR1R2
microwave
C
R1
Br
O
N
R2
Scheme 1 Microwave-assisted aminocarbonylation
Our synthetic route to the lead compound SR142948A
and its structural analogues 7a–c and 8 relied on the aryl
bromide 2 as a bifunctional building block. Employing
NBS under NH4OAc catalysis,7 the 4-bromo-2-isopropyl-
aniline (2) was prepared from 2-isopropylaniline (1) in
81% yield (Scheme 2). The aryl bromide was subjected to
diazotation upon treatment with NaNO2 in HCl followed
by reduction to the corresponding hydrazine. The crude
product was treated with methyl 4-(2,6-dimethoxyphe-
nyl)-2,4-dioxobutyrate4 to afford the pyrazole derivative
3. The methyl carboxylate 3 was cleaved under alkaline
conditions to give the free acid 4, which was converted
into the carboxamide 5a using isobutyl chloroformate as
an activating agent. To facilitate the coupling reaction, the
reaction partner 2-aminoadamantane-2-carboxylic acid
had to be protected intermediately with TMSCl.8 The silyl
ester was subsequently cleaved during an aqueous work-
up. The aryl bromide 5a was converted to the differently
substituted carboxamides 7a–c and SR142948A (7d) by
microwave-assisted aminocarbonylation (140 °C, 30
O
O
COOH
COOH
NH
NH
Me
Me
Me
Me
O
O
N
N
N
N
O
O
Cl
Me
N
N
10
min). Herrmann’s palladacycle9 and [(t-Bu)3PH]BF4
N
Me
SR142948A
Me
O
were chosen as the catalytic system, Mo(CO)6 as the car-
bonyl source, and DBU in combination with microwave
irradiation, as these conditions have been extensively in-
vestigated by Larhed et al.11 In our hands, increasing the
amount of ligand and catalyst (70/25 mol%, compared to
7/2.5 mol%5) resulted in higher yield and purity of the
crude product. Interestingly, the use of diamines having
metal-chelating properties did not negatively influence
SR48692
Figure 1 Neurotensin receptor 1 antagonists
SYNTHESIS 2013, 45, 2474–2480
Advanced online publication: 11.07.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1338497; Art ID: SS-2013-T0334-OP
© Georg Thieme Verlag Stuttgart · New York

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Microwave-Assisted Aminocarbonylation
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O
O
O
OH
NHR
OMe
Me
Me
Me
O
O
NH2
O
N
N
N
b
c
d, e
N
N
N
O
O
O
Me
Me
Me
X
1: X = H
2: X = Br
Br
Br
Br
a
5a: R = 2-aminoadamantane-
3
4
2-carboxylic acid
5b: R = L-Leu-Ot-Bu
6: R = L-Leu
f
O
O
COOH
COOH
NH
NH
Me
Me
O
O
N
N
N
g
g
N
7a: R = HN(CH2)6Me
5a
6
7b: R = HN(CH2)3NMe2
7c: R = N(Me)(CH2)3NHMe
O
O
7d: R = N(Me)(CH2)3NMe2 (SR142948A)
Me
Me
Me
N
R
N
Me
Me
O
O
8
Scheme 2 Synthesis of the target compounds 7a–d and 8. Reagents and conditions: (a) NBS, NH4OAc, MeCN, r.t., 10 min, 81%; (b) 1.
NaNO2, HCl, H2O, 0 °C, 15 min, 2. SnCl2·2H2O, HCl, 0 °C, 30 min, 3. methyl 4-(2,6-dimethoxyphenyl)-2,4-dioxobutyrate, EtOH, reflux, 20
min, 56%; (c) KOH, 1,4-dioxane, H2O, reflux, 4 h, >99%; (d) 1. Reaction 1: 4, isobutyl chloroformate, Et3N, MeCN, r.t., 25 min, Reaction 2:
2-aminoadamantane-2-carboxylic acid HCl, Et3N, TMSCl, MeCN, r.t., 5 min, 2. Addition of reaction 1 to reaction 2: 60 °C, 2 h, microwave,
62%; (e) 1. 4, isobutyl chloroformate, Et3N, MeCN, r.t., 25 min, 2. L-Leu-Ot-Bu·HCl, Et3N, r.t., 5 h, 62%; (f) TFA, CH2Cl2, r.t., 1 h, >99%; (g)
amine, Mo(CO)6, Herrmann’s palladacycle, [(t-Bu)3PH]BF4, DBU, 1,4-dioxane, 140 °C, microwave, 30 min, 26–71%.
the reaction.12 Both secondary and tertiary carboxamide cleaved with TFA in dichloromethane to obtain the
groups could be effectively installed (yield: 26–71%).
SR142948A derivatives 12a–d.
As an exchange of 2-aminoadamantane-2-carboxylic acid
by lipophilic amino acids can lead to partial agonism at
NTS1 receptors,13 we intended to access a leucinyl cou-
pled surrogate of SR142948A. Thus, the pyrazole carbox-
ylic acid 4 was coupled with L-Leu-Ot-Bu using isobutyl
chloroformate as an activating agent to give the product
5b. The tert-butyl ester was cleaved using TFA in dichlo-
romethane to furnish the free acid 6, which was subjected
to aminocarbonylation resulting in the formation of the
carboxamide 8.
3
a
O
O
NHR
O–X
Me
Me
Me
O
O
N
N
N
c
N
O
O
Me
Me
Me
N
N
The endogenous ligand of the NTS1 receptor is the pep-
tide neurotensin. To efficiently synthesize more peptide
mimicking amino acid derivatives of type 12, we changed
the order of the reaction sequence allowing variation at
the last step. Thus, intermediate 3 was subjected to the
aminocarbonylation reaction with N,N,N′-trimethylpro-
pane-1,3-diamine to give the benzamide 9 (Scheme 3).
Avoiding the use of a high excess of amine to prevent am-
inolysis of the ester, the product could be obtained in good
yield (48%). The resulting ester 9 was hydrolyzed with
potassium hydroxide and coupled with natural tert-butyl
protected amino acids to afford the coupling products
11a–d. Finally, the protecting groups of 11a–d were
N
Me
N
Me
O
O
Me
Me
9: X = Me
11a: R = L-Phe-Ot-Bu
11b: R = L-Tyr-Ot-Bu
11c: R = L-Val-Ot-Bu
11d: R = L-Glu-Ot-Bu
b
10: X = H
d
12a: R = L-Phe
12b: R = L-Tyr
12c: R = L-Val
12d: R = L-Glu
Scheme 3 Synthesis of pyrazole carboxamides 12a–d. Reagents and
conditions: (a) N,N,N′-trimethylpropane-1,3-diamine, Mo(CO)6, Her-
rmann’s palladacycle, [(t-Bu)3PH]BF4, DBU, 1,4-dioxane, 140 °C,
microwave, 30 min, 48%; (b) KOH, 1,4-dioxane, H2O, reflux, 4 h,
>99%; (c) 1. isobutyl chloroformate, Et3N, MeCN, r.t., 25 min, 2. L-
amino acid-Ot-Bu HCl, Et3N, r.t., 5 h, 25–60%; (d) TFA, CH2Cl2, r.t.,
1 h, 58–82%.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2474–2480

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C. Lang, P. Gmeiner
PAPER
with 50% aq NaOH, the mixture was concentrated in vacuo, treated
with H2O (100 mL), and extracted with EtOAc (3 × 200 mL). The
combined organic layers were dried (MgSO4), evaporated, and the
residue was purified by flash column chromatography (cyclohex-
ane–EtOAc, 25:2) to give 3 (4.80 g, 56%) as a colorless solid; mp
181 °C.
In conclusion, microwave-assisted aminocarbonylation
reaction mediated by Mo(CO)6, Herrmann’s palladacycle,
[(t-Bu)3PH]BF4, and DBU provided a highly efficient and
flexible route to arylpyrazolyl substituted arylcarbox-
amides. The pathway opens an easy access to focused
compound libraries enabling detailed structure-activity
relationship studies starting from the drug candidate
SR142948A. The target compounds are currently investi-
gated for neurotensin receptor binding and activation.
IR (ATR): 2965, 1723, 1605, 1589, 1475, 1253, 1230, 1111 cm–1.
1H NMR (360 MHz, CDCl3): δ = 0.95 (br s, 6 H), 2.65 (hept, J = 6.9
Hz, 1 H), 3.64 (s, 6 H), 3.94 (s, 3 H), 6.46 (d, J = 8.4 Hz, 2 H), 6.93
(s, 1 H), 7.20 (d, J = 8.4 Hz, 1 H), 7.25 (dd, J = 8.4, 2.2 Hz, 1 H),
7.25 (t, J = 8.4 Hz, 1 H), 7.31 (d, J = 2.2 Hz, 1 H).
13C NMR (90 MHz, CDCl3): δ = 23.8, 27.7, 51.9, 55.5, 103.5,
106.7, 111.2, 123.2, 128.4, 129.1, 130.0, 131.4, 137.0, 138.9, 143.6,
148.2, 158.3, 163.1.
All chemicals and solvents were obtained from commercial sources
and used as received. Microwave reactions were conducted with a
Biotage Initiator apparatus. For TLC, silica gel 60 F254 aluminum
plates were used (UV, KMnO4, I2, and ninhydrin detection). Flash
chromatography was performed using 60 μm silica gel. Solvents
were removed by rotary evaporation or lyophilization under re-
duced pressure. All final compounds except 7a were purified by
preparative HPLC. IR spectroscopy was carried out on a FT/IR
spectrometer as film on a NaCl plate or as solid using ATR-IR.
NMR spectra were measured on a Bruker Avance 600 or a Bruker
Avance 360 at 300 K unless otherwise noted. NMR chemical shifts
are reported in ppm relative to TMS. HPLC-MS analyses were car-
ried out on an analytical HPLC system with a VWL detector, cou-
pled to a Bruker Esquire 2000-mass spectrometer with electron
spray or atmospheric pressure chemical ionization (ESI or APCI,
respectively). ESI-TOF high mass accuracy and resolution experi-
ments were performed on a Bruker maXis MS in the laboratories of
the Chair of Bioinorganic Chemistry (Prof. Ivana Ivanović-
Burmazović), Department of Pharmacy and Chemistry, FAU. Puri-
ties of the final products were assessed using the Agilent 1200 ana-
lytical HPLC equipped with a Zorbax Eclipse XDB-C8 column
(4.6 × 150 mm, 5 μm, flow rate: 0.5 mL/min) and a diode array de-
tector employing the following gradient systems:
MS (APCI): m/z = 459.1 [M + H]+, 461.0 [M + H]+.
1-(4-Bromo-2-isopropylphenyl)-5-(2,6-dimethoxy phenyl)-1H-
pyrazole-3-carboxylic Acid (4)
To a solution of 3 (638 mg, 1.39 mmol) in 1,4-dioxane–H2O (10
mL, 1:1) was added KOH (195 mg, 3.48 mmol). The reaction mix-
ture was refluxed for 4 h, acidified with aq 2 N HCl, and extracted
with CH2Cl2 (3 × 20 mL). The combined organic layers were dried
(MgSO4) and evaporated to give 4 (618 mg, >99%) as a colorless
solid; mp 198 °C.
IR (ATR): 2965, 2359, 1698, 1605, 1590, 1475, 1254, 1110 cm–1.
1H NMR (360 MHz, CDCl3): δ = 0.98 (d, J = 6.9 Hz, 6 H), 2.67
(hept, J = 6.9 Hz, 1 H), 3.65 (s, 6 H), 6.47 (d, J = 8.4 Hz, 2 H), 6.97
(s, 1 H), 7.17 (d, J = 8.1 Hz, 1 H), 7.26 (t, J = 8.4 Hz, 1 H), 7.27 (dd,
J = 8.1, 2.2 Hz, 1 H), 7.34 (d, J = 2.2 Hz, 1 H).
13C NMR (90 MHz, CDCl3): δ = 23.0, 27.7, 55.5, 103.5, 106.5,
111.3, 123.4, 128.5, 129.3, 129.6, 131.6, 136.6, 139.7, 143.0, 148.2,
158.3, 164.7.
MS (ESI): m/z = 445.1 [M + H]+, 447.1 [M + H]+.
System 1: MeOH (A)–H2O + 0.1% HCO2H in H2O. Gradient: 0–3
min 10%, 3–18 min: 10–100% A, 18–24 min: 100% A.
2-({[1-(4-Bromo-2-isopropylphenyl)-5-(2,6-dimethoxyphenyl)-
1H-pyrazol-3-yl]carbonyl}amino)adamantane-2-carboxylic
Acid (5a)
System 2: MeCN (B)–H2O + 0.1% HCO2H in H2O. Gradient: 0–18
min: 5–80% B, 18–20 min: 80–95% B, 20–22 min: 95% B.
To a solution of 4 (380 mg, 0.85 mmol) in MeCN (5 mL) were add-
ed Et3N (172 mg, 0.24 mL, 1.7 mmol) and isobutyl chloroformate
(116 mg, 0.11 mL, 0.85 mmol). The mixture was stirred under N2
atmosphere at r.t. for 25 min (Reaction 1). To a suspension of 2-
aminoadamantane-2-carboxylic acid HCl (294 mg, 1.28 mmol) in
MeCN (5 mL) in a N2 flushed microwave vessel (20 mL) were add-
ed Et3N (194 mg, 0.27 mL, 1.91 mmol) and Me3SiCl (277 mg, 0.32
mL, 2.55 mmol). The mixture was stirred at r.t. for 5 min (Reaction
2). Reaction 1 was transferred to Reaction 2 via syringe and stirred
in microwave at 60 °C for 2 h under cooling. The mixture was acid-
ified with aq 2 N HCl and extracted with CH2Cl2 (3 × 20 mL). The
combined organic layers were dried (MgSO4), evaporated, and the
residue was purified by flash column chromatography [cyclohex-
ane–EtOAc (4:1) + 0.1% HCO2H] to give 5a (328 mg, 62%) as a
colorless solid; mp 259 °C.
System 3: MeOH (A)–H2O + 0.1% HCO2H in H2O. Gradient: 0–1
min: 30% A, 1–12 min: 30–100% A, 12–15 min: 100% A.
4-Bromo-2-isopropylaniline (2)14
To a solution of 2-isopropylaniline (2.70 g, 2.83 mL, 20 mmol) and
NH4OAc (154 mg, 2 mmol) in MeCN (100 mL) was added NBS
(3.74 g, 21 mmol). The mixture was stirred at r.t. for 10 min fol-
lowed by concentration in vacuo. After addition of H2O (100 mL)
and extraction with EtOAc (3 × 100 mL), the combined organic lay-
ers were dried (MgSO4), evaporated, and the residue was purified
by flash column chromatography (cyclohexane–EtOAc, 10:1) to
give 2 (3.45 g, 81%) as a brown oil.
1H NMR (360 MHz, CDCl3): δ = 1.17 (d, J = 6.8 Hz, 6 H), 2.77
(hept, J = 6.8 Hz, 1 H), 3.56 (br s, 2 H), 6.48 (d, J = 8.4 Hz, 1 H),
7.03 (dd, J = 8.4, 2.3 Hz, 1 H), 7.14 (d, J = 2.3 Hz, 1 H).
IR (ATR): 3413, 2918, 2862, 1751, 1719, 1678, 1530, 1491, 1474,
1433, 1254, 1112 cm–1
MS (APCI): m/z = 213.9 [M + H]+, 215.9 [M + H]+.
.
1H NMR (600 MHz, CDCl3): δ = 1.01–1.11 (m, 6 H), 1.69–1.94 (m,
8 H), 2.00–2.09 (m, 2 H), 2.19–2.27 (m, 2 H), 2.65 (hept, J = 6.8 Hz,
1 H), 2.70–2.74 (m, 2 H), 3.67 (s, 6 H), 6.47 (d, J = 8.4 Hz, 2 H),
6.89 (s, 1 H), 7.07 (d, J = 8.3 Hz, 1 H), 7.21–7.24 (m, 2 H), 7.26 (t,
J = 8.4 Hz, 1 H), 7.39 (d, J = 2.3 Hz, 1 H).
13C NMR (150 MHz, CDCl3): δ = 23.9, 26.6, 26.7, 27.9, 32.1, 32.5,
33.6, 37.4, 55.6, 65.5, 103.5, 106.6, 109.5, 123.4, 128.6, 128.9,
129.7, 131.6, 136.5, 139.9, 145.1, 148.3, 158.4, 164.7, 172.1.
Methyl 1-(4-Bromo-2-isopropylphenyl)-5-(2,6-dimethoxyphe-
nyl)-1H-pyrazole-3-carboxylate (3)
Concd HCl (32 mL) was added to vigorously stirred 2 (4 g, 18.7
mmol) at 0 °C. After 15 min, a solution of NaNO2 (1.27 g, 18.4
mmol) in H2O (7.8 mL) was added over a period of 15 min. This
mixture was additionally stirred for 15 min followed by addition of
SnCl2·2H2O (9.37 g, 41 mmol) in concd HCl (9.4 mL) and 30 min
of stirring without cooling. Methyl 4-(2,6-dimethoxyphenyl)-2,4-
dioxobutyrate (4.97 g, 18.7 mmol) in EtOH (160 mL) was added to
the reaction mixture and refluxed for 20 min. After neutralization
MS (APCI): m/z = 622.7 [M + H]+, 624.1 [M + H]+.
Synthesis 2013, 45, 2474–2480
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Microwave-Assisted Aminocarbonylation
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tert-Butyl N-{[1-(4-Bromo-2-isopropylphenyl)-5-(2,6-dimeth-
oxyphenyl)-1H-pyrazol-3-yl]carbonyl}-L-leucinate (5b)
To a solution of 4 (100 mg, 0.22 mmol) in MeCN (1 mL) were add-
ed Et3N (44.6 mg, 60.2 μL, 0.44 mmol) and isobutyl chloroformate
(30 mg, 28.6 μL, 0.22 mmol). After stirring the mixture under N2 at-
mosphere at r.t. for 30 min, a solution of L-leucine tert-butyl ester
HCl (73.8 mg, 0.33 mmol) and Et3N (66.9 mg, 90.3 μL, 0.66 mmol)
in MeCN (1 mL) was added and stirred for 5 h. The mixture was
treated with H2O (10 mL) and extracted with EtOAc (3 × 10 mL).
The combined organic layers were dried (MgSO4), evaporated, and
the residue was purified by flash column chromatography (cyclo-
hexane–EtOAc, 9:1) to give 5b (83.4 mg, 62%) as a colorless solid;
mp 75 °C; [α]D23 –19.8 (c 1.3, MeOH).
1H NMR (600 MHz, CDCl3): δ = 0.89 (t, J = 7.0 Hz, 3 H), 1.12 (d,
J = 6.8 Hz, 6 H), 1.25–1.40 (m, 8 H), 1.57–1.64 (m, 2 H), 1.70–1.94
(m, 8 H), 2.02–2.08 (m, 2 H), 2.20–2.26 (m, 2 H), 2.72 (br s, 2 H),
2.79 (hept, J = 6.8 Hz, 1 H), 3.43 (dt, J = 7.3, 5.9 Hz, 2 H), 3.67 (s,
6 H), 6.03–6.10 (m, 1 H), 6.46 (d, J = 8.3 Hz, 2 H), 6.92 (s, 1 H),
7.23–7.26 (m, 3 H), 7.42 (dd, J = 8.2, 1.9 Hz, 1 H), 7.73 (d, J = 1.9
Hz, 1 H).
13C NMR (150 MHz, CDCl3): δ = 14.0, 22.6, 26.5, 26.7, 27.0, 27.9,
28.9, 29.6, 29.7, 31.7, 32.1, 32.5, 33.6, 37.4, 40.2, 55.6, 65.4, 103.5,
106.6, 109.5, 123.5, 125.6, 127.4, 131.5, 135.8, 139.8, 139.9 145.1,
146.6, 158.4, 164.7, 167.0, 172.1.
MS (APCI): m/z = 685.8 [M + H]+.
IR (ATR): 3409, 2961, 1731, 1672, 1524, 1466, 1254, 1156, 1111,
909, 737 cm–1.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C40H52N4O6 + Na:
707.3779; found: 707.3760.
1H NMR (600 MHz, CDCl3): δ = 0.96 (d, J = 6.4 Hz, 3 H), 0.99 (d,
J = 6.4 Hz, 3 H), 1.03 (br s, 6 H), 1.47 (s, 9 H), 1.57–1.71 (m, 2 H),
1.73–1.81 (m, 1 H), 2.72 (hept, J = 6.8 Hz, 1 H), 3.65 (s, 6 H), 4.73
(dt, J = 9.1, 5.3 Hz, 1 H), 6.45 (d, J = 8.3 Hz, 2 H), 6.89 (s, 1 H),
7.12 (d, J = 8.3 Hz, 1 H), 7.20–7.25 (m, 3 H), 7.37 (d, J = 2.1 Hz, 1
H).
13C NMR (150 MHz, CDCl3): δ = 22.0, 22.9, 23.9, 24.9, 27.8, 28.0,
42.1, 51.0, 55.5, 81.5, 103.5, 107.2, 109.3, 123.1, 128.5, 129.3,
129.5, 131.2, 136.8, 139.0, 146.4, 148.4, 158.4, 161.9, 172.1.
2-[({5-(2,6-Dimethoxyphenyl)-1-[4-({[3-(dimethylamino)pro-
pyl]amino}carbonyl)-2-isopropylphenyl]-1H-pyrazol-3-yl}car-
bonyl)amino]adamantane-2-carboxylic Acid (7b)4
Prepared according to the general procedure using 5a (17.8 mg, 30
μmol); yield: 13.4 mg (67%), colorless lyophilisate.
HPLC: 254 nm; system 1, tR = 18.1 min (99.5%), system 2,
tR = 14.4 min (98.5%).
NMR (600 MHz, DMSO-d6): δ = 1.08 (d, J = 6.8 Hz, 6 H), 1.56–
1.82 (m, 10 H), 1.92–2.00 (m, 2 H), 2.04–2.12 (m, 2 H), 2.14 (s, 6
H), 2.27 (t, J = 7.1 Hz, 2 H), 2.53 (br s, 2 H), 2.67 (hept, J = 6.8 Hz,
1 H), 3.25 (dt, J = 7.1, 5.8 Hz, 2 H), 3.64 (s, 6 H), 6.60 (d, J = 8.5
Hz, 2 H), 6.69 (s, 1 H), 7.20 (d, J = 8.3 Hz, 1 H), 7.29 (t, J = 8.5 Hz,
1 H), 7.33 (br s, 1 H), 7.60 (dd, J = 8.3, 1.8 Hz, 1 H), 7.80 (d, J = 1.8
Hz, 1 H), 8.57 (t, J = 5.8 Hz, 1 H).
MS (APCI): m/z = 614.7 [M + H]+, 616.3 [M + H]+.
N-{[1-(4-Bromo-2-isopropylphenyl)-5-(2,6-dimethoxyphenyl)-
1H-pyrazol-3-yl]carbonyl}-L-leucine (6)
To a solution of 5b (71.6 mg, 0.12 mmol) in CH2Cl2 (1 mL) was
added TFA (1 mL). After stirring at r.t. for 1 h, the solvent was
evaporated to give 6 (67.0 mg, >99%) as a colorless solid; mp
92 °C; [α]D23 –24.3 (c 1.16, MeOH).
MS (APCI): m/z = 672.7 [M + H]+.
2-[({5-(2,6-Dimethoxyphenyl)-1-[2-isopropyl-4-({methyl[3-
(methylamino)propyl]amino}carbonyl)phenyl]-1H-pyrazol-3-
yl}carbonyl)amino]adamantane-2-carboxylic Acid (7c)4
Prepared according to the general procedure using 5a (90 mg, 0.15
mmol); yield: 71.4 mg (71%); colorless lyophilisate.
IR (ATR): 3404, 3001, 2961, 1726, 1643, 1470, 1254, 1210, 1165,
1106 cm–1.
1H NMR (600 MHz, CDCl3): δ = 0.95–1.06 (m, 12 H), 1.70–1.85
(m, 3 H), 2.66 (hept, J = 6.8 Hz, 1 H), 3.66 (s, 6 H), 4.78–4.84 (m,
1 H), 6.46 (d, J = 8.3 Hz, 2 H), 6.93 (s, 1 H), 7.14 (d, J = 8.3 Hz, 1
H), 7.25–7.29 (m, 2 H), 7.37 (d, J = 2.3 Hz, 1 H), 7.50 (d, J = 8.1
Hz, 1 H).
13C NMR (150 MHz, CDCl3): δ = 21.6, 22.8, 23.9, 24.9, 27.6, 27.8,
40.7, 50.9, 55.5, 103.5, 106.4, 109.8, 123.6, 128.6, 129.3, 129.6,
131.6, 136.3, 140.0, 144.8, 148.4, 158.3, 163.5, 176.3.
HPLC: 254 nm; system 1, tR = 18.1 min (97.5%), system 3,
tR = 12.4 min (96.8%).
1H NMR (600 MHz, DMSO-d6): δ (rotamers were observed) = 1.03
(s, 6 H), 1.51–2.03 (m, 12 H), 2.03–2.74 (m, 10 H), 2.79 (s, 1.5 H),
2.92 (s, 1.5 H), 3.11 (br s, 1 H), 3.46 (br s, 1 H), 3.62 (s, 6 H), 6.60
(d, J = 8.4 Hz, 2 H), 6.66 (s, 1 H), 7.07–7.39 (m, 5 H).
MS (APCI): m/z = 559.9 [M + H]+.
MS (APCI): m/z = 672.8 [M + H]+.
Aminocarbonylation of 5a and 6 to give 7a–d and 8; General
Procedure
2-[({5-(2,6-Dimethoxyphenyl)-1-[4-({[3-(dimethylamino)pro-
pyl](methyl)amino}carbonyl)-2-isopropylphenyl]-1H-pyrazol-
3-yl}carbonyl)amino]adamantane-2-carboxylic Acid (7d)4
Prepared according to the general procedure using 5a (10 mg, 16
μmol); yield: 6.3 mg (57%); colorless lyophilisate.
A microwave vial (0.5–2 mL, except 7c: 2–5 mL) was charged with
5a or 6 (1 equiv), the respective amine (10 equiv), Herrmann’s pal-
ladacycle (25 mol%), [(t-Bu)3PH]BF4 (70 mol%), and Mo(CO)6 (1
equiv). After sealing the vial and flushing with N2, 1,4-dioxane
(0.7–1.5 mL) and DBU (3 equiv) were added. The reaction was con-
ducted in a microwave reactor (140 °C, 30 min). Crude products
were purified by preparative HPLC (MeCN–H2O + 0.1% HCO2H in
H2O, gradient) (except for 7a).
HPLC: 254 nm; system 2, tR = 15.2 min (>99%), system 3, tR = 12.5
min (98.9%).
1H NMR (600 MHz, DMSO-d6): δ (rotamers were observed) = 1.04
(br s, 6 H), 1.50–1.84 (m, 10 H), 1.87–2.01 (m, 6.5 H), 2.05–2.19
(m, 4.5 H), 2.22–2.23 (m, 1 H), 2.54 (br s, 2 H), 2.60–2.69 (m, 1 H),
2.83 (s, 1.5 H), 2.93 (s, 1.5 H), 3.07–3.13 (m, 1 H), 3.39–3.43 (m, 1
H), 3.64 (s, 6 H), 6.61 (d, J = 8.4 Hz, 2 H), 6.69 (s, 1 H), 7.11–7.21
(m, 2 H), 7.29 (t, J = 8.4 Hz, 1 H), 7.30–7.36 (m, 2 H).
2-{[(5-(2,6-Dimethoxyphenyl)-1-{4-[(heptylamino)carbonyl]-2-
isopropylphenyl}-1H-pyrazol-3-yl)carbonyl]amino}adaman-
tane-2-carboxylic Acid (7a)
Prepared according to the general procedure using 5a (14.6 mg, 23
μmol). The crude mixture was extracted with CH2Cl2 (3 × 10 mL).
The residue was purified by flash column chromatography [cyclo-
hexane–EtOAc (4:1) + 0.1% HCO2H] to give 7a as a colorless solid;
yield: 6.3 mg (40%); mp 145 °C.
MS (APCI): m/z = 687.0 [M + H]+.
N-{[5-(2,6-Dimethoxyphenyl)-1-(4-{[[3-(dimethylamino)pro-
pyl](methyl)amino]carbonyl}-2-isopropylphenyl)-1H-pyrazol-
3-yl]carbonyl}-L-leucine (8)
Prepared according to the general procedure using 6 (20 mg, 40
μmol); yield: 6.4 mg (26%); colorless lyophilisate.
HPLC: 254 nm; system 1, tR = 22.7 min (95.8%), system 2,
tR = 24.8 min (98.9%).
HPLC: 254 nm; system 1, tR = 17.4 min (99.2%), system 2,
tR = 13.9 min (96.6%).
IR (ATR): 3360, 2917, 1736, 1633, 1608, 1535, 1470, 1436, 1249,
1111, 909, 732 cm–1.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2474–2480

2478
C. Lang, P. Gmeiner
PAPER
IR (ATR): 3395, 2956, 1604, 1474, 1252, 1105, 784 cm–1.
(m, 1 H), 2.06–2.19 (m, 4 H), 2.24–2.37 (m, 3 H), 2.38–2.48 (m, 1
H), 2.78 (hept, J = 6.8 Hz, 1 H), 2.93 (s, 1.5 H), 3.07 (s, 1.5 H),
3.14–3.20 (m, 2 H), 3.20–3.26 (m, 1 H), 3.52–3.59 (m, 1 H), 3.65
(s, 6 H), 4.94–5.02 (m, 1 H), 6.44 (d, J = 8.4 Hz, 2 H), 6.86–6.93
(m, 1 H), 7.06–7.32 (m, 9 H), 7.42 (d, J = 8.3 Hz, 1 H).
13C NMR (150 MHz, CDCl3): δ (rotamers were observed) = 23.9,
25.0, 27.7 27.9, 29.7, 37.7, 38.6, 45.2, 45.9, 53.4, 55.5, 82.0, 103.5,
107.2, 109.2, 123.6, 123.9, 124.8, 125.0, 126.8, 127.5, 128.3, 129.6,
131.3, 136.5, 139.0, 146.2, 146.6, 158.4, 161.8, 170.6, 171.1.
1H NMR (600 MHz, DMSO-d6): δ (rotamers were observed) = 0.90
(d, J = 6.4 Hz, 6 H), 0.97 (br s, 6 H), 1.38–1.80 (m, 5 H), 2.04 (s, 4
H), 2.31 (s, 3 H), 2.47 (br s, 1 H), 2.62 (hept, J = 6.9 Hz, 1 H), 2.82
(s, 1.5 H), 2.94 (s, 1.5 H), 3.07–3.13 (m, 1 H), 3.40–3.46 (m, 1 H),
3.63 (s, 6 H), 4.40 (br s, 1 H), 6.60 (d, J = 8.7 Hz, 2 H), 6.73 (s, 1
H), 7.13–7.24 (m, 1 H), 7.25–7.33 (m, 3 H), 8.05 (s, 1 H).
13C NMR (150 MHz, DMSO-d6): δ (rotamers were observed)
= 21.5, 23.0, 23.8, 24.5, 25.3, 26.3, 27.2, 32.2, 37.0, 39.1, 44.3,
44.5, 44.9, 48.6, 50.5, 54.9, 55.5, 55.7, 55.9, 63.4, 103.7, 106.1,
108.5, 123.5, 124.0, 124.1, 124.5, 127.8, 131.6, 137.5, 137.7, 137.8,
138.7, 145.7, 146.3, 157.9, 161.1, 169.4, 169.9, 174.2.
MS (APCI): m/z = 712.5 [M + H]+.
tert-Butyl O-(tert-Butyl)-N-{[5-(2,6-dimethoxyphenyl)-1-(4-
{[[3-(dimethylamino)propyl](methyl)amino]carbonyl}-2-iso-
propylphenyl)-1H-pyrazol-3-yl]carbonyl}-L-tyrosinate (11b)
Prepared according to the general procedure using 10 (20 mg, 0.04
mmol) and L-tyrosine di-tert-butyl ester HCl (19.2 mg, 0.06 mmol);
yield: 15.1 mg (48%); colorless foam.
MS (APCI): m/z = 622.7 [M + H]+.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C34H47N5O6 + Na:
644.3419; found: 644.3402.
Methyl 5-(2,6-Dimethoxyphenyl)-1-(4-{[[3-(dimethylami-
no)propyl](methyl)amino]carbonyl}-2-isopropylphenyl)-1H-
pyrazole-3-carboxylate (9)4
IR (NaCl): 3405, 2973, 1730, 1672, 1632, 1475, 1366, 1254, 1158,
1110 cm–1.
A microwave vial (2–5 mL) was charged with 3 (184 mg, 0.4
mmol), N,N,N′-trimethylpropane-1,3-diamine (69.7 mg, 87.9 μL,
0.6 mmol), Mo(CO)6 (106 mg, 0.4 mmol), Herrmann’s palladacycle
(46.9 mg, 0.05 mmol), and [(t-Bu)3PH]BF4 (40.5 mg, 0.14 mmol).
After the vial was sealed and flushed with N2, 1,4-dioxane (4 mL),
and DBU (183 mg, 0.18 mL, 1.2 mmol) were added. The reaction
was conducted in a microwave reactor (140 °C, 30 min), the solvent
was evaporated, and the residue was purified by flash column chro-
matography [EtOAc → EtOAc–EtOH (9:1) + 1% NH4OH] to give
9 (99.9 mg, 48%) as a viscous brown oil.
1H NMR (600 MHz, CDCl3): δ (rotamers were observed) = 0.98 (br
s, 6 H), 1.65–1.73 (m, 0.8 H), 1.82–1.96 (m, 1.2 H), 2.08–2.15 (m,
0.8 H), 2.19 (s, 3 H), 2.32–2.43 (m, 3 H), 2.45–2.56 (m, 1.2 H), 2.71
(hept, J = 6.8 Hz, 1 H), 2.89 (s, 1.8 H), 3.06 (s, 1.2 H), 3.15–3.22
(m, 0.8 H), 3.49–3.58 (m, 1.2 H), 3.65 (s, 6 H), 3.94 (s, 3 H), 6.45
(d, J = 8.1 Hz, 2 H), 6.91–6.96 (m, 1 H), 7.08–7.26 (m, 3 H), 7.33–
7.39 (m, 1 H).
1H NMR (600 MHz, CDCl3): δ (rotamers were observed) = 1.03–
1.15 (m, 6 H), 1.28–1.32 (s, 9 H), 1.36 (s, 9 H), 2.09–2.31 (m, 2 H),
2.35–3.07 (m, 12 H), 3.11–3.20 (m, 2 H), 3.31 (br s, 0.5 H), 3.57–
3.63 (m, 1.5 H), 3.65 (s, 6 H), 4.91–4.98 (m, 1 H), 6.42–6.48 (m, 2
H), 6.85–6.91 (m, 3 H), 7.08–7.17 (m, 3 H), 7.18–7.26 (m, 2 H),
7.33 (br s, 1 H), 7.38–7.44 (m, 1 H).
13C NMR (150 MHz, CDCl3): δ (rotamers were observed) = 23.1,
24.1, 27.8, 28.0, 28.8, 37.8, 38.1, 43.2, 43.4, 45.1, 53.4, 53.5, 55.5,
56.0, 78.3, 82.0, 103.5, 107.1, 109.2, 123.9, 124.0, 125.3, 127.6,
127.7, 130.0, 131.3, 131.4, 136.2, 139.0, 146.2, 146.7, 154.1, 158.4,
161.7, 170.6, 171.6.
MS (APCI): m/z = 784.8 [M + H]+.
tert-Butyl N-{[5-(2,6-Dimethoxyphenyl)-1-(4-{[[3-(dimethyl-
amino)propyl](methyl)amino]carbonyl}-2-isopropylphenyl)-
1H-pyrazol-3-yl]carbonyl}-L-valinate (11c)
Prepared according to the general procedure using 10 (30 mg, 0.06
mmol) and L-valine tert-butyl ester HCl (18.9 mg, 0.09 mmol);
yield: 13.9 mg (35%); colorless foam.
MS (ESI): m/z = 523.3 [M + H]+.
5-(2,6-Dimethoxyphenyl)-1-(4-{[[3-(dimethylamino)pro-
pyl](methyl)amino]carbonyl}-2-isopropylphenyl)-1H-pyrazole-
3-carboxylic Acid (10)4
To a solution of 9 (99.9 mg, 0.19 mmol) in 1,4-dioxane–H2O (6 mL,
1:1) was added KOH (26.6 mg, 0.48 mmol). The reaction mixture
was refluxed for 2 h. After acidification with concd HCl, the solvent
was removed in vacuo. The resulting solid was treated with MeCN
(20 mL) and filtered. The filtrate was evaporated to give 10 (96.5
mg, >99%) as a colorless solid; mp 183–185 °C.
IR (ATR): 3421, 2973, 1731, 1671, 1635, 1534, 1474, 1254, 1110
cm–1.
1H NMR (360 MHz, CDCl3): δ (rotamers were observed) = 0.94–
0.99 (m, 3 H), 1.00–1.04 (m, 3 H), 1.07–1.12 (m, 6 H), 1.46–1.49
(m, 9 H), 2.13–2.31 (m, 3 H), 2.70–2.87 (m, 7 H), 2.92–3.04 (m, 3
H), 3.04–3.10 (m, 2 H), 3.58–3.64 (m, 2 H), 3.64–3.68 (m, 6 H),
4.61–4.69 (m, 1 H), 6.40–6.49 (m, 2 H), 6.86–6.91 (m, 1 H), 7.10–
7.16 (m, 1 H), 7.23 (t, J = 8.4 Hz, 1 H), 7.26 (d, J = 8.2 Hz, 1 H),
7.32–7.37 (m, 1 H), 7.39–7.43 (m, 1 H).
13C NMR (90 MHz, CDCl3): δ (rotamers were observed) = 17.7,
19.1, 22.9, 24.0, 27.8, 28.0, 31.7, 37.8, 43.0, 43.2, 45.0, 55.5, 55.9,
57.1, 81.7, 103.5, 107.2, 109.2, 123.9, 125.4, 125.7, 127.5, 131.3,
135.6, 139.0, 146.4, 146.7, 158.4, 162.0, 171.0, 172.5.
MS (ESI): m/z = 509.3 [M + H]+.
Compounds 11a–d; General Procedure
To solution of 10 (1 equiv) in MeCN (1 mL) was added Et3N (2
equiv) and isobutyl chloroformate (1 equiv) under N2 atmosphere.
After stirring the mixture at r.t. for 30 min, a solution of the respec-
tive L-aminoacid tert-butyl ester HCl (1–1.5 equiv) and Et3N (3
equiv) in MeCN was added and stirred for an additional 5 h. The
solvents were evaporated and the residue was purified by flash col-
umn chromatography (CH2Cl2–MeOH) to give 11a–d.
MS (APCI): m/z = 664.6 [M + H]+.
Di-tert-Butyl N-{[5-(2,6-Dimethoxyphenyl)-1-(4-{[[3-(dimethyl-
amino)propyl](methyl)amino]carbonyl}-2-isopropylphenyl)-
1H-pyrazol-3-yl]carbonyl}-L-glutamate (11d)
Prepared according to the general procedure using 10 (30 mg, 0.06
mmol) and L-glutamic acid di-tert-butyl ester HCl (26.6 mg, 0.09
mmol); yield: 11.2 mg (25%); colorless foam.
tert-Butyl N-{[5-(2,6-Dimethoxyphenyl)-1-(4-{[[3-(dimethyl-
amino)propyl](methyl)amino]carbonyl}-2-isopropylphenyl)-
1H-pyrazol-3-yl]carbonyl}-L-phenylalaninate (11a)
Prepared according to the general procedure using 10 (20 mg, 0.04
mmol) and L-phenylalanine tert-butyl ester HCl (9.54 mg, 0.04
mmol); yield: 16.7 mg (60%); colorless foam.
IR (ATR): 3407, 2966, 1730, 1672, 1633, 1528, 1475, 1110 cm–1.
1H NMR (600 MHz, CDCl3): δ (rotamers were observed) = 1.02–
IR (ATR): 3404, 2972, 1730, 1674, 1634, 1475, 1254, 1154, 1111
cm–1.
1H NMR (600 MHz, CDCl3): δ (rotamers were observed) = 1.07 (br
s, 6 H), 1.42–1.44 (m, 9 H), 1.47–1.49 (m, 9 H), 1.66–1.93 (m, 2 H),
1.94–2.05 (m, 2 H), 2.09–2.18 (m, 3 H), 2.18–2.28 (m, 2 H), 2.29–
2.36 (m, 3 H), 2.37–2.49 (m, 2 H), 2.80 (hept, J = 6.8 Hz, 1 H), 2.93
(s, 1.5 H), 3.07 (s, 1.5 H), 3.21–3.27 (m, 1 H), 3.53–3.59 (m, 1 H),
1.12 (m, 6 H),1.36–1.40 (m, 9 H), 1.65–1.73 (m, 1 H), 1.83–1.91
Synthesis 2013, 45, 2474–2480
© Georg Thieme Verlag Stuttgart · New York

PAPER
Microwave-Assisted Aminocarbonylation
2479
3.60–3.67 (m, 6 H), 4.70–4.77 (m, 1 H), 6.39–6.47 (m, 2 H), 6.87–
6.92 (m, 1 H), 7.09–7.15 (m, 1 H), 7.22 (t, J = 8.4 Hz, 1 H), 7.24–
7.32 (m, 2 H), 7.40 (d, J = 8.2 Hz, 1 H).
13C NMR (150 MHz, CDCl3): δ (rotamers were observed) = 24.8,
25.0, 26.5, 27.7, 28.0, 28.1, 28.3, 28.4, 29.7, 31.7, 32.9, 37.7, 45.2,
45.3, 45.9, 49.4, 51.7, 53.4, 55.5, 56.4, 56.9, 80.5, 82.1, 82.1, 103.5,
103.5, 107.1, 109.2, 109.3, 123.6, 123.9, 124.0, 124.8, 125.0, 125.1,
127.7, 127.9, 131.2, 131.3, 139.1, 146.2, 146.2, 146.5, 158.4, 162.0,
166.6, 171.0, 171.1, 172.1.
N-{[5-(2,6-Dimethoxyphenyl)-1-(4-{[[3-(dimethylamino)pro-
pyl](methyl)amino]carbonyl}-2-isopropylphenyl)-1H-pyrazol-
3-yl]carbonyl}-L-valine (12c)
Prepared according to the general procedure using 11c (11.5 mg, 20
μmol); yield: 7.0 mg (58%); colorless lyophilisate.
HPLC: 254 nm; system 2, tR = 13.1 min (99.5%), system 3,
tR = 11.1 min (98.4%).
IR (ATR): 3410, 2962, 1671, 1475, 1253, 1179, 1131, 1107, 972,
720 cm–1.
MS (APCI): m/z = 750.6 [M + H]+.
1H NMR (600 MHz, DMSO-d6): δ (rotamers were observed) = 0.92
(d, J = 6.5 Hz, 3 H), 0.95 (d, J = 6.5 Hz, 3 H), 0.98–1.09 (m, 6 H),
1.79–1.98 (m, 2 H), 2.15–2.26 (m, 1 H), 2.61–2.68 (m, 1 H), 2.67–
2.83 (m, 6 H), 2.86 (s, 2 H), 2.96 (s, 1 H), 3.04–3.12 (m, 2 H), 3.18
(br s, 0.6 H), 3.46–3.51 (m, 1.4 H), 3.61–3.68 (m, 6 H), 4.37 (br s,
1 H), 6.50–6.64 (m, 2 H), 6.78–6.80 (m, 1 H), 7.15–7.28 (m, 2 H),
7.28–7.33 (m, 1 H), 7.33–7.41 (m, 1 H), 7.57–7.71 (m, 1 H).
Compounds 12a–d; General Procedure
Compounds 11a–d were treated with CH2Cl2–TFA (1:1, 2 mL) and
stirred at r.t. for 4 h. The mixture was lyophilized, the residue was
purified by preparative HPLC (MeOH–H2O + 0.1% TFA in H2O,
gradient) to give 12a–d.
N-{[5-(2,6-Dimethoxyphenyl)-1-(4-{[[3-(dimethylamino)pro-
pyl](methyl)amino]carbonyl}-2-isopropylphenyl)-1H-pyrazol-
3-yl]carbonyl}-L-phenylalanine (12a)
Prepared according to the general procedure using 11a (13.2 mg, 20
μmol); yield: 13.9 mg (68%); colorless lyophilisate.
13C NMR (150 MHz, DMSO-d6): δ (rotamers were observed) =
18.0, 19.2, 21.8, 27.4, 30.0, 36.9, 42.3, 42.3, 43.9, 54.5, 55.6, 103.8,
106.1, 108.5, 118.0, 124.7, 125.3, 127.3, 131.7, 138.2, 139.0, 141.8,
145.7, 158.0, 161.6, 169.9, 173.3.
MS (APCI): m/z = 608.4 [M + H]+.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C33H46N5O6: 608.3443;
HPLC: 254 nm; system 2, tR = 13.8 min (97.1%), system 3,
tR = 11.6 min (98.1%).
found: 608.3428.
IR (ATR): 3419, 2947, 1672, 1470, 1200, 1136, 1106, 1027, 723
cm–1.
N-{[5-(2,6-Dimethoxyphenyl)-1-(4-{[[3-(dimethylamino)pro-
pyl](methyl)amino]carbonyl}-2-isopropylphenyl)-1H-pyrazol-
3-yl]carbonyl}-L-glutamic Acid (12d)
Prepared according to the general procedure using 11d (14.3 mg, 20
μmol); yield: 10.4 mg (82%); colorless lyophilisate.
1H NMR (360 MHz, DMSO-d6): δ (rotamers were observed) =
0.94–1.09 (m, 6 H), 1.77–2.02 (m, 2 H), 2.60 (hept, J = 6.8 Hz, 1
H), 2.68–3.00 (m, 9 H), 3.03–3.25 (m, 4 H), 3.25–3.35 (m, 0.5 H),
3.41–3.55 (m, 1.5 H), 3.63 (s, 6 H), 4.61–4.77 (m, 1 H), 6.60 (d,
J = 8.4 Hz, 2 H), 6.69–6.74 (m, 1 H), 7.15–7.38 (m, 9 H), 7.93–8.12
(m, 1 H), 9.32–9.64 (m, 1 H).
HPLC: 254 nm; system 2, tR = 11.6 min (96.8%), system 3, tR = 9.6
min (>99%).
13C NMR (90 MHz, DMSO-d6): δ (rotamers were observed) = 23.9,
27.2, 36.2, 36.8, 42.3, 47.0, 51.1 53.0, 54.5, 55.5, 103.7, 106.1,
108.5, 120.8, 122.2, 124.1, 124.6, 126.4, 127.5, 128.1, 129.1, 131.6,
137.8, 138.7, 145.8, 145.9, 158.0, 161.0, 169.9, 172.8.
MS (APCI): m/z = 656.6 [M + H]+.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C37H45N5O6 + Na:
IR (ATR): 3493, 3385, 2840, 1605, 1434, 1194, 1167, 1107, 816,
719 cm–1.
1H NMR (600 MHz, DMSO-d6): δ (rotamers were observed) =
0.91–1.10 (m, 6 H), 1.79–2.16 (m, 4 H), 2.32 (t, J = 7.5 Hz, 2 H),
2.64 (hept, J = 6.8 Hz, 1 H), 2.69–2.83 (m, 6 H), 2.84 (s, 2 H), 2.96
(br s, 1 H), 3.05–3.13 (m, 2 H), 3.14–3.19 (m, 0.6 H), 3.45–3.52 (m,
1.4 H), 3.64 (s, 6 H), 4.38–4.51 (m, 1 H), 6.56–6.64 (m, 2 H), 6.73–
6.80 (m, 1 H), 7.16–7.37 (m, 4 H), 8.14–8.28 (m, 1 H), 9.30–9.72
(m, 1 H), 11.84–13.06 (m, 1 H).
13C NMR (150 MHz, DMSO-d6): δ (rotamers were observed) =
21.8, 25.9, 27.2, 30.2, 36.9, 42.1, 42.2, 42.3, 43.8, 51.1, 54.4, 55.5,
103.7, 106.1, 108.6, 116.0, 116.3, 118.0, 124.1, 127.7, 131.6, 138.7,
145.8, 146.1, 157.9, 161.4, 169.9, 173.2, 173.8.
678.3262; found: 678.3226.
N-{[5-(2,6-Dimethoxyphenyl)-1-(4-{[[3-(dimethylamino)pro-
pyl](methyl)amino]carbonyl}-2-isopropylphenyl)-1H-pyrazol-
3-yl]carbonyl}-L-tyrosine (12b)
Prepared according to the general procedure using 11b (15.8 mg, 20
μmol); yield: 7.9 mg (59%); colorless lyophilisate.
MS (APCI): m/z = 638.4 [M + H]+.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C33H43N5O8 + Na:
HPLC: 254 nm; system 2, tR = 12.6 min (96.9%), system 3,
tR = 10.4 min (>99%).
IR (ATR): 3493, 3385, 2833, 1608, 1440, 1281, 1223, 1195, 1166,
816, 766 cm–1.
660.3004; found: 660.2970.
1H NMR (600 MHz, DMSO-d6): δ (rotamers were observed) =
0.88–1.16 (m, 6 H), 1.78–2.00 (m, 2 H), 2.61 (hept, J = 6.8 Hz, 1
H), 2.66–2.83 (m, 6 H), 2.85 (s, 2 H), 2.96 (s, 1 H), 2.99–3.06 (m, 2
H), 3.05–3.13 (m, 2 H), 3.28–3.33 (m, 0.6 H), 3.46–3.51 (m, 1.4 H),
3.64 (s, 6 H), 4.56–4.67 (m, 1 H), 6.57–6.65 (m, 4 H), 6.68–6.76 (m,
1 H), 7.00–7.07 (m, 2 H), 7.11–7.40 (m, 4 H), 7.89–7.98 (m, 1 H),
9.22 (br s, 1 H), 9.37–9.65 (m, 1 H).
Acknowledgment
The German Research Foundation (DFG) is acknowledged for fi-
nancial support. We thank Prof. Ivana Ivanović-Burmazović (Chair
of Bioinorganic Chemistry, FAU) for HRMS measurements.
13C NMR (150 MHz, DMSO-d6): δ (rotamers were observed) =
21.8, 27.3, 35.4, 36.9, 42.2, 42.3, 48.6, 53.3, 54.4, 55.6, 103.7,
106.1, 108.5, 115.0, 121.0, 124.4, 124.8, 127.6, 130.0, 131.6, 137.7,
138.3, 138.7, 143.1, 145.9, 155.9, 158.0, 161.0, 169.9, 172.9.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
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References
MS (APCI): m/z = 672.4 [M + H]+.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C37H45N5O7 + Na:
694.3211; found: 694.3181.
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