Efficient and scalable synthesis of α,α-disubstituted β-amino amides

Article abstract of DOI:10.1039/c6ob01219a

A practical and efficient methodology for the preparation of 2-aminoethyl α,α-disubstituted β-amino amides in three steps from methyl cyanoacetate has been developed. The key step in the synthesis was the chemoselective reduction of the nitrile group in presence of an amide and aryl halide functionalities. Reduction with RANEY Nickel catalyst, either with molecular hydrogen (8-10 bar) or under transfer hydrogenation conditions, necessitated in situ protection of the resulting amines with Boc₂O, whereas aryl bromide containing nitriles could be chemoselectively reduced with ZnCl₂/NaBH₄ without debromination. The developed protocol involved only one chromatographic purification step and can be performed at gram scale.

Full text of DOI:10.1039/c6ob01219a

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DOI: 10.1039/C6OB01219A
Organic & Biomolecular Chemistry
Paper
Efficient and scalable synthesis of α,α-disubstituted β-amino
amides
Marianne Hagensen Paulsen,a Magnus Engqvistb, Dominik Ausbachera, Morten Bøhmer Strøma
Received 00th January 20xx,
Accepted 00th January 20xx
and Annette Bayer*,b
DOI: 10.1039/x0xx00000x
A practical and efficient methodology for the preparation of 2-aminoethyl α,α-disubstituted β-amino amides in three steps
from methyl 2-cyano acetate has been developed. The key step in the synthesis was the chemoselective reduction of the
nitrile group in presence of an amide and aryl halide functionalities. Reduction with Raney Nickel catalyst, either with
molecular hydrogen (8-10 bar) or under transferhydrogenation conditions, nessecitated in situ protection of the resulting
amines with Boc2O, whereas aryl bromide containing nitriles could be chemoselectively reduced with ZnCl2/NaBH4 without
debromination. The developed protocol involved only one chromatographic purification step and can be performed at
gram scale.
www.rsc.org/
such metabolic transformations by the introduction of electron
withdrawing groups such as fluoro or bromo substituents. This
spurred our interest in finding an efficient and scalable
synthesis allowing for the preparation of halogenated
analogues of α,α-disubstituted β-amino amides with the
general structure shown in Fig. 1.
Introduction
β-Amino acids are important building blocks that are found as
components of natural products such as taxol1 and
microcystin2 and in peptidomimetics3-5 to imitate the function
of bioactive peptides. Due to the additional methylene group,
proteases such as trypsin and α-chymotrypsin6, 7 are unable to
recognize β-amino acids. Thus, incorporation of β-amino acids
into peptides is a known strategy to increase proteolytic
stability.4, 8-10 Peptidomimetics consisting of β-amino acids can
also form unique secondary structures11, 12 due to increased
rotational possibilities that are useful for improving the
biological activity of peptides.10, 13
Naturally occurring antimicrobial peptides (AMP) have
attracted much attention due to their potential as a new class
of antibiotics and anticancer agents.14 Both, antimicrobial and
chemotherapeutic agents with a novel mechanism of action
are strongly needed to fight the emergence of therapy
resistant tumours and multi-drug resistant bacterial infections.
Our group has reported a series of antimicrobial and cytotoxic
α,α-disubstituted β-amino acid derivatives. These derivatives
have an amphipathic structure consisting of two cationic
groups and two lipophilic side-chains previously described as a
pharmacophore model for small cationic AMPs.15-17 However,
we have observed that the aromatic side-chains of the α,α-
disubstituted β-amino acid derivatives are subjected to
metabolism by liver microsomes, which can complicate drug
development.18 Aromatic systems can be protected against
A number of methods for the preparation of α,α-
disubstituted β-amino acids and derivatives have been
reported (Scheme 1). Dialkylation of cyano acetate alkyl ester
followed by nitrile reduction and ester hydrolysis (A) was first
described by Cronin and coworkers6 and has later been applied
by us16, 17 and others.19 Reddy et al. published an interesting
approach based on palladium-catalysed directed C-H activation
of cyanoacetamides followed by arylation (B1) and nitrile
reduction with Pd/C (B2).20 Capone et al. reported the direct
21
alkylation of protected β-alanine using KHMDS as base (C)
,
while Lin et al. reported a related approach based on the
alkylation and reduction of a β-alanine nickel(II) complex (D).22
Alkylated β-alanines were obtained after reduction of the
nickel complexes by NaBH4 or Pd/C. Strategies based on the
introduction of the amine on an alkylated precursor include
the Mitsunobu reaction of 3-hydroxypropionate and
phthalimide described by Ducry and coworkers (E),23 and
Mannich or Vilsmeier-Haack type reactions between silyl enol
ethers of 2,2-disubstituted acetic acids or esters and iminium
salts (F) developed by the group of Karoyan24 and Bélanger25,
Fig. 1. General structure of desired α,α-disubstituted β-amino acid derivatives
containing two halogenated aromatic side chains and a 2-aminoethyl C-terminus.
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DOI: 10.1039/C6OB01219A
Scheme 1 Reported approaches to α,α-disubstituted β-amino acids and derivatives.
respectively. However, these reported protocols require either experiments revealed that this protocol consisted of several
long reaction sequences, harsh reaction conditions or are not work-intensive steps and was not compatible with brominated
compatible with aryl bromides due to the use of transition substrates. Partial or complete debromination was observed
metal catalysts, which are prone to lead to dehalogenation.
during the nitrile reduction step with Raney nickel, leading to
Here we present an efficient and easily scalable synthesis product mixtures that were difficult to separate or unwanted
of 2-aminoethyl amides of α,α-disubstituted β-amino acids. products. Consequently, we developed a more efficient
Additionally, a bromide compatible variant was developed to synthesis as shown in Scheme 2B. Methyl cyano acetate was
allow for the preparation of aryl bromide substituted dialkylated, followed by aminolysis and nitrile reduction, as
derivatives.
described below. This strategy circumvented the amide
coupling with TFFH and the protection/deprotection steps of
the previous method and thereby significantly shortened the
protocol. A key challenge was, however, to find a method for a
chemoselective nitrile reduction.
Results and discussion
Our group has previously prepared analogues of the target
compounds. In the reported synthesis16, 17 (Scheme 2A), the
methyl cyano acetate was alkylated with a variety of alkyl and
aryl halides. This was followed by reduction of the nitrile group
with Raney nickel to provide the alkylated β-amino ester. After
Boc-protection of the amine, the methyl ester was hydrolysed
to the corresponding carboxylic acid. After activation of the
acids with fluoro-N,N,Nʹ,Nʹ-tetramethylformamidinium hexa-
fluorophosphate (TFFH), coupling with the desired amine
The dialkylation of cyano acetate esters is well known.26-30 In
the course of our work, several of the reported protocols were
investigated. A modification of Oedigers method30, the 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) mediated dialkylation of
methyl cyano acetate (2) in CH2Cl2, was found to be a fast and
convenient procedure providing the dialkylated cyano acetates
(3 a-j) in almost quantitative yields (> 95% for all derivatives,
except 3g) (Scheme 3). The reaction times were short and 10
min proved to be sufficient on a 1 mmol scale.
provided the disubstituted
β
2,2-amino amides.16 Initial
Scheme 2 A. Previous reported method for synthesis of α,α-disubstituted β-amino amides; B. improved method described in this work.
2 | Org. Biomol.Chem., 2016, 00, 1-3
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The reaction was easily scaled up to a 50 mmol scale. The 9 and 12). When chromatographic purification (C18 reverse
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crude products were recrystallized in MeOH.
phase flash chromatography) was nDeOcIe:s1s0a.1r0y39/tCh6eOB0y1i2e1l9dAs
A common method for the formation of amide bonds is the dropped (25–52%) for most of the products (Table 2, entries 4,
peptide coupling of amines with activated carboxylic acids like 6, 7, 9, 10 and 12). The reductions were routinely carried out
acid chlorides or in situ activated carboxylic acids. A variety of at a 0.2-0.6 mmol scale. To test the scalability of method A, a
attempts to couple in situ activated carboxylic acids, obtained reduction of 2.5 mmol of 4j (1 g) was carried out. The reaction
after hydrolysis of 3, with N-Boc ethylene diamine in analogy at this scale did not result in the desired conversion within 18h
to the previously reported method17 gave low yields and a reaction time.
significant amount of by-products thus requiring
Additionally, reduction of the nitrile group with a modified
chromatographic purification. Therefore, aminolysis of the protocol at 1 bar using transfer hydrogenation conditions
methyl esters was investigated as a more convenient and (Method B) with ammonium formate as hydrogen source was
economic procedure (Table 1). The dialkylated methyl esters (3 investigated (Table 2, entries 8, 11, 13 and 14). For substances
a-j) were dissolved in ethylene diamine as solvent and stirred 4h and 4j good yields (62% of 4h and 80% of 4j) were obtained
until TLC indicated completion (0.5–24 h). Precipitation of the within 48 h (entries 11 and 14), while other substrates (4f and
products by addition of water gave the corresponding 2- 4i) showed low conversion (< 30%) (entries 8 and 13). A
aminoethyl cyano amides 4a-j in good yields (72–98%) and reaction under transfer hydrogenation conditions (method B)
purity (> 95% as determined by analytical HPLC) (Table 1). The was performed at a 2.6 mmol scale with good results (80%
reaction was carried out up to a 50 mmol scale. Other yield).
protocols for assisted aminolysis31, 32 were examined but did
not provide significant improvement.
An important aim of this study was the preparation of
halogen-containing analogues of 1. As expected, the modified
Initially, the chemoselective reductions of nitriles in Raney nickel reduction did not prevent the unwanted
presence of amides with Raney nickel were investigated for debromination. In the reduction of 4a by Raney nickel with
the cyano amides 4a—j. In general, the reductions were slow ammonium formate at 1 bar in presence of Boc2O (Method B),
(1 bar, 45 °C, 5 days) and low yields were obtained (< 30%). substantial debromination was observed already after 1h
Not surprisingly, the reduction of the aryl bromide containing reaction time (Table 2, entry 1). Caddick and coworkers
nitriles 4a and 4b resulted in substantial debromination. We described selective reductions of nitriles in presence of either
hypothesise that the inefficient reduction with Raney nickel amides or aryl bromides employing catalytic nickel(II) chloride
might relate to coordination by the amine functionalities and with excess sodium borohydride.33 In our case, this protocol
formation of byproducts. Therefore, reductions were resulted in dehalogenation. Dehalogenation also occurred with
performed in presence of Boc2O to affect simultaneous CoCl2/NaBH4.19, 34, 35 Finally, we achieved the desired chemo-
reduction and protection of the amine groups. By addition of selectivity with a system of ZnCl2/NaBH4 as reducing agent.36
Boc2O (4 eq.), reductions at 8-10 bar in MeOH (Table 2,
Table 1 Aminolysis of methyl esters by ethylene diamine.
Method A) gave full conversion within 18 h determined by MS
and NMR of the crude. Deprotection (1.33 M HCl in dioxane) of
the crude provided the target amino amides 1c—j (Table 2,
entries 4-7, 9, 10 and 12). Yields were good (> 70%) when
purification by precipitation was possible (Table 2, entries 4, 5,
Starting
material
Entry
Rxn. time (h)
Yield (%)
1
2
3
4
5
6
7
2
1
97
94
92
96
98
76
85
3a
3b
3c
3d
3e
3f
5
3
0.5
6
2
3g
8
9
1
24a
92
72b
3h
3i
10
3j
24
82c
Scheme 3 Dialkylation of methyl 2-cyanoacetate 2.
a. The starting material was poorly soluble; b.10 g scale; c. 23 g scale
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Table 2 Chemoselective reductions of the nitrile group in presence of amides and aryl
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Reduction of nitriles 4a and 4b with ZnCl2/NaBH4 gave the
corresponding amines 1a in 75% and 1b in 80% yield after
decomplexation of any amine-boron complexes by boiling in 6
M aqueous HCl and chromatographic purification (C18 RP flash
chromatography). Interestingly, no significant hydrolysis of the
amides 1a and 1b was observed during the acidic treatment,
however prolonged acidic treatment resulted in
decarboxylative loss of the amide functionality.
bromides functionalities.
DOI: 10.1039/C6OB01219A
Starting
Entry
Methoda Rxn. time (h)
Yield (%)
material
Conclusions
1
B
C
C
A
A
A
A
B
A
A
B
A
B
B
1
ndb
75d
80d
80c / 25d
90c
40d
50b
30b
75c / 50d
52d
62d
4a
In summary, we have describe a convenient and robust
approach to α,α-dialkylated β-amino amides comprising of a
dialkylation with DBU, followed by aminolysis and
chemoselective reduction of the nitrile group. A nitrile
reduction method that tolerates the presence of bromoaryl
substituents was developed. Only one chromatographic
purification was needed to yield > 95% pure compounds in a
three step procedure with an overall yield of 21–84%.
2
1.5
1.5
18
18
18
18
48
18
18
48
20
24
48
3
4
4b
4c
4d
4e
5
6
7
4f
4g
4h
8
Experimental section
9
10
11
12
13
14
Materials and methods
All reagents and solvents were purchased from commercial
sources and used as supplied unless otherwise stated.
Anhydrous THF was prepared by storage over 4 Å molecular
sieves. Raney nickel was bought from Sigma Aldrich (CAS
no. 7440-02-0, 2800, slurry, in H2O, active catalyst). The
hydrogenations with Raney nickel at higher pressure (810 bar)
were carried out on a Parr Instrument, Series 4590 Micro
Stirred reactor, 50 mL, attached to a Parr 4843 Modular
Controller. Reactions were monitored by thin-layer
chromatography (TLC) with Merck pre-coated silica gel plates
(60 F254). Visualization was accomplished with either UV light
or by immersion in potassium permanganate or
phosphomolybdic acid (PMA) followed by light heating with a
heating gun. Purification of reactions was carried out by
chromatography using a RP C18 column preloaded on a
Samplet® cartridge belonging to a Biotage SP-1. Analytical
HPLC was carried out on a Waters 2695 Separations Module
equipped with an XBridge™ C18 5 µm, 4.6 mm x 250 mm
column and analysed at wavelengths 214 and 254 nm with a
Waters 996 PDA detector spanning from wavelengths 210 to
310 nm. The compounds were eluated with water and
acetonitrile, both containing 0.1% TFA. The gradient started at
10% acetonitrile, 3 minutes isocratic gradient, followed by a
linear increase to 90 % acetonitrile over 17 minutes, followed
by an 8 min acetonitrile wash and then 10 min equilibration to
the starting gradient. The flow rate was 1 ml/min. NMR
spectra were obtained on a 400 MHz Bruker Avance III HD
equipped with a 5 mm SmartProbe BB/1H (BB=19F, 31P-15N).
Data are represented as follows: chemical shift, multiplicity (s
= singlet, d = doublet, t = triplet, q = quartet, p = pentet, m =
multiplet), coupling constant (J, Hz) and integration. Chemical
shifts (δ) are reported in ppm relative to the residual solvent
peak (CDCl3: δH 7.26 and δC 77.16; Methanol-d4: δH 3.31 and δC
72c / 35d
27d
80d
4i
4j
a: Method A: i. Raney Ni, H2 (8–10 bar), Boc2O (approx. 4 eq.), MeOH, 45 °C ii.
1.33M HCl in dioxane; Method B: i. Raney Ni, ammonium formate (4 eq.), Boc2O
(4 eq.), EtOAc or MeOH, 45 °C ii. 1.33M HCl in dioxane; Method C: ZnCl2/NaBH4;
b. Dehalogenated product; c. Isolated yield after crystallisation; d. Isolated yield
after chromatographic purification.
49.00). Positive ion electrospray ionization mass spectrometry
was conducted on a Thermo electron LTQ Orbitrap XL
spectrometer.
General procedure for dialkylation of methyl cyanoacetate 2
Methyl cyanoacetate 2 was dissolved in CH2Cl2 (approx. 0.1 M,
prefiltered through K2CO3), cooled to 0 °C, added DBU (2 eq.)
and stirred for 2 min. The alkyl halide (2 eq.) was added in
small portions to avoid increase in temperature. The reaction
was left to stir at RT until completion. The reaction was
monitored on TLC (1:4 EtOAc/toluene). After completion, the
reaction was quenched with water and extracted with EtOAc.
The organic phase was washed with water (3 times) and brine,
dried over Na2SO4, filtered and evaporated to dryness. To
remove residual EtOAc, chloroform was added and re-
evaporated. If necessary, MeOH was added to precipitate the
crude. The resulting solid was recrystallized in MeOH.
Methyl
3-(2-bromophenyl)-2-[(2-bromophenyl)methyl]-2-
cyanopropionate (3a). Methyl cyanoacetate 2 (34 mmol, 2.99
mL), DBU (70.3 mmol, 10.5 mL) and 2-bromobenzyl bromide
(68 mmol, 16.94 g) gave the title compound (13.9 g, 94%) as
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1
white crystals. H NMR (400 MHz, CDCl3): δ 7.60 (dd, J = 8.0, 130.9, 129.7 (q, J = 29.6), 128.2, 126.7 (q, J = 5.8), 124.2 (q, J =
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+
1.4, 2H), 7.42 (dd, J = 7.7, 1.7, 2H), 7.30 (td, J = 7.5, 1.4, 2H), 274), 118.0, 53.9, 51.0, 38.3. HRMSDO(EI:S1I0).10m39/z/C: 6O[MB0+1N21a9]A
7.16 (td, J = 7.7, 1.7, 2H), 3.75 (s, 3H), 3.57 (dAB, J = 14.2, 2H), Calculated for C20H15F6NNaO2 438.0900; Found: 438.0883
3.52 (dAB, J = 14.2, 2H). 13C NMR (101 MHz, CDCl3): δ 168.5, Methyl
2-cyano-3-[4-(trifluoromethyl)phenyl]-2-{[4-
134.0, 133.3, 131.3, 129.5, 127.7, 125.9, 117.8, 53.8, 51.1, (trifluoromethyl)phenyl] methyl}propionate (3g). Methyl
40.9. HRMS (ESI) m/z: [M+Na]+ Calculated for cyanoacetate 2 (11.37 mmol 1.00 mL), DBU (23.88 mmol, 3.57
C18H1579Br2NNaO2 457.9359; Found: 457.9365.
mL) and 4-(trifluoromethyl)benzyl bromide (22.85 mmol, 5.46
1
Methyl
2-cyano-3-(3,5-dibromophenyl)-2-[(3,5- g) gave the title compound (3.75 g, 80%) as white crystals. H
methyl]propionate (3b). Methyl NMR (400 MHz, CDCl3): δ 7.61 (d, J = 8.2, 4H), 7.43 (d, J = 8.1,
dibromophenyl)
cyanoacetate 2 (7.39 mmol, 0.65 mL), DBU (17.1 mmol, 2.55 4H), 3.57 (s, 3H), 3.41 (dAB, J = 13.4, 2H), 3.17 (dAB, J = 13.4,
mL) and 3,5-dibromobenzyl bromide (15.2 mmol, 5.00 g) gave 2H). 13C NMR (101 MHz, CDCl3): δ 168.2, 137.8, 130.6 (q, J =
1
the title compound (4.90 g, 99%) as white crystals. H NMR 33.3), 130.5, 125.8 (q, J = 3.8), 124.1 (q, J = 272.7), 117.9, 53.6,
(400 MHz, CDCl3): δ 7.64 (t, J = 1.8, 2H), 7.36 (d, J = 1.8, 4H), 52.9, 43.0. HRMS (ESI) m/z: [M+Na]+ Calculated for
3.67 (s, 3H), 3.24 (dAB, J = 13.5, 2H), 2.99 (dAB, J = 13.5, 2H). 13
NMR (101 MHz, CDCl3): δ 168.0, 137.4, 134.2, 131.8, 123.4,
117.2, 53.9, 52.6, 42.2. HRMS (ESI) m/z: [M+Na]+ Calculated
for C18H1379Br4NNaO2 613.7571 Found: 613. 7563
C
C20H15F6NNaO2 438.0900; Found: 438.0882
Methyl
3-[3,5-bis(trifluoromethyl)phenyl]-2-{[3,5-
bis(trifluoromethyl)phenyl]methyl}-2-cyanopropionate
(3h).
Methyl cyanoacetate 2 (5.46 mmol, 0.48 mL), DBU (11.4 mmol,
1.71 mL) and 3,5-di(trifluoromethyl)benzyl bromide (10.9
mmol, 2.0 mL) gave the title compound (2.98 g, 99%) as white
2-fluorophenyl)-2-[(2-fluorophenyl)methyl]propionate
(3c).
Methyl cyanoacetate 2 (8.41 mmol, 0.74 mL), DBU (16.8 mmol,
2.51 mL) and 2-fluorobenzyl bromide (16.8 mmol, 2.03 mL)
crystals. 1H NMR (400 MHz, CDCl3):
δ
7.88 (s, 2H), 7.75 (s, 4H),
3.60 (s, 3H), 3.53 (dAB, J = 13.6, 2H), 3.25 (dAB, J = 13.6, 2H).
13C NMR (101 MHz, CDCl3):
167.8, 136.0, 132.4 (q, J = 33.6),
1
gave the title compound (2.62 g, 98%) as white crystals. H
NMR (400 MHz, CDCl3):
3.69 (s, 3H), 3.39 (dAB, J = 13.8, 2H), 3.29 (dAB, J = 13.9, 2H). 13
NMR (101 MHz, CDCl3): 168.4, 161.4 (d, J = 247.2), 132.1 (d, J
δ 7.36-7.27 (m, 4H), 7.15-7.05 (m, 4H),
δ
C
130.3, 123.1 (q, J = 274.3), 122.6 (p, J = 3.8), 116.8, 54.0, 52.8,
42.7. HRMS (ESI) m/z: [M+Na]+ Calculated for
C22H13F12NNaO 574.0648; Found: 574.0631
δ
= 3.7), 130.1 (d, J = 8.4), 124.5 (d, J = 3.6), 121.4 (d, J = 15.3),
117.9, 115.7 (d, J = 22.4), 53.6, 51.6, 35.6 (d, J = 2.2). HRMS
(ESI) m/z: [M+Na]+ Calculated for C18H15F2NNaO2 338.0963;
Found: 338. 0951
Methyl
2-cyano-3-[4-(tert-butyl)phenyl]-2-{[4-(tert-
butyl)phenyl]methyl}propionate (3i). Methyl cyanoacetate 2
(37.34 mmol, 3.3 mL), DBU (77.51 mmol, 11.8 mL) and 4-
tertbutylbenzyl bromide (77.51 mmol, 17.65 g) gave the title
compound (13.92 g, 95%) as white crystals. 1H NMR (400 MHz,
CDCl3): δ 7.34 (d, J = 8.3, 4H), 7.22 (d, J = 8.2, 4H), 3.56 (s, 3H),
3.28 (dAB, J = 13.6, 2H), 3.08 (dAB, J = 13.6, 2H), 1.31 (s, 18H).
13C NMR (101 MHz, CDCl3): δ 169.0, 150.9, 131.1, 129.8, 125.7,
118.9, 53.5, 53.2, 42.9, 34.7, 31.5. HRMS (ESI) m/z: [M+H]+
Calculated for C26H34NO2 392.2584; Found: 392.2584
Methyl
2-cyano-3-(2,6-difluorophenyl)-2-[(2,6-
difluorophenyl)methyl]propionate (3d). Methyl cyanoacetate
2 (8.4 mmol, 0.74 mL), DBU (17 mmol, 2.51 mL) and 2,6-
difluorobenzyl bromide (17 mmol, 3.476 g) gave the title
1
compound (2.88 g, 97%) as pale yellow crystals. H NMR (400
MHz, CDCl3): δ 7.29 (ddd, J = 8.4, 6.6, 1.9, 2H), 6.93 (br dd, J =
7.9, 4H), 3.80 (s, 3H), 3.45 (dAB, J = 14.1, 2H), 3.40 (dAB, J = 14.1,
2H). 13C NMR (101 MHz, CDCl3): δ 168.2, 161.9 (dd, 249.4, 7.6),
130.3 (t, J = 10.5), 116.9, 112.0-111.4 (m), 110.6 (t, J = 19.6),
54.0, 50.0, 30.0. HRMS (ESI) m/z: [M+Na]+ Calculated for
C18H13F4NNaO2 374.0774; Found: 374.0772
Methyl
2-cyano-3-(2-naphthyl)-2-[(2-
naphthyl)methyl]propionate (3j). Methyl cyanoacetate 2
(50.46 mmol, 4.4 mL), DBU (105.8 mmol, 15.8 mL) and 2-
(bromomethyl)naphtalene (105.8 mmol, 23.40 g) gave the title
Methyl
2-cyano-3-(3,5-difluorophenyl)-2-[(3,5-
difluorophenyl)methyl]propionate (3e). Methyl cyanoacetate
2 (8.87 mmol, 0.78 mL), DBU (18 mmol, 2.76 g) and 3,5-
difluorobenzyl bromide (17 mmol, 2.25 mL) gave the title
1
compound (18.24 g, 95%) as slightly brown crystals. H NMR
(400 MHz, CDCl3): δ 7.87 (m, 8H), 7.52 (m, 6H), 3.58 (dAB, J =
13.5, 2H), 3.55 (s, 3H), 3.35 (dAB, J = 13.5, 2H). 13C NMR (101
MHz, CDCl3): δ 168.9, 133.4, 132.9, 131.6, 129.2, 128.4, 128.0,
127.8, 127.7, 126.4, 126.3, 118.6, 53.5, 53.2, 43.5. HRMS (ESI)
m/z: [M+H]+ Calculated for C26H22NO2 380.1644; Found:
380.1645
1
compound (3.05 g, 98%) as white crystals. H NMR (400 MHz,
CDCl3): δ 6.85-6.76 (m, 6H), 3.64 (s, 3H), 3.30 (dAB, J = 13.5,
2H), 3.06 (dAB, J = 13.5, 2H). 13C NMR (101 MHz, CDCl3): δ
168.0, 163.1 (dd, J = 249.7, 12.9), 137.2 (t, J = 9.1), 117.6,
113.2-113.0 (m), 104.1, (t, J = 25.2), 53.8, 52.6, 42.8. HRMS
(ESI) m/z: [M+Na]+ Calculated for C18H13F4NNaO2 374.0774;
Found: 374.0763
General procedure for aminolysis of 3a-j
The procedure was performed under N2. The alkylated
methylcyanoacetate (3a-j) was added ethylenediamine and
stirred at room temperature until completion. The reaction
was monitored on TLC. After completion, the reaction mixture
was cooled on ice and water was added to the reaction
mixture until precipitation occurred. The product was filtered
off, washed carefully with water and dried under vacuum.
Methyl
2-cyano-3-[2-(trifluoromethyl)phenyl]-2-{[2-
(trifluoromethyl)phenyl]methyl} propionate (3f). Methyl
cyanoacetate 2 (4.94 mmol, 0.44 mL), DBU (10.8 mmol, 1.65 g)
and 2-(trifluoromethyl)benzyl bromide (9.96 mmol, 2.38 g)
gave the title compound (2.1 g, 98%) as white crystals. 1H NMR
(400 MHz, CDCl3): δ 7.70 (d, J = 8, 2H), 7.58-7.51 (m, 4H), 7.42
(t, J = 7.5, 2H), 3.76 (s, 3H), 3.62 (dAB, J = 14.9, 2H), 3.42 (dAB, J
= 14.9, 2H). 13C NMR (101 MHz, CDCl3): δ 169.0, 133.0, 132.1,
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3-(2-Aminoethylamino)-2,2-bis[(o-bromophenyl)methyl]-3-
(dAB, J = 14.6, 2H), 3.56 (, t, J = 6.8, 2H), 3.35 (dAB,VJie=w1Ar4ti.c6le,O2nHlin)e,
oxopropiononitrile (4a). 3a (5.03 mmol, 2.20 g) and 3.05 (t, J = 6.8, 2H). 13C NMR (101 MHz, Methanol-d4): δ 170.4,
DOI: 10.1039/C6OB01219A
ethylenediamine (20 mL) (2 h) gave the title compound (2.31 g, 134.8, 133.3, 132.7, 130.7 (q, J = 29.3), 129.4, 127.6 (q, J = 5.8),
1
97%) as white powder. H NMR (400 MHz, Methanol-d4): δ 125.6 (q, J = 274.7), 119.5, 53.1, 39.8, 39.2, 39.0. HRMS (ESI)
7.62 (d, J = 8.1, 1.3, 2H), 7.43 (dd, J = 7.7, 1.7, 2H), 7.34 (td, J = m/z: [M+H]+ Calculated for C21H20F6N3O 444.1506; Found:
7.5, 1.3, 2H), 7.21 (td, J = 7.7, 1.8, 2H), 3.58 (dAB, J = 14.0, 2H), 444.1505
3.55 (dAB, J = 14.0, 2H), 3.48 (t, J = 6.7, 2H), 2.99 (t, J = 6.7, 2H). 3-(2-Aminoethylamino)-3-oxo-2,2-bis{[4-
13C NMR (101 MHz, Methanol-d4): δ 169.8, 135.9, 134.4, 132.8, (trifluoromethyl)phenyl]methyl}propiononitrile (4g). 3g (0.78
130.7, 128.8, 127.0, 119.5, 53.0, 41.7, 40.0, 39.1. HRMS (ESI) mmol, 0.325 g) and ethylenediamine (5 mL) (2 h) gave the title
m/z: [M+H]+ Calculated for C19H2079Br2N3O 463.9966; Found: compound (0.293 g, 85%) as white powder. 1H NMR (400 MHz,
463.9953
3-(2-Aminoethylamino)-2,2-bis[(3,5-
Methanol-d4): δ 7.64 (d, J = 8.1, 4H), 7.52 (d, J = 8.1, 4H), 3.51
(dAB, J = 13.3, 2H), 3.24 (dAB, J = 13.3, 2H), 3.05 (t, J = 6.6, 2H),
dibromophenyl)methyl]-3-oxopropiononitrile (4b). 3b (8.23 2.46 (t, J = 6.6, 2H). 13C NMR (101 MHz, Methanol-d4): δ 161.1,
mmol, 4.890 g) and ethylenediamine (50 mL) (1 h) gave the 140.8 (d, J = 1.4), 132.0, 131.0 (q, J = 32.4), 126.4 (q, J = 3.8),
1
title compound (4.80 g, 94%) as white powder. H NMR (400 125.6 (q, J = 272.7), 119.9, 54.6, 43.7, 43.6, 41.3. HRMS (ESI)
MHz, CDCl3): δ 7.66-7.61 (m, 2H), 7.38 (d, J = 1.7, 4H), 6.42 (s, m/z: [M+H]+ Calculated for C21H20F6N3O 444.1506; Found:
1H), 3.35 (d, J = 13.3, 2H), 3.17 (q, J = 5.8, 2H), 2.89 (d, J = 13.3, 444.1504
2H), 2.65 (t, J = 6.0, 2H), 0.88 (broad s, 1H). 13C NMR (101 MHz, 3-(2-Aminoethylamino)-2,2-bis{[3,5-
CDCl3): δ 165.3, 138.1, 133.9, 131.9, 123.2, 119.0, 53.2, 42.9, bis(trifluoromethyl)phenyl]methyl}-3-oxopropiononitrile
42.0, 40.6. HRMS (ESI) m/z: [M+H]+ Calculated for (4h). 3h (2.70 mmol, 0.95 g) and ethylenediamine (10 mL) (1 h)
C19H1879Br4N3O 619.8176; Found: 619.8186
gave the title compound (0.87 g, 92%) as white powder. H
NMR (400 MHz, Methanol-d4): δ 7.94 (s, 2H), 7.92 (s, 4H), 3.65
1
3-(2-Aminoethylamino)-2,2-bis[(2-fluorophenyl)methyl]-3-
oxopropiononitrile (4c). 3c (4.08 mmol, 1.284 g) and (dAB, J = 13.4, 2H), 3.41 (dAB, J = 13.4, 2H), 3.03 (t, J = 6.9, 2H),
ethylenediamine (10 mL) (5 h) gave the title compound (1.28 g, 2.42 (t, J = 6.9, 2H). 13C NMR (101 MHz, Methanol-d4): δ 167.5,
1
92%) as white powder. H NMR (400 MHz, Methanol-d4): δ 139.4, 132.8 (q, J = 33.3), 131.8, 124.7 (q, J = 272.9), 122.8-
7.38-7.30 (m, 4H), 7.16-7.09 (m, 4H), 3.40 (dAB, J = 13.6, 2H), 122.7 (m), 119.3, 54.6, 43.4, 43.0, 41.4. HRMS (ESI) m/z:
3.32 (dAB, J = 13.3, 2H), 3.15 (t, J = 6.5, 2H), 2.56 (t, J = 6.4, 2H). [M+H]+ Calculated for C23H18F12N3O+ 580.1260; Found:
13C NMR (101 MHz, Methanol-d4): δ 168.7, 162.7 (d, J = 242.4), 580.1253
133.2 (d, J = 3.7), 131.0 (d, J = 8.3), 125.3 (d, J = 3.6), 123.3 (d, J 3-(2-Aminoethylamino)-3-oxo-2,2-bis{[4-(tert-
= 15.4), 119.8, 116.5 (d, J = 22.7), 53.5, 43.9, 41.4, 36.4. HRMS butyl)phenyl]methyl}propiononitrile (4i). 3i (25.21 mmol,
(ESI) m/z: [M+H]+ Calculated for C19H20F2N3O 344.1569; Found: 9.857 g) and ethylenediamine (100 mL) (24 h) gave the title
1
344. 1555
compound (7.61 g, 72%) as white powder. H NMR (400 MHz,
Methanol-d4): δ 7.35 (d, J = 8.2, 4H), 7.24 (d, J = 8.2, 4H), 3.34
3-(2-Aminoethylamino)-2,2-bis[(2,6-difluorophenyl)methyl]-
3-oxopropiononitrile (4d). 3d (8.21 mmol, 2.88 g) and (ABd, J = 13.4, 2H), 3.07-3.04 (m, 4H), 2.47 (t, J = 6.3, 2H), 1.30
ethylenediamine (10 mL) (3 h) gave the title compound (2.98 g, (s, 18H). 13C NMR (101 MHz, Methanol-d4): δ 169.1, 151.7,
1
96%) as white powder. H NMR (400 MHz, Methanol-d4): δ 133.4, 130.9, 126.3, 120.7, 55.4, 43.8, 43.7, 35.3, 31.7. HRMS
7.42-7.35 (m, 2H), 7.01 (t, J = 8.1, 4H), 3.48 (dAB, J = 14.1, 2H), (ESI) m/z: [M+H]+ Calculated for C27H38N3O+ 420.3015; Found:
3.37 (dAB, J = 14.1, 2H), 3.23 (t, J = 6.5Hz, 2H), 2.68 (t, J = 6.5, 420.3009
2H). 13C NMR (101 MHz, Methanol-d4): δ 168.7, 163.2 (d, J = 3-(2-Aminoethylamino)-2,2-bis[(2-naphthyl)methyl]-3-
250), 131.6 (t, J = 10.1), 118.9, 112.6-112.4 (m), 112.2, 52.1, oxopropiononitrile (4j). 3j (62.20 mmol, 23.57 g) and
44.2, 41.5, 30.8. HRMS (ESI) m/z: [M+H]+ Calculated for ethylenediamine (100 mL) (24 h) gave the title compound
C19H22F4N3O 384.1693; Found: 384.1694
3-(2-Aminoethylamino)-2,2-bis[(3,5-difluorophenyl)methyl]-
(20.75 g, 82%) as white powder. 1H NMR (400 MHz, Methanol-
d4): δ 7.82-7.78 (m, 8H), 7.49-7.43 (m, 6H), 3.60 (dAB, J = 13.4,
3-oxopropiononitrile (4e). 3e (4.29 mmol, 1.507 g) and 2H), 3.30 (dAB, J = 13.4, 2H), 2.99 (t, J = 6.4, 2H), 2.35 (t, J = 6.4,
ethylenediamine (25 mL) (0.5 h) gave the title compound (1.60 2H). 13C NMR (101 MHz, Methanol-d4): δ 168.3, 134.7, 134.2,
1
g, 98%) as white powder. H NMR (400 MHz, Methanol-d4): δ 133.8, 130.2, 129.0, 129.0, 128.8, 128.6, 127.3, 127.1, 120.7,
6.96-6.85 (m, 6H), 3.40 (dAB, J = 13.3, 2H), 3.15 (dAB, J = 13.4, 55.5, 44.3, 43.6, 41.2. HRMS (ESI) m/z: [M+H]+ Calculated for
2H), 3.11 (t, J = 6.8, 2H), 2.51 (t, J = 6.7, 2H). 13C NMR (101 C27H26N3O+ 408.2075; Found: 408.2080
MHz, Methanol-d4): δ 167.9, 164.2 (dd, J = 247.6, 12.9), 140.3
General procedure for reduction with Raney Nickel at 8 bar
(Method A)
(t, J = 9.4), 119.9, 117.7 – 112.1 (m), 104.1 (t, J = 25.6), 54.3,
43.4, 43.3, 41.4. HRMS (ESI) m/z: [M+H]+ Calculated for
C19H18F4N3O 380.1381; Found: 380.1363
3-(2-Aminoethylamino)-3-oxo-2,2-bis{[2-
One spoon of Raney Nickel (approx. 5 g) was transferred to the
50 mL Parr hydrogenation bomb, washed with 3 x 15 mL
(trifluoromethyl)phenyl]methyl}propiononitrile (4f). 3f (0.539 MeOH before addition of substrate (0.2-2.5 mmol) and Boc2O
mmol, 0.224 g) and ethylenediamine (3 mL) (6h) gave the title (approx. 4 eq.). The reaction was stirred overnight (18 h) at 45
compound (0.18 g, 76%) as white powder. 1H NMR (400 MHz, °C at 8-10 bar. After completion, the bomb was cooled to room
Methanol-d4): δ 7.73 (d, J = 7.9, 2H), 7.67-7.46 (m, 6H), 3.66 temperature, the reaction mixture was purged and the catalyst
6 | Org. Biomol.Chem., 2016, 00, 1-3
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Paper
was filtered off through a pad of sand and celite under N2 and 40.7, 40.0, 38.5. HRMS (ESI) m/z: [M+H]+ Calculated for
View Article Online
DOI: 10.1039/C6OB01219A
79
the filtrate evaporated to dryness. The crude was dissolved in C19H22 Br4N3O 623.8491; Found: 623.8496
dioxane and added 4M HCl/dioxane and H2O and heated to 60 2-fluorophenyl)-2-[(2-fluorophenyl)methyl]-1-propanone
°C for 2 h. The reaction mixture was evaporated to dryness and (1c). 4c was reduced according to method A. 4c (0.57 mmol,
purified on C18 RP flash chromatography (acetonitrile/water) 0.20 g), Boc2O (2.3 mmol, 0.51 g) and 1 spoon of Raney Nickel
or dissolved in EtOAc and precipitated by addition of Et2O.
in MeOH gave the di-Boc-protected intermediate. The
Warning: Reactions at larger scale (12 mmol) are not intermediate was added 4 mL dioxane, 0.5 mL H2O and 2 mL
recommended in the 50 mL Parr bomb. Delayed, uncontrolled 4M HCl/dioxane to yield the crude, which was purified by C18
gas evolution after the release of hydrogen pressure was RP flash chromatography to yield the title compound as clear
1
observed.
crystals (0.053 g, 25%). H NMR (400 MHz, Methanol-d4): δ
7.38 – 7.33 (m, 4H), 7.21 – 7.10 (m, 4H), 3.56 (t, J = 6.2, 2H),
3.43 (dAB, J = 14.4, 2H), 3.16 (t, J = 6.2, 2H), 3.09 (dAB, J = 14.4,
2H) 2.95 (s, 2H). 13C NMR (101 MHz, Methanol-d4): δ 176.0,
General procedure for reduction with Raney Nickel at 1 bar
(Method B)
One spoon of Raney Nickel (approx. 5 g) was transferred to a 162.8 (d, J = 243.0), 134.1 (d, J = 4.1), 130.9 (d, J = 8.6), 125.7
round bottom flask, washed with 3 x 15 mL MeOH and 3 x 15 (d, J = 3.5), 123.4 (d, J = 15.7), 116.6 (d, J = 23.2), 51.2, 42.9,
mL EtOAc before addition of substrate dissolved in EtOAc. The 40.7, 38.8, 34.4. HRMS (ESI) m/z: [M+H]+ Calculated for
reaction was stirred for 48 h (unless otherwise stated) at 45 °C C19H24F2N3O 348.1887; Found: 348.1890
with a H2 containing balloon attached. The reaction mixture 1-(2-Aminoethylamino)-2-(aminomethyl)-3-(2,6-
was cooled to room temperature before the catalyst was difluorophenyl)-2-[(2,6-difluorophenyl)methyl]-1-propanone
filtered off through a pad of sand and celite under N2, washed (1d). 4d was reduced according to method A. 4d (0.65 mmol,
with brine, dried with Na2SO4 and evaporated to dryness. The 0.25 g), Boc2O (2.84 mmol, 0.61 g) and 1 spoon of Raney Nickel
product was purified by C18 RP flash chromatography in MeOH gave the di-Boc-protected intermediate. The
(acetonitrile/water).
intermediate was added 4 mL dioxane, 0.5 mL H2O and 2 mL
4M HCl/dioxane to yield the crude, which was dissolved in
EtOAc and precipitated in Et2O to yield the title compound as
General procedure for reduction with ZnCl2/NaBH4 (Method C)
The reducing agent was prepared by stirring ZnCl2 (1 eq., 1.15 white crystals (0.22 g, 90%). 1H NMR (400 MHz, Methanol-d4):
g) and NaBH4 (2 eq., 0.68 g) in dry THF (40 mL) overnight. The δ 7.41 (tt, J = 8.3, 6.6, 2H), 7.06 (t*, J = 8.2,, 4H), 3.57 (t, J = 6.0,
substrate (1 eq.) was dissolved in the reducing agent (2 eq.) 2H), 3.48 (dAB, J = 14.5, 2H), 3.18 (t, J = 6.0, 2H), 3.13 (dAB, J =
and refluxed for 1.5 h. The reaction mixture was allowed to 14.5, 2H), 2.90 (s, 2H). *broadened by 19F splitting. 13C NMR
cool down to RT, quenched with 0.1 mL water followed by 1 (101 MHz, Methanol-d4): δ 175.0, 163.2 (dd, J = 245.7, 8.1),
mL 6M aqueous HCl. The reaction mixture was refluxed for 10 131.4 (t, J = 10.7), 113.0-112.6 (m), 112.3 (t, J = 20.2), 51.5,
min until the boron-compound-complex had dissociated 42.2, 40.8, 39.1, 28.3. HRMS (ESI) m/z: [M+H]+ Calculated for
(followed by MS). The reaction mixture evaporated to dryness, C19H22F4N3O 384.1699; Found: 384.1694
redissolved in MeOH and purified by C18 RP flash 1-(2-Aminoethylamino)-2-(aminomethyl)-3-(3,5-
chromatography (acetonitrile/water).
difluorophenyl)-2-[(3,5-difluorophenyl)methyl]-1-propanone
(1e). 4e was reduced according to method A. 4e (0.54 mmol,
1-(2-Aminoethylamino)-2-(aminomethyl)-3-(2-bromophenyl)- 0.20 g), Boc2O (2.30 mmol, 0.50 g) and 1 spoon of Raney Nickel
2-[(2-bromophenyl)methyl]-1-propanone (1a). 4a was in MeOH gave the di-Boc-protected intermediate. The
reduced according to method C. 4a (1.01 mmol, 0.51 g) and intermediate was added 4 mL dioxane, 0.5 mL H2O and 2 mL
the reducing agent (7.0 mL) gave the title compound as clear 4M HCl/dioxane to yield the crude, which was purified by C18
1
crystals after purification (0.45 g, 75%). H NMR (400 MHz, RP flash chromatography to yield the title compound as clear
1
Methanol-d4) δ 7.63 (d, J = 8.0, 2H), 7.37 – 7.36 (m, 4H), 7.23 – crystals (0.074 g, 36%). H NMR (400 MHz, Methanol-d4): δ
7.19 (m, 2H), 3.61 (t, J = 6.2, 2H), 3.49 (dAB, J = 14.7, 2H), 3.44 6.97-6.87 (m, 6H), 3.55 (t, J = 6.2, 2H), 3.39 (dAB, J = 14.1, 2H),
(dAB, J = 14.8, 2H), 3.19 (t, J = 6.3, 4H), 3.13 (s, 2H). 13C NMR 3.15 (t, J = 6.2, 2H), 3.05 (dAB, J = 14.1, 2H), 3.06 (s, 2H). 13C
(101 MHz, Methanol-d4) 176.3, 136.2, 134.5, 133.4, 130.4, NMR (101 MHz, Methanol-d4): δ 175.7, 164.4 (dd, J = 247.7,
128.9, 127.1, 51.6, 43.4, 40.6, 40.5, 39.0. HRMS (ESI) m/z: 13.1), 140.8 (t, J = 9.2), 117.9 – 112.1 (m), 103.8 (t, J = 25.7),
[M+H]+ Calculated for C19H2479Br2N3O 468.0280; Found: 50.7, 43.0, 40.6, 40.5, 38.5. HRMS (ESI) m/z: [M+H]+ Calculated
468.0288
for C19H22F4N3O 384.1699; Found: 384.1698
1-(2-Aminoethylamino)-2-(aminomethyl)-3-[2-
(trifluoromethyl)phenyl]-2-{[2-
1-(2-Aminoethylamino)-2-(aminomethyl)-3-(3,5-
dibromophenyl)-2-[(3,5-dibromophenyl)methyl]-1-
propanone (1b). 4b was reduced according to method C. 4b (trifluoromethyl)phenyl]methyl}-1-propanone (1f). 4f was
(1.01 mmol, 0.66 g) and the reducing agent (7.1 mL) gave the reduced according to method A and B.
title compound as clear crystals after purification (0.54 g, 80 Method A: 4f (0.24 mmol, 0.11 g), Boc2O (0.95 mmol, 0.20 g)
1
%). H NMR (400 MHz, Methanol-d4): δ 7.68 (s, 2H), 7.48 (s, and 1 spoon of Raney Nickel in MeOH gave the di-Boc-
4H), 3.54 (t, J = 6.3, 2H), 3.27 (dAB, J = 14.1, 2H), 3.15 (t, J = 6.4, protected intermediate. The intermediate was added 4 mL
2H) 3.04 (s, 2H), 3.01 (dAB, J = 14.3, 2H). 13C NMR (101 MHz, dioxane, 0.5 mL H2O and 2 mL 4M HCl/dioxane to yield the
Methanol-d4): δ 175.4, 140.9, 134.1, 133.5, 124.0, 50.6, 43.3,
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crude, which was purified by C18 RP flash chromatography to Method A: 4i (0.606 mmol, 0.254 g), Boc2O (2.42 mmol, 0.53 g)
View Article Online
DOI: 10.1039/C6OB01219A
and 1 spoon of Raney nickel in MeOH gave the di-Boc-
yield the title compound as clear crystals (0.053 g, 50%).
Method B: 4f (0.50 mmol, 0.22 g), Boc2O (6 eq.), ammonium protected intermediate. The intermediate was added 4 mL
formate (4 eq.) and 1 spoon of Raney Nickel in EtOAc gave the dioxane, 0.5 mL H2O and 2 mL 4M HCl/dioxane to yield the
di-Boc-protected intermediate. The intermediate was added 4 crude, which was purified by C18 RP flash chromatography to
mL dioxane, 0.5 mL H2O and 2 mL 4M HCl/dioxane to yield the yield the title compound as clear crystals (0.092 g, 35%).
crude, which was purified by C18 RP flash chromatography to Method B: 4i (1.27 mmol, 0.53 g), Boc2O (2 eq.), ammonium
yield the title compound (0.066 g, 30 %).
formate (4 eq.) and 1 spoon of Raney Nickel in EtOAc (24h)
1H NMR (400 MHz, Methanol-d4): δ 7.77 (dd, J = 7.9, 1.4, 2H), gave the di-Boc-protected intermediate. The intermediate was
7.64 (td, J = 7.7, 1.4, 2H), 7.51 (t, J = 7.6, 2H), 7.40 (d, J = 7.8, added 4 mL dioxane, 0.5 mL H2O and 2 mL 4M HCl/dioxane to
2H), 3.54 (t, J = 6.9, 2H), 3.44 (dAB, J = 15.7, 2H), 3.37 (dAB, J = yield the crude, which was purified by C18 RP flash
16.0, 2H), 3.03 (s, 2H). 13C NMR (101 MHz, Methanol-d4): δ chromatography to yield the title compound (0.14 g, 27%).
177.3, 134.8, 133.4, 132.7, 130.8 (q, J = 29.4), 129.1, 128.1 (q, J 1H NMR (400 MHz, Methanol-d4): δ 7.39 (d, J = 8.3, 4H), 7.17
= 5.7), 125.8 (q, J = 274.7), 45.2, 39.9, 38.7, 37.7. HRMS (ESI) (d, J = 8.3, 4H), 3.51 (t, J = 6.4, 2H), 3.22 (A dAB, J = 14.2, 2H),
m/z: [M+H]+ Calculated for C21H24F6N3O 448.1824; Found: 3.11 (t, J = 6.4, 2H), 3.00 (s, 2H), 2.94 (dAB, J = 14.2, 2H), 1.31 (s,
448.1804
18H).13C NMR (101 MHz, Methanol-d4): δ 177.3, 151.6, 133.4,
131.2, 126.6, 50.5, 43.6, 40.7, 40.6, 38.6, 35.3, 31.7. HRMS
(ESI) m/z: [M+H]+ Calculated for C27H42N3O 424.3327; Found:
1-(2-Aminoethylamino)-2-(aminomethyl)-3-[4-
(trifluoromethyl)phenyl]-2-{[4-
(trifluoromethyl)phenyl]methyl}-1-propanone (1g). 4g was 424.3320.
reduced according to method A. 4g (0.18 mmol, 0.08 g), Boc2O 1-(2-Aminoethylamino)-2-(aminomethyl)-3-(2-naphthyl)-2-
(0.72 mmol, 0.15 g) and 1 spoon of Raney Nickel in MeOH gave [(2-naphthyl)methyl]-1-propanone (1j). 4j was reduced
the di-Boc-protected intermediate. The intermediate was according to method B: 4j (2.60 mmol, 1.06 g), Boc2O (4 eq.),
added 2 mL dioxane, 0.2 mL H2O and 1 mL 4M HCl/dioxane to ammonium formate (4 eq) and 1 spoon of Raney Nickel in
yield the crude, which was purified by C18 reversed phase EtOAc gave the di-Boc-protected intermediate. The di-Boc-
flash chromatography to yield the title compound as clear protected intermediate was purified by silica flash
1
crystals (0.042 g, 53%). H NMR (400 MHz, Methanol-d4): δ chromatography. The resulting compound was added 4 mL
7.65 (d, J = 7.7, 4H), 7.49 (d, J = 7.8, 4H), 3.54 (t, J = 6.0, 2H), dioxane, 0.5 mL H2O and 2 mL 4M HCl/dioxane to yield the
1
3.45 (dAB, J = 14.0, 2H), 3.18-3.13 (m, 2H), 3.10 (dAB, J = 14.0, crude (0.86 g, 80%). H NMR (400 MHz, Methanol-d4): δ 7.88-
2H), 3.01 (s, 2H). 13C NMR (101 MHz, Methanol-d4): δ 176.0, 7.7.84 (m, 6H), 7.75 (s, 2H), 7.55-7.45 (m, 4H), 7.38 (d, J = 8.4,
142.5 – 139.5 (m), 132.3, 130.7 (q, J = 32.4), 126.5 (q, J = 3.7), 2H), 3.35 (t, J = 6.6, 2H), 3.42 (dAB, J = 14.0, 2H), 3.21 (dAB, J =
125.6 (q, J = 272.2), 50.7, 43.1, 40.7, 38.7. HRMS (ESI) m/z: 14.2, 2H), 3.11-3.08 (m, 4H). 13C NMR (101 MHz, Methanol-d4):
[M+H]+ Calculated for C21H24F6N3O 448.1824; Found: 448.1824
1-(2-Aminoethylamino)-2-(aminomethyl)-3-[3,5-
δ 177.1, 134.8, 134.1, 133.9, 130.4, 129.3, 129.3, 128.7, 128.7,
127.5, 127.2, 50.9, 43.9, 41.4, 40.6, 38.7. HRMS (ESI) m/z:
[M+H]+ Calculated for C27H30N3O 412.2388; Found: 412.2382.
bis(trifluoromethyl)phenyl]-2-{[3,5-
bis(trifluoromethyl)phenyl]methyl}-1-propanone (1h). 4h was
reduced according to method A and B.
Acknowledgements
This work was financially supported by NRC grant (no:
214493/F20 – “fellesløftet”) and a UiT – The Arctic University
of Norway grant (no: A23259).
Method A: 4h (0.52 mmol, 0.30 g), Boc2O (2.74 mmol, 0.60 g)
and 1 spoon of Raney Nickel in MeOH gave the di-Boc-
protected intermediate. The intermediate was added 4 mL
dioxane, 0.5 mL H2O and 2 mL 4M HCl/dioxane to yield the
crude, which was purified by C18 RP flash chromatography to
yield the title compound as clear crystals (0.067 g, 23%).
Method B: 4h (0.59 mmol, 0.35 g), Boc2O (6 eq.), ammonium
formate (4 eq.) and 1 spoon of Raney Nickel in EtOAc gave the
di-Boc-protected intermediate. The intermediate was added 4
mL dioxane, 0.5 mL H2O and 2 mL 4M HCl/dioxane to yield the
crude (0.34 g, 97 %).
Notes and references
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