Photochemical synthesis of 2-azabicyclo[3.2.0]heptanes: advanced

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Photochemical synthesis of 2-azabicyclo[3.2.0]heptanes: advanced building blocks for drug discovery. Synthesis of 2,3-ethanoproline. Tetiana Druzhenko, Yevhen Skalenko, Maryna Samoilenko, Aleksandr Denisenko, Sergey Zozulya, Petro O. Borysko, Maria I. Sokolenko, Alexandr Tarasov, and Pavel K. Mykhailiuk J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02910 • Publication Date (Web): 03 Jan 2018 Downloaded from http://pubs.acs.org on January 3, 2018

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The Journal of Organic Chemistry

Photochemical synthesis of 2-azabicyclo[3.2.0]heptanes: advanced building blocks for drug discovery. Synthesis of 2,3-ethanoproline. Tetiana Druzhenko,a,b Yevhen Skalenko,a,b Maryna Samoilenko,b Aleksandr Denisenko,b Sergey Zozulia,b Petro O. Borysko,b Maria I. Sokolenko,b Alexandr Tarasov,b Pavel K. Mykhailiukb,c* a

Institute of High Technologies, Taras Shevchenko National University of Kyiv, Glushkov avenue 4g, Kyiv 03022, Ukraine. Enamine Ltd., Oleksandra Matrosova Street 23, Kyiv 01103, Ukraine, www.mykhailiukchem.org, www.enamine.net c Department of Chemistry, National Taras Shevchenko University of Kyiv, Volodymyrska 64, Kyiv 01033, Ukraine b

ABSTRACT: Intramolecular photochemical [2+2]-cyclization of acetophenone enamides gave 2-azabicyclo[3.2.0]heptanes: advanced building blocks for drug discovery. Synthesis of a conformationally restricted analogue of Proline - 2,3-ethanoproline - was performed. Introduction. Conformationally restricted compounds are popular in modern medicinal chemistry.1 Fixation of functional groups in a biologically active conformation often leads to an enhanced biological activity, selectivity and metabolic stability.2 In this context, in recent years medicinal chemists often use 3D-shaped building blocks with high fractions of (F)sp3-hybridized carbon atoms.3,4 Bicyclic amines A-D can be considered as conformationally restricted surrogates for pyrrolidine, piperidine and azepane that altogether are present in more than 100 FDA-approved drugs (Table 1, Figure 1).

Surprisingly, although motifs A-C play an important role in drug discovery projects,5,6 compounds D remain in the shadow. We presume that the key reason behind is the lack of the synthetic approaches. Motifs D only with the multiple substitution at the 2-azabicyclo[3.2.0]heptane skeleton are described in the literature.7 Therefore, herein we report a practical synthesis and physicochemical properties of building blocks D with two exit vectors and no additional substitution (Figure 1).

Table 1. Bicyclic pyrrolidines A-D in drug discovery. Motif Bioactive compoundsa Patentsb

a

1589

160

403

16

667

86

157

9

Figure 1. Mono- and bicyclic cores in drug discovery.

Results and Discussion. [2+2]-Photocycloaddition is used for the synthesis of cyclobutanes for more than 100 years.8 In 1999, Piotrowski described the [2+2]-photocyclization of substrates 1 into the substituted pyrrolidines 2.9 Also, this methodology was used in the synthesis of 2,4-methanoprolines (2, R=CO2Et).10 We decided to take advantage of this approach by replacing the fragment of allylamine with homoallylamine (Scheme 1).11

Substructure search in ChEMBL db; bSubstructure search in Reaxys db.5

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a) Piotr owski (1999)9

a Conversion of the reaction according to 19F NMR. bSlow formation of two compounds 7a and 6 (1/1) was observed. c100% conversion, 90% purity by 19F NMR.

head-to-tail Hg-lamp PhCOMe

N R CO2Et

N R CO2 Et

R N CO2Et

C6 H6 52%

2

1 b) T his wor k head-to-head

R = Ar, Alk

head-to-tail

365 nm Ph2CO

N

N R COCF3

R

COCF3

N R COCF3

CH3 CN 52-99%

N Ph COCF3 not obser ved

4

3

Scheme 1. Previous (a) and this work (b).

1. Starting compounds. First, we prepared a Shiff base 5 from acetophenone and homoallylamine. When the subsequent reaction of 5 with (CF3CO)2O was performed in pyridine, an unexpected product 6 was isolated in 38% yield. Performing the reaction in THF with NEt3, however, gave the needed enamide 7 in 93% yield (Scheme 2). (CF3 CO)2O

PTSA, C6 H6 reflux 77%

N 5

Acetophenone

All experiments above were performed under high dilution of 5 mM to avoid the intermolecular cyclizations. For the large scale synthesis, we found out that the reaction could be performed in up to 100 mM concentration (Table 2, entry 8). At higher concentrations, however, formation of the unidentified side products was observed (Table 2, entry 9). 3. Scale. Finally, we studied this photochemical reaction in different scales. The synthesis in milligram scale was performed at 5mM in 5 mL glass vials. The reaction in 25 g scale was efficiently performed at 100 mM in common 1L-glass flask (Scheme 3). H 365 nm Ph2CO

N

N H 6

Ph

N

CH3 CN 48h, rt 87%

Ph

COCF3

NH2

Ph

After 48 h of irradiation at 365 or 419 nm, the reaction did not proceed at all. However, performing the reaction at 365 nm in the presence of benzophenone as a triplet sensitizer, smoothly gave the “head-to-head” product 7a (Table 2, entry 5). In strict contrast to pyrrolidines 2, formation of analogous “headto-tail” piperidines was not observed (Scheme 1).12

COCF3

Py, ice bath 38%

O

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Ph COCF3 7a 25 g

7

Ph (CF3 CO)2O NEt3 , THF ice bath 93%

N Ph COCF3 7

Scheme 2. Synthesis of the staring compound 7.

20 mg glass f lask (5 mL)

2. Optimization. Next, we tried the [2+2]-photocyclization of compound 7 under different conditions (Table 2). In acetonitrile at 254 nm at room temperature, formation of a complex mixture was observed. At 310 nm, after 24 h at room temperature the conversion of the reaction reached only 11%. Moreover, two products 7a and 6 (1/1) slowly formed.

Scheme 3. Scaled up synthesis of compound 7a.

4. Scope. Having a practical procedure in hand, we next 1)

O

R

N Ph COCF3

N Ph COCF 3

N

not obser ved

N

N T FA

λ (nm)

c (mM)

Sensitizer

Conversion (%)a

1

254

5

-

compl. mix.

2

310

5

-

11 (7a+6)b

3

365

5

-

0

4

419

5

5

365

5

Ph2CO (1.0 eq.)

100

6

365

25

Ph2CO (1.0 eq.)

100

7

365

50

Ph2CO (1.0 eq.)

100

0

8

365

100

Ph2CO (1.0 eq.)

9

365

200

Ph2CO (1.0 eq.) 100c(side prod.)

H

TFA

N

N

OMe

9a (83%)

8a (78%) H

10a (91%) H

H

N T FA O

N T FA S

11a (65%)

12a (93%)

H

N T FA

H

H

N

N

N

T FA

Bz

Br 14a (0%)a


15a (0%)a

N N

13a (91%)

T FA

100

N

N T FA

N

TFA

7a (87%)

Entry

7a-13a H

7a

7

N R COCF3

OMe

Ph

COCF3

CH3 CN 48h, rt 65-93%

N R COCF3 7-16

H

H

CH3 CN 48h, rt [2+2]

365 nm Ph2CO

head-to-tail

hv

N Ph COCF3

H

NH2 PTSA, C6 H6 reflux, 24h

2) (CF3 CO)2 O, Py, ice bath 30 min

Table 2. Optimization of the synthesis of compound 7a. head-to-head

25 g glass f lask ( 1 L)

I

CO2 Et

16a (0%)b

2

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Scheme 4. Scope of the reaction. aAfter 2 weeks of irradiation. b Complex mixture.

studied its scope (Scheme 4). Aromatic (7, 8), six-(9, 10) and five-membered (11-13) heteroaromatic substrates smoothly gave the needed products 7a-13a in 65-93% yield. Aromatic compounds 14 and 15 with C-Br and C-I bonds, did not react, however, even after 2 weeks of irradiation presumably due to heavy atom effect. On the other hand, substrate 17 after 24 h of irradiation afforded the unidentified complex mixture. Nevertheless, product 14a was obtained in 34% yield after 2 weeks of irradiation under photoredox-catalysis: 419 nm, cat. Ir(ppy)3 (Scheme 5).13,14 We failed, however, to perform [2+2]-photocyclization of substrate 15.

Scheme 5. Photoredox-catalyzed synthesis of compound 14a.

H

H

*HCl 1) Boc2O, NaOH

N H 9b

N

2) H2/Pd MeOH 50°C 81%

N Boc 17

H N H

Scheme 7. Synthesis of monoprotected N-Boc diamine 17.

followed by a hydrogenation of the pyridine ring, gave the mono N-Boc protected diamine 17 as a mixture of two diastereomers. The reaction was performed in methanol at 50 ºC over Pd/C as a catalyst (Scheme 7). c) Amino acid. Finally, synthesis of amino acid 1816 – a conformationally rigid analogue of L-Proline – was undertaken. An attempted oxidative cleavage of the phenyl ring in compound 8a with NaIO4/RuCl3 (cat.) unexpectedly gave the product of iodination 19 (X-Ray, Scheme 8).15 Ozonolysis of 8a, followed by a cleavage of protecting groups gave the target amino acid 18 in low yield of 7%. Therefore, we next N-Bz protected the furan derivative 11b, and oxidized the furane ring with NaIO4/RuCl3 (cat). After hydrolysis of N-Bz group, the product 18 was isolated in 47% yield.

5. Synthesis of building blocks. We also wanted to show that the obtained herein compounds could easily be transformed into the appropriate building blocks for the direct use in drug discovery projects. a) Amines. The alkaline cleavage of CF3CO-N group in 7a13a easily gave the needed amines 7b-13b as hydrochlorides in 89-98% yield. Compound 7b was obtained in 10 g scale in one synthesis run. Structures of products 7b and 12b were confirmed by X-Ray analysis (Scheme 6).15

Scheme 8. Synthesis of amino acid 18 – a conformationally restricted analogue of L-Proline.

6. Physicochemical properties (ADME). Next, we measured the physicochemical characteristics of 2-azabicyclo[3.2.0]heptanes (core D), and compared them to the established scaffolds of pyrrolidine, piperidine and azepane. All four compounds 20-23 demonstrated very close lipophilicity and water solubility. However, compound 23 was also less metabolically stable over 20−22. These data show that monosubstituted 2-azabicyclo[3.2.0]heptanes indeed have a potential to be considered as conformationally restricted surrogates for pyrrolidines, piperidines and azapanes, needed in modern medicinal chemistry projects (Table 3). Table 3. Experimental physicochemical parameters (ADME) of model compounds 20-23.

Scheme 6. Synthesis of amines 7b-13b.

b) Diamine. The standard N-Boc protection of amine 9b, Compound

LogD(10)a b

Sol(7.4)


2.3

2.4

2.4

2.2

81

73

61

95

3


CLintc

17

77

176

586

a

b

Experimental n-octanol/water distribution coefficient (log) at pH 10.0. Thermodynamic aqueous solubility (µM) in 50 mM phosphate buffer (pH 7.4). cIntrinsic clearance rate CLint (mg/(min·µL)) measured in mouse liver microsomes.

7. Synthesis of drug analogues. To demonstrate the high potential of the synthesized bicyclic building blocks for drug discovery, we synthesized compound 24 – a conformationally restricted fused analogue of Bupivacaine, which is an FDAapproved local anesthetic (Scheme 9). Previously, we showed that spirocyclic analogue 25 was more active over Bupivacaine.4c a)

1) Boc2 O 2)

fused core *HCl

H2 N IBCF

N H

CO2 H

O

N

3) TFA 21% 4) BuI DIPEA 5) HCl

HN

17

24

b)

spirocyclic core

*HCl

*HCl

O

N

O

Pr evious wor k 4c

HN ANIE 2017, 8865

Bupivacaine

N

HN

25

Local anaesthetic

Scheme 9. Synthesis of conformationally restricted analogues of Bupivacaine – compounds 24 (a) and 25 (b, previous work).4c

Unfortunately, compound 24 showed no anesthetic activity in vivo on mice using tail flick test (Figure 2). To validate the utility of 2-azabicyclo[3.2.0]heptanes in drug discovery, indeed, more biological targets are needed.

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inactive – it showed no anesthetic activity in vivo on mice using tail flick test. Nevertheless, given the available starting materials, and the practical synthesis, we believe that medicinal chemists will soon start to use 2-azabicyclo[3.2.0]heptanes in drug discovery programs. Experimental Section. All starting materials were taken at Enamine. Column chromatography was performed using Kieselgel Merck 60 (230-400 mesh) as the stationary phase. Reverse phase column chromatography was performed using C18-modified silica gel as a stationary phase, column: SunFire Waters, 5 µm, 19 mm × 100 mm. 1H-, 19F-, 13C-NMR spectra were recorded on at 500 or 400 MHz, 376 MHz and 125 or 101 MHz respectively. Chemical shifts are reported in ppm downfield from TMS (1H, 13 C) or CFCl3 (19F) as internal standards. Mass spectra were recorded on an LC-MS instrument with chemical ionization (CI). LC-MS data were acquired on Agilent 1200 HPLC system equipped with DAD/ELSD/LCMS-6120 diodematrix and massselective detector, column: Poroshell 120 SBC18, 4.6 mm × 30 mm. Eluent, A, acetonitrile–water with 0.1% of FA (99: 1); B, water with 0.1% of FA. ((1E)-N-(but-3-en-1-yl)-1-phenylethan-1-imine (5) Acetophenone (12.0 g, 100 mmol, 1.0 equiv.), ptoluenesulfonic acid monohydrate (190 mg, 0.01 equiv., 1.0 mmol) and 10% solution of homoallylamine (10.6 g, 150 mmol, 1.5 equiv.) in benzene were mixed in 250 mL round-bottom flask and heated to reflux with Dean-Stark apparatus. After 48 h of reflux (the reaction was monitored by NMR), the reaction mixture was evaporated under reduced pressure and the product (13.3 g, 77% yield), was immediately proceeded in the next step without purification. (Z)-4-(But-3-en-1-ylamino)-1,1,1-trifluoro-4-phenylbut-3en-2-one (6) Imine 5 (1.7 g, 10 mmol, 1.0 equiv.) was dissolved in pyridine (10 mL), cooled to -100C under argon atmosphere and trifluoroacetic anhydride (2.5 g, 12 mmol, 1.2 equiv.) was added dropwise under inert atmosphere. Reaction mixture was warmed to room temperature, stirred for 30 min and evaporated under reduced pressure. The residue was purified via column chromatography (hexanes/EtOAc = 10/1) to afford products 6 (1.0 g, 38% yield) and 7 (1.1 g, 42% yield) as yellow oils. 1 H NMR (400 MHz, Chloroform-d) δ 11.12 (s, 1H), 7.63 – 7.39 (m, 3H), 7.33 (dd, J = 7.5, 2.2 Hz, 2H), 5.69 (m, 1H), 5.38 (s, 1H), 5.27 – 4.88 (m, 2H), 3.33 (q, J = 6.7 Hz, 2H), 2.29 (q, J = 6.7 Hz, 2H). 13

Figure 2. Anesthetic activity of compound 24 and Bupivacaine in mice in vivo (tail flick test).

C NMR (126 MHz, Chloroform-d) δ 176.2 (q, J = 32.9 Hz), 170.6, 134.0, 133.6, 130.5, 128.9, 127.5, 118.7, 117.8 (q, J = 288.5 Hz), 90.3, 44.8, 34.4. 19

F NMR (376 MHz, Chloroform-d) δ -77.05.

LCMS (m/z): 270 (M + H+).

Summary. We developed a two-step synthesis of 2-azabicyclo[3.2.0]heptanes with two exit vectors. The syntheses commenced from the aromatic and heteroaromatic acetophenones. The photochemical [2+2]-cycloaddition step was performed in 25 g scale. The model 2-azabicyclo[3.2.0]heptanes possessed similar lipophilicity and water solubility compared to the corresponding pyrrolidines and piperidines, but had a lower metabolic stability. The corresponding analogue 24 of Bupivacaine was

Anal. calcd for C14H14F3NO: C, 62.45; H, 5.24; N, 5.20. Found: C, 62.64; H, 5.05; N, 5.48. N-(But-3-en-1-yl)-2,2,2-trifluoro-N-(1phenylvinyl)acetamide (7) Enamide 6 (26.9 g, 100 mmol, 1.0 equiv.) was dissolved in triethylamine (150 mL), cooled to -100C and trifluoroacetic anhydride (25.2 g, 120 mmol, 1.2 equiv.) was added dropwise under inert atmosphere. The reaction mixture was warmed to room tem-


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perature, stirred for 30 min and evaporated under reduced pressure. The residue was purified via column chromatography (hexanes/EtOAc = 10/1) to give the product (25.0 g, 93% yield) as a yellow oil.

13 C NMR (101 MHz, Chloroform-d) δ 157.1 (q, J = 36.0 Hz), 147.7, 144.4, 144.1, 141.4, 140.6, 133.9, 120.7, 117.3, 116.2 (q, J = 288.3 Hz), 47.6, 31.2. 19


1

H NMR (500 MHz, Chloroform-d) δ 7.41 (s, 5H), 5.83 (s, 1H), 5.73 (m, 1H), 5.29 (s, 1H), 5.13 – 5.00 (m, 2H), 4.09 (broad s, 1H), 2.63 (broad s, 1H), 2.36 (s, 2H). 13

C NMR (126 MHz, Chloroform-d) δ 157.6 (q, J = 35.7 Hz), 143.5, 134.3, 134.2, 129.6, 129.0, 126.3, 117.4, 115.0, 116.7 (q, J = 288.4 Hz), 47.0, 31.4. 19

Anal. calcd for C14H14F3NO: C, 62.45; H, 5.24; N, 5.20. Found: C, 62.13; H, 5.37; N, 5.03. N-(But-3-en-1-yl)-N-(1-(2,4-dimethoxyphenyl)vinyl)-2,2,2trifluoroacetamide (8) Yellow oil. 2.7 g, 81% yield. Eluent for chromatography: hexanes/EtOAc = 4/1.

LCMS (m/z): 260 (M + H+). N-(But-3-en-1-yl)-2,2,2-trifluoro-N-(1-(thiophen-2yl)vinyl)acetamide (12) Yellow oil. 19.9 g, 72% yield. Eluent for chromatography: hexanes/EtOAc = 7/1. 1

1

H NMR (500 MHz, Chloroform-d) δ 7.13 (d, J = 8.4 Hz, 1H), 6.46 (m, 2H), 5.85 – 5.53 (m, 2H), 5.24 (s, 1H), 5.15 – 4.80 (m, 2H), 3.76 (m, 7H), 3.58 – 3.17 (broad s, 1H), 2.27 (m, 2H). 13

C NMR (126 MHz, Chloroform-d) δ 161.9, 159.1, 157.4 (q, J = 35.3 Hz), 140.4, 134.6, 130.5, 117.0, 116.8 (q, J = 288.0 Hz), 116.7, 115.5, 104.9, 99.1, 55.4, 55.3, 46.5, 31.2.

H NMR (500 MHz, Chloroform-d) δ 7.29 (dd, J = 5.0, 1.4 Hz, 1H), 7.14 – 6.81 (m, 2H), 5.91 – 5.57 (m, 2H), 5.28 – 4.92 (m, 3H), 4.14 (broad s, 1H), 3.13 (broad s, 1H), 2.40 (s, 2H). 13 C NMR (126 MHz, Chloroform-d) δ 157.2 (q, J = 35.9 Hz), 139.2, 138.2, 134.2, 127.9, 127.0, 126.1, 117.6, 116.5 (q, J = 288.2 Hz), 114.5, 47.6, 31.6. 19



LCMS (m/z): 276 (M + H+).

LCMS (m/z): 330 (M + H+). Anal. calcd for C16H18F3NO3: C, 58.35; H, 5.51; N, 4.25. Found: C, 58.19; H, 5.35; N, 4.17. N-(But-3-en-1-yl)-2,2,2-trifluoro-N-(1-(pyridin-3yl)vinyl)acetamide (9) Yellow oil. 20.6 g, 76% yield. Eluent for chromatography: hexanes/EtOAc = 2/1.

Anal. calcd for C12H12F3NOS: C, 52.36; H, 4.39; N, 5.09; S, 11.65. Found: C, 52.65; H, 4.08; N, 4.86; S, 11.33. N-(But-3-en-1-yl)-2,2,2-trifluoro-N-(1-(1-methyl-1Hpyrazol-4-yl)vinyl)acetamide (13) Slightly yellow solid. 2.3 g, 83% yield. Eluent for chromatography: MTBE. 1

1

H NMR (400 MHz, Chloroform-d) δ 8.59 (d, J = 2.8 Hz, 1H), 8.47 (m, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.21 (m, 1H), 5.79 (s, 1H), 5.56 (m Hz, 1H), 5.27 (s, 1H), 5.02 – 4.75 (m, 2H), 4.22 – 2.57 (broad m, 2H), 2.23 (m, 2H). 13 C NMR (101 MHz, Chloroform-d) δ 157.2 (q, J = 35.7 Hz), 150.4, 147.5, 140.7, 133.8, 133.2, 129.8, 123.5, 117.4, 116.9 (q, J = 2.4 Hz), 116.3 (q, J = 288.2 Hz), 46.6, 31.1.

H NMR (400 MHz, Chloroform-d) δ 7.42 (s, 1H), 7.32 (s, 1H), 5.62 (m, 1H), 5.43 (s, 1H), 4.95 (m, 3H), 4.19 – 3.84 (broad s, 1H), 3.78 (s, 3H), 3.08 (broad s, 1H), 2.26 (m, 2H). 13 C NMR (101 MHz, Chloroform-d) δ 156.8 (q, J = 35.7 Hz), 137.3, 136.0, 134.1, 128.2, 118.6, 117.2, 116.4 (q, J = 288.1 Hz), 112.7 (q, J = 2.0 Hz), 46.8, 39.0, 31.3. 19


LCMS (m/z): 274 (M + H+).


LCMS (m/z): 271 (M + H+). Anal. calcd for C13H13F3N2O: C, 57.78; H, 4.85; N, 10.37. Found: C, 57.45; H, 4.49; N, 10.71. N-(But-3-en-1-yl)-2,2,2-trifluoro-N-(1-(pyrazin-2yl)vinyl)acetamide (10) Yellow oil. 2.4 g, 89% yield. Eluent for chromatography: MTBE (was obtained in ca. 90% purity). 1

Yellow oil. 29.1 g, 56% yield. Eluent for chromatography: hexanes/EtOAc = 10/1 (was obtained in ca. 90% purity). H NMR (400 MHz, Chloroform-d) δ 7.43 (s, 1H), 6.43 (s, 1H), 6.32 (s, 1H), 5.85 (s, 1H), 5.75 (m, 1H), 5.22 (s, 1H), 5.16 – 5.01 (m, 2H), 4.13 (broad s, 1H), 3.16 (broad s, 1H), 2.39 (s, 2H).

LCMS (m/z): 270 (M + H ).

19

N-(But-3-en-1-yl)-2,2,2-trifluoro-N-(1-(furan-2yl)vinyl)acetamide (11)

1

F NMR (376 MHz, Chloroform-d) δ -67.26. +

19

LCMS (m/z): 272 (M + H+).

H NMR (400 MHz, Chloroform-d) δ 8.61 (d, J = 1.5 Hz, 1H), 8.54 – 8.25 (m, 2H), 6.39 (s, 1H), 5.83 – 5.40 (m, 2H), 4.98 – 4.83 (m, 2H), 4.43 – 3.75 (broad s, 1H), 3.24 – 2.58 (broad s, 1H), 2.31 – 2.12 (m, 2H).

Anal. calcd for C12H14F3N3O: C, 52.75; H, 5.16; N, 15.38. Found: C, 52.46; H, 5.38; N, 15.69. N-(1-(4-Bromophenyl)vinyl)-N-(but-3-en-1-yl)-2,2,2trifluoroacetamide (14) Yellow oil. 2.7 g, 78% yield. Eluent for chromatography: hexanes/EtOAc = 10/1. 1

H NMR (400 MHz, Chloroform-d) δ 7.49 (d, J = 8.5 Hz, 2H), 7.25 (d, J = 8.5 Hz, 2H), 6.02 – 5.55 (m, 2H), 5.26 (s, 1H), 5.18 – 4.77 (m, 2H), 4.07 (broad s, 1H), 3.23 – 2.59 (broad s, 1H), 2.31 (q, J = 5.6 Hz, 2H).


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The Journal of Organic Chemistry 19

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13 C NMR (101 MHz, Chloroform-d) δ 160.2, 157.6, 154.2 (q, J = 36.1 Hz), 131.0, 121.3, 116.2 (q, J = 288.8 Hz), 103.4, 98.6, 71.4, 55.2, 54.9, 48.7 (q, J = 3.8 Hz), 44.8, 31.4, 26.9, 21.6.


LCMS (m/z): 348, 350 (M + H+).

19

Anal. calcd for C14H13BrF3NO: C, 48.30; H, 3.76; N, 4.02. Found: C, 48.62; H, 3.82; N, 3.83.


LCMS (m/z): 330 (M + H+).

N-(But-3-en-1-yl)-2,2,2-trifluoro-N-(1-(4iodophenyl)vinyl)acetamide (15)

Anal. calcd for C16H18F3NO3: C, 58.35; H, 5.51; N, 4.25. Found: C, 58.67; H, 5.56; N, 4.43.

Yellow oil. 2.7 g, 67% yield. Eluent for chromatography: hexanes/EtOAc = 10/1.

2,2,2-Trifluoro-1-(1-(pyridin-3-yl)-2azabicyclo[3.2.0]heptan-2-yl)ethan-1-one (9a)

1

H NMR (400 MHz, Chloroform-d) δ 7.71 (d, J = 8.2 Hz, 2H), 7.12 (d, J = 8.2 Hz, 2H), 5.81 (s, 1H), 5.69 (m, 1H), 5.28 (s, 1H), 5.16 – 4.84 (m, 2H), 4.07 (broad s, 1H), 2.89 (broad s, 1H), 2.32 (m, 2H). 13 C NMR (101 MHz, Chloroform-d) δ 157.4 (q, J = 35.9 Hz), 142.5, 138.1, 134.0, 133.6, 127.8, 117.5, 116.4 (q, J = 288.2 Hz), 115.7, 95.6, 46.8, 31.2. 19

1

H NMR (500 MHz, Chloroform-d) δ 8.56 – 8.44 (s, 1H), 8.41 (d, J = 4.8 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.18 (dd, J = 8.0, 4.8 Hz, 1H), 4.11 (m, 2H), 2.95 (q, J = 7.7 Hz, 1H), 2.82 (dt, J = 13.1, 9.5 Hz, 1H), 2.38 (ddd, J = 13.1, 9.5, 3.9 Hz, 1H), 2.26 (m, 1H), 2.15 (m, 1H), 2.07 – 1.90 (m, 1H), 1.81 (m, 1H). 13

C NMR (126 MHz, Chloroform-d) δ 155.0 (q, J = 36.9 Hz), 148.4, 147.3, 137.3, 133.6, 123.1, 116.1 (q, J = 288.3 Hz), 71.1, 48.2 (q, J = 3.8 Hz), 46.4, 29.8, 26.9, 20.6.


LCMS (m/z): 396 (M + H+). Anal. calcd for C14H13F3INO: C, 42.55; H, 3.32; N, 3.54. Found: C, 42.63; H, 3.45; N, 3.71. 2,2,2-Trifluoro-1-(1-phenyl-2-azabicyclo[3.2.0]heptan-2yl)ethan-1-one (7a) Enamide 7 (26.9 g, 100 mmol, 1.0 equiv.) and benzophenone (1.82 g, 10.0 mmol, 0.1 equiv.) were mixed in dry acetonitrile (1 L). The reaction mixture was degassed by bubbling of argon for 15 minutes and then irradiated at 365 nm. After 48 h of irradiation (the reaction was monitored by NMR) the solvent was evaporated under reduced pressure. The residue was purified via column chromatography (hexanes/EtOAc = 10/1) to get the product (23.4 g, 87% yield) as a yellow oil. 1

H NMR (400 MHz, Chloroform-d) δ 7.39 – 7.15 (m, 5H, Ph), 4.16 (m, 2H, 3-CH2), 3.07 – 2.76 (m, 2H, 5-CH, 7-CHH), 2.45 (ddd, J = 14.0, 9.3, 4.0 Hz, 1H, 7-CHH), 2.39 – 2.26 (m, 1H, 4CHH), 2.26 – 2.10 (m, 1H, 6-CHH), 2.03 (dt, J = 14.0, 5.6 Hz, 1H, 4-CHH), 1.82 (dq, J = 12.1, 8.8 Hz, 1H, 6-CHH). 13 C NMR (126 MHz, Chloroform-d) δ 154.6 (q, J = 36.6 Hz, COCF3), 141.7 (C, Ph), 128.5 (CH, Ph), 127.0 (CH, Ph), 125.3 (CH, Ph), 116.0 (q, J = 288.6 Hz, CF3), 72.7 (1-C), 48.1 (3-CH2), 46.4 (5-CH), 29.6 (CH2), 26.9 (CH2), 20.5 (6-CH2). 19

Yellow oil. 15.2 g, 83% yield. Eluent for chromatography: hexanes/MTBE = 1/1, then MTBE.

19


LCMS (m/z): 271 (M + H+). Anal. calcd for C13H13F3N2O: C, 57.78; H, 4.85; N, 10.37. Found: C, 57.95; H, 4.67; N, 10.55. 2,2,2-Trifluoro-1-(1-(pyrazin-2-yl)-2azabicyclo[3.2.0]heptan-2-yl)ethan-1-one (10a) Yellow oil. 1.1 g, 91% yield. Eluent for chromatography: MTBE. 1

H NMR (500 MHz, Chloroform-d) δ 8.49 (d, J = 1.5 Hz, 1H), 8.41 (dd, J = 2.6, 1.5 Hz, 1H), 8.32 (d, J = 2.6 Hz, 1H), 4.10 (m, 2H), 3.06 (dt, J = 12.9, 9.6 Hz, 1H), 2.96 (q, J = 7.8 Hz, 1H), 2.26 (m, 2H), 2.19 – 2.02 (m, 1H), 2.02 – 1.86 (m, 1H), 1.86 – 1.69 (m, 1H). 13 C NMR (126 MHz, Chloroform-d) δ 155.5, 155.1 (q, J = 37.1 Hz), 143.8, 142.9, 142.3, 116.1 (q, J = 288.0 Hz), 72.2, 48.6 (q, J = 3.6 Hz), 45.4, 29.7, 26.1, 20.4. 19


LCMS (m/z): 272 (M + H+). Anal. calcd for C12H12F3N3O: C, 53.14; H, 4.46; N, 15.49. Found: C, 53.39; H, 4.71; N, 15.40.


LCMS (m/z): 270 (M + H+). Anal. calcd for C14H14F3NO: C, 62.45; H, 5.24; N, 5.20. Found: C, 62.70; H, 4.92; N, 5.23. 1-(1-(2,4-Dimethoxyphenyl)-2-azabicyclo[3.2.0]heptan-2yl)-2,2,2-trifluoroethan-1-one (8a) Yellow oil. 1.5 g, 78% yield. Eluent for chromatography: hexanes/MTBE = 40/1, then hexanes/MTBE = 4/1. 1 H NMR (400 MHz, Chloroform-d) δ 7.38 (d, J = 8.4 Hz, 1H), 6.47 (dd, J = 8.4, 2.4 Hz, 1H), 6.39 (d, J = 2.4 Hz, 1H), 4.09 (t, J = 7.5 Hz, 2H), 3.77 (s, 3H), 3.73 (s, 3H), 3.06 (q, J = 7.8 Hz, 1H), 2.89 (dt, J = 12.7, 9.4 Hz, 1H), 2.62 – 2.37 (m, 2H), 2.23 – 2.06 (m, 1H), 1.98 – 1.85 (m, 1H), 1.72 (ddd, J = 16.3, 12.7, 8.0 Hz, 1H).

2,2,2-Trifluoro-1-(1-(furan-2-yl)-2-azabicyclo[3.2.0]heptan2-yl)ethan-1-one (11a) Yellow oil. 10.5 g, 51% yield. Eluent for chromatography: hexanes/EtOAc = 10/1. 1

H NMR (400 MHz, Chloroform-d) δ 7.28 (s, 1H), 6.29 (d, J = 3.4 Hz, 1H), 6.17 (d, J = 3.4 Hz, 1H), 4.05 (m, 2H), 3.04 (q, J = 7.5 Hz, 1H), 2.78 (m, 1H), 2.40 (ddd, J = 13.3, 9.3, 4.3 Hz, 1H), 2.33 – 2.03 (m, 2H), 1.95 (m, 1H), 1.77 (m, 1H). 13

C NMR (126 MHz, Chloroform-d) δ 154.9 (q, J = 36.2 Hz), 153.8, 141.5, 116.1 (q, J = 289.6 Hz), 110.4, 106.0, 67.7, 48.2, 44.2, 29.7, 27.3, 20.6. 19



6

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The Journal of Organic Chemistry LCMS (m/z): 260 (M + H+).

Anal. calcd for C12H12F3NO2: C, 55.60; H, 4.67; N, 5.40. Found: C, 55.82; H, 4.54; N, 5.23. 2,2,2-Trifluoro-1-(1-(thiophen-2-yl)-2azabicyclo[3.2.0]heptan-2-yl)ethan-1-one (12a) Yellow oil. 12.1 g, 93% yield. Eluent for chromatography: hexanes/EtOAc = 5/1. 1

H NMR (400 MHz, Chloroform-d) δ 7.17 (dd, J = 3.8, 2.6 Hz, 1H), 6.94 (m, 2H), 4.25 – 3.93 (m, 2H), 3.01 (q, J = 7.8 Hz, 1H), 2.82 (dt, J = 12.8, 9.4 Hz, 1H), 2.56 (m, 1H), 2.42 – 2.07 (m, 2H), 1.98 (m, 1H), 1.80 (m, 1H). 13

C NMR (126 MHz, Chloroform-d) δ 154.9 (q, J = 37.0 Hz), 146.5, 126.9, 124.2, 123.8, 116.2 (q, J = 288.2 Hz), 70.2, 48.2 (q, J = 3.8 Hz), 47.4, 29.4, 29.2, 20.4. 19


LCMS (m/z): 276 (M + H+).

Anal. calcd for C14H13BrF3NO: C, 48.30; H, 3.76; N, 4.02. Found: C, 48.14; H, 3.56; N, 3.99. 1-Phenyl-2-azabicyclo[3.2.0]heptane (7b) Amide 7a (25.0 g, 93 mmol, 1.0 equiv.) and NaOH (7.4 g, 186 mmol, 2.0 equiv.) were dissolved in methanol (250 mL). Reaction mixture stirred overnight and evaporated. Methyl tert-butyl ether (250 mL) and water (150 mL) were added to the residue. Organic layer was separated, washed with water (150 mL) and acidified with 2 N aqueous hydrochloric acid (150 mL). Aqueous layer was separated and washed with methyl tert-butyl ether (150 mL). Then, 2 N aqueous NaOH (200 mL) added to the aqueous solution, it was extracted with MTBE (3×200 mL). The combined organic layers were dried over anhydrous Na2SO4 and evaporated to give product (12.6 g, 78% yield) as a colourless oil. 1 H NMR (400 MHz, Chloroform-d) δ 7.48 – 7.10 (m, 5H), 3.45 – 3.20 (m, 2H), 3.06 (q, J = 7.4 Hz, 1H), 2.54 (m, 1H), 2.32 – 2.00 (m, 2H), 1.93 – 1.64 (m, 3H), 1.46 (m, 1H). 13

Anal. calcd for C12H12F3NOS: C, 52.36; H, 4.39; N, 5.09; S, 11.65. Found: C, 52.03; H, 4.67; N, 5.00; S, 11.45.

C NMR (126 MHz, Chloroform-d) δ 147.0, 128.4, 126.6, 125.4, 69.7, 47.3, 44.7, 34.5, 33.62, 19.8. LCMS (m/z): 174 (M + H+).

2,2,2-Trifluoro-1-(1-(1-methyl-1H-pyrazol-4-yl)-2azabicyclo[3.2.0]heptan-2-yl)ethan-1-one (13a)

Anal. calcd for C12H15N: C, 83.19; H, 8.73; N, 8.08. Found: C, 83.01; H, 8.80; N, 8.31.

Yellow oil. 1.2 g, 91% yield. Eluent for chromatography: MTBE, then EtOAc.

Crystals of 7b.HCl, suitable for an X-Ray diffraction study were obtained by a slow evaporation of a diluted solution of 7b.HCl in methanol.

1 H NMR (400 MHz, Chloroform-d) δ 7.31 (s, 2H), 4.02 (q, J = 7.8 Hz, 2H), 3.84 (s, 3H), 3.14 – 2.92 (m, 1H), 2.63 – 2.40 (m, 2H), 2.40 – 2.09 (m, 2H), 2.09 – 1.88 (m, 1H), 1.77 (m, 1H). 13

C NMR (126 MHz, Chloroform-d) δ 154.9 (q, J = 36.3 Hz), 136.5, 128.5, 123.9, 116.3 (q, J = 288.5 Hz), 66.9, 48.0 (q, J = 3.8 Hz), 45.7, 39.0, 29.8, 29.7, 20.8. 19


LCMS (m/z): 274 (M + H+). Anal. calcd for C12H14F3N3O: C, 52.75; H, 5.16; N, 15.38. Found: C, 52.97; H, 5.05; N, 15.29. 1-(1-(4-Bromophenyl)-2-azabicyclo[3.2.0]heptan-2-yl)2,2,2-trifluoroethan-1-one (14a) Enamide 14 (0.35 g, 1.0 mmol, 1.0 equiv.) were mixed in dry acetonitrile (40 mL). The reaction mixture was degassed by bubbling of argon for 15 minutes, and Ir(ppy)3 (0.13 g, 0.2 mmol, 0.2 equiv.) was added. The reaction mixture was irradiated at 419 nm for two weeks and evaporated under reduced pressure. The residue was purified via reverse-phase column chromatography (gradient H2O/acetonitrile from 50/50 to 25/75) to get the product (0.12 g, 34% yield) as a yellow oil. 1

H NMR (500 MHz, Chloroform-d) δ 7.45 (d, J = 8.2 Hz, 2H), 7.15 (d, J = 8.2 Hz, 2H), 4.16 (m, 2H), 2.95 (q, J = 7.7 Hz, 1H), 2.86 (m, 1H), 2.44 (m, 1H), 2.32 (m, 1H), 2.18 (m, 1H), 2.04 (m, 1H), 1.83 (m, 1H). 13 C NMR (126 MHz, Chloroform-d) δ 154.9 (q, J = 36.9 Hz), 140.9, 131.4, 127.3, 121.1, 116.1 (q, J = 288.3 Hz), 72.3, 48.1 (q, J = 4.0 Hz), 46.4, 29.7, 27.0, 20.4. 19


LCMS (m/z): 348, 350 (M + H+).

1-(2,4-Dimethoxyphenyl)-2-azabicyclo[3.2.0]heptane drocloride (8b.HCl)

hy-

White solid. 550 mg, 89% yield. 1 H NMR (500 MHz, Deuterium Oxide) of both rotamers δ 7.29 (s, 1H, CH, Ar), 6.69 – 6.48 (m, 2H, 2×CH, Ar), 3.78 (s, 6H, 2×CH3), 3.65 (m, 2H, CH2NH2), 3.43 (s, 1H, CH), 2.53 – 2.39 (m, 2H, CCH2), 2.15 (m, 2H, CHHCHCHH), 2.00 (m, 1H, CHHCH2N), 1.66 (d, J = 8.1 Hz, 1H, CCH2CHHCH). 13

C NMR (101 MHz, Deuterium Oxide) of both rotamers δ 161.2, 161.1 (2×s, C, Ar), 158.1 (s, C, Ar), 127.9, 127.8 (2×s, CH, Ar), 118.0 (s, C, Ar), 104.7 (s, CH, Ar), 98.9 (s, CH, Ar), 69.8 (s, C), 55.5 (s, CH3), 55.2 (s, CH3), 45.5 (s, CH2N), 40.1 (s, CH), 30.4 (s, CH2CH2N), 28.0 (s, CCH2), 19.1 (s, CCH2CH2CH). LCMS (m/z): 234 (M – Cl-). Anal. calcd for C14H20ClNO2: C, 62.33; H, 7.47; N, 5.19. Found: C, 62.48; H, 7.64; N, 5.46. 1-(Pyridin-3-yl)-2-azabicyclo[3.2.0]heptane (9b) Colourless oil. 8.5 g, 91% yield. 1

H NMR (400 MHz, Chloroform-d) δ 8.54 (s), 8.38 (d, J = 4.6 Hz, 1H), 7.56 (d, J = 7.6 Hz, 1H), 7.14 (dd, J = 7.6, 4.6 Hz, 1H), 3.42 – 3.14 (m, 2H), 3.07 – 2.80 (m, 1H), 2.50 – 2.34 (m, 1H), 2.25 – 1.90 (m, 3H), 1.84 – 1.49 (m, 2H), 1.49 – 1.20 (m, 1H). 13 C NMR (126 MHz, Chloroform-d) δ 147.7 (s), 147.3 (s), 142.0 (s), 132.9 (s), 123.0 (s), 67.4 (s), 46.8 (s), 44.6 (s), 33.7 (s), 33.2 (s), 19.7 (s).

LCMS (m/z): 175 (M + H+).


7


Anal. calcd for C11H14N2: C, 75.82; H, 8.10; N, 16.08. Found: C, 75.66; H, 8.45; N, 16.23. 1-(Pyrazin-2-yl)-2-azabicyclo[3.2.0]heptane hydrochloride (10b.HCl) White solid. 420 mg, 85% yield. 1

H NMR (400 MHz, Deuterium Oxide) δ 8.80 (d, J = 1.6 Hz, 1H), 8.49 (dd, J = 2.7, 1.6 Hz, 1H), 8.43 (d, J = 2.7 Hz, 1H), 3.90 – 3.48 (m, 2H), 3.25 (s, 1H), 2.70 – 2.50 (m, 1H), 2.50 – 2.20 (m, 2H), 2.11 – 1.87 (m, 2H), 1.78 – 1.60 (m, 1H). 13

C NMR (101 MHz, Deuterium Oxide) δ 153.7, 144.6, 142.4, 140.6, 70.2, 45.7, 42.9, 30.3, 27.5, 19.1. LCMS (m/z): 176 (M – Cl-). Anal. calcd for C10H14ClN3: C, 56.74; H, 6.67; N, 19.85. Found: C, 56.60; H, 6.84; N, 19.62. 1-(Furan-2-yl)-2-azabicyclo[3.2.0]heptane (11b) Colourless oil. 9.1 g, 90% yield. H NMR (400 MHz, Chloroform-d) δ 7.29 (s, 1H), 6.25 (s, 1H), 6.13 (s, 1H), 3.35 – 3.20 (m, 2H), 2.88 (m, 1H), 2.56 (m, 1H), 2.12 – 1.46 (m, 5H), 1.36 (m, 1H). 13

C NMR (101 MHz, Chloroform-d) δ 158.8, 141.4, 110.0, 104.1, 64.7, 46.7, 44.1, 33.3, 31.3, 19.6. LCMS (m/z): 164 (M + H+).

1-(Piperidin-3-yl)-2-azabicyclo[3.2.0]heptane (17) The solution of amine 9b (20.0 g, 115 mmol, 1.0 equiv.) in MTBE (250 mL) was mixed with 10% aqueous solution of NaOH (25 g, 625 mmol, 5.4 equiv.). The vigorously stirred reaction mixture was treated dropwise with Boc2O (30.0 g, 137 mmol, 1.2 equiv.). After stirring overnight the organic layer was washed with 10% Na2SO4 solution (100 mL), dried over anhydrous Na2SO4 and evaporated. Hexanes (100 mL) were added to the residue, the formed crystals were filtered and washed with hexanes (2×50 mL) to afford Boc-protected amine. The obtained product was dissolved in methanol (200 mL), treated with 10% palladium on charcoal (1.5 g, 14 mmol, 0.12 equiv.) and stirred for 48 h at 50ºC under hydrogen atmosphere (60 atm.). Palladium on charcoal was filtered off, the solution was evaporated to afford the product (26.1 g, 81% yield) as a colourless oil. H NMR of both diastereomers (400 MHz, Chloroform-d) δ 3.69 (s, 1H), 3.44 (m, 1H), 3.17 – 2.71 (m, 3H), 2.43 – 1.97 (m, 4H), 1.95 – 1.66 (m, 4H), 1.66 – 1.41 (m, 6H), 1.36 (s, 9H). 13

C NMR of both diastereomers (126 MHz, Chloroform-d) δ 154.5 (s), 153.7 (s), 79.0 (s), 70.8 (s), 70.0 (s), 50.0 (s), 48.4 (s), 48.0 (s), 47.0 (s), 41.5 (s), 40.1 (s), 39.1 (s), 29.1 (s), 28.6 (s), 27.8 (s), 27.2 (s), 25.9 (s), 20.6 (s), 20.4 (s). LCMS (m/z): 281 (M + H+).

Anal. calcd for C10H13NO: C, 73.59; H, 8.03; N, 8.58. Found: C, 73.85; H, 8.41; N, 8.21. 1-(Thiophen-2-yl)-2-azabicyclo[3.2.0]heptane ride (12b.HCl)

hydrochlo-

M. p. 178-179ºC. White solid. 10.3 g, 97% yield. 1

H NMR (400 MHz, Deuterium Oxide) δ 7.41 (d, J = 5.2 Hz, 1H), 7.11 (d, J = 2.8 Hz, 1H), 7.00 (dd, J = 5.2, 2.8 Hz, 1H), 3.76 – 3.60 (m, 2H), 3.33 (m, 1H), 2.53 (m, 2H), 2.21 (m, 2H), 2.04 – 1.93 (m, 1H), 1.65 (m, 1H). 13

C NMR (101 MHz, Deuterium Oxide) δ 141.3, 127.8, 127.4, 126.6, 67.6, 46.0, 43.4, 30.6, 29.5, 19.1. LCMS (m/z): 180 (M – Cl-). Anal. calcd for C10H14ClNS: C, 55.67; H, 6.54; N, 6.49; S, 14.86. Found: C, 55.78; H, 6.32; N, 6.81; S, 14.59. Crystals of 12b.HCl, suitable for an X-Ray diffraction study were obtained by a slow evaporation of a diluted solution of 12b HCl in methanol. 1-(1-Methyl-1H-pyrazol-4-yl)-2-azabicyclo[3.2.0]heptane hydrochloride (13b.HCl) White solid. 610 mg, 93% yield. 1 H NMR (400 MHz, Deuterium Oxide) δ 7.90 (s, 1H), 7.80 (s, 1H), 3.87 (s, 3H), 3.77 – 3.55 (m, 2H), 3.19 (m, 1H), 2.45 (m, 2H), 2.34 – 2.09 (m, 2H), 1.98 (dd, J = 13.8, 5.8 Hz, 1H), 1.70 – 1.57 (m, 1H).

C NMR (101 MHz, Deuterium Oxide) δ 135.4, 132.1, 120.8, 64.0, 45.9, 42.6, 38.3, 30.5, 28.6, 19.3. LCMS (m/z): 178 (M – Cl-).

Anal. calcd for C10H16ClN3: C, 56.20; H, 7.55; N, 19.66. Found: C, 56.55; H, 7.48; N, 19.28.

1

1

13

Page 8 of 10

Anal. calcd for C16H28N2O2: C, 68.53; H, 10.06; N, 9.99. Found: C, 68.90; H, 9.95; N, 10.11. 2-Azabicyclo[3.2.0]heptane-1-carboxylic acid hydrochloride (18) A solution of 11b (5.0 g, 30.7 mmol, 1.0 equiv.) and pyridine (3.2 g, 40.5 mmol, 1.3 equiv.) in acetonitrile (30 mL) was cooled to -20ºC under inert atmosphere. Benzoyl chloride (5.2 g, 37.0 mmol, 1.2 equiv.) was added dropwise and the reaction mixture was stirred overnight and evaporated under reduced pressure. The residue was dissolves in MTBE (100 mL), the formed solution was washed with 10% aqueous citric acid (100 mL) and saturated aqueous NaHCO3 (100 mL), dried over Na2SO4 and evaporated to yield protected amide. The crude product was dissolved in acetonitrile (50 mL) and added under inert atmosphere to a vigorously stirred mixture of NaIO4 (40.0 g, 187 mmol, 6.1 equiv.), RuCl3·H2O (0.35 g, 1.5 mmol, 0.05 equiv.), H2O (200 mL), CCl4 (300 mL) and acetonitrile (200 mL). The reaction mixture was stirred for 1 h. The color of the solution turned from yellowish to black. Then enough NaIO4 was added to restore the yellowish color. The reaction mixture was stirred for 1 h, then diluted with water (500 mL) and extracted with EtOAc (3×500 mL). The combined organic layers were washed with 20% aqueous NaHSO3 until colorless and brine and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. This residue was dissolved in saturated aqueous K2CO3 (500 mL) and washed with EtOAc (2×500 mL). The aqueous layer was acidified to pH 2 by addition of 2 N HCl and extracted with CH2Cl2 (2×500 mL). The combined organic layers were dried over Na2SO4 and evaporated to give Nprotected amino acid. Concentrated HCl (100 mL) was added to the product and heated at reflux for 24 h. The reaction mixture was evaporated,


8

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diluted with water (200 mL), washed with EtOAc (3×100 mL) and evaporated to afford the product (2.5 g, 47% yield) as a slightly yellow solid. 1

H NMR (400 MHz, DMSO-d6) δ 10.68 (broad s, 1H), 8.95 (broad s, 1H), 3.52 (m, 2H), 3.13 (m, 1H), 2.59 – 2.30 (m, 3H), 2.19 (m, 1H), 1.93 (m, 1H), 1.82 (dd, J = 12.5, 4.6 Hz, 1H), 1.70 (m, 1H). 13

C NMR (101 MHz, DMSO-d6) δ 171.3 (s), 68.1 (s), 45.7 (s), 40.9 (s), 30.3 (s), 24.5 (s), 20.3 (s).

Copies of NMR spectra and X-ray crystallography data are available free of charge via the Internet at http://pubs.acs.org.

Corresponding Author * [email protected] www.mykhailiukchem.org

Author Contributions The manuscript was written through contributions of all authors. All authors gave approval to the final version of the manuscript.

ACKNOWLEDGMENT

LCMS (m/z): 142 (M – Cl-). Anal. calcd for C7H12ClNO2: C, 47.33; H, 6.81; N, 7.89. Found: C, 47.65; H, 6.48; N, 8.02. 2,2,2-Trifluoro-1-(1-(5-iodo-2,4-dimethoxyphenyl)-2azabicyclo[3.2.0]heptan-2-yl)ethan-1-one (19) To a stirred solution of EtOAc (20 mL), acetonitrile (20 mL) and water (40 mL) were added NaIO4 (4.0 g, 18.8 mmol, 4.1 equiv.), 8b (1.5 g, 4.6 mmol, 1.0 equiv.) and RuCl3 (0.04 g, 0.19 mmol, 0.047 equiv.). The reaction mixture was stirred overnight under inert atmosphere at room temperature. EtOAc (200 mL) and water (200 mL) were added. The organic layer was separated, aqueous layer was washed with EtOAc (200 mL). The combined organic layers were dried over Na2SO4 and evaporated. The brown residue was purified by column chromatography to afford the product as white crystals (1.6 g, 76% yield).

Authors are grateful to Prof. A. Tolmachev for financial support, to Dr. A. Kozitskiy for 2D NMR spectra, to Dr. S. Shishkina for X-Ray analysis, to Prof. I. Komarov for fruitful discussions, to I. Pervak for help with ozonolysis.

REFERENCES (1)

(a) Mann, A. Conformational restriction and/or steric hindrance in medicinal chemistry. In The Practice of Medicinal Chemistry, 3rd ed.; Wermuth, C. G., Ed.; Academic Press/Elsevier: Amsterdam, 2008; p 363. (b) Komarov, I. V.; Grigorenko, A. O.; Turov, A. V.; Khilya, V. P. Russ. Chem. Rev. 2004, 73, 785.

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(a) Giannis, A.; Kolter, T. Angew. Chem., Int. Ed. 2003, 32, 1244. (b) Vagner, J.; Qu, H.; Hruby, V. J. Curr. Opin. Chem. Biol. 2008, 12, 292. (c) Ripka, A. S.; Rich, D. H. Curr. Opin. Chem. Biol. 1998, 2, 441. (a) Wlochal, J.; Davies, R. D. M.; Burton, J. Org. Lett. 2014, 16, 4094 (cubanes). (b) Chalmers, B. A.; Xing, H.; Houston, S.; Clark, C.; Ghassabian, S.; Kuo, A.; Cao, B.; Reitsma, A.; Murray, C.-E. P.; Stok, J. E.; Boyle, G. M.; Pierce, C. J.; Littler, S. W.; Winkler, D. A.; Bernhardt, P. V.; Pasay, C.; De Voss, J. J.; McCarthy, J.; Parsons, P. G.; Walter, G. H.; Smith, M. T.; Cooper, H. M.; Nilsson, S. K.; Tsanaktsidis, J.; Savage, G. P.; Williams, C. M. Angew. Chem. Int. Ed. 2016, 55, 3580 (cubanes). (c) Burkhard, J. A.; Wagner, B.; Fischer, H.; Schuler, F.; Müller, K.; Carreira, E. M. Angew. Chem. Int. Ed. 2010, 49, 3524 (spirocycles). (d) Stepan, A. F. et al. J. Med. Chem. 2012, 55, 3414 (bicyclo[1.1.1]pentanes); (e) Meanwell, N. A. J. Med. Chem. 2011, 54, 2529 (review). Our contribution: (a) Druzhenko, T.; Denisenko, O.; Kheylik, Y.; Zozulya, S.; Shishkina, S.; Tolmachev, A.; Mykhailiuk, P. K. Org. Lett. 2015, 17, 1922. (b) Denisenko, A. V.; Mityuk, A. P.; Grygorenko, O. O.; Volochnyuk, D. M.; Shishkin, O. V.; Tolmachev, A. A.; Mykhailiuk, P. K. Org. Lett. 2010, 12, 4372. (c) Kirichok, A. A.; Shton, I.; Kliachyna, M.; Pishel, I.; Mykhailiuk, P. K. Angew. Chem. Int. Ed. 2017, 56, 8865. (d) Chalyk, B.; Isakov, A.; Butko, M.; Hrebeniuk, K.; Savych, O.; Kucher, O.; Gavrilenko, K.; Druzhenko, T.; Yarmolchuk, V.; Zozulya, S.; Mykhailiuk, P. K. Eur. J. Org. Chem. 2017, 31, 4530. (e) Chalyk, B.; Butko, M.; Yanshyna, O.; Gavrilenko, K.; Druzhenko, T.; Mykhailiuk, P. K. Chem. Eur. J. 2017, 23, 16782. The search was performed at www.drugbank.ca, and www.ebi.ac.uk/chembl databases in July 2017. More than 1000 papers on the topic: (a) Kriis, K.; Ausmees, K.; Pehk, T.; Lopp, M.; Kanger, T. Org. Lett. 2010, 12, 2230; (b) Pedrosa, R.; Andre´s, C.; Nieto, J.; del Pozo, S. J. Org. Chem. 2003, 68, 4923; (c) Denisenko, A. V.; Druzhenko, T.; Skalenko, Y.; Samoilenko, M.; Grygorenko, O. O.; Zozulya, S.; Mykhailiuk, P. K. J. Org. Chem. 2017, 82, 9627; (d) Gonzalez, A.; Benitez, D.; Tkatchouk, E.; Goddard, W.; Toste, D. J. Am. Chem. Soc. 2011, 133, 5500; (e) Artamonov, O. S.; Slobodyanyuk, E. Y.; Volochnyuk, D. M.; Komarov, I. V.; Tolmachev, A. A.; Mykhailiuk, P. K. Eur. J. Org. Chem. 2014, 3592. Tricyclic systems containing core D: (a) Basler, B; Schuster, O.; Bach, T. J. Org. Chem. 2005, 70, 9798; (b) Albrecht, D.; Basler, B.; Bach, T. J. Org. Chem. 2008, 73, 2345; (c) Fort, D. A.; Woltering, T. J.; Nettekoven, M; Knust, H; Bach, T. Angew. Chem. Int. Ed. 2012, 51, 10169; (d) Ikeda, M.; Ohno, K.; Homma, K.; Ishibashi, H; Tamura, Y. Chem. Pharm. Bull.

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1

H NMR (400 MHz, Chloroform-d) δ 7.75 (s, 1H), 6.33 (s, 1H), 4.08 (t, J = 7.4 Hz, 2H), 3.83 (s, 3H), 3.77 (s, 3H), 3.01 (q, J = 7.9 Hz, 1H), 2.84 (q, J = 10.5 Hz, 1H), 2.48 (m, 1H), 2.42 – 2.28 (m, 1H), 2.14 (m, 1H), 1.93 (m, 1H), 1.77 – 1.59 (m, 1H). 13 C NMR (101 MHz, Chloroform-d) δ 158.4, 158.1, 154.2 (q, J = 36.0 Hz), 140.1, 123.4, 116.2 (q, J = 288.7 Hz), 95.6, 73.7, 70.9, 56.4, 55.2, 48.7 (q, J = 3.9 Hz), 45.0, 31.3, 26.9, 21.4. 19

F NMR (376 MHz, Chloroform-d) δ -73.39. (4)

LCMS (m/z): 456 (M + H+). Anal. calcd for C16H17F3INO3: C, 42.22; H, 3.76; N, 3.08. Found: C, 42.49; H, 3.59; N, 3.41. 2-Butyl-N-(2,6-dimethylphenyl)-2azabicyclo[3.2.0]heptane-1-carboxamide (24) The synthesis was performed according to the described procedure4c. White solid. 210 mg, 21% yield. 1

H NMR (400 MHz, Chloroform-d) δ 8.78 (s, 1H), 7.07 (s, 3H), 3.49 – 3.32 (m, 1H), 2.99 (dd, J = 14.0, 7.4 Hz, 1H), 2.87 – 2.65 (m, 2H), 2.61 – 2.46 (m, 2H), 2.25 – 2.12 (m, 6H), 2.04 – 1.88 (m, 2H), 1.66 (dd, J = 12.5, 5.3 Hz, 2H), 1.57 – 1.20 (m, 4H), 0.93 (t, J = 7.3 Hz, 3H).

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13

C NMR (101 MHz, Chloroform-d) δ 172.7 (s), 135.1 (s), 134.4 (s), 128.1 (s), 126.7 (s), 72.0 (s), 51.5 (s), 49.7 (s), 44.8 (s), 31.8 (s), 30.4 (s), 20.8 (s), 20.3 (s), 18.4 (s), 16.0 (s), 14.1 (s). LCMS (m/z): 301 (M + H+). Anal. calcd for C19H28N2O: C, 75.96; H, 9.39; N, 9.32. Found: C, 76.16; H, 9.05; N, 9.48.

Supporting Information

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1981, 29, 2062; (e) Roupany, A. J. A.; Baker, J. R. RSC Adv. 2013, 3, 10650; (f) Blanco-Ania, D.; Gawade, S. A.; Zwinkels, L. J. L.; Maartense, L.; Bolster, M. G.; Benningshof, J. C. J.; Rutjes, F. P. J. T. Org. Process Res. Dev. 2016, 20, 409; (g) Tang, P. C.; Lin, Z. G.; Wang, Y.; Yang, F. L.; Wang, Q.; Fu, J. H.; Zhang, L.; Gong, A. S.; Luo, J. J.; Dai, J.; She, G. H.; Si, D. D.; Feng, J. Chin. Chem. Lett. 2010, 21, 253. (a) G. Ciamician, P. Silber Ber. 1908, 41, 1928; (b) Poplata, S.; Troster, A.; Zou, Y.-Q.; Bach, T. Chem.Rev. 2016, 116, 9748 (review). Piotrowski, D. W. Synlett 1999, 7, 1091. (a) Pirrung, M. C. Tetrahedron Lett. 1980, 21, 4577; (b) Hughes, P.; Martin, M.; Clardy, J. Tetrahedron Lett. 1980, 21, 4579; (c) Esslinger, C. S.; Koch, H. P.; Kavanaugh, M. P.; Philips, D. P.; Chamberlin, A. R.; Thompson, C. M.; Bridges, R. J. Bioorg. Med. Chem. Lett. 1998, 8, 3101; (d) Tkachenko, A. N.; Radchenko, D. S.; Mykhailiuk, P. K.; Grygorenko, O. O.; Komarov, I. V. Org. Lett. 2009, 11, 5674; (e) Malpass, J. R.; Patel, A. B.; Davies, J. W.; Fulford, S. Y. J. Org. Chem. 2003, 68, 9348; (f) Varnes, J. G.; Lehr, G. S.; Moore, G. L.; Hulsizer, J. M.; Albert, J. S. Tetrahedron Lett. 2010, 51, 3756; (g) Mykhailiuk, P. K.; Kubyshkin, V.; Bach, T.; Budisa, N. J. Org. Chem. 2017, 82, 8831. Homoallylamine was previously used in the synthesis of polysubstituted 2-azabicyclo[3.2.0]heptanes: Refs 7. Pioneering work on the regioselectivity of substituted 1,6-heptadienes: Matlin, A. R.; George, C. F.; Wolff, S.; Agosta, W. C. J. Am. Chem. Soc. 1986, 108, 3385. We think, that the reaction mechanism changes. Reaction at 366nm/PhCOMe proceeds via the triplet biradical, while at 412 nm/Ir(ppy)3 – via the cation-radical. (a) Ischay, M. A.; Lu, Z.; Yoon, T. P. J. Am. Chem. Soc. 2010, 132, 8572; (b) Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C. Chem. Rev. 2013, 113, 5322 (review). CCDC numbers: 1521343 (7b), 1521342 (12b), 1521345 (18). Alternative synthesis of 18 is described in a PhD-thesis available online: Kopylova, N.: 2010, Universität Konstanz: http://dnb.info/1006534660/34.


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Photochemical synthesis of 2-azabicyclo[3.2.0]heptanes: advanced

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