CC BY ND NC 4.0 · SynOpen 2017; 01(01): 0084-0090
DOI: 10.1055/s-0036-1588544
paper
Copyright with the author

An Approach to 1,1-Disubstituted Pyrazolylcyclopropane Building Blocks

Pavel S. Nosika, b, Oleksiy S. Artamonova, Sergey V. Ryabukhin*b, Oleksandr O. Grygorenkob
  • aInstitute of Organic Chemistry, National Academy of Sciences of Ukraine, Murmanska Street 5, Kyiv 02660, Ukraine   Email: s.v.ryabukhin@gmail.com
  • bTaras Shevchenko National University of Kyiv, Volodymyrska Street 64, Kyiv 01601, Ukraine
The work was supported by Ukrainian Government Funding (state registry No. 0114U003956) and Life Chemicals Group.
Further Information

Publication History

Received: 03 July 2017

Accepted after revision: 31 July 2017

Publication Date:
14 August 2017 (online)

 

Abstract

An approach to isomeric 1,1-disubstituted pyrazolylcyclopropanes that relies on lithium diisopropylamide (LDA) mediated bis-alkylation­ of the corresponding pyrazolylacetonitriles is developed. The building blocks obtained can be considered as lead-like bioisosteres of arylpyrazole and pyrazolecarboxamide moieties and are thus useful for early drug discovery projects.


#

1,1-Disubstituted (het)arylcyclopropanes are important chemotypes for the discovery of biologically active compounds. Arylcyclopropane derivatives are found among marketed drugs and drug candidates, including Lumacaftor 1, a drug for the treatment of cystic fibrosis approved by the FDA in 2015,[1] CHF5074 or CSP-1103 (2), which has recently completed phase II clinical trials for Alzheimer’s disease treatment,[2] and MK-2894 (3), a potent and selective prostaglandin E2 subtype 4 receptor antagonist with potent anti-inflammatory activity that is currently in preclinical studies[3] (Figure [1]). The corresponding hetarylcyclopropanes have also demonstrated significant potential in medicinal chemistry, with derivatives showing nanomolar-range activity as GPR142 agonists 4 (EC50 = 54 nM),[4] cannabinoid-1 (CB1) antagonists 5 (IC50 = 0.7 nM),[5] poly(ADP-ribose) polymerase (PARP) inhibitors 6 (IC50 = 25 nM),[6] and cathepsin S (Cat S) inhibitors 7 (IC50 = 0.5 nM).[7]

Zoom Image
Figure 1 Biologically active 1,1-disubstituted (het)arylcyclopropanes
Zoom Image
Figure 2 Bioisosteric replacements with 1,1-disubstituted cyclo­propanes

The 1,1-disubstituted cyclopropane motif has been considered as a bioisosteric replacement of the double bond, amide carbonyl group, and ortho-disubstituted phenylene ring or its hetero-analogues (Figure [2]).[8] The latter idea was implemented into the design of highly potent inhibitors of Factor Xa (FXa).[9]

A general approach to the synthesis of 1,1-disubstituted (het)arylcyclopropanes relies on alkylation of (het)arylacetonitriles 8 with 1,2-dibromoethane or related bis-electrophiles in the presence of base (Scheme [1]). The resulting 1-(het)arylcyclopropanecarbonitriles 9 are versatile key intermediates for the preparation of other building blocks, for example, carboxylic acids and amines, as well as for the construction of heterocyclic rings. Most of the reports on the synthesis of compounds of general formula 9 are related to the substituted benzene derivatives. Several reports on the development of general procedures for the preparation of 1-arylcyclopropanecarbonitriles 9 (R = Ar) from the corresponding arylacetonitriles 8 (R = Ar) have appeared;[10] [11] however, their hetaryl-substituted counterparts are far less studied in analogous transformations. A number of isolated examples that have been reported involve pyrrole,[12] indole,[10,13] thiophene,[14] and pyridine[15] derivatives. In some cases, it has been reported that arylation of cyclopropylcarbonitrile 10 [16] or heterocyclizations involving 1-cyanocyclopropanecarboxylic acid or its derivatives 11 [17] were more convenient for the preparation of 1-hetarylcyclopropanecarbonitriles (9, R = HetAr).

Zoom Image
Scheme 1 Selected general approaches to the preparation of 1-(het)arylcyclopropanecarbonitriles 9

Recently, we[18] and others[19] have looked into the design and preparation of medicinal building blocks[20] that are compatible with the concept of lead-oriented synthesis.[21] As a part of this ongoing project, we became interested in the preparation of pyrazolyl-substituted building blocks 1214 (Figure [3]). Nitriles 9ac are obvious key precursors for the preparation of these compounds. Since the corresponding pyrazolylacetonitriles 8ac can be prepared from the known aldehydes 15ac,[22] we turned to their double alkylation as a possible method for the preparation of 9ac. It should be noted that, of the compounds 8ac, only 8b was described previously.[23] This was prepared by reaction of aldehyde 15b with TOSMIC in 65% yield. For the preparation of 8c, we used the same procedure, which gave the target product in 63% yield. In the case of 8a, the method did not work well, and the target compound was formed in less than 20% yield; therefore, an alternative three-step route was used.

Zoom Image
Figure 3 1,1-Disubstituted pyrazolylcyclopropane building blocks and precursors for their synthesis

To our knowledge, no examples of bis-alkylation of hetarylacetonitriles 8 having a basic nitrogen atom with 1,2-dibromoethane have been reported (the closest analogue contained an α-chloropyridine moiety,[15] which has low basicity). Typical conditions reported for alkylation of other substrates 8 with 1,2-dibromoethane are: (1) NaOH or KOH, phase-transfer catalyst, toluene or CH2Cl2–H2O, r.t. to reflux; (2) NaH, DMF or DMSO, r.t. to 60 °C; (3) t-BuOK, DMSO­, r.t. to 60 °C; (4) KHMDS, THF, –78 °C to r.t.

Surprisingly, these methods did not give satisfactory results for alkylation of the substrate 8b (Table [1], entries 1–6). Therefore, we turned to screening of other bases, and found that the use of LDA in THF led to the formation of the target product 9b in good yield (entry 8). Further experiments showed that the reaction could be performed without preliminary cooling to –78 °C. Hence, an operationally simple procedure was developed that allowed for the preparation of the target product in 69% yield (entry 9).

Table 1 Alkylation of the Substrates 8b with 1,2-Dibromoethane under Various Reaction Conditions

Entry

Conditions

Yield of 9b (%)a

1

NaOH, benzyl thiethylammonium chloride, r.t.

0

2

NaOH, tetrabutylammonium bromide, 50 °C

0

3

NaH, DMF, r.t.

0

4

t-BuOK, DMSO, 60 °C

0

5

KHMDS, THF, –78 °C

0

6

KHMDS, THF, 0 °C to r.t.

40

7

LDA, THF, –78 °C

31

8

LDA, THF, –78 °C to r.t.

70b

9

LDA, THF, 0 °C to r.t.

69b

a Unless noted otherwise, yield was based on LCMS or 1H NMR analysis.

b Isolated yield.

This simple and robust procedure for the transformation of 8 into 9 worked well with all three pyrazolylacetonitriles 8ac, with the corresponding cyclopropanes 9ac being obtained in up to 10 g amounts and 57–82% yields. The versatility of these synthetic intermediates was demonstrated by their transformation into our initial target building blocks 1214 (Scheme [2]). In particular, alkaline hydrolysis of 9ac gave carboxylic acids 12ac in 94–99% yields (isolated as hydrochlorides). A modified Curtius reaction of 12ac, followed by quenching of the intermediate isocyanate with tert-butanol, gave Boc derivatives 16ac (51–64% yields), which were transformed into amines 13ac (isolated as dihydrochlorides) in nearly quantitative yields. Alternatively, 9ac were reduced with borane–dimethylsulfoxide complex to give amines 14ac (78–98% yield).

Zoom Image
Scheme 2 Synthesis of pyrazolylcyclopropane building blocks 1214

In conclusion, a convenient approach to 1,1-disubstituted pyrazolylcyclopropane building blocks has been developed that is amendable for multigram-scale preparation. These products are promising building blocks for lead-oriented synthesis in medicinal chemistry, in particular as lead-like bioisosteric replacements of arylpyrazole or pyrazolecarboxamide moieties. They are low-molecular-weight (MW = 137–166), hydrophilic (cLog P = –0.16 to 1.06), have a limited number of polar atoms and rotatable bonds, and a reasonable fraction of sp3 carbon atoms (Fsp3 = 0.50–0.63) (Table [2]).[24] Moreover, the pyrazolylcyclopropane scaffold complies with the ‘biocore’ concept for the scaffold design proposed by Kombarov and co-workers.[25] The procedure described can also be useful for the preparation of other 1,1-disubstituted (het)arylcyclopropanes, especially those containing basic nitrogen atoms.

Table 2 Calculated Physicochemical Parameters of the Building Blocks 1214 Prepared in this Worka

Compound

MW

cLog P

HAcc

HDon

RotB

TPSA (Å2)

Fsp3

12a

166

1.06

3

1

2

55.1

0.50

12b

166

0.56

3

1

2

55.1

0.50

12c

166

0.47

3

1

2

55.1

0.50

13a

137

0.30

2

1

1

43.8

0.57

13b

137

–0.08

2

1

1

43.8

0.57

13c

137

–0.16

2

1

1

43.8

0.57

14a

151

0.48

2

1

2

43.8

0.63

14b

151

0.09

2

1

2

43.8

0.63

14c

151

0.01

2

1

2

43.8

0.63

a MW: molecular weight; cLog P: calculated partitioning coefficient logarithm; HAcc: hydrogen-bond acceptor count; HDon: hydrogen-bond donor count; RotB: number of rotatable bonds; TPSA: total polar surface area; Fsp3: fraction of sp3 carbon atoms.

The solvents were purified according to standard procedures.[26] Compounds 15a,[22a] 8b,[23] and 15c [22b] were prepared by using reported methods. All other starting materials were purchased from commercial sources. Analytical TLC was performed using Polychrom SI F254 plates. Column chromatography was performed using Kieselgel Merck 60 (230–400 mesh) as the stationary phase. 1H and 13C NMR spectra were recorded with a Varian Gemini 2000 spectrometer (at 400 MHz for 1H and 101 MHz for 13C NMR). Chemical shifts are reported in ppm downfield from TMS (1H, 13C) as an internal standard. Mass spectra were recorded with an Agilent 1100 LCMSD SL instrument (electrospray ionization (APESI)).


#

(1-Methyl-1H-pyrazol-3-yl)methanol (17)

To a solution of aldehyde 15a (58.3 g, 0.529 mol) in MeOH (750 mL), NaBH4 (40.0 g, 1.06 mol) was added portionwise at 0 °C. The resulting mixture was stirred overnight at r.t., then evaporated, diluted with 10% aq NaOH (500 mL), and extracted with EtOAc (3 × 250 mL). The combined organic layers were dried over Na2SO4, filtered, and evaporated in vacuo to give 17, which was pure enough for the next step. An analytically pure sample was obtained by vacuum distillation.

Yield: 49.5 g (84%); colorless oil; bp 70–72 °C/1 mbar.

1H NMR (CDCl3, 400 MHz): δ = 7.28 (d, J = 2.2 Hz, 1 H), 6.22 (d, J = 2.2 Hz, 1 H), 4.79 (br. s, 1 H), 4.64 (s, 2 H), 3.85 (s, 3 H).

13C NMR (CDCl3, 101 MHz): δ = 152.0, 130.6, 104.0, 57.9, 38.3.

MS (ESI): m/z = 113 [MH+].

Anal. Calcd for C5H8N2O: C, 53.56; H, 7.19; N, 24.98. Found: C, 53.47; H, 6.84; N, 24.75.


#

3-(Chloromethyl)-1-methyl-1H-pyrazole Hydrochloride (18)

To a solution of 17 (12.0 g, 0.107 mol) in anhydrous CH2Cl2 (150 mL), SOCl2 (19.1 g, 0.16 mol) was added dropwise at 0 °C. The reaction mixture was stirred overnight at r.t., then evaporated in vacuo, and the solid was triturated with anhydrous Et2O (200 mL), filtered, washed with anhydrous Et2O (100 mL), and dried under reduced pressure to give 18. An analytically pure sample was obtained by recrystallization from acetone.

Yield: 17.0 g (95%); white solid; mp 136–138 °C.

1H NMR (400 MHz, DMSO-d 6): δ = 9.86 (br. s, 1 H), 7.64 (d, J = 2.1 Hz, 1 H), 6.27 (d, J = 2.1 Hz, 1 H), 4.64 (s, 2 H), 3.79 (s, 3 H).

13C NMR (101 MHz, DMSO-d 6): δ = 147.4, 131.9, 105.2, 39.2, 38.4.

MS (ESI): m/z = 131/133 [MH+].

Anal. Calcd for C5H8Cl2N2: C, 35.95; H, 4.83; N, 16.77; Cl, 42.45. Found: C, 35.91; H, 4.72; N, 16.81; Cl, 42.70.


#

2-(1-Methyl-1H-pyrazol-3-yl)acetonitrile (8a)

Compound 18 (9.70 g, 58.1 mmol) was dissolved in DMSO (300 mL), KCN (15.1 g, 0.232 mol) was added, and the mixture was stirred at r.t. overnight, then diluted with H2O (600 mL), and extracted with EtOAc (3 × 250 mL). The combined extracts were washed with brine (250 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give 8a. An analytically pure sample was obtained by column chromatography (EtOAc–hexanes, 1:2).

Yield: 6.51 g (92%); reddish oil; Rf 0.62 (EtOAc–hexanes, 1:2).

1H NMR (400 MHz, CDCl3): δ = 7.30 (d, J = 2.2 Hz, 1 H), 6.20 (d, J = 2.2 Hz, 1 H), 3.82 (s, 3 H), 3.69 (s, 2 H).

13C NMR (101 MHz, CDCl3): δ = 140.8, 131.3, 116.9, 104.5, 38.6, 17.2.

MS (ESI): m/z = 122 [MH+].

Anal. Calcd for C6H7N3: C, 59.49; H 5.82; N, 34.69. Found: C, 59.49; H 5.82; N, 34.69.


#

2-(1-Methyl-1H-pyrazol-5-yl)acetonitrile (8c)

Potassium tert-butoxide (23.5 g, 95%, 0.199 mol) was suspended in anhydrous 1,2-dimethoxyethane (90 mL), and the mixture was cooled to –60 °C. TosMIC (23.8 g, 0.122 mol) was dissolved in anhydrous 1,2-dimethoxyethane (75 mL), and the resulting solution was added dropwise to the potassium tert-butoxide solution over 20 min. After stirring for 20 min at –60 to –55 °C, aldehyde 15c (9.00 g, 0.0816 mol) in anhydrous 1,2-dimethoxyethane (55 mL) was added over 23 min. The mixture was stirred at –55 to –50 °C for 1 h to yield a thick suspension. MeOH (90 mL) was then added, which gave a clear brown solution. The cooling bath was removed and, after stirring at r.t. for 5 min, the reaction flask was placed into an oil bath preheated to 85 °C. The reaction mixture was stirred for 1 h, then cooled and concentrated in vacuo. The residue was dissolved in H2O (180 mL) and AcOH (9 mL). The mixture was extracted with EtOAc (3 × 250 mL), and the combined extracts were washed with brine (100 mL), dried over Na2SO, filtered, and concentrated in vacuo to give a brown oil. The crude product was distilled under reduced pressure to give 8c.

Yield: 6.22 g (63%); reddish oil; bp 65–66 °C / 0.1 mbar.

1H NMR (400 MHz, CDCl3): δ = 7.37 (d, J = 1.9 Hz, 1 H), 6.22 (d, J = 1.9 Hz, 1 H), 3.80 (s, 3 H), 3.72 (s, 2 H).

13C NMR (101 MHz, CDCl3): δ = 138.2, 130.2, 114.8, 106.3, 36.3, 15.1.

MS (ESI): m/z = 122 [MH+].

Anal. Calcd for C6H7N3: C, 59.49; H 5.82; N, 34.69. Found: C, 59.61; H, 6.18; N, 34.77.


#

Preparation of Nitriles 9; General Procedure

To a solution of diisopropylamine (30.4 g, 0.300 mol) in THF (150 mL), n-BuLi (78.8 mL, 0.260 mol, 3.3 M in hexanes) was added at –30 °C, and the mixture was stirred at r.t. for 1 h. Nitrile 8ac (12.1 g, 0.100 mol) in THF (50 mL) was added at 0 °C, and the resulting mixture was stirred at r.t. for 1 h. 1,2-Dibromoethane (9.48 mL, 0.110 mol) was added at 0 °C, and the reaction mixture was stirred for an additional 1 h, then quenched with saturated aq NH4Cl (100 mL) and extracted with CH2Cl2 (2 × 100 mL). The combined organic extracts were dried over Na2SO4, filtered, and evaporated in vacuo. The crude product was purified by column chromatography (hexanes–EtOAc, 4:1).


#

1-(1-Methyl-1H-pyrazol-3-yl)cyclopropanecarbonitrile (9a)

Yield: 5.62 g (57%); reddish oil; Rf 0.70 (hexanes–EtOAc, 4:1).

1H NMR (400 MHz, CDCl3): δ = 7.26 (d, J = 2.2 Hz, 1 H), 6.24 (d, J = 2.2 Hz, 1 H), 3.81 (s, 3 H), 1.65–1.59 (m, 2 H), 1.52–1.47 (m, 2 H).

13C NMR (101 MHz, CDCl3): δ = 147.3, 130.8, 121.9, 103.3, 38.7, 17.8, 9.0.

MS (ESI): m/z = 148 [MH+], 121 [M+–CN].

Anal. Calcd for C8H9N3: C, 65.29; H, 6.16; N, 28.55. Found: C, 65.07; H, 5.79; N, 28.67.


#

1-(1-Methyl-1H-pyrazol-4-yl)cyclopropanecarbonitrile (9b)

Yield: 6.80 g (69%); yellowish oil; Rf 0.68 (hexanes–EtOAc, 4:1).

1H NMR (400 MHz, CDCl3): δ = 7.37 (s, 1 H), 7.31 (s, 1 H), 3.86 (s, 3 H), 1.64–1.59 (m, 2 H), 1.24–1.20 (m, 2 H).

13C NMR (101 MHz, CDCl3): δ = 136.6, 128.7, 122.6, 118.5, 39.3, 17.8, 5.6.

MS (ESI): m/z = 148 [MH+].

Anal. Calcd for C8H9N3: C, 65.29; H, 6.16; N, 28.55. Found: C, 65.31; H, 6.12; N, 28.45.


#

1-(1-Methyl-1H-pyrazol-5-yl)cyclopropanecarbonitrile (9c)

Yield: 8.09 g (82%); colorless oil; Rf 0.73 (hexanes–EtOAc, 4:1).

1H NMR (400 MHz, CDCl3): δ = 7.35 (d, J = 1.9 Hz, 1 H), 6.07 (d, J = 1.9 Hz, 1 H), 3.99 (s, 3 H), 1.70 (dd, J = 7.6, 4.9 Hz, 2 H), 1.34 (dd, J = 7.6, 4.9 Hz, 2 H).

13C NMR (101 MHz, CDCl3): δ = 137.8, 136.5, 119.9, 105.9, 36.8, 15.9, 5.0.

MS (ESI): m/z = 148 [MH+], 121 [M+–CN].

Anal. Calcd for C8H9N3: C, 65.29; H, 6.16; N, 28.55. Found: C, 65.48; H, 6.33; N, 28.39.


#

Preparation of Carboxylic Acids 12; General Procedure

A suspension of nitrile 9 (3.50 g, 0.0238 mol) in 10% aq NaOH (100 mL) was heated at reflux overnight (until NH3 evolution ceased). The homogeneous solution was washed with Et2O (50 mL), the aqueous layer was acidified with 6 M aq HCl to pH 3, and evaporated to dryness. The residue was triturated with i-PrOH (100 mL), the solid was filtered off, washed with i-PrOH (50 mL), and the combined filtrates were evaporated in vacuo. The residue was triturated with acetone (50 mL), filtered, and dried under reduced pressure to give 12. An analytically­ pure sample was obtained by recrystallization from acetone­–EtOH.


#

1-(1-Methyl-1H-pyrazol-3-yl)cyclopropanecarboxylic Acid (12a)

Yield: 4.62 g (96%); white solid; mp 182–183 °C.

1H NMR (400 MHz, DMSO-d 6): δ = 7.60 (d, J = 1.8 Hz, 1 H), 6.32 (d, J = 2.0 Hz, 1 H), 3.77 (s, 3 H), 1.41 (dd, J = 6.7, 3.4 Hz, 2 H), 1.24 (dd, J = 6.7, 3.5 Hz, 2 H), COOH is exchanged with HDO.

13C NMR (101 MHz, DMSO-d 6): δ = 174.2, 149.3, 131.3, 105.8, 38.2, 21.9, 17.1.

MS (ESI): m/z = 167 [MH+], 149 [M+–OH], 121 [M+–COOH].

Anal. Calcd for C8H10N2O2: C, 57.82; H, 6.07; N, 16.86. Found: C, 58.20; H, 5.81; N, 17.20.


#

1-(1-Methyl-1H-pyrazol-4-yl)cyclopropanecarboxylic Acid (12b)

Yield: 4.50 g (94%) ;white solid; mp 168–170 °C.

1H NMR (400 MHz, DMSO-d 6): δ = 7.72 (s, 1 H), 7.43 (s, 1 H), 3.79 (s, 3 H), 1.48–1.39 (m, 2 H), 1.10–1.05 (m, 2 H), COOH is exchanged with HDO.

13C NMR (101 MHz, DMSO-d 6): δ = 175.4, 138.1, 130.9, 121.0, 38.7, 19.4, 18.1.

MS (ESI): m/z = 167 [MH+], 121 [M+–COOH].

Anal. Calcd for C8H10N2O2: C, 57.82; H, 6.07; N, 16.86. Found: C, 57.83; H, 5.8; N, 16.95.


#

1-(1-Methyl-1H-pyrazol-5-yl)cyclopropanecarboxylic Acid (12c)

Yield: 4.81 g (99%); white solid; mp 177–179 °C.

1H NMR (400 MHz, DMSO-d 6): δ = 7.42 (s, 1 H), 6.20 (s, 1 H), 3.77 (s, 3 H), 1.53 (dd, J = 7.0, 3.9 Hz, 2 H), 1.23 (dd, J = 7.1, 3.9 Hz, 2 H), COOH is exchanged with HDO.

13C NMR (101 MHz, DMSO-d 6): δ = 173.1, 141.6, 136.4, 106.3, 36.3, 19.3, 16.2.

MS (ESI): m/z = 167 [MH+], 121 [M+–COOH].

Anal. Calcd for C8H10N2O2: C, 57.82; H, 6.07; N, 16.86. Found: C, 58.08; H, 6.18; N, 16.53.


#

Preparation of 16; General Procedure

To a solution of carboxylic acid 12 (1.60 g, 9.58 mmol) in toluene (20 mL), NEt3 (2.96 mL, 0.0213 mol) was added, followed by DPPA (3.25 g, 0.0118 mol) in toluene (5 mL) dropwise at 40 °C. The resulting mixture was heated at reflux for 3 h. tert-Butanol (5.90 g, 0.0797 mol) was added, and the resulting mixture was heated at reflux overnight. The solvent was evaporated and the residue was dissolved in EtOAc (50 mL), washed with H2O (20 mL), 15% aq citric acid (20 mL), and saturated aq NaHCO3 (20 mL). The organic layer was dried over Na2SO4, filtered, and evaporated in vacuo. The crude product was purified by column chromatography (EtOAc–hexanes, 1:1).


#

tert-Butyl 1-(1-Methyl-1H-pyrazol-3-yl)cyclopropylcarbamate (16a)

Yield: 0.953 g (51%); yellowish oil; Rf 0.43 (EtOAc–hexanes, 1:1).

1H NMR (400 MHz, CDCl3): δ = 7.21 (d, J = 2.2 Hz, 1 H), 6.10 (br. s, 1 H), 5.34 (br. s, 1 H), 3.80 (s, 3 H), 1.45 (s, 9 H), 1.33–1.26 (m, 2 H), 1.21–1.14 (m, 2 H).

13C NMR (101 MHz, CDCl3): δ (two rotamers) = 155.4 and 154.6, 130.3, 129.3 and 124.7, 102.4, 79.0, 38.4, 30.9 and 29.4, 28.1, 17.2.

MS (ESI): m/z = 260 [MNa+], 238 [MH+], 182 [MH+–C4H9], 138 [MH+–CO2–C4H8].

Anal. Calcd for C12H19N3O2: C, 60.74; H, 8.07; N, 17.71. Found: C, 60.82; H, 7.81; N, 17.55.


#

tert-Butyl 1-(1-Methyl-1H-pyrazol-4-yl)cyclopropylcarbamate (16b)

Yield: 1.10 g (59%); white solid; mp 112–114 °C; Rf 0.38 (EtOAc–hexanes­, 1:1).

1H NMR (400 MHz, CDCl3): δ = 7.28 (s, 1 H), 7.27 (s, 1 H), 5.23 (s, 1 H), 3.83 (s, 3 H), 1.44 (s, 9 H), 1.17–1.11 (m, 2 H), 1.04–0.97 (m, 2 H).

13C NMR (101 MHz, CDCl3): δ (two rotamers) = 156.6 and 155.6, 136.8, 128.7 and 127.9, 125.8 and 124.1, 79.4, 38.8, 28.3, 16.9, 16.3.

MS (ESI): m/z = 238 [MH+], 182 [MH+–C4H9].

Anal. Calcd for C12H19N3O2: C, 60.74; H, 8.07; N, 17.71. Found: C, 60.73; H, 8.47; N, 17.48.


#

tert-Butyl 1-(1-Methyl-1H-pyrazol-5-yl)cyclopropylcarbamate (16c)

Yield: 1.17 g (64%); white solid; mp 97–99 °C; Rf 0.40 (EtOAc–hexanes­, 1:1).

1H NMR (400 MHz, CDCl3): δ = 7.33 (d, J = 0.9 Hz, 1 H), 6.18 (br. s, 1 H), 5.24 (br s, 1 H), 4.00 (s, 3 H), 1.39 (s, 9 H), 1.31–1.21 (m, 2 H), 1.20–1.05 (m, 2 H).

13C NMR (101 MHz, CDCl3): δ = 154.4, 143.0, 137.4, 106.0, 79.4, 36.9, 28.0, 26.9, 15.0.

MS (ESI): m/z = 238 [MH+], 182 [MH+–C4H9], 138 [MH+–CO2–C4H8], 121 [M+ – NHBoc].

Anal. Calcd for C12H19N3O2: C, 60.74; H, 8.07; N, 17.71. Found: C, 61.14; H, 7.89; N, 17.91.


#

Preparation of 13·2HCl; General Procedure

To a solution of 16 (0.500 g, 2.11 mmol) in Et2O (10 mL), saturated HCl in Et2O (20 mL) was added, and the reaction mixture was stirred at r.t. overnight. The precipitate was filtered, washed with Et2O (10 mL), and dried under reduced pressure. An analytically pure sample was obtained by recrystallization from acetone.


#

1-(1-Methyl-1H-pyrazol-3-yl)cyclopropanamine Dihydrochloride (13a·2HCl)

Yield: 0.424 g (95%); white solid; mp 184–186 °C.

1H NMR (400 MHz, DMSO-d 6): δ = 8.99 (br. s, 3 H), 7.68 (d, J = 2.1 Hz, 1 H), 6.25 (d, J = 2.1 Hz, 1 H), 3.80 (s, 3 H), 1.49–1.34 (m, 2 H), 1.15–1.07 (m, 2 H), 1 H is exchanged with HDO.

13C NMR (101 MHz, DMSO-d 6): δ = 149.3, 132.2, 101.8, 38.4, 31.6, 12.8.

MS (ESI): m/z = 138 [MH+], 121 [MH+–NH3].

Anal. Calcd for C7H13Cl2N3: C, 40.02; H, 6.24; N, 20.00; Cl, 33.75. Found: C, 40.27; H, 6.36; N, 19.92; Cl, 33.70.


#

1-(1-Methyl-1H-pyrazol-4-yl)cyclopropanamine Dihydrochloride (13b·2HCl)

Yield: 0.440 g (100%); white solid; mp 170–172 °C.

1H NMR (400 MHz, DMSO-d 6): δ = 10.30 (br. s, 1 H), 9.00 (br. s, 3 H), 7.82 (s, 1 H), 7.56 (s, 1 H), 3.78 (s, 3 H), 1.32 (dd, J = 6.7, 5.4 Hz, 2 H), 0.96 (dd, J = 6.7, 5.4 Hz, 2 H).

13C NMR (101 MHz, DMSO-d 6): δ = 137.0, 130.0, 119.8, 38.6, 28.8, 12.2.

MS (ESI): m/z = 138 [MH+].

Anal. Calcd for C7H13Cl2N3: C, 40.02; H, 6.24; N, 20.00; Cl, 33.75. Found: C, 39.94; H, 6.16; N, 20.23; Cl, 33.84.


#

1-(1-Methyl-1H-pyrazol-5-yl)cyclopropanamine Dihydrochloride (13c·2HCl)

Yield: 0.446 g (100%); white solid; mp 161–163 °C.

1H NMR (400 MHz, DMSO-d 6): δ = 9.10 (s, 3 H), 7.39 (d, J = 1.9 Hz, 1 H), 6.38 (d, J = 1.9 Hz, 1 H), 3.97 (s, 3 H), 1.50 (dd, J = 7.0, 5.7 Hz, 2 H), 1.15 (dd, J = 7.0, 5.7 Hz, 2 H), 1 H is exchanged with HDO.

13C NMR (101 MHz, DMSO-d 6): δ = 138.5, 137.3, 108.4, 37.4, 26.8, 11.1.

MS (ESI): m/z = 138 [MH+], 121 [MH+–NH3].

Anal. Calcd for C7H13Cl2N3: C, 40.02; H, 6.24; N, 20.00; Cl, 33.75. Found: C, 39.85; H, 6.63; N, 20.31; Cl, 33.97.


#

Preparation of Amines 14; General Procedure

To the solution of nitrile 9 (0.500 g, 3.40 mmol) in anhydrous THF (20 mL), BH3·Me2S (1.70 mL, 1.36 g, 0.0179 mol) was added. This mixture was stirred under reflux overnight, and then cooled to r.t. MeOH (20 mL) was added and the solution was stirred at r.t. for 0.5 h. The solvent was evaporated, and the residue was dissolved in saturated methanolic HCl (20 mL). The mixture was heated at reflux for 1 h to destroy the intermediate complex. After cooling, the solvent was evaporated, 10% aq NaOH was added to the residue to pH 8, and the mixture was extracted with CH2Cl2 (3 × 20 mL). The combined organic phases were dried over Na2SO4, filtered, and evaporated in vacuo to give 14. An analytical sample was obtained by column chromatography (CHCl3–MeOH–NEt3, 24:1:0.2).


#

(1-(1-Methyl-1H-pyrazol-3-yl)cyclopropyl)methanamine (14a)

Yield: 0.453 g (88%); yellowish oil; Rf 0.35 (CHCl3–MeOH–NEt3, 24:1:0.2).

1H NMR (400 MHz, CDCl3): δ = 7.19 (d, J = 2.1 Hz, 1 H), 5.89 (d, J = 2.1 Hz, 1 H), 3.78 (s, 3 H), 2.82 (s, 2 H), 2.51 (br. s, 2 H), 0.89–0.82 (m, 2 H), 0.75–0.71 (m, 2 H).

13C NMR (CDCl3, 101 MHz): δ = 154.7, 130.2, 102.0, 49.2, 38.4, 22.3, 13.2.

MS (ESI): m/z = 152 [MH+], 135 [MH+–NH3].

Anal. Calcd for C8H13N3: C, 63.55; H, 8.67; N, 27.79. Found: C, 63.87; H, 8.42; N, 27.66.


#

(1-(1-Methyl-1H-pyrazol-3-yl)cyclopropyl)methanamine (14b)

Yield: 0.407 g (78 %); colorless oil.

1H NMR (400 MHz, CDCl3): δ = 7.36 (d, J = 0.7 Hz, 1 H), 7.28 (s, 1 H), 3.85 (s, 3 H), 2.77 (s, 2 H), 2.67 (br. s, 2 H), 0.75 (s, 4 H).

13C NMR (101 MHz, CDCl3): δ = 138.7, 130.2, 121.9, 49.2, 39.1, 15.6, 13.5.

MS (ESI): m/z = 152 [MH+], 135 [MH+–NH3].

Anal. Calcd for C8H13N3: C, 63.55; H, 8.67; N, 27.79. Found: C, 63.47; H, 9.04; N, 27.43.


#

(1-(1-Methyl-1H-pyrazol-3-yl)cyclopropyl)methanamine (14c)

Yield: 0.502 g (98%); colorless oil.

1H NMR (400 MHz, CDCl3): δ = 7.36 (d, J = 1.9 Hz, 1 H), 6.08 (d, J = 1.8 Hz, 1 H), 3.90 (s, 3 H), 2.68 (s, 2 H), 1.67 (br. s, 2 H), 0.85–0.82 (m, 4 H).

13C NMR (101 MHz, CDCl3): δ = 143.1, 137.6, 107.0, 49.3, 36.5, 20.3, 11.0.

MS (ESI): m/z = 152 [MH+], 135 [MH+–NH3].

Anal. Calcd for C8H13N3: C, 63.55; H, 8.67; N, 27.79. Found: C, 63.86; H, 8.36; N, 27.84.


#
#

Supporting Information

  • References

  • 1 U. S. Food and Drug Administration. Official Website, 2015. www.fda.gov (accessed 08 Dec 2015).
  • 2 Peretto I. Radaelli S. Parini C. Zandi M. Raveglia LF. Dondio G. Fontanella L. Misiano P. Bigogno C. Rizzi A. Riccardi B. Biscaioli M. Marchetti S. Puccini P. Catinella S. Rondelli I. Cenacchi V. Bolzoni PT. Caruso P. Villetti G. Facchinetti F. Del GiudiceE. Moretto N. Imbimbo BP. J. Med. Chem. 2005; 48: 5705
  • 3 Blouin M. Han Y. Burch J. Farand J. Mellon C. Gaudreault M. Wrona M. Lévesque JF. Denis D. Mathieu MC. Stocco R. Vigneault E. Therien A. Clark P. Rowland S. Xu D. O’Neill G. Ducharme Y. Friesen R. J. Med. Chem. 2010; 53: 2227
  • 4 Du X. Kim YJ. Lai S. Chen X. Lizarzaburu M. Turcotte S. Fu Z. Liu Q. Zhang Y. Motani A. Oda K. Okuyama R. Nara F. Murakoshi M. Fu A. Reagan JD. Fan P. Xiong Y. Shen W. Li L. Houze J. Medina JC. Bioorg. Med. Chem. Lett. 2012; 22: 6218
  • 5 Sasmal PK. Talwar R. Swetha J. Balasubrahmanyam D. Venkatesham B. Rawoof KA. Neelima DeviB. Jadhav VP. Khan SK. Mohan P. Srinivasa ReddyD. Nyavanandi VK. Nanduri S. Shiva KumarK. Kannan M. Srinivas P. Nadipalli P. Chaudhury H. Sebastian VJ. Bioorg. Med. Chem. Lett. 2011; 21: 4913
  • 6 Zeng H. Zhang H. Jang F. Zhao L. Zhang J. Chem. Biol. Drug Des. 2011; 78: 333
  • 7 Moss N. Xiong Z. Burke M. Cogan D. Gao DA. Haverty K. Heim-Riether A. Hickey ER. Nagaraja R. Netherton M. O’Shea K. Ramsden P. Schwartz R. Shih DT. Ward Y. Young E. Zhang Q. Bioorg. Med. Chem. Lett. 2012; 22: 7189
  • 8 Meanwell NA. J. Med. Chem. 2011; 54: 2529
  • 9 Qiao JX. Cheney DL. Alexander RS. Smallwood AM. King SR. He K. Rendina AR. Luettgen JM. Knabb RM. Wexler RR. Lam PY. Bioorg. Med. Chem. Lett. 2008; 18, 4118
    • 10a Papahatjis DP. Nikas S. Tsotinis A. Vlachou M. Makriyannis A. Chem. Lett. 2001; 3: 192
    • 10b Barbasiewicz M. Marciniak K. Fedoryński M. Tetrahedron Lett. 2006; 47: 3871
    • 11a Langer P. Freiberg W. Chem. Rev. 2004; 104: 4125
    • 11b Arava VR. Siripalli UB. R. Dubey PK. Tetrahedron Lett. 2005; 46: 7247
    • 11c Fedoryński M. Jonczyk A. Org. Prep. Proced. Int. 1995; 27: 355
    • 11d Petrosyan VA. Vasil’ev AA. Tatarinova VI. Russ. Chem. Bull. 1994; 43: 84
  • 12 Bryson TA. Roth GA. Jing-hau L. Tetrahedron Lett. 1986; 27: 3685
    • 13a Horwell DC. McKiernan MJ. Osborne S. Tetrahedron Lett. 1998; 39: 8729
    • 13b Tsotinis A. Vlachou M. Papahatjis DP. Calogeropoulou T. Nikas SP. Garratt PJ. Piccio V. Vonhoff S. Davidson K. Teh MT. Sugden D. J. Med. Chem. 2006; 49: 3509
  • 14 Huang H. Ji X. Wu W. Jiang H. Chem. Commun. 2013; 3351
  • 15 Isabel E. Bateman KP. Chauret N. Cromlish W. Desmarais S. Duong LT. Falgueyret JP. Gauthier JY. Lamontagne S. Lau CK. Léger S. LeRiche T. Lévesque J.-F. Li CS. Massé F. McKay DJ. Mellon C. Nicoll-Griffith DA. Oballa RM. Percival MD. Riendeau D. Robichaud J. Rodan GA. Rodan SB. Seto C. Thérien M. Truong VL. Wesolowski G. Young RN. Zamboni R. Black WC. Bioorg. Med. Chem. Lett. 2010; 20: 887
    • 16a Klapars A. Waldman JH. Campos KR. Jensen MS. McLaughlin M. Chung JY. Cvetovich RJ. Chen CY. J. Org. Chem. 2005; 70: 10186
    • 16b McCabe Dunn JM. Kuethe JT. Orr RK. Tudge M. Campeau L.-C. Org. Lett. 2014; 16: 6314
    • 16c Thompson AD. Huestis MP. J. Org. Chem. 2013; 78: 762
    • 17a Salikov RF. Platonov DN. Frumkin AE. Lipilin DL. Tomilov YV. Tetrahedron 2013; 69: 3495
    • 17b Furet P. Guagnano V. Fairhurst RA. Imbach-Weese P. Bruce I. Knapp M. Fritsch C. Blasco F. Blanz J. Aichholz R. Hamon J. Fabbro D. Caravatti G. Bioorg. Med. Chem. Lett. 2013; 23: 3741
    • 18a Ryabukhin SV. Panov DM. Granat DS. Ostapchuk EN. Kryvoruchko DV. Grygorenko OO. ACS Comb. Sci. 2014; 16: 146
    • 18b Ivonin SP. Kurpil’ BB. Volochnyuk DM. Grygorenko OO. Tetrahedron Lett. 2015; 56: 6248
    • 18c Borisov AV. Voloshchuk VV. Nechayev MA. Grygorenko OO. Synthesis 2013; 45: 2413
    • 18d Ivonin SP. Kurpil’ BB. Bezdudny AV. Volochnyuk DM. Grygorenko OO. J. Fluorine Chem. 2015; 176: 78
    • 18e Zhersh S. Karpenko OV. Ripenko V. Tolmachev AA. Grygorenko OO. Cent. Eur. J. Chem. 2014; 12: 67
    • 18f Artamonov OS. Bulda T. Fam TK. Slobodyanyuk EY. Volochnyuk DM. Grygorenko OO. Heterocycl. Commun. 2015; 21: 391
    • 19a McLellan P. Nelson A. Chem. Commun. 2013; 2383
    • 19b Doveston R. Marsden S. Nelson A. Drug Discovery Today 2014; 19: 813
    • 19c James T. MacLellan P. Burslem GM. Simpson I. Grant JA. Warriner S. Org. Biomol. Chem. 2014; 12: 2584
    • 19d Foley DJ. Doveston RG. Churcher I. Nelson A. Marsden SP. Chem. Commun. 2015; 11174
    • 19e Doveston RG. Tosatti P. Dow M. Foley DJ. Li HY. Campbell AJ. House D. Churcher I. Marsden SP. Nelson A. Org. Biomol. Chem. 2015; 13: 859
  • 20 Goldberg FW. Kettle JG. Kogej T. Perry MW. D. Tomkinson NP. Drug Discovery Today 2015; 20: 11
  • 21 Nadin A. Hattotuwagama C. Churcher I. Angew. Chem. Int. Ed. 2012; 51: 1114
    • 22a Nosik PS. Ryabukhin SV. Artamonov OS. Grygorenko OO. Monatsh. Chem. 2016; 147: 1629
    • 22b Azami H. Barrett D. Tanaka A. Sasaki H. Matsuda K. Sakurai M. Terasawa T. Shirai F. Chiba T. Matsumoto Y. Tawara S. Bioorg. Med. Chem. 2001; 9: 961
  • 23 Labroli M. Paruch K. Dwyer MP. Alvarez C. Keertikar K. Poker C. Rossman R. Duca JS. Fischmann TO. Madison V. Parry D. Davis N. Seghezzi W. Wiswell D. Guzi TJ. Bioorg. Med. Chem. Lett. 2011; 21: 471
  • 24 Instant JChem was used for prediction of the physicochemical properties of the compounds, Instant JChem version 17.2.13.0, 2017, ChemAxon ( http://www.chemaxon.com).
  • 25 Kombarov R. Altieri A. Genis D. Kirpichenok M. Kochubey V. Rakitina N. Titarenko Z. Mol. Diversity 2010; 14, 193
  • 26 Armarego WL. F. Chai CL. L. Purification of Laboratory Chemicals . Elsevier; Oxford; 2003

  • References

  • 1 U. S. Food and Drug Administration. Official Website, 2015. www.fda.gov (accessed 08 Dec 2015).
  • 2 Peretto I. Radaelli S. Parini C. Zandi M. Raveglia LF. Dondio G. Fontanella L. Misiano P. Bigogno C. Rizzi A. Riccardi B. Biscaioli M. Marchetti S. Puccini P. Catinella S. Rondelli I. Cenacchi V. Bolzoni PT. Caruso P. Villetti G. Facchinetti F. Del GiudiceE. Moretto N. Imbimbo BP. J. Med. Chem. 2005; 48: 5705
  • 3 Blouin M. Han Y. Burch J. Farand J. Mellon C. Gaudreault M. Wrona M. Lévesque JF. Denis D. Mathieu MC. Stocco R. Vigneault E. Therien A. Clark P. Rowland S. Xu D. O’Neill G. Ducharme Y. Friesen R. J. Med. Chem. 2010; 53: 2227
  • 4 Du X. Kim YJ. Lai S. Chen X. Lizarzaburu M. Turcotte S. Fu Z. Liu Q. Zhang Y. Motani A. Oda K. Okuyama R. Nara F. Murakoshi M. Fu A. Reagan JD. Fan P. Xiong Y. Shen W. Li L. Houze J. Medina JC. Bioorg. Med. Chem. Lett. 2012; 22: 6218
  • 5 Sasmal PK. Talwar R. Swetha J. Balasubrahmanyam D. Venkatesham B. Rawoof KA. Neelima DeviB. Jadhav VP. Khan SK. Mohan P. Srinivasa ReddyD. Nyavanandi VK. Nanduri S. Shiva KumarK. Kannan M. Srinivas P. Nadipalli P. Chaudhury H. Sebastian VJ. Bioorg. Med. Chem. Lett. 2011; 21: 4913
  • 6 Zeng H. Zhang H. Jang F. Zhao L. Zhang J. Chem. Biol. Drug Des. 2011; 78: 333
  • 7 Moss N. Xiong Z. Burke M. Cogan D. Gao DA. Haverty K. Heim-Riether A. Hickey ER. Nagaraja R. Netherton M. O’Shea K. Ramsden P. Schwartz R. Shih DT. Ward Y. Young E. Zhang Q. Bioorg. Med. Chem. Lett. 2012; 22: 7189
  • 8 Meanwell NA. J. Med. Chem. 2011; 54: 2529
  • 9 Qiao JX. Cheney DL. Alexander RS. Smallwood AM. King SR. He K. Rendina AR. Luettgen JM. Knabb RM. Wexler RR. Lam PY. Bioorg. Med. Chem. Lett. 2008; 18, 4118
    • 10a Papahatjis DP. Nikas S. Tsotinis A. Vlachou M. Makriyannis A. Chem. Lett. 2001; 3: 192
    • 10b Barbasiewicz M. Marciniak K. Fedoryński M. Tetrahedron Lett. 2006; 47: 3871
    • 11a Langer P. Freiberg W. Chem. Rev. 2004; 104: 4125
    • 11b Arava VR. Siripalli UB. R. Dubey PK. Tetrahedron Lett. 2005; 46: 7247
    • 11c Fedoryński M. Jonczyk A. Org. Prep. Proced. Int. 1995; 27: 355
    • 11d Petrosyan VA. Vasil’ev AA. Tatarinova VI. Russ. Chem. Bull. 1994; 43: 84
  • 12 Bryson TA. Roth GA. Jing-hau L. Tetrahedron Lett. 1986; 27: 3685
    • 13a Horwell DC. McKiernan MJ. Osborne S. Tetrahedron Lett. 1998; 39: 8729
    • 13b Tsotinis A. Vlachou M. Papahatjis DP. Calogeropoulou T. Nikas SP. Garratt PJ. Piccio V. Vonhoff S. Davidson K. Teh MT. Sugden D. J. Med. Chem. 2006; 49: 3509
  • 14 Huang H. Ji X. Wu W. Jiang H. Chem. Commun. 2013; 3351
  • 15 Isabel E. Bateman KP. Chauret N. Cromlish W. Desmarais S. Duong LT. Falgueyret JP. Gauthier JY. Lamontagne S. Lau CK. Léger S. LeRiche T. Lévesque J.-F. Li CS. Massé F. McKay DJ. Mellon C. Nicoll-Griffith DA. Oballa RM. Percival MD. Riendeau D. Robichaud J. Rodan GA. Rodan SB. Seto C. Thérien M. Truong VL. Wesolowski G. Young RN. Zamboni R. Black WC. Bioorg. Med. Chem. Lett. 2010; 20: 887
    • 16a Klapars A. Waldman JH. Campos KR. Jensen MS. McLaughlin M. Chung JY. Cvetovich RJ. Chen CY. J. Org. Chem. 2005; 70: 10186
    • 16b McCabe Dunn JM. Kuethe JT. Orr RK. Tudge M. Campeau L.-C. Org. Lett. 2014; 16: 6314
    • 16c Thompson AD. Huestis MP. J. Org. Chem. 2013; 78: 762
    • 17a Salikov RF. Platonov DN. Frumkin AE. Lipilin DL. Tomilov YV. Tetrahedron 2013; 69: 3495
    • 17b Furet P. Guagnano V. Fairhurst RA. Imbach-Weese P. Bruce I. Knapp M. Fritsch C. Blasco F. Blanz J. Aichholz R. Hamon J. Fabbro D. Caravatti G. Bioorg. Med. Chem. Lett. 2013; 23: 3741
    • 18a Ryabukhin SV. Panov DM. Granat DS. Ostapchuk EN. Kryvoruchko DV. Grygorenko OO. ACS Comb. Sci. 2014; 16: 146
    • 18b Ivonin SP. Kurpil’ BB. Volochnyuk DM. Grygorenko OO. Tetrahedron Lett. 2015; 56: 6248
    • 18c Borisov AV. Voloshchuk VV. Nechayev MA. Grygorenko OO. Synthesis 2013; 45: 2413
    • 18d Ivonin SP. Kurpil’ BB. Bezdudny AV. Volochnyuk DM. Grygorenko OO. J. Fluorine Chem. 2015; 176: 78
    • 18e Zhersh S. Karpenko OV. Ripenko V. Tolmachev AA. Grygorenko OO. Cent. Eur. J. Chem. 2014; 12: 67
    • 18f Artamonov OS. Bulda T. Fam TK. Slobodyanyuk EY. Volochnyuk DM. Grygorenko OO. Heterocycl. Commun. 2015; 21: 391
    • 19a McLellan P. Nelson A. Chem. Commun. 2013; 2383
    • 19b Doveston R. Marsden S. Nelson A. Drug Discovery Today 2014; 19: 813
    • 19c James T. MacLellan P. Burslem GM. Simpson I. Grant JA. Warriner S. Org. Biomol. Chem. 2014; 12: 2584
    • 19d Foley DJ. Doveston RG. Churcher I. Nelson A. Marsden SP. Chem. Commun. 2015; 11174
    • 19e Doveston RG. Tosatti P. Dow M. Foley DJ. Li HY. Campbell AJ. House D. Churcher I. Marsden SP. Nelson A. Org. Biomol. Chem. 2015; 13: 859
  • 20 Goldberg FW. Kettle JG. Kogej T. Perry MW. D. Tomkinson NP. Drug Discovery Today 2015; 20: 11
  • 21 Nadin A. Hattotuwagama C. Churcher I. Angew. Chem. Int. Ed. 2012; 51: 1114
    • 22a Nosik PS. Ryabukhin SV. Artamonov OS. Grygorenko OO. Monatsh. Chem. 2016; 147: 1629
    • 22b Azami H. Barrett D. Tanaka A. Sasaki H. Matsuda K. Sakurai M. Terasawa T. Shirai F. Chiba T. Matsumoto Y. Tawara S. Bioorg. Med. Chem. 2001; 9: 961
  • 23 Labroli M. Paruch K. Dwyer MP. Alvarez C. Keertikar K. Poker C. Rossman R. Duca JS. Fischmann TO. Madison V. Parry D. Davis N. Seghezzi W. Wiswell D. Guzi TJ. Bioorg. Med. Chem. Lett. 2011; 21: 471
  • 24 Instant JChem was used for prediction of the physicochemical properties of the compounds, Instant JChem version 17.2.13.0, 2017, ChemAxon ( http://www.chemaxon.com).
  • 25 Kombarov R. Altieri A. Genis D. Kirpichenok M. Kochubey V. Rakitina N. Titarenko Z. Mol. Diversity 2010; 14, 193
  • 26 Armarego WL. F. Chai CL. L. Purification of Laboratory Chemicals . Elsevier; Oxford; 2003

Zoom Image
Figure 1 Biologically active 1,1-disubstituted (het)arylcyclopropanes
Zoom Image
Figure 2 Bioisosteric replacements with 1,1-disubstituted cyclo­propanes
Zoom Image
Scheme 1 Selected general approaches to the preparation of 1-(het)arylcyclopropanecarbonitriles 9
Zoom Image
Figure 3 1,1-Disubstituted pyrazolylcyclopropane building blocks and precursors for their synthesis
Zoom Image
Scheme 2 Synthesis of pyrazolylcyclopropane building blocks 1214