Photochemical Synthesis of 3-Azabicyclo[3.2.0]heptanes: Advanced Building Blocks for Drug Discovery

Article abstract of DOI:10.1021/acs.joc.7b01678

We have developed a rapid two-step synthesis of substituted 3-azabicyclo[3.2.0]heptanes which are attractive building blocks for drug discovery. This new method utilizes very common chemicals, benzaldehyde, allylamine, and cinnamic acid, via intramolectul

Full text of DOI:10.1021/acs.joc.7b01678

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Article
Photochemical synthesis of 3-azabicyclo[3.2.0]heptanes:
advanced building blocks for drug discovery.
Aleksandr V. Denisenko, Tetiana Druzhenko, Yevhen Skalenko, Maryna
Samoilenko, Oleksandr O. Grygorenko, Sergey Zozulya, and Pavel K. Mykhailiuk
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01678 • Publication Date (Web): 16 Aug 2017
Downloaded from http://pubs.acs.org on August 16, 2017
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The Journal of Organic Chemistry
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Photochemical synthesis of 3-azabicyclo[3.2.0]heptanes: advanced
building blocks for drug discovery
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Aleksandr V. Denisenko,a,b Tetiana Druzhenko,b,c Yevhen Skalenko,a,b Maryna Samoilenko,b Oleksandr
O. Grygorenko,a Sergey Zozulya,b,d and Pavel K. Mykhailiuk*a
aDepartment of Chemistry, National Taras Shevchenko University of Kyiv, Volodymyrska 64, Kyiv 01033 (Ukraine)
bEnamine Ltd., Chervonotkatska 78, Kyiv 02094 (Ukraine), www.enamine.net
cInstitute of High Technologies, Academician Glushkov av. 4G, Kyiv 03022 (Ukraine)
dChemBioCenter, National Taras Shevchenko University of Kyiv, Volodymyrska 64, Kyiv 01601 (Ukraine)
ABSTRACT: We have developed a rapid twoꢀstep synthesis of substituted 3ꢀazabicyclo[3.2.0]heptanes which are attractive
building blocks for drug discovery. This new method utilizes very common chemicals ꢀ benzaldehyde, allylamine and cinnamic
acid, ꢀ via intramolectular [2+2]ꢀphotochemical cyclization.
INTRODUCTION
Modern drug discovery has been changing rapidly with terms like scaffold hopping,1 escape flatland2 and conformational
restriction3 emerging which has gained great recognition in the scientific community. In this context chemists are currently looking
for novel 3Dꢀshaped Fsp3ꢀrich building blocks.4,5
To this end substituted 3ꢀazabicyclo[3.2.0]ꢀheptanes were introduced as conformationally restricted surrogates for common
piperidine motifs (Figure 1, a). This concept has already been validated by several bioactive compounds currently under clinical
investigation (Figure 1, b).
Nevertheless, in spite of their significant potential, 3ꢀazabicyclo[3.2.0]ꢀheptanes remain quite rare in drug discovery (only 14 hits
in ChEMBL database,6 Figure 1a) due to the lack of a practical synthetic approach from available starting materials.7
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a)
Common
38155 hits (ChEMBL)
100 drugs (FDA)
Innovative
monocyclic
bicyclic
only 14 hits
1
(ChEMBL)
2
3
4
5
conformational
restriction
R
R
H
H
21th century
N
N
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b)
F
O
N
H
F
CO2H
O
N
H
N
N
N
O
N
H
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H
H2N
Belaperidone
Antischizophrenia agent
Ecenofloxacin
Antibacterial agent
Figure 1. a) Motifs of piperidine and 3ꢀazabicyclo[3.2.0]heptane in drug discovery; b) Bioactive 3ꢀazabicyclo[3.2.0]heptanes.
There are only a few reports in the literature on 3ꢀazabicyclo[3.2.0]heptanes with the a substituent on the cyclobutane ring
(Scheme 1)8 – the core of the antischizophrenia drug Belaperidone being an example (Figure 1, b).9ꢀ12 In 1995, Steiner and
colleagues8a performed [2+2]ꢀintramolecular photocyclization of dienes 1 (R = H, Scheme 1) using a mercury quartz lamp
apparatus to produce 3ꢀazabicyclo[3.2.0]heptane skeletons. Later, in 2000, Bach and coworkers8b protected the Nꢀatom (R = Boc,
Cbz, Ac) which enabled them to perform the reaction at 300 nm in the presence of acetophenone as a sensitizer in a quartz
apparatus. Finally, in 2003 Pedrosa and Andres8c synthesized the optically pure 3ꢀazabicyclo[3.2.0]ꢀheptanes by [2+2]ꢀ
photocyclization of chiral substrate 2 using a medium pressure mercury quartz lamp apparatus.
Also worth mentioning the work of Yoon, who synthesized several 3ꢀazabicyclo[3.2.0]heptanes with two substituents at the
cyclobutane ring by [Ir]ꢀcatalyzed photoredox intramolecular [2+2]ꢀcyclizations.10
Scheme 1. Approaches to monoꢀsubstituted 3ꢀazabicyclo[3.2.0]ꢀheptanes.
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In spite of the ongoing interest of medicinal chemists in 3ꢀazabicyclo[3.2.0]heptanes, however, these methods have not found
wide practical application to date, presumably due the low availability of the starting materials. Also, the need for a quartz
photochemical apparatus might have to some extent inhibited the practical synthesis on a large scale.
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In this work, we have developed a multigram twoꢀstep approach to monosubstituted 3ꢀazabicyclo[3.2.0]ꢀheptanes from very basic
starting materials, ꢀ benzaldehyde, allylamine, cinnamic acids, and common chemical glassware available.
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RESULTS AND DISCUSSION
Design. Previous intramolecular [2+2] photocyclizations of substrates 1 and 2 (Scheme 1) were performed at 254ꢀ300 nm with
(300 nm) or without (254 nm) sensitizer in a quartz apparatus. At the same time ordinary chemical flasks completely transmit the
light at only above 350 nm.13 Our aim was to find the conditions to force reaction to proceed at this or higher wavelength.
Therefore, we added a carbonyl group to substrates 1, 2 to elongate the conjugated chromophore chain (redꢀtoꢀblue, Scheme 2). We
envisioned that substrate 3 might absorb the light at a higher wavelength.
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Scheme 2. Design of substrate 3 for [2+2]ꢀphotocyclization at λmax > 350 nm.
Optimization of synthesis. We first tested the simplest amide 4, synthesized from cinnamic acid and allylamine (Table 1).
Unfortunately, all our attempts to perform [2+2]ꢀphotocyclization14 at 366 nm failed. Only the starting material was remained.
Next, to facilitate the reaction, we protected the Nꢀatom in amide 4 with a benzyl group. Indeed, substrate 5 underwent
[2+2]ꢀphotocyclization at 366 nm, however, after 12 h the conversion reached only ca. 20%. After some experimentation (Table 1),
we found that adding benzophenone as a triplet sensitizer significantly facilitated the reaction, and the sole transꢀisomer 5a was
easily formed. Also, we reduced the amount of sensitizer to 0.1 equiv, and increased the concentration up to 50 mM without any
significant effect on the reaction outcome. At higher concentrations, formation of unidentified side products was observed.
Table 1. Optimization studies.
Entry
λmax
Concentration
Ph2CO
Conversiona
1 (4)
2 (4)
3 (5)
4 (5)
366 nm
366 nm
366 nm
366 nm
5 mM
5 mM
5 mM
5 mM
–
0%
0%
1.0 eq.
–
20%
100%
1.0 eq.
5 (5)
6 (5)
7 (5)
8 (5)
9 (5)
366 nm
366 nm
366 nm
366 nm
366 nm
5 mM
5 mM
0.5 eq.
0.1 eq.
0.1 eq.
0.1 eq.
0.1 eq.
100%
100%
100%
100%
100%
10 mM
20 mM
30 mM
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10 (5)
11 (5)
366 nm
366 nm
50 mM
75 mM
0.1 eq.
0.1 eq.
100%
1
2
100% (ca. 10%
side products
a Conversion of the reaction was determined by 1H NMR of the reaction mixture.
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Large-scale synthesis. When protecting the Nꢀatom in amide 4 with benzyl group, we also kept in mind the availability of the
corresponding starting materials. In fact, we easily synthesized 200 g of the needed substrate 5 in only two steps using very basic
reagents (Scheme 3): benzaldehyde (20 USD/kg), allylamine (20 USD/kg) and cinnamic acid (25 USD/kg).
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Ph
Ph
H2N
CO2H
O
Cinnamic acid
Allylamine
HN
Ph
NaBH4
91%
(COCl)2/NEt3
93%
O
N
Ph
Benzaldehyde
Ph
(200 g)
5
Scheme 3. Scaled up synthesis of diene 5a.5
Finally, we studied this photochemical method in different scales. The synthesis in milligram scale was performed at 5 mM in 5
mL glass vials. The reaction in 10 g scale was efficiently performed at 50 mM in common 1Lꢀglass flask (Scheme 4).15
Ph
H
Ph
366 nm
H
CH3CN, Ph2CO
O
O
N
N
rt
89%
Ph
Ph
5a
5
20 mg
10 g
glass f lask (1 L)
glass flask (5 mL)
Scheme 4. Scaled up synthesis of compound 5a.
Scope. Having a practical procedure in hands, we next studied its scope (Table 2). First, we varied substituents in cinnamic acids
(alkenes 5ꢀ12). The reaction was found to be effective with all – orthoꢀ, metaꢀ or paraꢀsubstituents on the phenyl ring. Electronꢀ
donating (OMe), and withdrawing (F, CF3) substituents on the benzene ring did not have a significant effect on the reaction
outcome. The corresponding products 5aꢀ11a were isolated in 61ꢀ89% yield. Even the substitution at the C=C double bond did not
influence the reaction, as the corresponding fluorinated bicycle 12a was obtained in 62% yield.
Next, we challenged the synthesis of optically active compounds. In fact, replacing Bn group with (R)ꢀphenylethyl one (alkenes
13 and 14) allowed to synthesize the individual optically pure diastereomers 13a, 13b and 14a, 14b. In each pair the stereoisomers
were separated by column chromatography on silica gel. The stereoconfiguration of compounds 13a, 14a and 14b was determined
by an XꢀRay analysis (please, see SI).16
Variation of the structure of allylamine was next performed (alkenes 15ꢀ19). Substrates with substituted allylamines 15ꢀ18
smoothly underwent the photocyclization to afford the products 15aꢀ18a in good yields of 80ꢀ85%. Alkene 19 with the fragment of
homoallylamine selectively gave the piperidine derivative 19a. Herein, we did not go further in elaboration of the scope of
homoallylamines, but it seems that the current method can also be used towards preparation of diversely substituted bicyclic
piperidines.
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Table 2. Scope of the reaction.
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Alkene
Product
Yield
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5a
89%
80%
61%
85%
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61%
74%
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9a
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10a
11a
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12a
62%
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15a
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80%
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89%
aReagent 1, TFA, EtOAc, rt; bReagent 1, LiF, CH3CN, 60 °C; cmixture of diastereomers (2/1). dmixture of diastereomers (3/1).
Synthesis of building blocks. Next, we wanted to show that the obtained compounds could be easily transformed into the
appropriate building blocks for drug discovery. In fact, reduction of the model compound 5a with LiAlH4 followed by cleavage of
the Nꢀbenzyl protecting group with H2/Pd gave the target amine 20 (XꢀRay, please see SI)16 in 25 g scale (Scheme 5).
The individual diastereomers 14b and 14a were similarly transformed into the pure enantiomers (R)ꢀ21 and (S)ꢀ21. It is important
to mention that the current method represents a novel synthetic approach to amine (S)ꢀ21: the key component of Belaperidone
drug.17
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Scheme 5. Synthesis of racemic amine 20 (XꢀRay) and the optically pure (R)ꢀ21 and (S)ꢀ21: the key component of Belaperidone.
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Physico-chemical properties. We measured the physicochemical characteristics of 3ꢀazabicyclo[3.2.0]heptanes and compared them to
the established piperidine scaffolds. In fact, all model compounds 22–24 (Table 3) had nearly identical lipophilicity (logD), water
solubility (Sol.) and metabolic stability (CLint): important characteristics in drug discovery. This data shows that monosubstituted
3ꢀazabicyclo[3.2.0]heptanes are good conformationally restricted surrogates for piperidines needed in modern medicinal chemistry
projects.
Table 3. Measured physicoꢀchemical properties of models 22–24.
b
Compound
LogD(10)a
3.7
Sol(7.4)c
344
CLint
99
22
23
3.6
370
100
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2
24
3.5
365
88
3
4
5
aExperimental nꢀoctanol/water distribution coefficient (log) at pH 10.0. bIntrinsic clearance rate CLint (mg/(min·ꢁL)) measured in mouse liver microsomes. cThermodynamic
aqueous solubility (µM) in 50 mM phosphate buffer (pH 7.4).
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Conformational properties. To compare spatial arrangement of the substitutents provided by 3ꢀazabicyclo[3.2.0]heptane scaffold with
that of piperidine derivatives, we used exit vector plots (EVP) tool.18,19 In this approach, the substituents mounted onto the disubstituted
scaffold were simulated by two exit vectors n1 and n2 (Figure 2). Relative spatial arrangement of these vectors can be described by four
geometric parameters: the distance between the variation points C and N – r, the plane angles ϕ1 (between vectors n1 and CN) and ϕ2
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(between n2 and NC), and the dihedral angle
θ defined by vectors n1, CN and n2. Exit vector plots (EVP) were obtained by depicting the
values of these parameters in r –
θ
,
θ
–
ϕ1
/
ϕ2, and ϕ1
–
ϕ2 coordinates.
a
b
Figure 2. a) Definition of vectors n1, n2 (1,3ꢀdisubstituted piperidine scaffold is used as an example). b) Definition of geometric parameters
r, ϕ1 2, and
,
ϕ
θ.
We calculated the values of r, ϕ1, ϕ2, and θ from the XꢀRay data for the compounds 20⋅HCl, 13a, 14a and 14b (from this work), as well
as piperidine derivatives 25-28 (described in the literature)20ꢀ23 (Table 4). Analysis of the data obtained using EVP (Figure 3) showed that
3,6ꢀdisubstituted 3ꢀazabicyclo[3.2.0]heptane scaffolds (3,6ꢀABH, r = 3.11–3.34 Å) were larger than both 1,3ꢀ and 1,4ꢀdisubstituted
piperidines (r = 2.50–2.52 Å and 2.89–2.94 Å, respectively). 3,6ꢀABH scaffold appeared to have some flexibility related to the
= 106–156°). ϕ1 ϕ2 plot (Figure 3b) showed that the values of angles ϕ1 2, and for most conformations of 3,6ꢀABH could be
considered as intermediate between those found for 1,3ꢀdisubstituted piperidines 25, 26 and 1,4ꢀdisubstituted piperidone 27. According to
ϕ1 2 plot (Figure 3c), the 3,6ꢀABH scaffolds provided more dissymmetry (which is characterized by the distance from ϕ1 2 line) than
piperidineꢀderived scaffolds.
θ angle (θ
θ
–
/
,
ϕ
θ
–
ϕ
= ϕ
All three EVPs demonstrated that 3,6ꢀdisubstituted 3ꢀazabicyclo[3.2.0]heptanes occupy slightly different area of chemical space
compared with piperidine derivatives. Therefore, 3ꢀazabicyclo[3.2.0]heptanes must be considered as surrogates for piperidines, ideally
featuring them in comprehensive structureꢀactiviry relationship (SAR) studies in medicinal chemistry projects.
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F
F
1
2
3
H
H
H
H
H
H
H
H
4
5
6
7
O
N
O
O
N
N
N
H
Ph
Ph
Ph
20.HCl
13a
14a
14b
8
9
Br
O
.HCl
S
O
10
11
12
13
14
15
16
.HCl
N
O
N
HO
Ph
O
Ph
O
N
Boc
N
nPr
25.
26
27
28
HCl
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
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Table 4. The values of geometric parameters r, ϕ1
,
ϕ
2, and
θ
for 3ꢀazabicyclo[3.2.0]heptanes and piperidine derivatives.
Ref.
ϕ1, deg
ϕ2, deg
|θ
|, dega
Compound
20⋅HCl
13a
r, Å
106.1
132.7
113.7
149.9
142.5
156.3
90.5
75.8
138.0
4.2
3.113
3.326
3.288
3.318
3.335
3.333
2.521
2.498
2.886
2.942
2.944
51.9
33.7
32.1
35.8
33.0
34.2
43.2
36.8
6.1
20.8
25.9
23.7
24.6
24.1
24.5
37.0
42.0
17.2
28.4
25.0
This work
This work
This work
This work
This work
This work
20
14a (I)b
14a (II)b
14b (I)b
14b (I)b
25
26
27
21
22
23
23
28 (I)c
28 (II)c
25.5
22.6
10.1
aSince the signs of
θ
angle are opposite for different enantiomers, only absolute values of
θ
were considered. bTwo different molecules in the crystal cell. cTwo polymorphs.
a
b
c
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Figure 3. 3,6ꢀDisubstituted 3ꢀazabicyclo[3.2.0]heptanes and piperidine derivatives shown in a) r –
θ plot (polar coordinates); b) θ – ϕ1/ϕ2
1
2
3
plot; c) ϕ1
– ϕ2 plot
CONCLUSIONS
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In summary, this work describes three important findings:
(1) We developed a multigram twoꢀstep approach to racemic and optically pure monoꢀsubstituted 3ꢀazabicyclo[3.2.0]ꢀheptanes
from benzaldehyde, allylamine and cinnamic acid.
9
(2) The photochemical method was optimized to be performed at 366 nm in common noneꢀquartz chemical glassware.
(3) 3ꢀAzabicyclo[3.2.0]ꢀheptanes may be considered as conformationally restricted piperidine surrogates for medicinal
chemistry, which have very similar physicochemical properties, but occupy slightly different part of the chemical space according
to the analysis of exit vectors.
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The Ecenofloxacin and Belaperidone examples have demonstrated the potential of 3ꢀazabicyclo[3.2.0]ꢀheptanes in drug
discovery. However, the lack of a practical synthetic approach to them from cheap starting materials has constrained their wide use.
Given the high efficiency, simplicity, and low costs of our method, we believe that scientists will soon use it to prepare
3ꢀazabicyclo[3.2.0]ꢀheptanes, and they will soon become as popular in medicinal chemistry as piperidines.
EXPERIMENTAL SECTION
General methods
All starting materials were taken at Enamine. Column chromatography was performed using Kieselgel Merck 60 (230ꢀ400 mesh) as
the stationary phase. Reverse phase column chromatography was performed using C18ꢀmodified silica gel as a stationary phase,
column: SunFire Waters, 5 µm, 19 mm × 100 mm. 1Hꢀ, 19Fꢀ, 13CꢀNMR 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, 13C) or CFCl3 (19F) as internal
standards. Mass spectra were recorded on an LCꢀMS instrument with chemical ionization (CI). LCꢀMS data were acquired on
Agilent 1200 HPLC system equipped with DAD/ELSD/LCMSꢀ6120 diodematrix and massꢀselective 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.
General procedure for synthesis of amides 5-19
DMF (0.02 equiv) was added to 1M solution of cinnamic acid (1.0 equiv) in CH2Cl2. Then, (COCl)2 (2.0 equiv) was added
dropwise. The resulted reaction mixture was stirred for 2 h. Solvent and volatile byꢀproducts were removed under reduced pressure.
Formed acyl chloride was added dropwise to the previously cooled mixture of 1M solution of allylbenzylamine (0.8 equiv) in
º
CH2Cl2 and triethylamine (1.0 equiv) at ꢀ20 C. Reaction mixture was warmed to room temperature, stirred overnight and washed
with 0.5 M aqueous solution of citric acid (approx. 1 equiv), saturated aqueous solution of NaHCO3 (approx. 1 equiv) and water.
The organic layer was separated, dried over Na2SO4, filtered and evaporated under reduced pressure. The product was purified via
filtration through silica gel using pure MTBE as an eluent.
(2E)-N-allyl-N-benzyl-3-phenylacrylamide (5)
Yellow oil. 201 g, 93% yield.
1H NMR of both amide rotamers (400 MHz, CDCl3) δ 7.79 (d, PhCH=CH, 3J(H,H) = 15.3 Hz, 1H), 7.56 – 7.19 (m, 10H), 6.84 (d,
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PhCH=CH, J(H,H) = 15.3 Hz, 1H), 5.83 (m, 1H), 5.21 (m, 2H), 4.71, 4.66 (2×s, 2H), 4.11, 3.99 (2×s, 2H). 13C NMR of both
amide rotamers (126 MHz, CDCl3) δ 167.0, 166.8, 143.5, 143.1, 137.6, 137.0, 135.3, 135.2, 133.0, 129.6, 129.0, 128.8, 128.6,
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128.3, 127.8, 127.7, 127.4, 126.5, 117.7, 117.6, 117.4, 117.0, 50.2, 49.3, 49.1, 48.6. MS (CI, m/z): 278 [M++H]. Anal. calcd for
C19H19NO: C, 82.28 H, 6.90 N, 5.05 Found: C, 82.61 H, 6.65 N, 5.20.
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(2E)-N-allyl-N-benzyl-3-(4-fluorophenyl)acrylamide (6)
Yellow oil. 252 mg, 83% yield.
1H NMR of both amide rotamers (400 MHz, CDCl3) δ 7.74 (d, ArCH=CH, 3J(H,H) = 15.4 Hz, 1H), 7.54 – 6.92 (m, Ph + Ar, 9H),
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6.75 (d, PhCH=CH, J(H,H) = 15.4 Hz, 1H), 5.80 (m, CH2=CH, 1H), 5.18 (m, CH2=CH, 2H), 4.68, 4.64 (2×s, CH2Ph, 2H), 4.10,
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3.96 (2×s, CH2N, 2H). 13C NMR of both amide rotamers (101 MHz, CDCl3) δ 166.9, 166.7, 164.7, 162.3, 142.2, 142.0, 137.6,
137.0, 133.0, 131.6, 131.4, 129.7, 129.6, 129.0, 128.6, 128.3, 127.7, 127.4, 126.5, 117.7, 117.3, 117.2, 117.0, 115.99, 115.95,
115.8, 115.7, 50.2, 49.2, 49.1, 48.7. 19F NMR of both amide rotamers (376 MHz, CDCl3) δ ꢀ111.07, ꢀ111.12 (2×s). MS (CI, m/z):
296 [M++H]. Anal. calcd for C19H18FNO: C, 77.27 H, 6.14 N, 4.74 Found: C, 77.05 H, 5.93 N, 5.03.
(2E)-N-allyl-N-benzyl-3-(3-fluorophenyl)acrylamide (7)
Yellow oil. 311 mg, 62% yield.
1H NMR of both amide rotamers (400 MHz, CDCl3) δ 7.72 (d, ArCH=CH, 3J(H,H) = 15.4 Hz, 1H), 7.40 – 6.93 (m, Ar + Ph, 9H),
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6.81 (d, ArCH=CH, J(H,H) = 15.4 Hz, 1H), 5.81 (m, CH2=CH, 1H), 5.19 (m, CH2=CH, 2H), 4.69, 4.64 (2×s, PhCH2, 2H), 4.09,
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3.97 (2xs, CHCH2N, 2H). 13C NMR of both amide rotamers (126 MHz, CDCl3) δ 166.6, 166.4, 163.0 (d, Ph, J(C,F) = 246.4 Hz),
142.1, 141.9, 137.6, 137.6, 137.5, 137.5, 136.9, 132.9, 130.4, 130.3, 129.0, 128.6, 128.3, 127.7, 127.5, 126.5, 123.9, 118.9, 118.8,
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117.8, 117.1, 116.5 (d, J(C,F) = 21.4 Hz), 114.0 (d, J(C,F) = 22.0 Hz), 114.0 (d, J(C,F) = 21.8 Hz), 50.2, 49.3, 49.2, 48.7. 19F
NMR of both amide rotamers (376 MHz, CDCl3) δ ꢀ113.3 (s). MS (CI, m/z): 296 [M++H]. Anal. calcd for C19H18FNO: C, 77.27 H,
6.14 N, 4.74 Found: C, 77.58 H, 6.28 N, 4.56.
(2E)-N-allyl-N-benzyl-3-(2-fluorophenyl)acrylamide (8)
Yellow oil. 272 mg, 60% yield.
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1H NMR of both amide rotamers (400 MHz, CDCl3) δ 7.85 (d, ArCH=CH, J(H,H) = 15.6 Hz, 1H), 7.50 – 6.93 (m, Ar + Ph +
ArCH=CH, 10H), 5.78 (m, CH2=CH, 1H), 5.16 (s, CH2=CH, 2H), 4.68, 4.62 (2xs, PhCH2, 2H), 4.09, 3.94 (2×s, CHCH2N, 2H). 13
C
NMR of both amide rotamers (101 MHz, CDCl3) δ 166.9, 166.7, 162.6, 162.5, 160.04, 159.99, 137.6, 137.0, 136.3, 136.1, 132.9,
131.0, 130.9, 129.64, 129.61, 129.51, 129.48, 128.9, 128.6, 128.3, 127.7, 127.4, 126.6, 124.42, 124.39, 123.3, 123.24, 123.21,
123.1, 120.6, 120.5, 120.4, 120.3, 117.8, 117.1, 116.22, 116.19, 116.00, 115.97, 50.2, 49.3, 49.2, 48.7. 19F NMR of both amide
rotamers (376 MHz, CDCl3) δ ꢀ114.6 (s), ꢀ114.7 (s). MS (CI, m/z): 296 [M++H]. Anal. calcd for C19H18FNO: C, 77.27 H, 6.14 N,
4.74. Found: C, 77.59 H, 6.01 N, 4.93.
(2E)-N-allyl-N-benzyl-3-(4-methoxyphenyl)acrylamide (9)
Yellow oil. 201 mg, 75% yield.
1H NMR of both amide rotamers (400 MHz, CDCl3) δ 7.74 (d, ArCH=CH, 3J(H,H) = 15.3 Hz, 1H), 7.26 (m, Ar + Ph, 9H), 6.70 (d,
ArCH=CH, 3J(H,H) = 15.3 Hz, 1H), 5.78 (m, CH2=CH, 1H), 5.16 (m, CH2=CH, 2H), 4.67, 4.61 (2×s, PhCH2, 2H), 4.08, 3.94 (2×s,
CHꢀCH2N, 2H), 3.73, 3.71 (2×s, CH3O, 3H). 13C NMR of both amide rotamers (126 MHz, CDCl3) δ 167.2, 167.1, 137.8, 137.2,
133.2, 129.4, 128.9, 128.6, 128.3, 128.0, 127.9, 127.6, 127.3, 126.5, 117.6, 116.9, 115.0, 114.9, 114.2, 55.3, 50.2, 49.2, 49.1, 48.6.
MS (CI, m/z): 308 [M++H]. Anal. calcd for C20H21NO2: C, 78.15 H, 6.89 N, 4.56. Found: C, 78.39 H, 6.74 N, 4.66.
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(2E)-N-allyl-N-benzyl-3-(3-methoxyphenyl)acrylamide (10)
Yellow oil. 239 mg, 69% yield.
1H NMR of both amide rotamers (400 MHz, CDCl3) δ 7.74 (d, ArCH=CH, 3J(H,H) = 15.4 Hz, 1H), 7.07 (m, Ar + Ph + ArCH=CH,
10H), 5.78 (m, CH2=CH, 1H), 5.15 (m, CH2=CH, 2H), 4.67, 4.62 (2×s, PhCH2, 2H), 4.09, 3.94 (2×s, CH2N, 2H), 3.74, 3.70 (s,
OCH3, 3H). 13C NMR of both amide rotamers (126 MHz, CDCl3) δ 166.9, 166.7, 159.9, 159.8, 143.3, 143.1, 137.6, 137.1, 136.7,
136.6, 133.1, 133.0, 129.82, 129.78, 128.9, 128.6, 128.3, 127.7, 127.4, 126.5, 120.4, 117.9, 117.8, 117.7, 117.0, 115.2, 115.1,
113.4, 113.2, 55.2, 50.2, 49.3, 49.1, 48.7. MS (CI, m/z): 308 [M++H]. Anal. calcd for C20H21NO2: C, 78.15 H, 6.89 N, 4.56. Found:
C, 78.41 H, 7.10 N, 4.38.
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(2E)-N-allyl-N-benzyl-3-(2-methoxyphenyl)acrylamide (11)
Yellow oil. 268 mg, 48% yield.
1H NMR of both amide rotamers (500 MHz, CDCl3) δ 8.07 (dd, ArCH=CH, 1H), 7.53 – 6.77 (m, Ph + Ar + ArCH=CH, 10H), 5.81
(m, CH2=CH, 1H), 5.18 (m, CH2=CH, 2H), 4.69, 4.62 (2xs, CH2Ph, 2H), 4.12, 3.95 (2×s, NCH2СH, 2H), 3.79, 3.70 (2xs, OCH3,
3H). 13C NMR of both amide rotamers (126 MHz, CDCl3) δ 167.5, 167.4, 158.3, 139.0, 138.7, 137.8, 137.3, 133.23 (s), 133.18 (s),
130.8, 129.2, 129.0, 128.9, 128.6, 128.3, 127.5, 127.3, 126.6, 124.3, 124.2, 120.7, 118.6, 118.5, 117.5, 116.9, 111.2, 55.4, 55.3,
50.3, 49.3, 49.1, 48.7. MS (CI, m/z): 308 [M++H]. Anal. calcd for C20H21NO2: C, 78.15 H, 6.89 N, 4.56. Found: C, 77.84 H, 6.62 N,
4.72.
(2Z)-N-allyl-N-benzyl-2-fluoro-3-[4-(trifluoromethyl)phenyl]acrylamide (12)
Yellow oil. 273 mg, 61% yield.
1H NMR of both amide rotamers (400 MHz, CDCl3) δ 7.63 – 6.95 (m, 9H), 6.52, 6.49,(2xd, 3J(H,F) = 20 Hz, 3J(H,F) = 24 Hz, 1H),
5.63 (m, 1H), 5.15 (m, 2H), 4.61, 4.44 (2xs, 2H), 3.94, 3.79 (2×d, 3J(H,H) = 6.0 Hz, 3J(H,H) = 5.7 Hz, 2H). 13C NMR of both amide
rotamers (101 MHz, CDCl3) δ 162.6, 162.5, 162.2, 162.1, 153.6, 153.5, 151.0, 150.9, 135.7, 135.1, 134.7, 134.6, 132.2, 131.0,
128.81, 128.75, 128.7, 128.59, 128.57, 128.48, 128.45, 128.0, 127.9, 127.6, 125.7, 125.63, 125.58, 125.55, 125.31, 125.28, 122.61,
122.57, 119.4, 119.1, 111.5, 111.3, 111.0, 51.1, 50.0, 46.8, 46.1. 19F NMR of both amide rotamers (376 MHz, CDCl3) δ ꢀ63.2, 63.3
(2×s, CF3, 3F), ꢀ103.37, ꢀ104.44 (2×s, CF, F). MS (CI, m/z): 364 [M++H]. Anal. calcd for C20H17F4NO: C, 66.11 H, 4.72 N, 3.85.
Found: C, 66.39 H, 4.50 N, 3.69.
Amides 13 (yellow oil, 311 mg, 84% yield, MS (CI, m/z): 292 [M++H]) and 14 (yellow oil, 384 mg, 94% yield, MS (CI, m/z): 310
[M++H]) were obtained in 90ꢀ95% purity and used for the next step without additional purification.
N-benzyl-N-((E)-but-2-en-1-yl)cinnamamide (15)
Colorless oil. 229 mg, 91% yield.
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1H NMR of both amide rotamers (400 MHz, CDCl3) δ 7.78 (d, PhCH=CH, J(H,H) = 15.4 Hz, 1H), 7.57 – 7.21 (m, 10H), 6.88,
6.82 (2×d, PhCH=CH, 3J(H,H) = 15.4 Hz, 1H), 5.72 – 5.55 (m, 1H), 5.55 – 5.34 (m, 1H), 4.69, 4.65 (2×s, 2H), 4.04 (d, J = 5.1 Hz,
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1H), 3.92 (br s, 1H), 1.72 (d, CH3, J(H,H) = 6.7 Hz, 3H). 13C NMR of both amide rotamers of both amide rotamers (101 MHz,
CDCl3) δ 166.8, 137.8, 137.2, 135.4, 135.3, 129.6, 129.4, 128.9, 128.82, 128.6, 128.3, 127.9, 127.6, 127.3, 126.5, 125.8, 117.7,
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50.0, 48.8, 48.7, 47.9, 17.8. MS (CI, m/z): 292 [M++H]. Anal. calcd for C20H21NO: C, 82.44; H, 7.26; N, 4.81. Found: C, 82.74; H,
7.51; N, 4.68.
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N-benzyl-N-((E)-pent-2-en-1-yl)cinnamamide (16)
Yellow oil. 238 mg, 81% yield.
1H NMR of both amide rotamers (400 MHz, CDCl3) δ 7.81 (d, PhCH=CH, J(H,H) = 15.3 Hz, 1H), 7.56 – 7.22 (m, 10H), 6.88
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(2×d, PhCH=CH, 3J(H,H) = 14.2 Hz, 1H), 5.66 – 5.49 (m, 1H), 5.47 – 5.26 (m, 1H), 4.68 (2×s, 2H), 4.17 (d, J = 6.4 Hz, 1H), 4.00
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(d, J = 5.6 Hz, 1H), 2.10 – 1.96 (m, 2H), 0.98, 0.96 (2×t, J(H,H) = 7.3 Hz, 3H). 13C NMR of both amide rotamers (101 MHz,
CDCl3) δ 166.8, 166.6, 143.2, 143.0, 137.5, 137.0, 135.7, 135.2, 135.1, 134.9, 129.5, 128.8, 128.70, 128.65, 128.5, 128.1, 127.7,
127.6, 127.3, 126.4, 124.4, 123.7, 117.53, 117.45, 50.1, 49.0, 44.2, 42.4, 20.7, 20.5, 14.1, 14.0. MS (CI, m/z): 306 [M++H]. Anal.
calcd for C21H23NO: C, 82.58; H, 7.59; N, 4.59. Found: C, 82.74; H, 7.33; N, 4.72.
N-benzyl-N-(2-methylallyl)cinnamamide (17)
Colorless oil. 282 mg, 84% yield.
1H NMR of both amide rotamers (400 MHz, CDCl3) δ 7.80 (d, PhCH=CH, J(H,H) = 15.4 Hz, 1H), 7.53 – 7.18 (m, 10H), 6.89,
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6.81 (2×d, PhCH=CH, 3J(H,H) = 15.3 Hz, 1H), 4.93 (d, J(H,H) = 36.2 Hz, 1H), 4.85 (d, J(H,H) = 54.8 Hz, 1H), 4.66 (2×s, 2H),
4.09 (s, 1H), 3.84 (s, 1H), 1.72 (s, 3H). 13C NMR of both amide rotamers (101 MHz, CDCl3) δ 167.1, 166.8, 143.5, 143.0, 140.5,
140.0, 137.5, 136.8, 135.2, 135.0, 129.5, 128.8, 128.7, 128.5, 128.1, 127.7, 127.5, 127.2, 126.4, 117.4, 117.1, 112.5, 111.9, 52.2,
50.9, 49.6, 49.0, 20.0. MS (CI, m/z): 293 [M++H]. Anal. calcd for C20H21NO: C, 82.44; H, 7.26; N, 4.81. Found: C, 82.20; H, 7.51;
N, 4.98.
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N-benzyl-N-(2-methylenebutyl)cinnamamide (18)
Yellow oil. 219 mg, 87% yield.
1H NMR of both amide rotamers (400 MHz, CDCl3) δ 7.81, 7.80 (2×d, PhCH=CH, 3J(H,H) = 15.4 Hz, 1H), 7.51 – 7.20 (m, 10H),
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6.89, 6.79 (2×d, PhCH=CH, J(H,H) = 15.4 Hz, 1H), 4.96 (d, CH, J(H,H) = 33.5 Hz, 1H), 4.87 (d, CH, J(H,H) = 50.4 Hz, 1H),
4.70, 4.64 (2×s, 2H), 4.12, 3.89 (2×s, 2H), 2.08 – 1.97 (m, 2H), 1.09, 1.08 (2×t, J(H,H) = 7.3 Hz, 3H). 13C NMR of both amide
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rotamers (101 MHz, CDCl3) δ 167.3, 167.0, 146.2, 145.7, 143.7, 143.2, 137.7, 137.0, 135.4, 135.2, 129.69, 129.65, 129.0, 128.82,
128.78, 128.6, 128.3, 127.89, 127.85, 127.7, 127.4, 126.5, 117.6, 117.3, 110.5, 109.8, 51.3, 50.2, 49.8, 49.1, 26.6, 26.5, 12.3, 12.1.
MS (CI, m/z): 306 [M++H]. Anal. calcd for C21H23NO: C, 82.58; H, 7.59; N, 4.59. Found: C, 82.41; H, 7.87; N, 4.26.
N-benzyl-N-(but-3-en-1-yl)cinnamamide (19)
Yellow oil. 213 mg, 95% yield.
1H NMR of both amide rotamers (400 MHz, CDCl3) δ 7.81, 7.76 (2×d, PhCH=CH, 3J(H,H) = 15.6 Hz, 1H), 7.57 – 7.16 (m, 10H),
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6.91, 6.81 (2×d, PhCH=CH, J(H,H) = 15.4 Hz, 1H), 5.93 – 5.65 (m, 1H), 5.13 – 5.00 (m, 2H), 4.73, 4.67 (2×s, 2H), 3.55 (t,
3J(H,H) = 7.2 Hz, 1H), 3.44 (t, 3J(H,H) = 7.3 Hz, 1H), 2.43 – 2.28 (m, 2H). 13C NMR of both amide rotamers (101 MHz, CDCl3) δ
166.9, 166.5, 143.1, 143.0, 137.7, 137.1, 135.4, 135.2, 135.1, 134.2, 129.6, 129.5, 128.9, 128.8, 128.7, 128.5, 128.0, 127.8, 127.6,
127.3, 126.4, 117.6, 117.5, 117.3, 116.7, 51.5, 49.3, 46.7, 46.4, 33.6, 32.2. MS (CI, m/z): 292 [M++H]. Anal. calcd for C20H21NO:
C, 82.44; H, 7.26; N, 4.81. Found: C, 82.69; H, 7.10; N, 4.70.
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General procedure for [2+2] photocycloaddition (synthesis of amides 5a-19a, 13b, 14b)
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Benzophenone (0.1 equiv) was added to 0.05 M solution of starting material (1.0 equiv) in dry acetonitrile. Reaction mixture was
degassed by bubbling of argon for 15 minutes and irradiated at 365 nm. After the accomplishment (reaction was monitored by
NMR, typically it was conducted for 36ꢀ72 h) reaction mixture was concentrated. The final product was purified via column
chromatography.
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(1RS,5SR,7RS)-3-benzyl-7-phenyl-3-aza-bicyclo[3.2.0]heptan-2-one (5a)
Colorless oil. 10.1 g, 89% yield. Was used as a crude material for further synthetic transformations. In order to characterize this
compound, small amount was purified via a gradient reverse phase chromatography (H2O/acetonitrile from 65/35 to 40/60).
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1H NMR (400 MHz, CDCl3) δ 7.40 – 7.17 (m, 10H), 4.66 (d, J(H,H) = 14.6 Hz, 1H), 4.42 (d, J(H,H) = 14.6 Hz, 1H), 3.69 (m,
1H), 3.50 (m, 1H), 3.18 (d, 3J(H,H) = 10.6 Hz, 2H), 2.99 (m, 1H), 2.49 (m, 1H), 2.32 (m, 1H). 13C NMR (126 MHz, CDCl3) δ 176.0
(s, C=O), 144.5 (s, Ph), 136.6 (s, Ph), 128.8 (s. Ph), 128.6 (s, Ph), 128.2 (s, Ph), 127.6 (s, Ph), 126.4 (s, Ph), 126.3 (s, Ph), 53.2,
48.4, 46.8, 42.8, 33.7, 27.4. MS (CI, m/z): 278 [M++H]. Anal. calcd for C19H19NO: C, 82.28 H, 6.90 N, 5.05. Found: C, 82.08 H,
6.76 N, 5.27.
(1RS,5SR,7SR)-3-benzyl-7-(4-fluorophenyl)-3-azabicyclo[3.2.0]heptan-2-one (6a)
Yellow oil. 139 mg, 80% yield. Purified via gradient reverse phase chromatography (H2O/acetonitrile from 35/65 to 25/75).
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1H NMR (400 MHz, CDCl3 7.39 – 7.21 (m, Ar + Ph, 7H), 7.01 (t, J = 8.6 Hz, 2H), 4.65 (d, CH2Ph, 2J(H,H) = 14.6 Hz, 1H), 4.41
(d, CH2Ph, 2J(H,H) = 14.6 Hz, 1H), 3.65 (m, 1H), 3.50 (m, 1H), 3.17 (m, 2H), 2.98 (m, 1H), 2.44 (m, 1H), 2.33 (m, 1H). 13C NMR
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(126 MHz, CDCl3) δ 175.8 (s, C=O), 161.5 (d, J(C,F) = 244.6 Hz), 140.2 (d, J(C,F) = 3.0 Hz), 136.5, 128.8, 128.2, 127.9 (d,
3J(C,F) = 7.9 Hz), 127.6, 115.3 (d, 2J(C,F) = 21.2 Hz), 53.2, 48.6, 46.8, 42.1, 33.9, 27.2. 19F NMR (376 MHz, CDCl3) δ ꢀ117.4 (s).
MS (CI, m/z): 296 [M++H]. Anal. calcd for C19H18FNO: C, 77.27 H, 6.14 N, 4.74. Found: C, 76.96 H, 6.30 N, 5.06.
(1RS,5SR,7SR)-3-benzyl-7-(3-fluorophenyl)-3-azabicyclo[3.2.0]heptan-2-one (7a)
Yellow oil. 182 mg, 61% yield. Purified via gradient reverse phase chromatography (H2O/acetonitrile from 65/35 to 40/60).
1H NMR (400 MHz, CDCl3) δ 7.40 – 7.23 (m, Ar + Ph, 6H), 7.10 (d, Ar, 3J = 7.6 Hz, 1H), 7.04 (d, Ar, 3J = 9.8 Hz, 1H), 6.91 (t, Ar,
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3J = 7.6 Hz, 1H), 4.66 (d, CH2Ph, J(H,H) = 14.6 Hz, 1H), 4.42 (d, CH2Ph, J(H,H) = 14.6 Hz, 1H), 3.67 (m, 1H), 3.51 (m, 1H),
3.17 (m, 2H), 3.00 (m, 1H), 2.47 (m, 1H), 2.33 (m, 1H). 13C NMR (126 MHz, CDCl3) δ 175.7 (s, C=O), 163.1 (d, Ar, J(C,ꢀF) =
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245.8 Hz), 147.1 (d, Ar, 3J(C,F) = 7.1 Hz), 136.5, 130.0 (d, Ar, J(CꢀF) = 8.4 Hz), 128.8, 128.2, 127.7, 122.2 (d, Ar, J(C,F) = 2.8
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Hz), 113.3 (d, Ar, J(C,F) = 21.4 Hz), 113.2 (d, Ar, J(C,F) = 21.1 Hz), 53.1, 48.3, 46.8, 42.5 (d, ArCH, J(C,F) = 1.7 Hz), 33.6,
27.4. 19F NMR (376 MHz, CDCl3) δ ꢀ113.7 (s). MS (CI, m/z): 296 [M++H]. Anal. calcd for C19H18FNO: C, 77.27 H, 6.14 N, 4.74.
Found: C, 77.65 H, 6.05 N, 4.87.
(1RS,5SR,7SR)-3-benzyl-7-(2-fluorophenyl)-3-azabicyclo[3.2.0]heptan-2-one (8a)
Yellow oil. 171 mg, 85% yield. Purified via gradient reverse phase chromatography (H2O/acetonitrile from 35/65 to 30/70).
1H NMR (400 MHz, CDCl3) δ 7.42 – 6.97 (m, Ar + Ph, 9H), 4.66 (d, CH2Ph, J(H,H) = 14.5 Hz, 1H), 4.43 (d, CH2Ph, J(H,H) =
14.5 Hz, 1H), 3.84 (m, 1H), 3.50 (m, 1H), 3.32 (m, 1H), 3.05 (m, 1H), 2.46 (m, 1H), 2.36 (m, 1H). 13C NMR (126 MHz, CDCl3) δ
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175.9 (s, C=O), 160.8 (d, 1J(C,F) = 246.1 Hz), 136.6, 131.1 (d, 2J(C,F) = 14.3 Hz), 128.8, 128.2, 128.1 (d, 3J(C,F) = 8.3 Hz), 128.0
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(d, 3J(C,F) = 4.7 Hz), 127.6, 124.1 (d, J(C,F) = 3.5 Hz), 115.6 (d, J(C,F) = 22.0 Hz), 53.1, 46.8, 46.7, 37.6, 33.8, 27.3. 19F NMR
(376 MHz, CDCl3) δ ꢀ117.2 (s). MS (CI, m/z): 296 [M++H]. Anal. calcd for C19H18FNO: C, 77.27 H, 6.14 N, 4.74. Found: C, 76.96
H, 5.99 N, 4.94.
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(1RS,5SR,7SR)-3-benzyl-7-(4-methoxyphenyl)-3-azabicyclo[3.2.0]heptan-2-one (9a)
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Yellow oil. 151 mg, 82% yield. Purified via gradient reverse phase chromatography (H2O/acetonitrile from 35/65 to 30/70).
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1H NMR (400 MHz, CDCl3) δ 7.42 – 7.16 (m, Ph + Ar, 7H), 6.87 (d, Ar, J(H,H) = 8.6 Hz, 2H), 4.65 (d, J(H,H) = 14.6 Hz, 1H),
4.41 (d, 2J(H,H) = 14.6 Hz, 1H), 3.79 (s, OCH3, 3H), 3.62 (s, 1H), 3.48 (m, 1H), 3.15 (m, 2H), 2.97 (m, 1H), 2.44 (m, 1H), 2.29 (m,
1H). 13C NMR (126 MHz, CDCl3) δ 176.1(s, C=O), 158.1, 136.7, 128.7, 128.2, 127.6, 127.4, 113.9, 55.3, 53.2, 48.7, 46.8, 42.2,
33.9, 27.3. MS (CI, m/z): 308 [M++H]. Anal. calcd for C20H21NO2: C, 78.15 H, 6.89 N, 4.56. Found: C, 78.50 H, 7.15 N, 4.73.
(1RS,5SR,7SR)-3-benzyl-7-(3-methoxyphenyl)-3-azabicyclo[3.2.0]heptan-2-one (10a)
Yellow oil. 181 mg, 61% yield. Purified via gradient reverse phase chromatography (H2O/acetonitrile from 35/65 to 30/70).
1H NMR (400 MHz, CDCl3) δ 7.40 – 7.20 (m, 6H), 6.93 (d, Ar, 3J(H,H) = 7.6 Hz, 1H), 6.87 (s, Ar, 1H), 6.76 (d, Ar, 3J(H,H) = 8.1
Hz, 1H), 4.65 (d, CH2Ph, 2J(H,H) = 14.6 Hz, 1H), 4.41 (d, CH2Ph, 2J(H,H) = 14.6 Hz, 1H), 3.80 (s, OCH3, 3H), 3.65 (m, 1H), 3.48
(m, 1H), 3.17 (d, 3J(H,H) = 10.2 Hz, 2H), 2.99 (m, 1H), 2.48 (m, 1H), 2.31 (m, 1H). 13C NMR (126 MHz, CDCl3) δ 176.0 (s, C=O),
159.8 (s, Ph), 146.2 (s, Ph), 136.6 (s, Ph), 129.5 (s, Ph), 128.7 (s, Ph), 128.2 (s, Ph), 127.6 (s, Ph), 118.7 (s, Ph), 112.3 (s, Ph), 111.6
(s, Ph), 55.2, 53.1, 48.4, 46.8, 42.8, 33.7, 27.4. MS (CI, m/z): 308 [M++H]. Anal. calcd for C20H21NO2: C, 78.15 H, 6.89 N, 4.56.
Found: C, 77.87 H, 6.60 N, 4.44.
(1RS,5SR,7SR)-3-benzyl-7-(2-methoxyphenyl)-3-azabicyclo[3.2.0]heptan-2-one (11a)
Yellow oil. 159 mg, 74% yield. Purified via gradient reverse phase chromatography (H2O/acetonitrile from 40/60 to 25/75).
1H NMR (400 MHz, CDCl3) δ 7.43 – 6.80 (m, Ar + Ph, 9H), 4.65 (d, CH2Ph, J(H,H) = 14.7 Hz, 1H), 4.44 (d, CH2Ph, J(H,H) =
14.4 Hz, 1H), 3.90 (m, 1H), 3.83 (s, OCH3, 3H), 3.48 (m, 1H), 3.28 (m, 1H), 3.18 (d, J = 10.3 Hz, 1H), 2.96 (m, 1H), 2.42 (m, 1H),
2.30 (m, 1H). 13C NMR (126 MHz, CDCl3) δ 176.5 (s, C=O), 157.1, 136.8, 132.3, 128.7, 128.2, 127.54, 127.51, 126.6, 120.4,
110.5, 55.4, 53.2, 46.8, 46.6, 38.3, 33.6, 27.3. MS (CI, m/z): 308 [M++H]. Anal. calcd for C20H21NO2: C, 78.15 H, 6.89 N, 4.56.
Found: C, 77.93 H, 6.65 N, 4.34.
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(1SR,5RS,7RS)-3-benzyl-1-fluoro-7-(4-fluorophenyl)-3-azabicyclo[3.2.0]heptan-2-one (12a)
Yellow oil. 174 mg, 62% yield. Purified via gradient reverse phase chromatography (H2O/acetonitrile from 35/65 to 25/75).
1H NMR (400 MHz, CDCl3) δ 7.72 – 7.12 (m, Ph, Ar, 9H), 4.71 (d, CH2Ph, J(H,H) = 14.6 Hz, 1H), 4.47 (d, CH2Ph, J(H,H) =
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14.6 Hz, 1H), 3.99 (m, 1H, Hꢀ7), 3.58 (m, 1H, Hꢀ4), 3.25 (m, 1H, Hꢀ5), 3.10 (m, 1H, Hꢀ4), 2.53 (m, 1H, Hꢀ6), 1.79 (m, 1H, Hꢀ6).
13C NMR (101 MHz, CDCl3) δ 170.3 (d, J(C,F) = 24.6 Hz, СO), 141.3 (Car), 135.5 (Car), 129.4 (q, 2J(C,F) = 32.6 Hz, Car), 129.0
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(CHar), 128.6 (CHar), 128.3 (CHar), 128.1 (CHar), 125.5 (q, J(C,F) = 3.7 Hz, CHar), 124.2 (q, J(C,F) = 272.0 Hz, CF3), 92.8 (d,
1J(C,F) = 252.7 Hz, CF), 50.2 (s, Cꢀ4), 47.2 (s, CH2Ph), 45.5 (d, 2J(C,F) = 23.9 Hz, Cꢀ7), 36.3 (d, 2J(C,F) = 19.5 Hz, Cꢀ5), 25.5 (d,
3J(C,F) = 11.8 Hz, Cꢀ6). 19F NMR (376 MHz, CDCl3) δ ꢀ63.0 (s, CF3, 3F), ꢀ159.4 (s, CF, F). MS (CI, m/z): 364 [M++H]. Anal.
calcd for C20H17F4NO: C, 66.11 H, 4.72 N, 3.85. Found: C, 65.98 H, 4.58 N, 3.55.
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(1R,5S,7S)-7-phenyl-3-((R)-1-phenylethyl)-3-aza-bicyclo[3.2.0]heptan-2-one (13a)
Mp = 100ꢀ102 ºC. White crystals. 144 mg, 37% yield. Purified via column chromatography (hexanes/ethyl acetate = 80/20).
1H NMR (500 MHz, CDCl3) δ 7.46 – 7.26 (m, 10H), 5.63 (q, J = 7.1 Hz, 1H), 3.64 (s, 1H), 3.56 (m, 1H), 3.19 (m, 1H), 3.01 (m,
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1H), 2.91 (m, 1H), 2.40 (m, 1H), 2.14 (m, 1H), 1.59 (d, J(H,H) = 7.1 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 175.5 (s, C=O),
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144.6 (s, Ph), 140.6 (s, Ph), 128.6 (s, Ph), 128.5 (s, Ph), 127.5 (s, Ph), 127.0 (s, Ph), 126.4 (s, Ph), 126.3 (s, Ph), 48.89, 48.86, 48.5,
42.8, 33.4, 27.4, 15.7. MS (CI, m/z): 292 [M++H]. Anal. calcd for C20H21NO: C, 82.44 H, 7.26 N, 4.81. Found: C, 82.12 H, 7.54 N,
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(1S,5R,7R)-7-phenyl-3-[(1R)-1-phenylethyl]-3-azabicyclo[3.2.0]heptan-2-one (13b)
Mp = 101ꢀ103 ºC. White crystals. 123 mg, 41% yield. Purified via column chromatography (hexanes/ethyl acetate = 80/20).
1H NMR (400 MHz, CDCl3) δ 7.41 – 7.13 (m, Ph, 10H), 5.59 (m, PhCHN, 1H), 3.67 (m, 1H), 3.19 (m, 3H), 2.92 (m, 1H), 2.50 (m,
1H), 2.37 (m, 1H), 1.62 (d, J(H,H) = 6.8 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 175.5 (s, C=O), 144.5, 139.8, 128.6, 127.5,
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127.3, 126.4, 126.3, 49.2, 48.91, 48.86, 42.7, 33.8, 27.4, 16.3. MS (CI, m/z): 292 [M++H]. Anal. calcd for C20H21NO: C, 82.44 H,
7.26 N, 4.81. Found: C, 82.82 H, 7.03 N, 4.66.
(1R,5S,7S)-7-(4-fluorophenyl)-3-[(1R)-1-phenylethyl]-3-azabicyclo[3.2.0]heptan-2-one (14a)
Mp = 112ꢀ114 ºС. White crystals. 109 mg, 29% yield. Purified via column chromatography (hexanes/ethyl acetate = 80/20).
1H NMR (400 MHz, CDCl3) δ 7.30 (m, Ar + Ph, 7H), 6.99 (t, Ar, J = 8.5 Hz, 2H), 5.60 (q, PhCHCH3, 3J(H,H) = 7.0 Hz, 1H), 3.54
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(m, 2H), 3.10 (m, 1H), 2.96 (m, 1H), 2.87 (d, J(H,H) = 10.1 Hz, 1H), 2.31 (m, 1H), 2.10 (m, 1H), 1.55 (d, PhCHCH3, J(H,H) =
7.0 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 175.3 (s, C=O), 161.4 (d, Ar, 1J(C,F) = 244.3 Hz), 140.5 (s, Ph), 140.3 (d, Ar, 4J(C,F)
= 3.0 Hz), 128.6 (s, Ph), 127.9 (d, Ar, J(C,F) = 7.9 Hz), 127.5 (s, Ph), 127.0 (s, Ph), 115.3 (d, Ar, 2J(C,F) = 21.2 Hz), 49.0, 48.9,
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48.5, 42.2, 33.5, 27.3, 15.7. 19F NMR (376 MHz, CDCl3) δ ꢀ117.4. MS (CI, m/z): 310 [M++H]. Anal. calcd for C20H20FNO: C,
77.64 H, 6.52 N, 4.53. Found: C, 77.33 H, 6.73 N, 4.34.
(1S,5R,7R)-7-(4-fluorophenyl)-3-[(1R)-1-phenylethyl]-3-azabicyclo[3.2.0]heptan-2-one (14b)
Mp = 113ꢀ114 ºС. White crystals. 131 mg, 36% yield. Purified via column chromatography (hexanes/ethyl acetate = 80/20).
1H NMR (400 MHz, CDCl3) δ 7.28 (m, Ph + Ar, 7H), 7.00 (t, J = 8.6 Hz, 2H), 5.59 (q, PhCHCH3, 3J(H,H) = 7.0 Hz, 1H), 3.64 (m,
1H), 3.19 (m, 2H), 3.08 (m, 1H), 2.91 (m, 1H), 2.40 (m, 2H), 1.61 (d, PhCHCH3, J(H,H) = 7.1 Hz, 3H). 13C NMR (126 MHz,
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CDCl3) δ 175.3 (s, C=O), 161.4 (d, Ar, 1J(C,F) = 244.3 Hz), 140.2 (d, Ar, 4J(C,F) = 3.1 Hz), 139.8 (s, Ph), 128.6 (s, Ph), 127.9 (d,
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Ar, J(C,F) = 7.9 Hz), 127.6 (s, Ph), 127.3 (s, Ph), 115.3 (d, Ar, J(C,F) = 21.2 Hz), 49.2, 49.0, 48.9, 42.1, 33.9, 27.2, 16.3. 19F
NMR (376 MHz, CDCl3) δ ꢀ117.4 (s). MS (CI, m/z): 310 [M++H]. Anal. calcd for C20H20FNO: C, 77.64 H, 6.52 N, 4.53. Found: C,
77.76 H, 6.77 N, 4.24.
(1R,5S,7S)-3-benzyl-6-methyl-7-phenyl-3-azabicyclo[3.2.0]heptan-2-one (15a)
Colorless oil. 162 mg, 80% yield. .
1H NMR (400 MHz, CDCl3) Mixture of diastereomers : δ 7.56 – 6.72 (m, 10H), 4.68, 4.61 (d, 2J(H,H) = 14.6 Hz, 1H), 4.44, 4.40
(2×d, 2J(H,H) = 3.5 Hz, 1H), 3.80 – 3.72 (m, 1H), 3.52 – 3.41 (m, 1H), 3.40 – 3.28 (m, 1H), 3.20 – 3.10 (m, 1H), 3.03 – 2.89, 2.81
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– 2.69 (m, 1H), 2.63 – 2.53 (m, 1H), 1.05, 0.64 (d, 2J(H,H) = 7.1, 6.5 Hz, 1H).13C NMR (101 MHz, CDCl3) δ 176.5 (C=O), 140.4,
136.71, 128.9, 128.8, 128.6, 128.5, 128.32, 128.27, 128.2, 127.8, 127.7, 126.5, 126.4, 52.2, 51.3, 47.0, 46.9, 46.5, 45.8, 43.7, 39.1,
37.7, 36.8, 29.3, 16.3, 15.8. MS (CI, m/z): 292 [M++H]. Anal. calcd for C20H21NO: C, 82.44; H, 7.26; N, 4.81. Found: C, 82.20; H,
7.54; N, 4.93.
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Colorless oil. 151 mg, 83% yield. Purified via column chromatography (hexanes/ethyl acetate = 80/20).
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1H NMR (500 MHz, CDCl3) δ 7.62 – 7.04 (m, 10), 4.64, 4.57 (2×d, J = 14.5 Hz, 1H), 4.52 – 4.44 (m, 1H), 3.82 – 3.76 (m, 1H),
3.54 –3.35 (m, 1H), 3.29ꢀ3.12 (m, 1H), 3.12 – 2.96 (m, 1H), 2.71 – 2.53 (m, 1H), 2.42 – 2.28 (m, 1H), 1.11 – 0.92 (m, 2H), 0.78,
0.59 (2×t, J = 7.2 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 176.5, 140.7, 136.7, 128.9, 128.8, 128.7, 128.6, 128.5, 128.3, 128.2,
127.8, 127.7, 127.4, 127.1, 126.7, 126.4, 52.6, 50.0, 47.1, 46.9, 46.49, 46.47, 46.2, 45.9, 44.4, 44.0, 35.6, 28.5, 24.1, 11.6, 11.1. MS
(CI, m/z): 306 [M++H]. Anal. calcd for C21H23NO: C, 82.58; H, 7.59; N, 4.59. Found: C, 82.20; H, 7.91; N, 4.38.
(1R,5S,7S)-3-benzyl-5-methyl-7-phenyl-3-azabicyclo[3.2.0]heptan-2-one (17a)
Colorless oil. 176 mg, 85% yield.
1H NMR (400 MHz, CDCl3) δ 7.40 – 7.17 (m, 10H), 4.67 (d, 2J(H,H) = 14.8 Hz, 1H), 4.41 (d, 2J(H,H) = 14.7 Hz, 1H), 3.67 – 3.53
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(m, 1H), 3.35 (d, J(H,H) = 10.1 Hz, 1H), 3.11 (d, J(H,H) = 10.1 Hz, 1H), 2.92 (d, J = 4.4 Hz, 1H), 2.52 – 2.43 (m, 1H), 2.28 –
2.20 (m, 1H), 1.24 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 176.1, 144.0, 136.8, 128.9, 128.6, 128.2, 127.7, 126.6, 126.4, 60.1, 53.9,
46.8, 39.6, 33.9, 33.6, 25.7. MS (CI, m/z): 292 [M++H]. Anal. calcd for C20H21NO: C, 82.44; H, 7.26; N, 4.81. Found: C, 82.60; H,
7.12; N, 4.98.
(1R,5S,7S)-3-benzyl-5-ethyl-7-phenyl-3-azabicyclo[3.2.0]heptan-2-one (18a)
Colorless oil. 182 mg, 81% yield. .Purified via column chromatography (hexanes/ethyl acetate = 80/20).
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1H NMR (400 MHz, CDCl3) δ 7.47 – 7.14 (m, 10H), 4.64 (d, J(H,H) = 14.6 Hz, 1H), 4.43 (d, J(H,H) = 14.7 Hz, 1H), 3.62 (m,
1H), 3.30 (d, 2J(H,H) = 10.1 Hz, 1H), 3.19 (d, 2J(H,H) = 10.1 Hz, 1H), 2.94 (d, 3J(H,H) = 5.1 Hz, 1H), 2.43ꢀ2.37 (m, 1H), 2.29ꢀ2.24
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(m, 1H), 1.64 – 1.40 (m, 2H), 0.76 (t, J(H,H) = 7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 176.2 (s, C=O), 144.0, 136.7, 128.9,
128.6, 128.2, 127.7, 126.6, 126.3, 57.8, 52.2, 46.8, 39.7, 37.7, 31.5, 8.0. MS (CI, m/z): 306 [M++H]. Anal. calcd for C21H23NO: C,
82.58; H, 7.59; N, 4.59. Found: C, 82.25; H, 7.97; N, 4.41.
(1S,6R,8S)-3-benzyl-8-phenyl-3-azabicyclo[4.2.0]octan-2-one (19a)
Colorless oil. 171 mg, 89% yield. .
1H NMR (400 MHz, CDCl3) δ 7.50 – 7.14 (m, 10H), 4.70 (d, 2J(H,H) = 14.6 Hz, 1H), 4.62 (d, 2J(H,H = 14.6 Hz, 1H), 3.80 (q, J =
8.8 Hz, 1H), 3.44 – 3.32 (m, 1H), 3.32 – 3.19 (m, 2H), 2.75 – 2.62 (m, 1H), 2.45 – 2.34 (m, 1H), 2.24 – 2.11 (m, 1H), 2.04 – 1.93
(m, 1H), 1.93 – 1.73 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 171.9, 144.5, 137.5, 128.7, 128.4, 128.2, 127.5, 126.7, 126.2, 50.4,
45.9, 44.8, 42.7, 30.8, 29.9, 28.6. MS (CI, m/z): 292 [M++H]. Anal. calcd for C20H21NO: C, 82.44; H, 7.26; N, 4.81. Found: C,
82.21; H, 7.54; N, 4.98.
General procedure for synthesis of amines 20 and 21
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1M solution of product of [2+2] cycloaddition (1.0 equiv) was added dropwise to 2M suspension of LiAlH4 in THF (2.0 equiv) at
room temperature. The reaction mixture was heated at reflux for 5 h, cooled to ꢀ20 ºC and treated dropwise with 40% aqueous KOH
solution (approx. 5 equiv). Formed suspension was filtered through Na2SO4. The solution was concentrated. The obtained product
was distilled (0.1 mm Hg) and dissolved in methanol to get 1M solution. 10% Palladium on charcoal (0.1 equiv) and 2M aqueous
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Mp = 154ꢀ155 ºC. White crystals. 25.2 g, 83% yield.
1H NMR (400 MHz, D2O) δ 7.32 – 7.11 (m, Ph, 5H), 3.40 (m, 2H), 3.13 (m, 5H), 2.27 (m, 1H), 2.10 (m, 1H). 13C NMR (101 MHz,
D2O) δ 144.6 (s, Ph), 128.9 (s, Ph), 126.6 (s, Ph), 126.4 (s, Ph), 51.7, 51.7, 44.6, 40.8, 33.3, 30.1. MS (CI, m/z): 174 [MꢀꢀCl]. Anal.
calcd for C12H16ClN: C, 68.73 H, 7.69 N, 6.68. Found: C, 68.40 H, 7.97 N, 6.47.
(1S,5R,6S)-6-(4-fluorophenyl)-3-azoniabicyclo[3.2.0]heptane chloride ((S)-21)
Mp = 147ꢀ148 ºC. White crystals. 89 mg, 72% yield.
1H NMR (400 MHz, MeOD) δ 7.29 (dd, J = 8.5, 5.4 Hz, 2H), 7.02 (t, J = 8.7 Hz, 2H), 3.51 (m, 2H), 3.26 (m, 5H), 2.32 (m, 2H).
13C NMR (101 MHz, MeOD) δ 161.5 (d, Ar, 1J(C,F) = 243.1 Hz), 140.2 (d, Ar, 4J(C,F) = 3.1 Hz), 127.8 (d, Ar, 3J(C,F) = 8.0 Hz),
114.8 (d, Ar, 2J(C,F) = 21.5 Hz), 51.39, 51.37, 45.4, 40.3, 33.4, 30.4. 19F NMR (376 MHz, MeOD) δ ꢀ119.3 (s). MS (CI, m/z): 192
[M++H]. Anal. calcd for C12H15ClFN: C, 63.30 H, 6.64 N, 6.15. Found: C, 63.61 H, 6.42 N, 6.32.
(1R,5S,6R)-6-(4-fluorophenyl)-3-azoniabicyclo[3.2.0]heptane chloride ((R)-21)
Mp = 147ꢀ148 ºC. 92 mg, 86% yield.
1H NMR (400 MHz, MeOD) δ 7.29 (dd, J = 8.6, 5.4 Hz, 2H), 7.03 (t, J = 8.6 Hz, 2H) 3.54 (m, 2H), 3.26 (m, 5H), 2.33(m, 2H). 13
C
1
4
3
NMR (101 MHz, MeOD) δ 161.6 (d, Ar, J(C,F) = 243.2 Hz), 140.2 (d, Ar, J(C,F) = 3.1 Hz), 127.8 (d, Ar, J(C,F) = 8.0 Hz),
114.8 (d, Ar, 2J(C,F) = 21.5 Hz), 51.41, 51.39, 45.3, 40.3, 33.4, 30.4. 19F NMR (376 MHz, MeOD) δ ꢀ119.4 (s). MS (CI, m/z): 192
[M++H]. Anal. calcd for C12H15ClFN: C, 63.30 H, 6.64 N, 6.15. Found: C, 63.01 H, 6.80 N, 6.39.
General procedure for synthesis of amides 22-24 for biophysical studies
DMF (0.02 equiv) was added to 1 M solution of 4ꢀfluorobenzoic acid (1.0 equiv) in CH2Cl2. Then, SOCl2 (3.0 equiv) was added
dropwise at room temperature and reaction mixture was heated at reflux for 2 h. Solvent and volatile byꢀproducts were removed
º
under reduced pressure; 4ꢀfluorobenzoyl chloride was distilled (44ꢀ46 C at 3 mm Hg) and added dropwise to 1M solution of the
º
corresponding amine (0.8 equiv) with triethylamine (1.1 equiv) at ꢀ20 C. Reaction mixture was warmed to room temperature,
stirred overnight and washed with 0.5 M aqueous solution of citric acid (approx. 1 equiv), saturated aqueous solution of NaHCO3
(approx. 1 equiv) and water. Organic layer was separated, dried over Na2SO4 and concentrated under reduced pressure to afford
pure product (87ꢀ92% yield).
Measurement of lipophilicity, aqueous solubility and metabolic stability of compounds 22-24
Metabolic stability is defined as the percentage of parent compound lost over time in the presence of a metabolically active test
system.
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The Journal of Organic Chemistry
ASSOCIATED CONTENT
Supporting Information
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Measurement of lipophilicity, aqueous solubility and metabolic stability of compounds 22ꢀ24. Xꢀray crystallography information.
Copies of NMR spectra. This material is available free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
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* Eꢀmail: Pavel.Mykhailiuk@gmail.com
ACKNOWLEDGMENT
Authors are very grateful to Dr. S. Shishkina for XꢀRay studies, to Prof. A. Tolmachev for financial support. P.M. is very grateful to
Prof. T. Bach for the inspiration in photochemistry, and to Dr. Bill Heilman and Mrs. I. Sadkova for the helpful suggestions on the
manuscript.
Keywords: • drug discovery, • building blocks, • photochemistry, • conformational restriction, • amines
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