Photocycloaddition of N-Benzylmaleimide to Alkenes As an Approach to Functional 3-Azabicyclo[3.2.0]heptanes

Article abstract of DOI:10.1021/acs.joc.8b00077

A one-step synthesis of functionalized 3-azabicyclo[3.2.0]heptanes by [2+2]-photochemical intermolecular cycloaddition of N-benzylmaleimide to alkenes was elaborated. The obtained compounds were easily transformed into the bi- and tricyclic analogues of piperidine, morpholine, piperazine, and GABA, which are advanced building blocks for drug discovery.

Full text of DOI:10.1021/acs.joc.8b00077

Article
pubs.acs.org/joc
Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX
[2+2]-Photocycloaddition of N‑Benzylmaleimide to Alkenes
As an Approach to Functional 3‑Azabicyclo[3.2.0]heptanes
Yevhen A. Skalenko,‡,§ Tetiana V. Druzhenko,‡,§ Aleksandr V. Denisenko,†,‡ Maryna V. Samoilenko,‡
Oleksandr P. Dacenko,‡ Serhii A. Trofymchuk,‡ Oleksandr O. Grygorenko,†,‡ Andrey A. Tolmachev,†,‡
and Pavel K. Mykhailiuk*,†,‡
‡Enamine Ltd., Chervonotkatska 78, Kyiv 02094, Ukraine (www.enamine.net, www.mykhailiukchem.org)
§Institute of High Technologies, Academician Glushkov av. 4G, Kyiv 03022, Ukraine
†Department of Chemistry, Taras Shevchenko National University of Kyiv, Volodymyrska 64, Kyiv 01601, Ukraine
S
* Supporting Information
ABSTRACT: A one-step synthesis of functionalized 3-azabicyclo-
[3.2.0]heptanes by [2+2]-photochemical intermolecular cyclo-
addition of N-benzylmaleimide to alkenes was elaborated. The
obtained compounds were easily transformed into the bi- and
tricyclic analogues of piperidine, morpholine, piperazine, and
GABA, which are advanced building blocks for drug discovery.
INTRODUCTION
■
Over the past decade, drug discovery significantly changed with
the emerged terms scaffold hopping,1 escape from flatland,2 and
conformational restriction,3 which already gained great recogni-
tion in the scientific community. In this context, medicinal chem-
ists in pharmaceutical companies use more and more toward
saturated mono- and bicyclic building blocks with a high fraction
of Fsp3-carbon atoms.4,5
At the beginning of this century, bicyclic pyrrolidines were
introduced as conformationally restricted surrogates for the
common pyrrolidines and piperidines. This concept was already
validated by several bioactive compounds currently under clinical
investigation according to the ChEMBL database (Figure 1b).6
However, compared to the popular compounds in medicinal
chemistry, 3-azabicyclo[3.1.0]hexanes (A) and 3-azabicyclo[3.3.0]-
octanes (C) (Figure 1a), 3-azabicyclo[3.2.0]heptanes (B) remain
somewhat in the shadow. We presume that the main reason is the
lack of the practical synthetic approaches to 3-azabicyclo[3.2.0]-
heptanes (B) from inexpensive starting materials.
Two main approaches to 3-azabicyclo[3.2.0]heptanes were
described in the literature: intramolecular7−9 and intermolec-
ular cyclizations.10−13 The intramolecular approach usually
gives products in high yields due to the preorganization of
the conformation of the corresponding substrates. In particu-
lar, Bach and coworkers reported on the photochemical [2+2]-
intramolecular cyclizations of N-substituted bis-allylamines,7a−c
while Yonn and colleagues performed this reaction under the
photoredox catalysis conditions (Scheme 1a).8a−c Also, last year,
we developed a photochemical intramolecular [2+2]-cyclization
Figure 1. (a) Bioactive bicyclic motifs and the number of the corre-
sponding hits in the ChEMBL database. (b) Representative bioactive
compounds.
of allylamides of cinnamic acids. In 2010, Kanger and his team
developed a three-component cascade reaction to polysub-
stituted azabicyclo[3.2.0]heptanes (Scheme 1b).9
An intermolecular approach to 3-azabicyclo[3.2.0]heptanes
usually commences from the commercially available sub-
strates.10−13 In 2013, Wanner et al. developed the intermolecular
[2+2]-photochemical cycloaddition between N-trifluoroacetyl
2,5-dihydropyrrole and maleic anhydride (Scheme 1c).10a
Received: January 10, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.8b00077
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Scheme 1. State of the Art
RESULTS AND DISCUSSION
Optimization Studies. We started our investigation from
the test reaction of maleimide 1 with the simple monosub-
stituted alkene−methyl acrylate (2) (Table 1). All of our
■
Table 1. Optimization Studies
λmax
entry (nm)
concentration
of 1 (mM)
Ph2CO
(equiv)
2
a
(equiv)
conversion (%)
1
412
366
310
255
366
366
366
366
366
366
366
366
366
366
366
5
5
10
10
10
10
10
10
10
5
0
2
0
3
5
20
4
5
compl mix
5
5
1.0
0.5
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
100
6
5
100
7
5
100
8
5
100
9
5
2
100
10
11
12
13
14
15
5
1
100
10
20
30
50
75
1
100
1
100
1
100
1
100
1
100 (10% of 1a)
Aitken and colleagues performed the [2+2]-photochemical
reaction between N-substituted 1,5-dihydropyrrol-2-one and
ethylene (Scheme 1c).10b,c Many research groups were involved
in the development of the intermolecular [2+2]-photochemical
reactions of maleimides.11−13 Most of these transforma-
tions, however, were performed on maleimides with N-Alk
or N-Ar substitutents, making the further derivatization of
the N-atom impossible (Scheme 1d).11 None-substituted
NH-maleimides were also shown to participate in [2+2]-
cycloadditions by Booker-Milburn, Aitken, and others.12 In the
reaction with simple aliphatic alkenes, however, practical sepa-
ration of the formed cis- and trans-isomers was in some cases
problematic.
There are only several reports in the literature on the pho-
tochemical [2+2]-cycloadditions of N-benzyl maleimide (1).13
In 1974, Rynbrandt showed its high potential by reacting
maleimide 1 with enamines (Scheme 1).12a Subsequently,
amide groups were reduced with LiAlH4, followed by a cleavage
of the N-Bn group by hydrogenolysis. Remarkably, this
approach was not extended into other simple alkenes. In 2015,
chemists from Roche published a patent on the photochem-
ical dimerization of maleimide 1 into a tricyclic piperazine
mimic.12b Apart from that, the huge potential of compound
1(50 USD/kg) for the preparation of the appropriately
N-protected 3-azabicyclo[3.2.0]heptanes for drug discovery
remains not elaborated.13
a
Conversion of the reaction was determined by 1H NMR of the
reaction mixture after 24 h.
attempts to perform [2+2]-photocyclization at 412 and 366 nm
failed.14,15 Only the starting material was recovered from the
reaction mixture. At 310 nm, substrate 1 underwent the [2+2]-
photocyclization with 2; however, after 24 h, the conversion
reached only ca. 20%. At 255 nm, a formation of the complex
mixture was observed (Table 1, entries 1−4). After some exper-
imentation, we found that the addition of benzophenone as a
sensitizer, which transfers a triplet excited state to a substrate,
significantly facilitated the reaction, and the mixture 2a/2b
was formed with no starting material remaining. Furthermore,
we reduced the amount of sensitizer to 0.1 equiv, without
any significant effect on the reaction outcome (Table 1, entries
5−7).
It is important to note that, for the potential scale up, we also
wanted to minimize the excess of alkene 2 and to maximally
increase the concentration of substrate 1. In fact, an initially
used 10 molar excess of alkene 2 was reduced to an equimolar
mixture of compounds 1 and 2 (Table 1, entries 7−10). In addi-
tion, the concentration of alkene 2 was successfully increased up
to 50 mM. At higher concentrations, the formation of dimer 1a
was observed (Table 1, entries 10−15).
Scale Up. With the optimized procedure in hand, we stud-
ied the reaction at different scales. The synthesis on a milligram
scale was carried out at 5 mM in 5 mL glass vials. The reaction
at a 10 g scale was also efficiently performed at a high concen-
tration (50 mM) of 1 using an equimolar mixture of compounds
1 and 2 in a common 1 L glass flask (Scheme 2).16 Technically,
the reaction was very easy to run: a solution of maleimide 1,
alkene 2, and benzophenone in degassed acetonitrile was
In this context, herein, we have elaborated the [2+2]-
photochemical cycloaddition of N-benzylmaleimide (1) with
various simple alkenes toward the preparation of building
blocks for drug discovery. In particular, the conformationally
restricted bi- and tricyclic analogues of piperidine, morpholine,
and GABA were synthesized. The photochemical step was
performed in up to a 10 g scale.
B
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f
Table 2. Scope of the Reaction
Scheme 2. Scaled Up Synthesis of Compounds 2a/2b
irradiated at room temperature for 48 h. The solvent was
evaporated under reduced pressure, and the residue was
purified on silica gel to obtain the individual stereoisomers 2a
and 2b.
Reaction Scope. Having an established procedure, we next
studied the scope of alkenes. In every experiment, an equimolar
mixture of 1 and alkene was used. The [2+2]-photocycloaddition
of 1 was successfully performed with nonactivated (3, 6, 23,
24, 26, 27), push−pull (21, 29), electron-poor (1, 2, 4, 5, 7, 8,
11−14, 16−19, 22, 28), and electron-rich (15, 20, 25) substrates
(Table 2). Among them were monosubstituted (2, 4−15),
1,1-disubstituted (16−21), 1,2-disubstituted (22−28), and 1,1,2-
trisubstituted (29) alkenes. Predominantly, the major trans-
cyclobutane isomers were formed. In some cases, however, the
minor cis-isomers were also isolated by standard column chro-
matography on SiO2. The combined yield of products was
mainly within 50−90%; however, with electron-withdrawing
alkenes 8, 11−13, and 28, the yield was poor. With 1 equiv of
alkene 13, an extensive dimerization of maleimide 1 into prod-
uct 1a was observed. Therefore, we increased an excess of
alkene to 10 times, and the desired product 13a was isolated in
29% yield. The reaction of alkene 26 at 366 nm led to a signif-
icant Paterno−Buchi transformation with benzophenone. The
reaction was performed at 310 nm to obtain product 26a in
47% yield.
The structure of compounds 2a, 4a, 5a, 5b, 6a, 7a, 8a, 12a,
14b, 16a, 16b, 19a, 21a, 23a-1, and 23a-2 was confirmed by
1D (NOE) and 2D NMR techniques (COSY, NOESY). The
structure of compound 18a was assigned using the HOESY
technique based on H−F correlations. Products of [2+2]-
photocycloaddition of 1-substituted alkenes can be also quickly
1
empirically assigned by H NMR; the signals of the benzylic
protons in trans-isomers and cis-isomers were singlets and two
doublets, respectively (Figure 2). The structure of compounds
6a, 12a, 17a, 23a-1, 23a-2, and 24a was additionally confirmed
by X-ray crystallography (Figure 3).
Synthesis of Building Blocks. Quite recently, we showed
that 3-azabicyclo[3.2.0]heptanes might be considered as con-
formationally restricted bicyclic analogues of piperidine.7h
Therefore, we next 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.
In particular, the reduction of the amide groups in 3a with
LiAlH4, followed by a cleavage of N-Bn group via hydrogenolysis
over Pd/C accomplished the synthesis of the bicyclic piperidine
analogue 30 (Scheme 3).
C
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Table 2. continued
Table 2. continued
a
b
Structure of only main products (a) is shown. Isolated yields.
c
d
e
10 times excess of alkene 13a. Mixture of stereoisomers. The reac-
f
tion was performed at 310 nm. Reaction conditions: CH3CN,
1/alkene = 1:1, rt, 366 nm, 24 h.
Figure 2. Signals of benzylic protons of compounds 2a and 2b in
1H NMR.
Similar transformations of compound 9a/b gave amino
alcohol 31. The standard N-Boc protection and the subsequent
oxidation of the alcohol group with the Dess−Martin reagent
provided the N-protected amino ketone 32. Finally, the
reaction with NH2OH followed by reduction of the inter-
mediate oxime with the Ni Raney alloy accomplished the
synthesis of N-Boc diamine 33 as an inseparable mixture (4:1)
of diastereomers. Alternatively, the monoprotected N-Bn
diamine 34 was prepared in one step by reduction of com-
pound 5a with LiAlH4 in 87% isolated yield (Scheme 4).
The synthesis of bicyclic amino alcohol 36a was realized by
an extensive reaction of amide and ester functions in compound
2a with LiAlH4 (35a), followed by a hydrogenolysis of N-Bn
bond with Pd/C as a catalyst (Scheme 5). The synthesis of an
isomeric compound 36b was performed analogously from
compound 2b via the intermediate 35b.
It is worth mentioning that the reduction of the amide
group in 15a with LiAlH4, followed by a cleavage of the N-Bn
group by hydrogenolysis over Pd/C gave a racemic amine 37,
D
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Scheme 4. Synthesis of Bicyclic Diamines 33 and 34
transformations proceeded via the formation of the inter-
mediate carbocation A (Scheme 7).
Also, we envisioned that the tricyclic core in compounds 1a
and 23a−28a might serve as an elongated lipophilic analogue of
morpholine, piperazine, and SO2-morpholine. In this context,
we undertook the synthesis of the corresponding building
blocks 40, 42, and 44 (Scheme 8).
In particular, the reduction of amide groups in 24a with
LiAlH4, followed by a cleavage of the N-Bn group by hydro-
genolysis over Pd/C as a catalyst gave the tricyclic morpholine
analogue 40. The synthesis of homologues of piperazine (42)
and SO2-morpholine (44) was carried out alternatively from
compounds 1a and 27a, correspondingly. The structure of
intermediates 41 and 43 was confirmed by X-ray crystallog-
raphy (Figure 3).
Figure 3. X-ray crystal structure of compounds 6a, 12a, 17a, 23a-1,
23a-2, 24a, 41, and 43.
Scheme 3. Synthesis of Bicyclic Amine 30
Scheme 5. Synthesis of Bicyclic Aminoalcohols 36a and 36b
the component of an antischizophrenia agent, belaperidone
(Scheme 6).
All attempts to replace the hydroxyl group with a fluorine
atom in compounds 35a and 35b with DAST or Morph-DAST
afforded only the complex mixtures. Surprisingly, treatment of
both 35a and 35b with SF4/HF selectively provided amine 38
as a sole stereoisomer in 75−78% yield. Presumably, the both
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Scheme 6. Synthesis of Bicyclic Amine 37, a Key Component
of Belaperidone
Scheme 9. Synthesis of N-Boc Protected Amino Acid 47
furnished the preparation of amino acid 47 as a mixture (1:1)
of isomers.
Scheme 7. Formation of an Unexpected Fluorinated Amine 38
Finally, to show the high potential of this strategy, we per-
formed the photochemical [2+2]-photocycloaddition of mal-
eimide 1 to the sedative drug aprobarbital (48). The corre-
sponding product 49 was obtained after the column
chromatography in 69% yield as an 70:30 inseparable mixture
of stereoisomers (Scheme 10). Given that many FDA-approved
Scheme 10. Synthesis of Cyclobutane 49
Scheme 8. Synthesis of Tricyclic Amines 40, 42, and 44
drugs contain the double CC bond,6 we believe that this strat-
egy could also be used for the late-stage modification of drugs.17
3D-Vector Analysis. To compare the three-dimensional
structure of the bi- and tricyclic ring systems obtained in this
work with that of the corresponding monocyclic scaffolds
(piperidine, piperazine, morpholine, and thiomorpholine
1,1-dioxide), we used the exit vector plots (EVP) tool.18 The
key feature of this method is a simulation of the substituents
attached to the disubstituted scaffold by so-called exit vectors
(n1 and n2, Figure 4). To describe a relative spatial arrangement
Figure 4. (a) Definition of vectors n1 and n2 (1,3-disubstituted
piperidine scaffold used as an example). (b) Definition of geometric
parameters r, φ1, φ2, and θ.
of two exit vectors, four geometric parameters are necessary.
These can be the distance between the attachment points C
and N (r), two plane angles, φ1 (between vectors n1 and CN)
and φ2 (between n2 and NC), and dihedral angle, θ (defined by
vectors n1, CN and n2). When these parameters are shown in
r − θ, θ − φ1/φ2, and φ1 − φ2 coordinates, exit vector plots
(EVP) are obtained. While the r parameter can be considered
The synthesis of the tricyclic analogue 47 of GABA was per-
formed from compound 23a (Scheme 9). Extensive reduc-
tion of the amide and ester functions in 23a with LiAlH4 (45)
followed by treatment with CbzCl gave N-protected alcohol
(46). Oxidation of the alcohol group in 46 with CrO3 and
cleavage of the N-Cbz moiety followed by N-Boc protection
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Table 3. Values of Geometric Parameters r, φ1, φ2, and θ for 3-Azabicyclo[3.2.0]heptanes and Piperidine Derivatives
a
compound
r (Å)
φ1 (°)
φ2 (°)
|θ| (°)
ref
6a
3.221
3.301
3.308
5.147
5.143
5.176
5.059
4.916
5.464
2.492
2.458
2.778
2.728
2.873
3.105
32.2
28.8
28.3
9.6
23.7
29.1
26.3
4.8
108.8
132.8
125.9
28.2
26.2
154.5
166.4
180
this work
this work
this work
this work
this work
this work
this work
this work
this work
19
14a
17a
b
23a-1 (I)
b
23a-1 (II)
23a-2
24a
41
10.7
14.1
14.9
45.4
56.1
30.3
31.2
14.3
16.1
25
1.9
89.3
48.7
45.4
21.2
49.8
40.9
16.9
39.8
25
43
7.4
50
35.2
39.1
173
51
20
52
21
53
1.8
22
54
180
23
55
28.7
18.2
178.8
24
a
b
Since the signs of θ angle are opposite for different enantiomers, only absolute values of θ are considered. Two different molecules in the crystal cell.
Figure 5. 3,6-Disubstituted 3-azabicyclo[3.2.0]heptanes, 4,9-disubstituted 4-azatricyclo[5.3.0.02,6]decanes, piperidine derivatives, and their
heterocyclic analogues shown in the (a) r − θ plot (polar coordinates), (b) θ − φ1/φ2 plot, and (c) φ1 − φ2 plot.
G
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as a measure of the size of a scaffold, the angular parameters cor-
relate with the scaffold’s three-dimensionality (as defined by the
exit vectors). In particular, for the linear geometry, φ1/φ2 = 0°;
flat scaffolds have θ = 0° or 180°.
and low costs of our method, we believe that scientists will soon
use it, and 3-azabicyclo[3.2.0]-heptanes will soon become very
popular in medicinal chemistry.
The values of r, φ1, φ2, and θ parameters were calculated
from the X-ray data for compounds 6a, 12a, 17a, 23a-1, 23a-2,
24a, 41, and 43 from this work, as well as derivatives 50−55,
which are either close structural analogues thereof or known
biologically active compounds19−24 (Table 3). The exit vector
plot analysis (Figure 5) showed that 3,6-disubstituted
3-azabicyclo[3.2.0]heptane-2,4-diones (3,6-ABH, compounds 6a,
12a, and 17a) are slightly larger (r = 3.22−3.31 Å) than both
1,3- and 1,4-disubstituted piperidine derivatives (r = 2.46−2.78
Å). Although the values of φ1 and (to a lesser extent) φ2 angles
are similar for the 3,6-ABH (φ1/φ2 ∼ 30°) and 1,3-disub-
stituted piperidine (φ1 ∼ 30°and φ2 ∼ 45°) scaffolds, the
absolute values of the θ angle differ significantly. In fact, for the
3,6-ABH core (|θ| ∼ 120°), they are intermediate between those
for the 1,3- and 1,4-disubstituted piperidines (|θ| ∼ 40° and 180°,
respectively). Therefore, while being similar in overall shape, the
3,6-disubstituted 3-azabicyclo[3.2.0]heptane-2,4-dione scaffold
occupies a slightly different area of the chemical space as com-
pared to the corresponding piperidine derivatives.
EXPERIMENTAL SECTION
■
General Methods. 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, and 13C NMR spectra were recorded 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 LC-MS
instrument with chemical ionization (CI). LC-MS data were acquired
on an Agilent 1200 HPLC system equipped with DAD/ELSD/LCMS-
6120 diodematrix and mass-selective 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.
For solid and liquid alkenes (2, 4−6, 8−29), the 0.05 M solution of
1 (1.0 equiv), the alkene (1.0 equiv), and benzophenone (0.1 equiv)
in dry acetonitrile was degassed by bubbling argon for 15 min.
No significant evaporation even of volatile alkenes was detected during
the bubbling of argon. In case of gaseous alkenes (3, 7), the already
degassed solution of 1 (1.0 equiv) and benzophenone (0.1 equiv) was
treated with an excess of alkene. The reaction vessel was closed and
irradiated with 366 nm UV light. After the accomplishment (indicated
by 1H NMR, typical reaction time 24−72 h), the reaction mixture was
concentrated under reduced pressure and purified via column
chromatography to give the desired product.
(3aR,3bR,6aS,6bS)-2,5-Dibenzyldihydrocyclobuta[1,2-c:3,4-c′]-
dipyrrole-1,3,4,6(2H,3aH,3bH,5H)-tetraone (1a). The product was
filtered from the reaction mixture and washed with acetonitrile to give
the product as a white solid, mp above 270 °C; 84% yield (15.7 g).
1H NMR (500 MHz, DMSO-d6): δ 7.29 (m, Ph, 10H), 4.63 (s, CH2Ph,
4H), 3.45 (s, CH, 4H). 13C NMR (126 MHz, DMSO-d6): δ 176.4
(s, CO), 136.4 (s, C, Ph), 129.1 (s, CH, Ph), 128.1 (s, CH, Ph), 42.7
(s, CH2Ph), 41.7 (s, CH). LCMS (m/z): 375 (M + H+). Anal. Calcd
for C22H18N2O4: C, 70.58; H, 4.85; N, 7.48. Found: C, 70.27; H, 4.62; N,
7.67.
(1S*,5S*,6S*)-Methyl 3-Benzyl-2,4-dioxo-3-azabicyclo[3.2.0]-
heptane-6-carboxylate (2a). The solution of 1 (10.0 g, 53 mmol,
1.0 equiv), methyl acrylate (4.6 g, 53 mmol, 1.0 equiv), and benzophe-
none (0.96 g, 5.3 mmol, 0.1 equiv) in dry acetonitrile (1 L) was
degassed by the bubbling of argon for 15 min. The reaction flask
was closed by a septum and irradiated with 366 nm UV light for 48 h.
The reaction mixture was filtered or concentrated under reduced
pressure and purified via column chromatography to give the desired
products 2a and 2b. White solid, mp 71−72 °C; 58% yield (8.4 g).
Purified via column chromatography (hexanes/EtOAc = 2:1). 1H NMR
(400 MHz, CDCl3): δ 7.36 (m, Ph, 5H), 4.67 (s, CH2Ph, 2H), 3.73
(s, OCH3, 3H), 3.53 (t, CH, 3J(H,H) = 5.4 Hz, 1H), 3.28 (m, CH, 1H),
3.12 (m, CH, 1H), 2.80 (m, CHH, 1H), 2.38 (m, CHH, 1H). 13C
NMR (126 MHz, CDCl3): δ 177.9 (s, CO), 176.6 (s, CO), 172.6
(s, CO), 135.3 (s, C, Ph), 128.4 (s, CH, Ph), 128.3 (s, CH, Ph),
127.7 (s, CH, Ph), 52.2 (s, OCH3), 42.6 (s, CH2Ph), 41.0 (s, CH), 38.5
(s, CH), 35.8 (s, CH), 26.0 (s, CH2). LCMS (m/z): 274 (M + H+).
Anal. Calcd for C15H15NO4: C, 65.93; H, 5.53; N, 5.13. Found: C,
66.21; H, 5.36; N, 5.38.
As expected, 4,9-disubstituted 4-azatricyclo[5.3.0.02,6]decane
cores (4,9-ATD, compounds 23a-1, 23a-2, 24a, 41, and 43) are
significantly (by ca. 2.3 Å) larger than 1,4-disubstituted
piperidine or the corresponding heterocyclic analogues. More-
over, while for the monocyclic prototypes, the molecular
geometry (as defined by the exit vectors) can be described as
flattened (|θ| is close to 0° or 180°) and even nearly linear
(small values of φ1/φ2, ca. 20°), the 4,9-ATD-derived scaffolds
show more 3D diversity. (This is especially remarkable in the
angular EVPs, Figure 5b,c.) In particular, whereas the exit
vector disposition in the molecule of 23a-1 is even more linear
than for the 1,4-disubstituted piperidines (φ1/φ2 = 1.8−10.7°),
23a-2 is the most three-dimensional and dissymmetric among
the 4,9-ATD derivatives studied (φ1 = 14.1°, φ2 = 89.3°).
Meanwhile, the |θ| values (154.5° for 23a-1, 26.2−28.2° for
23a-2) show some distortion of the tricyclic ring system. In our
opinion, tricyclic compounds like 23a-1 and 23a-2 can be
considered as analogues for 1,4-disubstituted piperidines with
an equatorial and axial position of the substituent at the C-4
atom, respectively. 9-Hetera-substituted 4,9-ATD scaffolds (com-
pounds 24a, 41, and 43) also show more three-dimensionality as
compared to the corresponding piperazine, SO2-morpholine, and
morpholine derivatives (larger φ1/φ2 values), but unlike for
23a, this is not achieved through the scaffold distortion.
(|θ| does not go far from 0° or 180°.)
CONCLUSIONS
■
In summary, in this work, we have elaborated an one-step syn-
thesis of 3-azabicyclo[3.2.0]-heptanes by [2+2]-photochemical
cyclization of N-Bn maleimide (1) with alkenes. The photo-
chemical step was performed in up to a 10 g scale. The obtained
compounds were easily transformed into bi- and tricyclic ana-
logues of piperidine, morpholine, piperazine, and GABA, which
are advanced building blocks ready for the direct use in drug
discovery.
(1S*,5S*,6R*)-Methyl 3-Benzyl-2,4-dioxo-3-azabicyclo[3.2.0]-
heptane-6-carboxylate (2b). White solid, mp 82−83 °C; 20% yield
(2.9 g). Purified via column chromatography (hexanes/EtOAc = 2:1).
1H NMR (400 MHz, CDCl3): δ 7.36 (m, Ph, 5H), 4.68 (d, CHHPh,
2J(H,H) = 14.2 Hz, 1H), 4.64 (d, CHHPh, J(H,H) = 14.2 Hz, 1H),
2
The ecenofloxacin and belaperidone examples have demon-
strated the potential of 3-azabicyclo[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. Taking into account the high efficiency, simplicity,
3.59 (q, CH, 3J(H,H) = 9.9 Hz, 1H), 3.52 (s, OCH3, 3H), 3.48
(m, CH, 1H), 3.22 (m, CH, 1H), 2.69 (m, CHH, 1H), 2.48 (m, CHH,
1H). 13C NMR (101 MHz, CDCl3): δ 178.2 (s, CO), 176.0 (s, CO),
171.4 (s, CO), 135.7 (s, C, Ph), 128.9 (s, CH, Ph), 128.6 (s, CH, Ph),
127.9 (s, CH, Ph), 52.2 (s, OCH3), 42.7 (s, CH2Ph), 40.8 (s, CH), 37.2
H
DOI: 10.1021/acs.joc.8b00077
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
3
(s, CH), 35.5 (s, CH), 25.5 (s, CH2). LCMS (m/z): 274 (M + H+).
Anal. Calcd for C15H15NO4: C, 65.93; H, 5.53; N, 5.13. Found: C,
65.57; H, 5.81; N, 4.92.
3-Benzyl-3-azabicyclo[3.2.0]heptane-2,4-dione (3a). White
solid, mp 134−135 °C; 80% yield (17.2 g). Purified via column
chromatography (hexanes/EtOAc = 1:1). 1H NMR (400 MHz,
CDCl3): δ 7.31 (m, 5H), 4.70 (s, 2H), 3.27 (s, 2H), 2.64 (s, 2H), 2.12
(s, 2H). 13C NMR (126 MHz, CDCl3): δ 179.5 (s), 136.0 (s), 128.7 (s),
128.6 (s), 127.9 (s), 42.4 (s), 38.4 (s), 22.9 (s). LCMS (m/z): 216
(M + H+).
(1S*,5S*,6S*)-Benzyl 3-Benzyl-2,4-dioxo-3-azabicyclo[3.2.0]-
heptane-6-carboxylate (4a). White solid, mp 64−65 °C; 46% yield
(1.61 g). Purified via column chromatography twice (hexanes/EtOAc
= 2:1, then 3:1). 1H NMR (400 MHz, CDCl3): δ 7.34 (m, 2 × Ph, 10H),
5.16 (s, OCH2Ph, 2H), 4.68 (s, NCH2Ph, 2H), 3.55 (dd, CHCHCON,
3J(H,H) = 6.0, 5.1 Hz, 1H), 3.29 (m, CH2CHCON, 1H), 3.16
(dd, CHCHCON, J(H,H) = 6.9, 4.4, 1H), 2.76 (m, CH, 1H), 2.44
(m, CHH, 1H), 2.30 (m, CHH, 1H). 13C NMR (126 MHz, CDCl3):
δ 178.6 (s, CO), 177.4 (s, CO), 135.8 (s, C, Ph), 128.7 (s, CH, Ph),
128.6 (s, CH, Ph), 128.0 (s, CH, Ph), 43.6 (s, CHCHCON), 42.6
(s, NCH2Ph), 38.4 (s, CH), 36.6 (s, CH2Br), 35.1 (s, CH), 28.1
(s, CHCH2CH). LCMS (m/z): 308, 310 (M + H+). Anal. Calcd for
C14H14BrNO2: C, 54.56; H, 4.58; N, 4.55. Found: C, 54.85; H, 4.39;
N, 4.80.
(1S*,5S*,6R*)-3-Benzyl-6-(bromomethyl)-3-azabicyclo-
[3.2.0]heptane-2,4-dione (6b). Yellow oil, 16% yield (49 mg).
Purified via column chromatography (hexanes/MTBE = 1:2).
1H NMR (400 MHz, CDCl3): δ 7.30 (m, 5H), 4.70 (d, 2J(H,H)
2
= 14.0 Hz, 1H), 4.64 (d, J(H,H) = 14.0 Hz, 1H), 3.45 (dd, J(H,H)
= 10.0, 5.4, 1H), 3.37 (dd, J(H,H) = 10.0, 6.8, 1H), 3.17 (m, 2H), 2.96
(t, J(H,H) = 10.0, 1H), 2.79 (q, J(H,H) = 10.9, 1H), 1.85 (m, 1H).
13C NMR (101 MHz, CDCl3): δ 178.8 (s), 175.9 (s), 135.7 (s), 128.9 (s),
(m, CHCO2Bn, 1H), 2.79 (m, CHH, 1H), 2.38 (m, CHH, 1H). 13C
NMR (126 MHz, DMSO-d6): δ 179.2 (s, CH2CHCON), 177.8
(s, CHCHCON), 172.8 (s, CO2Bn), 136.7 (s, C, Ph), 136.5 (s, C, Ph),
129.2 (s, CH, Ph), 129.1 (s, CH, Ph), 128.7 (s, CH, Ph), 128.6
(s, CH, Ph), 128.0 (s, CH, Ph), 66.91 (s, OCH2Ph), 42.3 (s, NCH2Ph),
41.9 (s, CHCHCON), 38.8 (s, CHCO2Bn), 36.4 (s, CH2CHCON),
25.8 (s, CH2). LCMS (m/z): 350 (M + H+). Anal. Calcd for
C21H19NO4: C, 72.19; H, 5.48; N, 4.01. Found: C, 72.45; H, 5.65; N,
3.76.
128.8 (s), 128.2 (s), 42.6 (s), 42.2 (s), 35.5 (s), 34.3 (s), 33.2 (s), 29.4 (s).
LCMS (m/z): 308, 310 (M + H+). Anal. Calcd for C14H14BrNO2: C,
54.56; H, 4.58; N, 4.55. Found: C, 54.88; H, 4.87; N, 4.28.
(1S*,5S*,6S*)-3-Benzyl-6-(trifluoromethyl)-3-azabicyclo-
[3.2.0]heptane-2,4-dione (7a). White solid, mp 80−81 °C; 48%
yield (136 mg). Purified via column chromatography (hexanes/EtOAc
= 4:1). 1H NMR (400 MHz, CDCl3): δ 7.29 (m, Ph, 5H), 4.68
(s, CH2Ph, 2H), 3.33 (m, 2 × CH, 2H), 2.96 (m, CHCF3, 1H), 2.71
(m, CHH, 1H), 2.31 (m, CHH, 1H). 13C NMR (126 MHz, CDCl3):
δ 177.7 (s, CO), 175.7 (s, CO), 135.5 (s, C, Ph), 128.8 (s, CH, Ph),
128.7 (s, CH, Ph), 128.2 (s, CH, Ph), 126.2 (q, 1J(C,F) = 276.3 Hz, CF3),
(1S*,5S*,6R*)-Benzyl 3-Benzyl-2,4-dioxo-3-azabicyclo[3.2.0]-
heptane-6-carboxylate (4b). White solid, mp 72−73 °C; 15% yield
(0.53 g). Purified via column chromatography twice (hexanes/EtOAc =
2:1, then 1:1). 1H NMR (500 MHz, CDCl3): δ 7.36 (m, 2 × Ph, 10H),
3
42.8 (s, NCH2Ph), 39.0 (q, J(C,F) = 3.4 Hz, CHCHCON), 38.5
(q, 2J(C,F) = 32.0 Hz, CHCF3), 36.0 (s, CH2CHCON), 23.1
2
3
(q, J(C,F) = 3.3 Hz, CH2). 19F NMR (376 MHz, CDCl3): δ −74.9.
5.03 (s, OCH2Ph, 2H), 4.67 (d, NCHHPh, J(H,H) = 14.1 Hz, 1H),
4.59 (d, NCHHPh, 2J(H,H) = 14.1 Hz, 1H), 3.65 (m, CH, 1H),
3.52 (m, CH, 1H), 3.22 (m, CH, 1H), 2.72 (m, CHH, 1H), 2.55
(m, CHH, 1H). 13C NMR (126 MHz, CDCl3): δ 178.2 (s, CO),
175.9 (s, CO), 171.0 (s, CO), 135.8 (s, C, Ph), 135.4 (s, C, Ph),
128.9 (s, CH, Ph), 128.8 (s, CH, Ph), 128.7 (s, CH, Ph), 128.6
(s, CH, Ph), 128.0 (s, CH, Ph), 67.4 (s, OCH2Ph), 42.8 (s, NCH2Ph),
41.0 (s, CH), 37.5 (s, CH), 35.7 (s, CH), 25.7 (s, CH2). LCMS (m/z):
350 (M + H+). Anal. Calcd for C21H19NO4: C, 72.19; H, 5.48; N, 4.01.
Found: C, 71.88; H, 5.74; N, 4.29.
LCMS (m/z): 284 (M + H+). Anal. Calcd for C14H12F3NO2: C,
59.37; H, 4.27; N, 4.95. Found: C, 59.02; H, 4.53; N, 4.86.
(1S*,5S*,6R*)-6-Acetyl-3-benzyl-3-azabicyclo[3.2.0]-
heptane-2,4-dione (8a). White solid, mp 73−74 °C; 5% yield
(13 mg). Purified via column chromatography (hexanes/MTBE = 1:3).
1H NMR (500 MHz, CD3CN): δ 7.35 (m, Ph, 5H), 4.67 (s, CH2Ph, 2H),
3.54 (t, CHCHCON, 3J(H,H) = 5.8 Hz, 1H), 3.35 (m, CHCOMe, 1H),
3.16 (m, CH2CHCON, 1H), 2.72 (m, CHH, 1H), 2.30 (m, CHH, 1H),
2.14 (s, CH3, 3H). 13C NMR (101 MHz, CDCl3): δ 204.7 (s, MeCO),
178.4 (s, CO), 177.5 (s, CO), 135.7 (s, C, Ph), 128.8 (s, CH, Ph),
128.7 (s, CH, Ph), 128.0 (s, CH, Ph), 46.3 (s, CHCOMe), 42.6
(s, CH2Ph), 40.3 (s, CHCHCON), 35.6 (s, CH2CHCON), 27.3
(s, CH3), 25.1 (s, CH2). LCMS (m/z): 258 (M + H+). Anal. Calcd for
C15H15NO3: C, 70.02; H, 5.88; N, 5.44. Found: C, 69.83; H, 5.75; N,
5.32.
(1S*,5R*,6S*)-3-Benzyl-2,4-dioxo-3-azabicyclo[3.2.0]-
heptane-6-carboxamide (5a). White solid, mp 163−164 °C; 47%
yield (12.1 g). Purified via column chromatography (CH2Cl2/methanol/
1
NEt3 = 1000:50:2). H NMR (400 MHz, DMSO-d6): δ 7.42 (s, NHH,
1H), 7.27 (m, Ph, 5H), 7.06 (s, NHH, 1H), 4.59 (s, CH2Ph, 2H), 3.41
(dd, CHCHCONBn, 3J(H,H) = 11.2, 5.3 Hz, 1H), 3.26 (m, CH, 1H),
3.00 (m, CH, 1H), 2.56 (m, CHH, 1H), 2.19 (m, CHH, 1H). 13C
NMR (126 MHz, DMSO-d6): δ 179.7 (s, CO), 178.7 (s, CO),
174.1 (s, CO), 136.9 (s, C, Ph), 129.2 (s, CH, Ph), 128.0 (s, CH,
Ph), 128.0 (s, CH, Ph), 42.1 (s, NCH2Ph), 41.4 (s, CHCHCONBn),
39.7 (s, CH), 36.4 (s, CH), 26.5 (s, CH2). LCMS (m/z): 259
(M + H+). Anal. Calcd for C14H14N2O3: C, 65.11; H, 5.46; N, 10.85.
Found: C, 65.50; H, 5.14; N, 11.18.
(1S*,5R*,6R*)-3-Benzyl-2,4-dioxo-3-azabicyclo[3.2.0]-
heptane-6-carboxamide (5b). White solid, mp 169−170 °C; 11%
yield (2.8 g). Purified via column chromatography (CH2Cl2/
methanol/NEt3 = 1000:50:2). 1H NMR (500 MHz, DMSO-d6):
δ 7.46 (s, NH2, 1H), 7.33 (m, Ph, 5H), 6.97 (s, NH2, 1H), 4.63
(d, CH2Ph, 2J(H,H) = 15.1 Hz, 1H), 4.48 (d, CH2Ph, 2J(H,H) = 15.1 Hz,
1H), 3.46 (m, 2 × CH, 2H), 3.23 (m, CH, 1H), 2.56 (q, CHH,
3J(H,H) = 10.7, 1H), 2.22 (m, CHH, 1H). 13C NMR (126 MHz,
(1S*,5S*,6S*)-3-Benzyl-2,4-dioxo-3-azabicyclo[3.2.0]heptan-
6-yl acetate (9a). White solid, mp 66−67 °C; 71% yield (19.4 g).
1H NMR (400 MHz, DMSO-d6): δ 7.31 (m, Ph, 5H), 4.98 (s, CHOAc,
1H), 4.58 (s, CH2Ph, 2H), 3.45 (m, 2 × CH, 2H), 2.54 (s, CH2, 2H),
2.06 (s, CH3, 3H). 13C NMR (126 MHz, DMSO-d6): δ 178.8
(s, CO), 175.8 (s, CO), 169.8 (s, OCO), 136.6 (s, C, Ph),
129.0 (s, CH, Ph), 127.9 (s, CH, Ph), 69.7 (s, CHOAc), 47.4 (s, CH),
42.3 (s, CH2Ph), 34.6 (s, CH), 31.1 (s, CH2), 21.1 (s, CH3). LCMS
(m/z): 274 (M + H+). Anal. Calcd for C15H15NO4: C, 65.92; H, 5.53;
N, 5.13. Found: C, 65.58; H, 5.75; N, 5.32.
(1S*,5S*,6R*)-3-Benzyl-2,4-dioxo-3-azabicyclo[3.2.0]-
heptan-6-yl acetate (9b). White solid, mp 79−80 °C; 21% yield
1
(5.7 g). H NMR (400 MHz, DMSO-d6): δ 7.30 (m, Ph, 5H), 5.31
3
(td, CHOAc, J(H,H) = 8.8, 5.8 Hz, 1H), 4.61 (s, CH2Ph, 2H), 3.72
3
(t, J(H,H) = 7.2 Hz, CH, 1H), 3.13 (m, CH, 1H), 3.02 (m, CHH,
1H), 2.02 (m, CHH, 1H), 1.86 (s, CH3, 3H). 13C NMR (126 MHz,
DMSO-d6): δ 179.3 (s, CO), 174.8 (s, CO), 169.4 (s, OCO),
136.6 (s, C, Ph), 128.9 (s, CH, Ph), 127.8 (s, CH, Ph), 127.7 (s, CH,
Ph), 65.1 (s, CHOAc), 45.2 (s, CH), 42. 0 (s, CH2Ph), 33.6 (s, CH),
31.4 (s, CH2), 20.8 (s, CH3). LCMS (m/z): 274 (M + H+). Anal.
Calcd for C15H15NO4: C, 65.92; H, 5.53; N, 5.13. Found: C, 65.65; H,
5.76; N, 5.43.
DMSO-d6): δ 179.6 (s, CO), 177.4 (s, CO), 172.7 (s, CO),
136.8 (s, C, Ph), 128.9 (s, CH, Ph), 128.0 (s, CH, Ph), 127.7 (s, CH,
Ph), 42.2 (s, NCH2Ph), 41.1 (s, CH), 37.9 (s, CH), 35.7 (s, CH), 24.8
(s, CH2). LCMS (m/z): 259 (M + H+). Anal. Calcd for C14H14N2O3:
C, 65.11; H, 5.46; N, 10.85. Found: C, 64.85; H, 5.38; N, 10.69.
(1S*,5S*,6S*)-3-Benzyl-6-(bromomethyl)-3-azabicyclo-
[3.2.0]heptane-2,4-dione (6a). Yellow oil, 40% yield (124 mg).
Purified via column chromatography (hexanes/MTBE = 1:2).
1H NMR (500 MHz, CDCl3): δ 7.38 (m, Ph, 5H), 4.69 (s, CH2Ph,
2H), 3.58 (d, CH2Br, 3J(H,H) = 6.3 Hz, 2H), 3.22 (m, CH, 1H), 3.14
(1S*,5R*,6S*)-3-Benzyl-6-(trimethylsilyl)-3-azabicyclo[3.2.0]-
heptane-2,4-dione (10a). Yellow oil, 62% yield (8.9 g). Purified via
column chromatography (hexanes/EtOAc = 4:1). 1H NMR
I
DOI: 10.1021/acs.joc.8b00077
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
2
(500 MHz, CDCl3): δ 7.39 (m, 5H), 4.70 (s, 2H), 3.16 (s, 1H), 2.97
(d, CHHPh, J(H,H) = 13.8 Hz, 1H), 4.52 (d, CHHPh, 2J(H,H)
= 13.8 Hz, 1H), 4.09 (q, CH, 3J(H,H) = 10.0 Hz, 1H), 3.67 (dd, CH,
3J(H,H) = 10.6, 6.6 Hz, 1H), 3.34 (s, CH, 1H), 2.98 (dt, CHH,
3
3
(m, 1H), 2.39 (q, J(H,H) = 8.9, 1H), 2.19 (t, J(H,H) = 10.5, 1H),
1.80 (m, 1H), 0.08 (s, 9H). 13C NMR (126 MHz, CDCl3):
δ 179.9 (s), 179.5 (s), 136.1 (s), 128.7 (s), 128.6 (s), 127.8 (s),
42.4 (s), 39.2 (s), 38.0 (s), 24.0 (s), 23.9 (s), −4.1 (s). LCMS (m/z):
288 (M + H+). Anal. Calcd for C16H21NO2Si: C, 66.86; H, 7.36; N,
4.87. Found: C, 67.21; H, 7.12; N, 5.03.
J(H,H) = 13.0, 10.0 Hz, 1H), 2.39 (s, CHH, 1H). 13C NMR
(126 MHz, CDCl3): δ 178.6 (s, CO), 175.3 (s, CO), 149.8
(s, CH, Py), 146.6 (s, C, Py), 135.7 (s, C, Ph), 129.2 (s, CH, Ph), 128.7
(s, CH, Ph), 128.1 (s, CH, Ph), 122.4 (s, CH, Py), 43.8 (s, CH), 42.4
(s, CH2Ph), 38.0 (s, CH), 35.2 (s, CH), 27.3 (s, CH2). LCMS (m/z):
293 (M + H+). Anal. Calcd for C18H16N2O2: C, 73.95; H, 5.52; N,
9.58. Found: C, 74.03; H, 5.36; N, 9.81.
(1S*,5R*,6S*)-3-Benzyl-6-(4-fluorophenyl)-3-azabicyclo-
[3.2.0]heptane-2,4-dione (15a). White solid, mp 58−59 °C; 58%
yield (180 mg). Purified via column chromatography (hexanes/EtOAc
= 4:1). 1H NMR (400 MHz, CDCl3): δ 7.42 (d, 3J(H,H) = 6.7 Hz, Ar,
2H), 7.33 (m, Ar, 3H), 7.22 (dd, 3J = 8.4, 5.4 Hz, Ar, 2H), 7.03 (t, J =
8.4 Hz, Ar, 2H), 4.73 (s, CH2Ph, 2H), 3.56 (td, 3J(H,H) = 8.7, 5.0 Hz,
CH, 1H), 3.34 (m, 2 × CH, 2H), 2.70 (m, CHH, 1H), 2.61 (m, CHH,
1H). 13C NMR (126 MHz, CDCl3): δ 179.0 (s, CO), 178.0 (s, CO),
162.8 (d, 1J(C,F) = 245.8 Hz, CF), 137.9 (d, 4J(C,F) = 3.2 Hz,
CCHCHCF), 135.9 (s, C, Ph), 128.8 (s, CH, Ph), 128.7 (s, CH, Ph),
(1S*,5R*,6R*)-3-Benzyl-6-(trimethylsilyl)-3-azabicyclo[3.2.0]-
heptane-2,4-dione (10b). Yellow oil, 16% yield (2.3 g). Purified
via column chromatography (hexanes/EtOAc = 4:1). 1H NMR
(400 MHz, CDCl3): δ 7.29 (m, 5H), 4.69 (d, 2J(H,H) = 13.8 Hz, 1H),
2
4.63 (d, J(H,H) = 13.8 Hz, 1H), 3.41 (m, 1H), 3.29 (dd, J(H,H) =
11.2, 7.0 Hz, 1H), 2.67 (q, J(H,H) = 11.2 Hz, 1H), 2.38 (q, J(H,H) =
10.3 Hz, 1H), 1.98 (m, 1H), −0.10 (s, 9H). 13C NMR (126 MHz,
CDCl3): δ 179.6 (s), 179.2 (s), 135.9 (s), 129.2 (s), 128.6 (s),
127.9 (s), 42.5 (s), 40.0 (s), 38.4 (s), 24.2 (s), 23.6 (s), −3.3 (s).
LCMS (m/z): 288 (M + H+). Anal. Calcd for C16H21NO2Si: C, 66.86;
H, 7.36; N, 4.87. Found: C, 67.23; H, 7.10; N, 5.07.
(1S*,5R*,6S*)-3-Benzyl-6-(methylsulfonyl)-3-azabicyclo-
[3.2.0]heptane-2,4-dione (11a). White solid, mp 101−102 °C; 48%
yield (140 mg). Purified via column chromatography (hexanes/EtOAc
= 1:1). 1H NMR (400 MHz, CDCl3): δ 7.31 (m, Ph, 5H), 4.68
(s, CH2Ph, 2H), 3.61 (m, 2 × CH, 2H), 3.37 (m, CH, 1H), 3.12
(m, CHH, 1H), 2.92 (s, CH3, 3H), 2.44 (m, CHH, 1H). 13C NMR
(101 MHz, CDCl3): δ 177.0 (s), 175.0 (s), 135.3 (s), 128.9 (s), 128.7
(s), 128.3 (s), 55.8 (s), 43.0 (s), 40.6 (s), 38.5 (s), 35.6 (s), 22.9 (s).
LCMS (m/z): 294 (M + H+). Anal. Calcd for C14H15NO4S: C, 57.32;
H, 5.15; N, 4.77. Found: C, 57.01; H, 5.01; N, 5.06.
3
128.0 (s, CH, Ph), 127.9 (d, J(C,F) = 8.0 Hz, CHCHCF), 115.6
2
(d, J(C,F) = 21.5 Hz, CHCF), 46.6 (s, CH), 42.6 (s, CH2Ph), 41.2
(s, CH), 35.6 (s, CH), 29.8 (s, CH2). 19F NMR (376 MHz, CDCl3):
δ −116.0 (s). LCMS (m/z): 310 (M + H+). Anal. Calcd for C19H16FNO2:
C, 73.77; H, 5.21; N, 4.53. Found: C, 74.01; H, 5.45; N, 4.48.
(1S*,5R*,6R*)-3-Benzyl-6-(4-fluorophenyl)-3-azabicyclo-
[3.2.0]heptane-2,4-dione (15b). White solid, mp 64−65 °C; 15%
yield (47 mg). Purified via column chromatography (hexanes/EtOAc
= 4:1). 1H NMR (400 MHz, CDCl3): δ 7.28 (m, Ph, 5H), 6.77 (s, Ar,
(1S*,5R*,6S*)-3-Benzyl-2,4-dioxo-3-azabicyclo[3.2.0]-
heptane-6-sulfonyl chloride (12a). White solid, mp 109−110 °C;
53% yield (167 mg). Purified via column chromatography (hexanes/
EtOAc = 3:1). 1H NMR (500 MHz, CDCl3): δ 7.34 (m, Ph, 5H), 4.71
3
4H), 4.55 (m, CH2Ph, 2H), 4.09 (q, J(H,H) = 11.2 Hz, CH, 1H),
3.59 (dd, 3J(H,H) = 10.5, 6.4 Hz, CH, 1H), 3.27 (dt, 3J(H,H) = 11.2,
5.7 Hz, CH, 1H), 2.96 (m, CHH, 1H), 2.35 (m, CHH, 1H). 13C NMR
(101 MHz, CDCl3): δ 179.2 (s, CO), 176.0 (s, CO), 161.7
(d, 1J(C,F) = 253.9 Hz, CF), 135.9 (s, C, Ph), 133.7 (d, 4J(C,F)
= 3.2 Hz, CCHCHCF), 129.2 (s, CH, Ph), 128.9 (d, 3J(C,F) = 8.1 Hz,
3
(s, CH2Ph, 2H), 4.29 (m, CHSO2Cl, 1H), 3.80 (dd, CH, J(H,H) =
7.4, 4.0 Hz, 1H), 3.49 (m, CH, 1H), 3.19 (m, CHH, 1H), 2.66
(m, CHH, 1H). 13C NMR (126 MHz, CDCl3): δ 176.0 (s, CO),
173.2 (s, CO), 135.1 (s, C, Ph), 128.9 (s, CH, Ph), 128.9 (s, CH, Ph),
128.4 (s, CH, Ph), 66.4 (s, CHSO2Cl), 43.2 (s, CH2Ph), 42.0 (s, CH),
35.2 (s, CH), 26.5 (s, CH2). LCMS (m/z): 314, 316 (M + H+). Anal.
Calcd for C13H12ClNO4S: C, 49.76; H, 3.85; N, 4.46. Found: C, 50.05;
H, 3.59; N, 4.71.
2
CHCHCF), 128.6 (s, CH, Ph), 128.0 (s, CH, Ph), 115.2 (d, J(C,F)
= 21.4 Hz, CHCF), 44.5 (s, CH), 42.3 (s, CH2Ph), 38.4 (s, CH), 35.1
(s, CH), 28.5 (s, CH2). 19F NMR (376 MHz, CDCl3): δ −115.7 (s).
LCMS (m/z): 310 (M + H+). Anal. Calcd for C19H16FNO2: C,
73.77; H, 5.21; N, 4.53. Found: C, 73.57; H, 5.50; N, 4.36.
(1S*,5R*,6S*)-3-Benzyl-2,4-dioxo-3-azabicyclo[3.2.0]-
heptane-6-sulfonyl fluoride (13a). White solid, mp 124−125 °C,
29% yield (86 mg). Purified via column chromatography (hexanes/
(1S*,5S*,6S*)-Methyl 3-Benzyl-6-methyl-2,4-dioxo-3-
azabicyclo[3.2.0]heptane-6-carboxylate (16a). White solid, mp
78−79 °C; 28% yield (0.81 g). Purified via column chromatography
1
1
EtOAc = 3:1). H NMR (500 MHz, CD3CN): δ 7.36 (m, Ph, 5H),
(hexanes/MTBE = 1:2). H NMR (400 MHz, CDCl3): δ 7.28 (s, Ph,
2
2
3
4.71 (d, J(H,H) = 14.8 Hz, 1H), 4.67 (d, J(H,H) = 14.8 Hz, 1H),
4.45 (s, CHSO2F, 1H), 3.79 (m, CH, 1H), 3.52 (m, CH, 1H), 3.11
(m, CHH, 1H), 2.75 (m, CHH, 1H). 13C NMR (126 MHz, CD3CN):
δ 177.0 (s, CO), 174.3 (s, CO), 136.0 (s, C, Ph), 128.8 (s, CH,
5H), 4.67 (s, CH2Ph, 2H), 3.74 (s, OCH3, 3H), 3.64 (d, J(H,H)
= 6.9 Hz, CH, 1H), 3.20 (s, CH, 1H), 2.95 (m, CHH, 1H), 1.92
3
(dd, J(H,H) = 13.2, 4.8 Hz, CHH, 1H), 1.13 (s, CH3, 3H). 13C
NMR (126 MHz, CDCl3): δ 178.9 (s, CO), 175.7 (s, CO), 175.5
(s, CO), 135.9 (s, C, Ph), 129.1 (s, CH, Ph), 128.8 (s, CH, Ph),
128.2 (s, CH, Ph), 52.8 (s, OCH3), 45.2 (s, CH), 44.0 (s, C), 42.7
(s, CH2Ph), 34.0 (s, CH2), 33.9 (s, CH), 20.8 (s, CH3). LCMS (m/z):
288 (M + H+). Anal. Calcd for C16H17NO4: C, 66.89; H, 5.96; N, 4.88.
Found: C, 67.11; H, 6.15; N, 4.71.
2
Ph), 128.2 (s, CH, Ph), 127.9 (s, CH, Ph), 53.53 (d, J(C,F) = 19.2
Hz, CHSO2F), 42.8 (s, CH2Ph), 41.1 (s, CH), 35.7 (s, CH), 25.1
(s, CH2). 19F NMR (376 MHz, CD3CN): δ 44.4 (s). LCMS (m/z):
298 (M + H+). Anal. Calcd for C13H12FNO4S: C, 52.52; H, 4.07; N,
4.71. Found: C, 52.19; H, 4.24; N, 4.62.
(1S*,5R*,6S*)-3-Benzyl-6-(pyridin-4-yl)-3-azabicyclo[3.2.0]-
heptane-2,4-dione (14a). White solid, mp 75−76 °C; 55% yield
(161 mg). 1H NMR (400 MHz, CDCl3): δ 8.56 (d, Py, 3J(H,H)
= 5.8 Hz, 2H), 7.41 (d, Ar, 3J(H,H) = 6.8 Hz, 2H), 7.30 (m, Ar, 3H),
7.18 (d, Py, 3J(H,H) = 5.8 Hz, 2H), 4.73 (s, CH2Ph, 2H), 3.56
(m, CH, 1H), 3.39 (t, CH, 3J(H,H) = 5.9 Hz, 1H), 3.32 (m, CH, 1H),
2.74 (m, CHH, 1H), 2.64 (m, CHH, 1H). 13C NMR (101 MHz,
CDCl3): δ 178.5 (s, CO), 177.5 (s, CO), 150.8 (s, C, Py), 150.2
(s, CH, Py), 135.7 (s, C, Ph), 128.8 (s, CH, Ph), 128.7 (s, CH, Ph),
128.1 (s, CH, Ph), 121.4 (s, CH, Py), 45.5 (s, CH), 42.7 (s, CH2Ph),
40.7 (s, CH), 35.8 (s, CH), 28.9 (s, CH2). LCMS (m/z): 293
(M + H+). Anal. Calcd for C18H16N2O2: C, 73.95; H, 5.52; N, 9.58.
Found: C, 73.67; H, 5.37; N, 9.89.
(1S*,5S*,6R*)-Methyl 3-Benzyl-6-methyl-2,4-dioxo-3-
azabicyclo[3.2.0]heptane-6-carboxylate (16b). White solid,
mp 91−92 °C, 12% yield (0.34 g). Purified via column
chromatography (hexanes/MTBE = 1:2). 1H NMR (400 MHz,
2
CDCl3): δ 7.30 (m, Ph, 5H), 4.68 (d, CHHPh, J(H,H) = 14.1 Hz,
1H), 4.63 (d, CHHPh, 2J(H,H) = 14.1 Hz, 1H), 3.42 (s, OCH3, 3H),
3.27 (m, CH, 1H), 3.06 (d, 3J(H,H) = 6.7 Hz, CH, 1H), 2.76
3
(dd, J(H,H) = 12.9, 5.5 Hz, CHH, 1H), 2.30 (m, CHH, 1H), 1.58
(s, CH3, 3H). 13C NMR (126 MHz, CDCl3): δ 178.4 (s, CO), 175.7
(s, CO), 172.8 (s, CO), 135.9 (s, C, Ph), 129.0 (s, CH, Ph), 128.7
(s, CH, Ph), 128.0 (s, CH, Ph), 52.3 (s, OCH3), 48.8 (s, CH), 44.5
(s, C), 42.8 (s, CH2Ph), 33.5 (s, CH), 33.4 (s, CH2), 25.1 (s, CH3).
LCMS (m/z): 288 (M + H+). Anal. Calcd for C16H17NO4: C,
66.89; H, 5.96; N, 4.88. Found: C, 66.66; H, 6.26; N, 5.12.
(1S*,5R*,6R*)-3-Benzyl-6-(pyridin-4-yl)-3-azabicyclo[3.2.0]-
heptane-2,4-dione (14b). White solid, mp 88−89 °C; 15% yield
(1S*,5S*,6S*)-Methyl 3-Benzyl-6-fluoro-2,4-dioxo-3-
azabicyclo[3.2.0]heptane-6-carboxylate (17a). White solid, mp
128−129 °C; 26% yield (0.76 g). Purified via column chromatography
1
(44 mg). H NMR (400 MHz, CDCl3): δ 8.32 (broad s, Py, 2H),
7.27 (m, Ph, 5H), 6.78 (d, 3J(H,H) = 4.7 Hz, Py, 2H), 4.57
J
DOI: 10.1021/acs.joc.8b00077
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1
(hexanes/MTBE = 1:2). H NMR (400 MHz, DMSO-d6): δ 7.82
(400 MHz, CDCl3): δ 7.31 (m, Ph, 5H), 4.67 (d, 2J(H,H) = 14.3 Hz,
(m, Ph, 5H), 5.18 (d, CHHPh, 2J(H,H) = 14.7 Hz, 1H), 5.12
CHHPh, 1H), 4.63 (d, J(H,H) = 14.3 Hz, CHHPh, 1H), 3.90 (q,
2
2
3J(H,H) = 2.3 Hz, CCH, 1H), 3.78 (s, CH3O, 3H), 3.28 (m, CH2CH,
1H), 2.90 (m, CHH, 1H), 2.62 (q, J(H,H) = 11.0 Hz, CHH, 1H), 1.47
(s, 2 × Boc, 18H). 13C NMR (126 MHz, CDCl3): δ 177.9 (s, CO),
(d, CHHPh, J(H,H) = 14.7 Hz, 1H), 4.48 (m, CFCH, 1H), 4.32
(s, CH3O, 3H), 3.76 (m, CH, CHH, 2H), 2.95 (m, CHH, 1H). 13C
NMR (126 MHz, (CD3)2CO): δ 177.8 (s, CH2CHCON), 171.7
3
2
t
(d, J(C,F) = 5.3 Hz, CFCHCON), 168.9 (d, J (C,F) = 26.8 Hz,
CO2Me), 136.4 (s, C, Ph), 128.7 (s, CH, Ph), 128.1 (s, CH, Ph), 127.8
(s, CH, Ph), 88.8 (d, J(C,F) = 231.5 Hz, CF), 52.9 (s, OCH3), 47.9
172.9 (s, CO), 172.4 (s, CO), 151.3 (s, CO2 Bu), 135.8 (s, C,
Ph), 128.6 (s, CH, Ph), 128.5 (s, CH, Ph), 127.9 (s, CH, Ph), 83.6
(s, C(CH3)3), 60.8 (s, CNBoc2), 53.2 (s, OCH3), 46.7 (s, CCH), 42.5
(s, CH2Ph), 36.2 (s, CH2), 34.3 (s, CH2CH), 27.9 (s, C(CH3)3).
LCMS (m/z): 489 (M + H+). Anal. Calcd for C25H32N2O8: C,
61.46; H, 6.60; N, 5.73. Found: 61.78; H, 6.31; N, 5.49.
1
2
2
(d, J(C,F) = 23.1 Hz, CFCH), 42.4 (s, CH2Ph), 35.0 (d, J(C,F) =
24.8 Hz, CH2), 31.9 (d, 3J(C,F) = 5.6 Hz, CH2CH). 19F NMR
(376 MHz, DMSO-d6): δ −155.1 (m). LCMS (m/z): 292 (M + H+).
Anal. Calcd for C15H14FNO4: C, 61.85; H, 4.84; N, 4.81. Found: C,
62.03; H, 4.62; N, 5.08.
(1S*,5S*,6R*)-Methyl 3-Benzyl-6-fluoro-2,4-dioxo-3-
azabicyclo[3.2.0]heptane-6-carboxylate (17b). White solid, mp
95−96 °C; 6% yield (0.18 g). Purified via column chromatography
(hexanes/MTBE = 1:2). 1H NMR (500 MHz, CD3CN): δ 7.48
(m, Ph, 5H), 4.74 (s, CH2Ph, 2H), 3.81 (dd, J = 20.2, 7.5 Hz, CFCH,
1H), 3.61 (m, CH3O, CH, 4H), 2.99 (m, CH2, 2H). 13C NMR
Ethyl 3-Benzyl-2,4-dioxo-7-(trifluoromethyl)-3-
azabicyclo[3.2.0]heptane-6-carboxylate (22ab). Yellow oil, 67%
1
yield (0.24 g). H NMR (400 MHz, CDCl3) of both diastereomers
δ 7.28 (m, Ph, 5H), 4.66 (m, CH2Ph, 2H), 4.07 (m, OCH2, 2H),
3.70−3.21 (m, 2 × CH, CH2, 4H), 1.21 (m, CH3, 3H). 13C NMR
(126 MHz, CDCl3) of both diastereomers δ 175.1 (s), 174.6 (s),
174.1 (s), 173.4 (s), 170.0 (s), 168.6(s), 135.1 (s), 135.0 (s), 129.1 (s),
128.9 (s), 128.7 (s), 128.2 (s), 128.2 (s), 125.2 (q, 1J(C,F) = 276.6 Hz),
3
1
(126 MHz, CD3CN): δ 177.3 (s, CH2CHCON), 172.7 (d, J(C,F)
= 8.5 Hz, CFCHCON), 167.2 (d, J(C,F) = 27.6 Hz, CO2Me), 135.8
124.1 (q, J(C,F) = 277.9 Hz), 62.4 (s), 62.3 (s), 43.2 (s), 43.1 (s),
2
41.3 (s), 40.8 (q, 2J(C,F) = 32.7 Hz), 39.9 (q, 2J(C,F) = 32.4 Hz), 39.7
3
3
(s, C, Ph), 128.3 (s, CH, Ph), 128.1 (s, CH, Ph), 127.5 (s, CH, Ph), 92.2
(d, 1J(C,F) = 223.4 Hz, CF), 52.1 (s, OCH3), 50.0 (d, 2J(C,F) = 28.4 Hz,
CFCH), 42.2 (s, CH2Ph), 33.8 (d, 2J(C,F) = 24.8 Hz, CH2), 32.7
(d, 3J(C,F) = 3.1 Hz, CH2CH). 19F NMR (376 MHz, CDCl3): δ −150.2
(m). LCMS (m/z): 292 (M + H+). Anal. Calcd for C15H14FNO4: C,
61.85; H, 4.84; N, 4.81. Found: C, 61.52; H, 4.94; N, 4.67.
(1S*,5S*,6S*)-3-Benzyl-2,4-dioxo-6-(trifluoromethyl)-3-
azabicyclo[3.2.0]heptane-6-carbonitrile (18a). White solid, mp
105−106 °C; 42% yield (0.13 g). 1H NMR (400 MHz, CDCl3): δ 7.31
(m, Ph, 5H), 4.81 (d, 2J(H,H) = 14.0 Hz, CHHPh, 1H), 4.71
(s), 38.4 (s), 38.4 (s), 38.0 (q, J(C,F) = 3.1 Hz), 36.4 (q, J(C,F) =
3.0 Hz), 36.2 (s). 19F NMR (376 MHz, CDCl3) of both diastereomers
δ −70.3 (s), −73.8 (s). LCMS (m/z): 356 (M + H+). Anal. Calcd for
C17H16F3NO4: C, 57.47; H, 4.54; N, 3.94. Found: C, 57.75; H, 4.79;
N, 3.83.
(3aR,3bS,5r,6aR,6bS)-Methyl 2-Benzyl-1,3-diox-
odecahydrocyclopenta[3,4]cyclobuta[1,2-c]pyrrole-5-carboxylate
1
(23a-1). White solid, mp 90−91 °C; 53% yield (1.66 g). H NMR
(500 MHz, CDCl3): δ 7.32 (m, Ph, 5H), 4.67 (s, CH2Ph, 2H), 3.72
3
(s, OCH3, 3H), 3.09 (t, J(H,H) = 8.3 Hz, CHCO2Me, 1H), 2.88
3
2
3
(s, CHCON, 2H), 2.84 (d, J(H,H) = 5.3 Hz, CH2CH, 2H), 2.42
(d, J(H,H) = 14.0 Hz, CHHPh, 1H), 3.62 (d, J(H,H) = 6.6 Hz,
CCH, 1H), 3.37 (m, CH2CH, 1H), 3.11 (m, CHH, 1H), 2.65
(dd, J(H,H) = 14.1, 4.6 Hz, CHH, 1H). 13C NMR (126 MHz,
CDCl3): δ 175.3 (s, CO), 171.1 (s, CO), 134.7 (s, C, Ph), 129.0
(s, CH, Ph), 128.9 (s, CH, Ph), 128.5 (s, CH, Ph), 123.3 (q, 1J(C,F) =
280.7 Hz, CF3), 112.7 (s, CN), 43.5 (s, CCH), 42.6 (s, CH2Ph), 40.3
(d, 2J(H,H) = 14.2 Hz, 2 × CHH, 2H), 2.05 (m, 2 × CHH, 2H). 13
C
NMR (101 MHz, CDCl3): δ 178.8 (s, CO), 175.7 (s, CO), 135.9
(s, C, Ph), 128.6 (s, CH, Ph), 128.4 (s, CH, Ph), 127.8 (s, CH, Ph),
52.0 (s, OCH3), 44.8 (s, CHCO2Me), 43.0 (s, CHCON), 42.4
(s, CH2CH), 42.3 (s, CH2Ph), 35.2 (s, CH2). LCMS (m/z): 314
(M + H+). Anal. Calcd for C18H19NO4: C, 68.99; H, 6.11; N, 4.47.
Found: C, 68.66; H, 6.46; N, 4.30.
( 3 a R , 3 b S , 5 s , 6 a R , 6 b S ) - M e t h y l 2 - B e n z y l - 1 , 3 -
dioxodecahydrocyclopenta[3,4]cyclobuta[1,2-c]pyrrole-5-car-
boxylate (23a-2). White solid, mp 142−143 °C; 17% yield (0.53 g).
1H NMR (500 MHz, CDCl3): δ 7.32 (m, Ph, 5H), 4.68 (s, CH2Ph,
(q, J(C,F) = 34.1 Hz, CCF3), 34.7 (s, CH2CH), 29.7 (s, CH2). 19F
2
NMR (376 MHz, CDCl3): δ −76.5 (s). LCMS (m/z): 309 (M + H+).
Anal. Calcd for C15H11F3N2O2: C, 58.45; H, 3.60; N, 9.09. Found: C,
58.80; H, 3.35; N, 9.28.
(1S*,5S*,6S*)-3-Benzyl-6-(difluoromethyl)-2,4-dioxo-3-
azabicyclo[3.2.0]heptane-6-carbonitrile (19a). White solid, mp
2H), 3.71 (s, OCH3, 3H), 3.05 (m, CHCO2Me, 1H), 2.90 (d, 3J(H,H)
= 4.1 Hz, CH2CH, 2H), 2.71 (s, CHCON, 2H), 2.12 (m, 2 × CHH,
2H), 1.92 (m, 2 × CHH, 2H). 13C NMR (126 MHz, CDCl3): δ 178.4
(s, CO), 174.6 (s, CO), 135.8 (s, C, Ph), 128.7 (s, CH, Ph), 128.5
(s, CH, Ph), 127.9 (s, CH, Ph), 52.0 (s, OCH3), 42.6 (s, CH), 42.5
(s, CH2Ph), 41.8 (s, CH), 36.4 (s, CH2). LCMS (m/z): 314 (M + H+).
Anal. Calcd for C18H19NO4: C, 68.99; H, 6.11; N, 4.47. Found: C,
68.80; H, 6.01; N, 4.20.
(3aR,3bS,6aR,6bS)-5-Benzyltetrahydro-1H-furo[3′,4′:3,4]-
cyclobuta[1,2-c]pyrrole-4,6(3bH,5H)-dione (24a). White solid,
mp 82−83 °C; 71% yield (1.82 g). Purified via column chromatog-
raphy (hexanes/EtOAc = 2:1). 1H NMR (400 MHz, CDCl3):
δ 7.30 (m, 5H), 4.68 (s, 2H), 4.10 (d, J(H,H) = 10.0 Hz, 2H),
3.51 (d, J(H,H) = 7.4 Hz, 2H), 2.95 (s, 2H), 2.88 (s, 2H). 13C NMR
(126 MHz, CDCl3): δ 178.4 (s), 135.8 (s), 128.7 (s), 128.6 (s), 128.0
(s), 73.3 (s), 42.5 (s), 42.4 (s), 42.2 (s). LCMS (m/z): 258 (M + H+).
Anal. Calcd for C15H15NO3: C, 70.02; H, 5.88; N, 5.44. Found: C,
70.30; H, 5.66; N, 5.69.
1
97−98 °C; 35% yield (0.10 g). H NMR (400 MHz, CDCl3): δ 7.30
(m, Ph, 5H), 6.09 (t, 2J(H,F) = 55.4 Hz, CHF2, 1H), 4.80 (d, 2J(H,H)
2
= 14.0 Hz, CHHPh, 1H), 4.71 (d, J(H,H) = 14.0 Hz, CHHPh, 1H),
3.55 (d, J(H,H) = 6.8 Hz, CCH, 1H), 3.29 (m, CH2CH, 1H), 3.06
3
(m, CHH, 1H), 2.52 (dd, J(H,H) = 13.9, 4.8 Hz, CHH, 1H). 13C
NMR (126 MHz, CDCl3): δ 176.0 (s, CO), 172.4 (s, CO), 134.9
(s, C, Ph), 128.9 (s, CH, Ph), 128.8 (s, CH, Ph), 128.4 (s, CH, Ph),
114.5 (s, CN), 112.4 (t, 1J(C,F) = 249.9 Hz, CHF2), 43.3 (s, CH2Ph),
41.6 (s, CCH), 39.2 (t, 2J(C,F) = 26.4 Hz, CCHF2), 35.0 (s, CH2CH),
28.2 (s, CH2). 19F NMR (376 MHz, CDCl3): δ −127.3 (m). LCMS
(m/z): 291 (M + H+). Anal. Calcd for C15H12F2N2O2: C, 62.07; H,
4.17; N, 9.65. Found: C, 62.20; H, 4.39; N, 9.34.
3-Benzyl-6,6-dimethoxy-3-azabicyclo[3.2.0]heptane-2,4-
dione (20a). White solid, mp 95−96 °C; 62% yield (17.1 g). Purified
1
via column chromatography (hexanes/MTBE = 1:3). H NMR (500
2
MHz, CDCl3): δ 7.33 (m, Ph, 5H), 4.71 (d, J(H,H) = 14.2 Hz,
CHHPh, 1H), 4.64 (d, 2J(H,H) = 14.2 Hz, CHHPh, 1H), 3.51
3
(d, J(H,H) = 6.7 Hz, CH, 1H), 3.26 (s, OCH3, 3H), 3.08 (m, CH,
(3aS,3bS,6aS,6bS)-5-Benzyltetrahydro-2H-furo[2′,3′:3,4]-
cyclobuta[1,2-c]pyrrole-4,6(3bH,5H)-dione (25a). White solid,
mp 73−74 °C; 10% yield (0.26 g). Purified via column chroma-
tography (hexanes/EtOAc = 2:1). 1H NMR (400 MHz, CDCl3):
OCH3, 4H), 2.63 (t, J(H,H) = 12.0 Hz, CHH, 1H), 2.38 (dd, J(H,H)
= 13.3, 3.6 Hz, CHH, 1H). 13C NMR (126 MHz, CDCl3): δ 178.6 (s),
173.6 (s), 135.9 (s), 128.6 (s), 128.6 (s), 127.9 (s), 100.7 (s), 50.4 (s),
49.4 (s), 49.0 (s), 42.7 (s), 34.9 (s), 30.7 (s). LCMS (m/z): 276
(M + H+). Anal. Calcd for C15H17NO4: C, 65.44; H, 6.22; N, 5.09.
Found: C, 65.81; H, 6.01; N, 5.20.
(1S*,5S*,6R*)-Methyl 3-Benzyl-6-(N,N-di-tert-butylcarbonyli-
mido)-2,4-dioxo-3-azabicyclo[3.2.0]heptane-6-carboxylate
(21a). White solid, mp 77−78 °C; 21% yield (0.10 g). 1H NMR
3
δ 7.32 (m, 5H), 4.67 (s, 2H), 4.60 (d, J(H,H) = 5.2 Hz, 1H), 4.26
(t, 3J(H,H) = 8.3 Hz, 1H), 3.88 (m, 1H), 3.10 (m, 2H), 2.78 (m, 1H),
1.94 (m, 2H). 13C NMR (126 MHz, CDCl3): δ 178.0 (s), 176.0 (s),
135.8 (s), 128.7 (s), 128.6 (s), 128.0 (s), 79.7 (s), 67.3 (s), 46.9 (s),
44.0 (s), 42.7 (s), 41.0 (s), 31.3 (s). LCMS (m/z): 258 (M + H+).
K
DOI: 10.1021/acs.joc.8b00077
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The Journal of Organic Chemistry
Article
Anal. Calcd for C15H15NO3: C, 70.02; H, 5.88; N, 5.44. Found: C,
70.34; H, 6.07; N, 5.15.
(s), 32.5 (s), 32.3 (s), 29.7 (s). LCMS (m/z): 114 (M + H+). Anal.
Calcd for C6H11NO: C, 63.68; H, 9.80; N, 12.38. Found: C, 63.35; H,
9.54; N, 12.70.
(3aR,3bS,6aR,6bS)-tert-Butyl 5-Benzyl-4,6-diox-
ooctahydrocyclobuta[1,2-c:3,4-c′]dipyrrole-2(3bH)-carboxy-
tert-Butyl 6-Oxo-3-azabicyclo[3.2.0]heptane-3-carboxylate
(32). A solution of 31 (6.8 g, 60 mmol, 0.1 equiv) in CH2Cl2 (200
mL), DMAP (0.70 g, 6.0 mmol, 0.1 equiv), NEt3 (6.2 g, 72 mmol,
1.2 equiv), and Boc2O (15.7 g, 72 mmol, 1.2 equiv) were added. The
reaction mixture was stirred for 12 h, then washed with a solution of
10% aqueous citric acid (200 mL), and concentrated under reduced
pressure. The crude product was dissolved in CH2Cl2 (400 mL), and
the solution was cooled to 0 °C; then DMP (30.5 g, 72 mmol, 1.2
equiv) was added. The reaction mixture was stirred for 16 h at room
temperature and quenched with NaHCO3. The formed precipitate was
filtered and washed with CH2Cl2 (2 × 200 mL). The solution was
washed with a 10% aqueous citric acid solution (200 mL) and brine
(200 mL), dried over anhydrous Na2SO4, and concentrated under
reduced pressure to give the desired product as a colorless oil (8.6 g,
1
late (26a). White solid, mp 79−80 °C; 47% yield (0.17 g). H NMR
(500 MHz, CDCl3): δ 7.34 (m, 5H), 4.69 (s, 2H), 3.88 (s, 2H), 3.22
3
(d, J(H,H) = 9.6 Hz, 2H), 2.92 (s, 4H), 1.48 (s, 9H). 13C NMR
(101 MHz, CDCl3): δ 178.0 (s), 155.1 (s), 135.7 (s), 128.7 (s),
128.6 (s), 128.0 (s), 80.3 (s), 51.5 (s), 42.7 (s), 42.6 (s), 40.9 (s),
28.4 (s). LCMS (m/z): 357 (M + H+). Anal. Calcd for C20H24N2O4:
C, 67.40; H, 6.79; N, 7.86. Found: C, 67.68; H, 6.46; N, 8.02.
(3aR,3bS,6aR,6bS)-5-Benzyltetrahydro-1H-thieno[3′,4′:3,4]-
cyclobuta[1,2-c]pyrrole-4,6(3bH,5H)-dione 2,2-Dioxide (27a).
White solid, mp 142−143 °C; 63% yield (0.19 g). Purified via column
chromatography (MTBE). 1H NMR (400 MHz, CDCl3): δ 7.30
(m, 5H), 4.68 (s, 2H), 3.38 (s, 2H), 3.22 (s, 6H). 13C NMR (101 MHz,
CDCl3): δ 176.8 (s), 135.4 (s), 128.8 (s), 128.6 (s), 128.2 (s), 53.8 (s),
42.8 (s), 42.4 (s), 35.8 (s). LCMS (m/z): 306 (M + H+). Anal. Calcd
for C15H15NO4S: C, 59.00; H, 4.95; N, 4.59. Found: C, 59.16; H,
4.83; N, 4.81.
(3aR,3bR,6aS,6bR)-5-Benzyltetrahydro-2H-thieno[2′,3′:3,4]-
cyclobuta[1,2-c]pyrrole-4,6(3bH,5H)-dione 1,1-Dioxide (28a).
White solid, mp 135−136 °C; 27% yield (82 mg). Purified via column
chromatography (MTBE). 1H NMR (400 MHz, CDCl3): δ 7.30
(m, 5H), 4.69 (s, 2H), 3.60 (m, 1H), 3.46 (m, 1H), 3.23 (m, 4H), 2.44
(m, 1H), 2.31 (m, 1H). 13C NMR (126 MHz, CDCl3): δ 176.1 (s),
174.1 (s), 135.2 (s), 128.9 (s), 128.7 (s), 128.3 (s), 55.9 (s), 47.1 (s),
43.1 (s), 41.5 (s), 40.4 (s), 39.4 (s), 26.4 (s). LCMS (m/z): 306
(M + H+). Anal. Calcd for C15H15NO4S: C, 59.00; H, 4.95; N, 4.59.
Found: C, 59.29; H, 4.62; N, 4.42.
2-Benzyl-6a-ethoxyhexahydrocyclopenta[3,4]cyclobuta[1,2-
c]pyrrole-1,3,4(2H)-trione (29a). White solid, mp 120−121 °C;
44% yield (0.14 g). Purified via column chromatography (EtOAc). 1H
NMR (400 MHz, CDCl3): δ 7.29 (m, 5H), 4.71 (s, 2H), 3.58
(m, 1H), 3.43 (m, 2H), 2.87 (m, 1H), 2.78 (s, 1H), 2.59 (m, 2H), 2.29
(m, 2H), 0.94 (t, 3J(H,H) = 6.9 Hz, 3H). 13C NMR (126 MHz, CDCl3):
δ 211.4 (s), 175.8 (s), 174.2 (s), 135.4 (s), 128.6 (s), 128.5 (s), 127.9 (s),
82.4 (s), 60.0 (s), 51.9 (s), 48.8 (s), 42.9 (s), 37.1 (s), 35.8 (s), 32.1 (s),
15.0 (s). LCMS (m/z): 314 (M + H+). Anal. Calcd for C18H19NO4: C,
68.99; H, 6.11; N, 4.47. Found: C, 68.68; H, 6.33; N, 4.64.
General Procedure for Reduction with LiAlH4. A suspension of
LiAlH4 (3.0 equiv) in THF was cooled to 0−10 °C under an argon
atmosphere. A solution of imide (1.0 equiv) in THF was added dropwise,
and the reaction mixture was refluxed for 5 h. The reaction mixture was
cooled to 0−5 °C under an argon atmosphere and quenched with a
mixture of THF/H2O (3:1). Then, a 30% aqueous solution of NaOH
was added, and the formed precipitate was filtered off and washed with
hot THF three times. The resulting solution was concentrated under
reduced pressure to give the crude product.
1
68% yield). H NMR (400 MHz, DMSO-d6): δ 3.71 (m, 2H), 3.59
(d, J(H,H) = 11.4 Hz, 1H), 3.36 (m, 2H), 3.15 (m, 1H), 3.04 (m, 1H),
2.68 (m, 1H), 1.39 (s, 9H). 13C NMR (126 MHz, DMSO-d6): δ 211.0
(s), 154.4 (s), 79.3 (s), 63.6 (s), 52.9 (s), 51.7 (s), 48.1 (s), 28.5 (s).
LCMS (m/z): 212 (M + H+). Anal. Calcd for C11H17NO3: C,
62.54; H, 8.11; N, 6.63. Found: C, 62.87; H, 8.37; N, 6.34.
tert-Butyl 6-Amino-3-azabicyclo[3.2.0]heptane-3-carboxy-
late (33). A mixture of 32 (12.0 g, 57 mmol, 1.0 equiv), NH2OH·
HCl (6.7 g, 96 mmol, 1.7 equiv), and NaHCO3 (8.1 g, 96 mmol,
1.7 equiv) in methanol (250 mL) was stirred for 16 h at room
temperature. The solvent was removed under reduced pressure. The
residue was dissolved in water (100 mL) and extracted with CH2Cl2
(2 × 100 mL). The combined organic layers were dried over Na2SO4,
filtered, and concentrated under reduced pressure. The crude product
was dissolved in a methanolic ammonia solution (150 mL), and Raney
nickel (2 g) was added. The reaction mixture was stirred for 16 h
under a hydrogen atmosphere (40 atm) at room temperature. The
catalyst was filtered off, and the solution was concentrated under
reduced pressure to afford the desired product as a colorless oil (9.4 g,
1
78% yield). dr = 81:19 according to the GCMS spectrum. H NMR
(500 MHz, CDCl3) of all diastereomers and Boc-rotamers: δ 3.91
(s, 1H), 3.68−2.36 (m, 8H), 1.49 (m, 9H), 1.37 (m, 2H). 13C NMR
(101 MHz, CDCl3) of all diastereomers and Boc-rotamers: δ 155.0
(s), 154.8 (s), 79.0 (s), 78.9 (s), 51.8 (s), 51.3 (s), 50.7 (s), 44.3 (s),
43.9 (s), 36.7 (s), 35.8 (s), 31.6 (s), 30.9 (s), 28.3 (s), 28.1 (s). LCMS
(m/z): 213 (M + H+). Anal. Calcd for C11H20N2O2: C, 62.23; H,
9.50; N, 13.20. Found: C, 62.04; H, 9.67; N, 13.51.
((1S*,5R*,6S*)-3-Benzyl-3-azabicyclo[3.2.0]heptan-6-yl)-
methanamine (34). Colorless oil, 87% yield (2.1 g). 1H NMR
(400 MHz, CDCl3): δ 7.38 (m, 5H), 3.65 (m, 2H), 2.80 (m, 2H), 2.67
(m, 3H), 2.37 (m, 1H), 2.08 (m, 3H), 1.88 (m, 1H), 1.71 (m, 1H), 1.33
(broad s, 2H). 13C NMR (101 MHz, CDCl3): δ 139.9 (s), 128.6 (s),
128.1 (s), 126.7 (s), 60.4 (s), 60.1 (s), 59.7 (s), 47.9 (s), 41.4 (s), 40.8 (s),
34.2 (s), 28.4 (s). LCMS (m/z): 217 (M + H+). Anal. Calcd for
C14H20N2: C, 77.73; H, 9.32; N, 12.95. Found: C, 77.37; H, 9.67; N,
12.67.
General Procedure for Removal of the Benzyl Group.
A mixture of benzylamine (1.0 equiv) and 10% palladium on charcoal
(0.1 equiv) in methanol was stirred for 12 h under a hydrogen
atmosphere (60 atm) at 40 °C. Palladium was filtered off and washed
with methanol twice. The solution was acidified with a 10% aqueous
hydrochloric acid solution and concentrated under reduced pressure to
give the desired product.
((1S*,5S*,6S*)-3-Benzyl-3-azabicyclo[3.2.0]heptan-6-yl)-
methanol (35a). Colorless oil, 87% yield (17.8 g). 1H NMR
(400 MHz, CDCl3): δ 7.38 (m, 5H), 3.69 (m, 4H), 2.81 (d, 3J(H,H) =
9.4 Hz, 2H), 2.67 (m, 1H), 2.47 (m, 1H), 2.11 (m, 4H), 1.87
(m, 2H). 13C NMR (101 MHz, CDCl3): δ 139.8 (s), 128.7 (s), 128.2 (s),
126.7 (s), 67.2 (s), 60.5 (s), 60.0 (s), 59.8 (s), 40.4 (s), 39.6 (s), 34.3 (s),
27.1 (s). LCMS (m/z): 218 (M + H+). Anal. Calcd for C14H19NO: C,
77.38; H, 8.81; N, 6.45. Found: C, 77.19; H, 8.93; N, 6.70.
((1S*,5S*,6R*)-3-Benzyl-3-azabicyclo[3.2.0]heptan-6-yl)-
3-Azabicyclo[3.2.0]heptane Hydrochloride (30). White solid,
1
mp 196−197 °C; 81% yield (8.5 g). H NMR (400 MHz, CDCl3): δ
10.20 (br s, 2H), 3.46 (dd, J = 11.5, 4.7 Hz, 2 × CHHN, 2H), 3.35−
2.91 (m, 2 × CHHN, 2 × CH, 4H), 2.29 (m, 2 × CHH, 2H), 2.05 (m,
2 × CHH, 2H). 13C NMR (126 MHz, CDCl3): δ 52.2 (s, CH2N), 36.3
(s, CH), 22.3 (s, CH2). LCMS (m/z): 98 (M − Cl−). Anal. Calcd for
C6H12ClN: C, 53.93; H, 9.05; N, 10.48. Found: C, 53.68; H, 9.21; N,
10.19.
1
methanol (35b). Colorless oil, 73% yield (0.32 g). H NMR (400
2
MHz, CDCl3): δ 7.31 (m 5H), 6.62 (br s, 1H), 3.89 (d, J(H,H) =
3-Azabicyclo[3.2.0]heptan-6-ol (31). White solid, mp 95−96
°C; 70% yield (16.0 g). dr = 81:19 according to the GCMS spectrum.
1H NMR (400 MHz, CDCl3) of both diastereomers: δ 4.36−3.15
(m, 2H), 3.03−2.36 (m, 7H), 2.15−1.24 (m, 2H). 13C NMR
(126 MHz, DMSO-d6) of both diastereomers: δ 69.5 (s), 62.3 (s),
61.2 (s), 53.7 (s), 52.8 (s), 51.9 (s), 50.1 (s), 46.5 (s), 35.7 (s), 35.6
12.6 Hz, 1H), 3.76 (d, J(H,H) = 11.8 Hz, 1H), 3.49 (s, 1H), 3.41
2
3
(d, J(H,H) = 12.6 Hz, 1H), 3.19 (d, J(H,H) = 10.3 Hz, 1H), 2.96
(dd, 3J(H,H) = 7.8, 7.3 Hz, 2H), 2.85 (d, 3J(H,H) = 9.7 Hz, 1H), 2.71
(m, 1H), 2.60 (s, 1H), 2.12 (m, 4H). 13C NMR (101 MHz, CDCl3):
δ 138.0 (s), 128.9 (s), 128.5 (s), 127.3 (s), 62.0 (s), 60.4 (s), 59.8 (s),
55.8 (s), 39.8 (s), 35.0 (s), 34.5 (s), 25.0 (s). LCMS (m/z): 218
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DOI: 10.1021/acs.joc.8b00077
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(M + H+). Anal. Calcd for C14H19NO: C, 77.38; H, 8.81; N,
6.45. Found: C, 77.07; H, 8.57; N, 6.62.
126.7 (s, CH, Ph), 60.2 (s, CH2), 60.0 (s, CH2), 42.2 (s, CH). LCMS
(m/z): 319 (M + H+). Anal. Calcd for C22H26N2: C, 82.97; H, 8.23; N,
8.80. Found: C, 82.62; H, 8.50; N, 8.56.
(3aR,3bR,6aS,6bS)-Decahydrocyclobuta[1,2-c:3,4-c′]-
dipyrrole Dihydrochloride (42). White solid, mp 265−269 °C; 84%
yield (7.8 g). 1H NMR (400 MHz, D2O): δ 2.79 (d, J(H,H) = 11.6 Hz,
2 × CHH, 4H), 2.45 (m, 2 × CHH, 4H), 2.11 (m, 4 × CH, 4H). 13C
NMR (101 MHz, D2O): δ 52.1 (s, CH2), 41.3 (s, CH). LCMS (m/z):
139 (M − HCl − Cl−). Anal. Calcd for C8H16N2Cl2: C, 45.51; H, 7.64;
N, 13.27. Found: C, 45.79; H, 7.56; N, 13.44.
((1S*,5S*,6S*)-3-Azabicyclo[3.2.0]heptan-6-yl)methanol Hy-
drochloride (36a). White solid, mp 79−80 °C; 80% yield (10.7 g).
1H NMR (400 MHz, D2O): δ 3.45 (d, 3J(H,H) = 7.0 Hz, 2H),
3.32−3.18 (m, 2H), 3.06 (m, 2H), 2.94 (m, 1H), 2.73 (m, 1H), 1.99
(m, 1H), 1.82 (m, 1H), 1.64 (m, 1H). 13C NMR (101 MHz, D2O):
δ 65.0 (s), 51.9 (s), 51.5 (s), 39.3 (s), 37.5 (s), 33.4 (s), 25.0 (s).
LCMS (m/z): 128 (M − Cl−). Anal. Calcd for C7H14ClNO: C, 51.38;
H, 8.62; N, 8.56. Found: C, 51.12; H, 8.84; N, 8.27.
(3aR,3bS,6aR,6bS)-5-Benzyloctahydro-1H-thieno[3′,4′:3,4]-
cyclobuta[1,2-c]pyrrole 2,2-Dioxide (43). TMSCl (10.4 g, 96 mmol,
6.0 equiv) was added dropwise to a suspension of LiAlH4 (3.6 g,
96 mmol, 6.0 equiv) in THF at room temperature under an argon
atmosphere. The reaction mixture was stirred for 1 h and cooled to
0 °C, and a solution of 27a (5.0 g, 16 mmol, 1.0 equiv) in THF
(20 mL) was added dropwise. The reaction mixture was stirred for
24 h, then cooled to 0 °C under an argon atmosphere, and quenched
with a mixture of water/THF (1:3) and then with a 30% aqueous
KOH solution. The formed precipitate was filtered off and washed
with THF three times. The solution was concentrated under reduced
pressure. Diethyl ether was added (100 mL), and the formed pre-
cipitate was filtered, washed with diethyl ether (50 mL), and dried to
afford the desired product as a white solid, mp 132−133 °C (3.5 g,
78% yield). 1H NMR (400 MHz, CDCl3): δ 7.29 (m, 5H),
3.65 (s, 2H), 3.12 (m, 2H), 2.98 (m, 2H), 2.86 (m, 4H), 2.72
(s, 2H), 2.06 (d, 3J(H,H) = 6.2 Hz, 2H). 13C NMR (101 MHz,
CDCl3): δ 139.5 (s), 128.5 (s), 128.2 (s), 126.9 (s), 59.3 (s), 59.3 (s),
55.2 (s), 42.0 (s), 37.0 (s). LCMS (m/z): 278 (M + H+). Anal. Calcd
for C15H19NO2S: C, 64.95; H, 6.90; N, 5.05. Found: C, 64.63; H,
6.63; N, 5.38.
((1S*,5S*,6R*)-3-Azabicyclo[3.2.0]heptan-6-yl)methanol
(36b). Colorless oil, 67% yield (85 mg). 1H NMR (400 MHz,
CDCl3): δ 3.76 (d, J(H,H) = 11.6 Hz, 1H), 3.50 (m, 1H), 3.34 (d,
J(H,H) = 10.5 Hz, 1H), 3.07 (d, J(H,H) = 9.1 Hz, 1H), 2.98 (m, 1H),
2.67 (m, 6H), 2.25 (m, 1H), 2.00 (m, 1H). 13C NMR (101 MHz,
CDCl3): δ 61.9 (s), 53.3 (s), 47.8 (s), 39.6 (s), 34.7 (s), 34.1 (s), 24.9
(s). LCMS (m/z): 128 (M + H+). Anal. Calcd for C7H13NO: C, 66.10;
H, 10.30; N, 11.01. Found: C, 66.32; H, 10.63; N, 11.29.
(1S*,5R*,6S*)-6-(4-Fluorophenyl)-3-azabicyclo[3.2.0]-
heptane Hydrochloride (37). White solid, mp 147−148 °C; 55%
1
yield (0.52 g). H 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),
1
2.32 (m, 2H). 13C NMR (101 MHz, MeOD): δ 161.5 (d, J(C,F) =
4
3
243.1 Hz), 140.2 (d, J(C,F) = 3.1 Hz), 127.8 (d, J(C,F) = 8.0 Hz),
2
114.8 (d, J(C,F) = 21.5 Hz), 51.39 (s), 51.37 (s), 45.4 (s), 40.3 (s),
33.4 (s), 30.4 (s). 19F NMR (376 MHz, MeOD): δ −119.3 (s). LCMS
(m/z): 192 (M − Cl−). Anal. Calcd for C12H15ClFN: C, 63.30; H,
6.64; N, 6.15. Found: C, 63.48; H, 6.85; N, 6.47.
(3aR,5s,6aS)-2-Benzyl-5-fluorooctahydrocyclopenta[c]-
pyrrole (38). A mixture of 35a or 35b (1.6 g, 7.4 mmol, 1.0 equiv),
anhydrous HF (2.0 mL), and SF4 (1.7 g, 15.8 mmol, 2.1 equiv) was kept
in a stainless steel autoclave overnight. The gaseous products were
removed under an effective fume hood. The reaction mixture was poured
into a 10% solution of KOH (150 mL) and extracted with CH2Cl2 (2 ×
100 mL). The combined organic layers were dried over Na2SO4,
filtered, and concentrated under reduced pressure to afford the desired
product as a colorless oil (1.3 g, 78% yield from 35a) or (1.2 g, 75%
(3aR,3bS,6aR,6bS)-Octahydro-1H-thieno[3′,4′:3,4]cyclobuta-
[1,2-c]pyrrole 2,2-Dioxide Hydrochloride (44). A mixture of 43
(2.8 g, 10 mmol, 1.0 equiv), Boc2O (2.6 g, 12 mmol, 1.2 equiv), and
10% palladium on charcoal (1.1 g, 1.0 mmol, 0.1 equiv) in methanol
(100 mL) was stirred for 12 h under a hydrogen atmosphere (60 atm)
at 40 °C. Palladium was filtered off and washed with methanol
(2 × 50 mL). The resulting solution was acidified with a 10% aqueous
hydrochloric acid solution, stirred for 6 h, and concentrated under
reduced pressure to give the product as a white solid (1.3 g, 60%
yield), mp 180−181 °C. 1H NMR (400 MHz, D2O): δ 3.45
(d, J(H,H) = 12.4 Hz, 2H), 3.24 (m, 6H), 3.08 (m, 2H), 2.90 (m, 2H).
13C NMR (101 MHz, D2O): δ 53.8 (s), 51.1 (s), 40.7 (s), 35.5 (s).
1
yield from 35b). H NMR (400 MHz, CDCl3): δ 7.30 (m, Ph, 5H),
5.08 (d, 3J(H,F) = 53.5 Hz, CHF, 1H), 3.57 (s, CH2Ph, 2H), 2.87 (m,
2 × CHHN, 2H), 2.67 (m, CHCH, 2H), 2.26 (m, 2 × CHHN, 2H),
1.89 (m, CH2CHFCH2, 4H). 13C NMR (101 MHz, CDCl3): δ 138.7
(s, C, Ph), 128.8 (s, CH, Ph), 128.2 (s, CH, Ph), 126.9 (s, CH, Ph),
98.1 (d, 1J(C,F) = 176.2 Hz, CF), 61.3 (s, CH2NBnCH2), 60.0
(s, NCH2Ph), 40.7 (s, CHCH), 37.9 (d, 2J(C,F) = 19.0 Hz,
CH2CHFCH2). 19F NMR (376 MHz, CDCl3): δ −173.3 (s). LCMS
(m/z): 220 (M + H+). Anal. Calcd for C14H18FN: C, 76.68; H, 8.27;
N, 6.39. Found: C, 76.97; H, 8.03; N, 6.16.
LCMS (m/z): 188 (M − Cl−). Anal. Calcd for C8H14ClNO2S: C,
42.95; H, 6.31; N, 6.26. Found: C, 42.62; H, 6.52; N, 6.48.
5-(Hydroxymethyl)decahydrocyclopenta[3,4]cyclobuta[1,2-
c]pyrrole Hydrochloride (45). White solid, mp 151−152 °C; 82%
yield (32.5 g). dr = 1:1 according to the 1H NMR spectrum. 1H NMR
(500 MHz, D2O) of both diastereomers: δ 3.59 (m, 2H), 3.39
(m, 2H), 3.13 (m, 2H), 2.71 (m, 1H), 2.55 (m, 1H), 2.31 (m, 2H),
2.09 (m, 2H), 1.71 (m, 1H), 1.41 (m, 1H), 1.22 (m, 1H). 13C NMR
(126 MHz, D2O) of both diastereomers: δ 65.5 (s), 65.4 (s), 51.8 (s),
51.7 (s), 45.2 (s), 42.3 (s), 41.1 (s), 40.9 (s), 40.4 (s), 40.2 (s), 36.3 (s),
35.6 (s). LCMS (m/z): 168 (M − Cl−). Anal. Calcd for C10H18ClNO:
C, 58.96; H, 8.91; N, 6.88. Found: C, 58.61; H, 8.69; N, 6.60.
(3aR,3bS,6aR,6bS)-5-Benzyloctahydro-1H-furo[3′,4′:3,4]-
cyclobuta[1,2-c]pyrrole (39). Yellow solid, mp 43−45 °C; 75%
1
yield (2.2 g). H NMR (500 MHz, CDCl3): δ 7.33 (m, 5H), 3.88
(d, J(H,H) = 9.3 Hz, 2H), 3.68 (s, 2H), 3.45 (m, 2H), 2.89 (d, J(H,H)
= 9.3 Hz, 2H), 2.58 (s, 2H), 2.33 (s, 2H), 2.08 (m, 2H). 13C NMR
(101 MHz, CDCl3): δ 139.7 (s), 128.6 (s), 128.2 (s), 126.8 (s),
73.9 (s), 59.7 (s), 43.1 (s), 41.3 (s). LCMS (m/z): 230 (M + H+).
Anal. Calcd for C15H19NO: C, 78.56; H, 8.35; N, 6.11. Found: C,
78.25; H, 8.18; N, 6.10.
(3aR,3bS,6aR,6bS)-Octahydro-1H-furo[3′,4′:3,4]cyclobuta-
[1,2-c]pyrrole (40). White solid, mp 83−84 °C; 85% yield (0.88 g).
1H NMR (400 MHz, CDCl3): δ 3.93 (d, J(H,H) = 9.1 Hz, 2H), 3.45
Benzyl 5-(Hydroxymethyl)octahydrocyclopenta[3,4]-
cyclobuta[1,2-c]pyrrole-2(3bH)-carboxylate (46). A solution of
45 (25.7 g, 0.1 mol, 1.0 equiv) in CH2Cl2 (400 mL) was mixed with
CbzCl (20.5 g, 0.12 mmol, 1.2 equiv) and NEt3 (15.2 g, 0.15 mmol, 1.5
equiv). The resulting reaction mixture was stirred at room temperature
for 6 h; then the organic phase was separated, washed with a 10%
K2CO3 aqueous solution (300 mL), dried over Na2SO4, filtered, and
concentrated under reduced pressure to afford the desired product as a
(d, J(H,H) = 8.0 Hz, 2H), 2.97 (d, J(H,H) = 11.0 Hz, 2H), 2.66 (d,
J(H,H) = 11.0 Hz, 2H), 2.34 (d, J(H,H) = 15.1 Hz, 4H), 2.23 (broad
s, NH, 1H). 13C NMR (126 MHz, CDCl3): δ 73.9 (s), 53.3 (s), 42.2
(s), 42.1 (s). LCMS (m/z): 140 (M + H+). Anal. Calcd for C8H13NO:
C, 69.03; H, 9.41; N, 10.06. Found: C, 69.29; H, 9.74; N, 10.25.
(3aR,3bR,6aS,6bS)-2,5-Dibenzyldecahydrocyclobuta[1,2-
c:3,4-c′]dipyrrole (41). White solid, mp 127−128 °C; 82% yield
1
yellow oil (27.2 g, 87% yield). dr = 1:1 according to the H NMR
spectrum. 1H NMR (400 MHz, CDCl3) of both diastereomers: δ 7.34
(m, 5H), 5.15 (s, 2H), 3.69 (m, 4H), 3.22 (m, 2H), 2.42 (m, 4H), 2.04
(m, 2H), 1.73 (m, 2H), 1.37 (m, 1H), 1.26 (m, 1H). 13C NMR
(126 MHz, CDCl3) of both diastereomers: δ 155.6 (s), 136.9 (s),
128.4 (s), 127.9 (s), 127.7 (s), 66.8 (s), 66.4 (s), 66.2 (s), 52.8 (s),
46.5 (s), 42.8 (s), 42.5 (s), 41.7 (s), 36.9 (s), 36.2 (s). LCMS (m/z): 302
1
(13.2 g). H NMR (500 MHz, DMSO-d6): δ 7.34 (m, 2 × Ph, 10H),
3.69 (s, 2 × PhCH2, 4H), 2.86 (d, J(H,H) = 9.1 Hz, 2 × CHH, 4H),
2.43 (s, 2 × CHH, 4H), 2.10 (m, 4 × CH, 4H). 13C NMR (126 MHz,
CDCl3): δ 140.1 (s, C, Ph), 128.7 (s, CH, Ph), 128.2 (s, CH, Ph),
M
DOI: 10.1021/acs.joc.8b00077
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The Journal of Organic Chemistry
Article
(M + H+). Anal. Calcd for C18H23NO3: C, 71.73; H, 7.69; N, 4.65.
Found: C, 71.41; H, 7.51; N, 4.91.
ORCID
Pavel K. Mykhailiuk: 0000-0003-1821-9011
2-(tert-Butoxycarbonyl)decahydrocyclopenta[3,4]cyclobuta-
[1,2-c]pyrrole-5-carboxylic Acid (47). A mixture of CrO3 (9.6 g,
96 mmol, 1.6 equiv) and H2SO4 (14.1 g, 60 mmol, 2.4 equiv) in water
(50 mL) was added to a solution of 46 (18.1 g, 60 mmol, 1.0 equiv) in
acetone (300 mL). The reaction mixture was stirred for 12 h, then
quenched with isopropanol (20 mL), concentrated under reduced
pressure, diluted with water (200 mL), and extracted with ethyl acetate
(2 × 200 mL). The combined organic phases were washed with a 10%
Na2SO4 aqueous solution, dried over anhydrous Na2SO4, filtered, and
concentrated under reduced pressure. The resulting crude product was
dissolved in methanol (200 mL) and 10% palladium on charcoal
(5.1 g, 4.8 mmol, 0.05 equiv) in methanol. The mixture was stirred for
12 h under a hydrogen atmosphere (60 atm) at 40 °C. Palladium was
filtered off and washed with methanol twice, and the solvent was
removed under reduced pressure. The crude product was dissolved in
CH2Cl2 (200 mL), and then DMAP (0.7 g, 6.0 mmol, 0.1 equiv), NEt3
(6.2 g, 72 mmol, 1.2 equiv), and Boc2O (15.7 g, 72 mmol, 1.2 equiv)
were added. The reaction mixture was stirred for 12 h, washed with a
10% aqueous citric acid solution (200 mL), dried over anhydrous
Na2SO4, filtered, and concentrated under reduced pressure. The
residue was dissolved in hexanes (100 mL), and the formed precipitate
was filtered to afford the product as a white solid, mp 68−69 °C (7.2 g,
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors are very grateful to Dr. S. Shishkina for X-ray
studies, I. Stadnyi for help with UV lamps and reaction vessels,
V. Polovinko and A. Kozitskiy for NMR spectra, A. Shukhaev
and O. Michurin for alkenes 18, 19, and 29, M. Nechayev for
high pressure hydrogenation, and Prof. I. Komarov for
incredible ideas and limitless inspiration.
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43% yield). dr = 51:49 according to the LCMS spectrum. H NMR
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(m, 2H), 3.03 (m, 3H), 2.10 (m, 8H), 1.46 (s, 9H). 13C NMR
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1
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3
0.90 (d, J(H,H) = 6.6 Hz, 3H). 13C NMR (126 MHz, DMSO) of
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136.8 (s), 129.0 (s), 127.8 (s), 127.7 (s), 57.1 (s), 43.8 (s), 41.9 (s),
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.8b00077.
■
S
(6) ChEMBL database: www.ebi.ac.uk/chembl.
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Copies of NMR spectra for all new compounds and
X-ray crystallography data (PDF)
Crystal data (CIF)
̈
AUTHOR INFORMATION
Corresponding Author
*E-mail: Pavel.Mykhailiuk@gmail.com; Pavel.Mykhailiuk@
mail.enamine.net.
■
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DOI: 10.1021/acs.joc.8b00077
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DOI: 10.1021/acs.joc.8b00077
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