Flavin-Mediated Visible-Light [2+2] Photocycloaddition of Nitrogen- and Sulfur-Containing Dienes

Article abstract of DOI:10.1002/ejoc.201601377

The [2+2] photocycloaddition mediated by 1-butyl-3-methyl-7,8-dimethoxyalloxazine (1) has been found to be an effective tool for cyclising ω-phenyl- and ω,ω′-diphenyl-4-aza-1,6-heptadienes, in which the nitrogen atom is protected by acylation or quaternisation, towards the synthesis of a variety of phenyl- and diphenyl-3-azabicyclo[3.2.0]heptanes and their corresponding quaternary salts. Thia derivatives, with the sulfur atom in the form of a sulfone group, underwent an analogous cyclisation. Advantageously, visible light (400 nm) was used for the cycloadditions in the presence of 1, in contrast to the previously described procedures affording azabicyclo[3.2.0]heptanes by using UV irradiation. Practical applications are demonstrated through the synthesis of bicyclic quaternary ammonium salts, 6-phenyl-azabicyclo[3.2.0]heptanes known to exhibit biological activity or chiral spiro ammonium salts. Flavin 1 was also found to promote the efficient E→Z isomerisation of electron-rich cinnamyl derivatives to produce mixtures enriched with the Z isomer (with Z/E ratios of up to 77:23).

Full text of DOI:10.1002/ejoc.201601377

A Journal of
Accepted Article
Title: Flavin-Mediated Visible Light [2+2] Photocycloadditon of Nitrogen
and Sulfur-Containing Dienes
Authors: Michael Jirásek, Karolína Straková, Tomáš Neveselý, Eva
Svobodová, Zdeňka Rottnerová, and Radek Cibulka
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201601377
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10.1002/ejoc.201601377
European Journal of Organic Chemistry
FULL PAPER
Flavin-Mediated Visible Light [2+2] Photocycloadditon of Nitrogen
and Sulfur-Containing Dienes
Michael Jirásek,[a] Karolína Straková,[a] Tomáš Neveselý,[a] Eva Svobodová,[a] Zdeňka Rottnerová,[b]
and Radek Cibulka*[a]
Dedication ((optional))
Abstract: [2+2] Photocycloaddition mediated by 1-butyl-3-methyl-
7,8-dimethoxyalloxazine (1) is shown as an effective tool to cyclise
ω-phenyl and ω,ω’-diphenyl-4-aza-1,6-heptadienes, with the
nitrogen atom protected by acylation or quaternisation, used towards
the synthesis of variety of phenyl- and diphenyl-3-
azabicyclo[3.2.0]heptanes and their corresponding quaternary salts.
Thia-derivatives with the sulfur atom in the form of a sulfone group
undergo an analogous cyclisation. Advantageously, visible light (400
nm) was used for the cycloadditions using 1, in contrast to the
previously described procedures affording azabicyclo[3.2.0]heptanes
via UV light irradiation. Practical applications are demonstrated using
the synthesis of bicyclic quaternary ammonium salts, 6-phenyl
azabicyclo[3.2.0]heptanes known to exhibit biological activity or
chiral spiro ammonium salts. Flavin 1 was also found to provide
efficient E→Z isomerisation of electron-rich cinnamyl derivatives to
produce a mixture enriched with the Z-isomer (with Z:E ratios up to
77:23).
electron transfer processes), which is not limited by the
electrochemical properties.[8,9] The previously developed visible
light energy transfer [2+2] photocycloadditions use iridium(III)
polypyridyl complex[10] or thioxanthone.[11] In a preliminary
communication, we reported a bio-inspired metal free system
with flavin derivative 1, which was efficient for the cyclisation of
both electron-rich and electron-poor substrates (Scheme 1).[12]
Introduction
Scheme 1. Intramolecular [2+2] photocycloaddtions of 1,6-dienes mediated by
UV light (A), visible light and a photocatalyst (B) and substate scope of flavin 1
- mediated photocycloaddition shown in preliminary report (C).[12]
The intramolecular [2+2] photocycloaddition of substituted 1,6-
dienes represents a conventional route to fused carbocyclic and
heterocyclic systems (Scheme 1).[1–3] This approach is
advantageous as the adjacent five-membered ring formation
favours the overall cyclisation process, which is, moreover,
constrained often affording a single diastereoisomer. In a typical
procedure, a molecule of diene is excited by strong UV light,
which allows the [2+2] cycloaddition to occur.[3] In the context of
the recent rapid development of photocatalysis,[4] systems
enabling visible light [2+2] cycloaddition have been described.
Since the substrates usually absorb in the UV region only, such
processes must be mediated by an appropriate visible-light-
absorbing photocatalyst. Besides the radical (electron transfer)
[2+2] cycloadditions promoted by Ru(bpy)3,[5] Eosin Y[6] or
triphenylpyrylium tetrafluoroborate,[7] there are few visible light
systems based on energy-transfer. This may be advantageous
offering increased substrate scope (when compared to the
3-Azabicyclo[3.2.0]heptanes represent compounds with
potential biological relevance as can be documented by the 6-
aryl-derivatives 2, which have been recognized as D4/5-HT2A
receptor antagonists, e.g. the most potent derivative 2a (LU-
111995),[13] 1-phenyl derivatives 3 (potential anti-depressants[14]
)
or quaternary salts 4 (potential hypotensive agents) (see Figure
1A for their structures).[15] 3-Azabicyclo[3.2.0]heptane derivatives
undergo ring-opening reactions and are thereby suitable
intermediates for cyclobutane GABA analogues[16] or
azepanes[17] (Figure 1B). Concerning the photochemical
synthesis of 3-azabicyclo[3.2.0]heptanes, the UV-light promoted
[2+2] cycloaddition of their corresponding allyl(cinnamyl)amines
in the presence of acetophenone or a Cu(I) salt[18] and the
intermolecular UV-light promoted [2+2] cycloaddition of the
corresponding alkene with pyrroline derivatives have been
reported.[16a]
[a]
M.Sc. M. Jirásek, M.Sc. K. Straková, T. Neveselý, Dr. E.
Svobodová, Dr. R. Cibulka
Surprisingly, despite their great synthetic potential and
advantages resulting from use of visible instead of UV light,[19]
intramolecular visible light [2+2] cycloadditions have been mostly
studied with substrates that afford carbocycles or oxygen-
containing heterocycles (also see Scheme 1 for the substrate
scope of our system with 1). To the best of our knowledge, with
the exception of an N-tosyl derivative,[5e,5g,10,11e] there are no
examples of fused 3-azabicyclo[3.2.0]heptanes prepared using
Department of Organic Chemistry
University of Chemistry and Technology, Prague
Technická 5, 166 28 Prague, Czech Republic
E-mail: cibulkar@vscht.cz; www.vscht.cz
Dr. Zdeňka Rottnerová
Central Laboratories
University of Chemistry and Technology, Prague
[b]
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/ejoc.201601377
European Journal of Organic Chemistry
FULL PAPER
this approach. Herein, we report a [2+2] photocycloaddition
reaction promoted by 1 and visible light as a versatile tool
allowing the transformation of substituted aza-1,6-dienes to 6-
aryl-, 1-aryl-, 6,7-diaryl- and 1,6-diaryl 3-azabicyclo-
[3.2.0]heptanes. When studying the system, we have paid great
attention to the nitrogen atom character, which significantly
influences the cyclisation process. To extend the substrate
scope, we also investigated sulfur analogues.
derivative 6a with a quaternary nitrogen was smoothly cyclized
to give product 7a. The beneficial effect of the quaternary
nitrogen for the cycloaddition reaction inspired us to “protect” the
nitrogen in free amine 5a by protonation, which is known to allow
cyclisation under UV irradiation.[18b] Indeed, formation of the
cyclobutane product was observed in the presence of one
equivalent of trifluoroacetic acid, used as a water-free acid,
which is not strong enough to protonate the alloxazine
catalyst.[20] Notably, the [2+2] cycloaddition of 5a∙CF3COOH was
slower when compared to the quaternary salt 6a and needed 10
mol-% of the catalyst to achieve remarkable conversion. In
addition, dienes with quaternised (6a) or acetylated (6b) nitrogen
seem to be superior in the cycloaddition reaction from the point
of view of stereoselectivity providing exclusively the exo-product.
Nevertheless, the Boc- and benzyl- protected substrates 6c and
6d also showed good diastereoselectivity as observed in the
acetophenone-sensitized cycloaddition reactions performed
upon UV irradiation.[18a]
Table 1. Effect of nitrogen atom substitution on [2+2] photocycloaddition of
allyl cinnamyl amines 5 and 6 mediated by flavin 1 and visible light.[a]
Figure 1. Examples of interesting 3-azabicyclo[3.2.0]heptanes (A) and their
possible transformations (B).
Results and Discussion
With the aim to prove the effect of the nitrogen atom
character on the flavin-mediated intramolecular [2+2]
cycloaddition reaction, we have investigated a series of allyl
cinnamyl amine derivatives with both an unprotected (5) and
protected (6) amino function as the model substrates (5 and 6
were prepared according to a literature procedure,[18a] see
Supporting Information). The substrate with a styrene subunit
was chosen as its triplet energy was found to fit that of 1 thus
allowing energy transfer.[12] The reaction conditions were
adapted from those optimized in our preliminary report,[12] i.e.
using 2.5 mol-% of catalyst 1 and 0.02M substrate in acetonitrile.
At first, the cycloadditions were performed on a 5 mg scale
monitoring the reaction conversion after 40 min of irradiation.
Based on these results, semi-preparative experiments with
product isolation were carried out under analogous conditions
(Table 1).
In accordance with the experiments under UV irradiation,
some protection of the amine was necessary to make the
cycloaddition feasible. Free amine 5a showed only very slow E/Z
isomerisation: 5% of the Z-isomer was formed under the
standard conditions on an analytical scale, 20% of the Z-isomer
was formed using 15 mol-% of the catalyst after 8 h of irradiation
(entry 1). Tertiary amines with an N-methyl or N-phenyl group
(substrates 5b and 5c) underwent partial decomposition but did
not cyclize to the desired product (entries 2 and 3). On the other
hand, all amides 6b-d afforded the cycloaddition products 7
(entries 4–7), though the tert-butyloxycarbonyl (Boc) substituted
amide 6c displayed lower reactivity and a higher amount of
catalyst 1 was required to obtain full conversion. Interestingly,
Entry
X
Diene
Product
Conv.[a]
[%]
Yield[b] d.r[c]
[%]
1
N-H
5a
5b
5c
6c
6c
6b
6d
-
0[d]
-
-
2
N-CH3
N-Ph
N-Boc
N-Boc
N-Ac
-
0[e]
-
-
3
-
0[e]
-
-
4
7c
7c
7b
7d
20
n.d.[g
80
94
91
n.d.[g]
78
n.d.[g]
6:1
5[f]
6
quant.
quant.
quant.
41
>10:1
10:1
>10:1
>10:1
7
N-Cbz
8[f]
9
NH2
5a∙CF3COOH 7e
7a
+
N+(CH3)2 6a
quant.
[a] Conversion based on 1H NMR data from experiments on analytical scale
after 40 min of irradiation: c(5 or 6) = 20 mM, c(1) = 0.5 mM, r.t., V = 1 mL.
[b] Isolated yields from the experiments on semipreparative scale (0.18-0.4
mmol, see Experimental). [c] Based on 1H NMR data. [d] Partial E/Z
isomerization. [e] Decomposition. [f] 10 mol-% of the catalyst. [g] Not
determined.
Initially, a substrate scope investigation (see Table 2) was
focused on the effect of the aryl group(s) position (relative to the
double bonds) on the cyclisation process. Symmetrical aza-
dienes 8 showed reactivity analogous to 6 with facile cyclisation
occurring using the quaternary salts and a decreased reactivity
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10.1002/ejoc.201601377
European Journal of Organic Chemistry
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intramolecular [2+2] cycloaddition of the corresponding free
amines did not proceed in any case. Cyclisation of 8 allows the
formation of three possible diastereomers, however, derivatives
with a exo-syn configuration were formed exclusively (in the
case of 12a and 12b) or as major products (in the case of 12c
and 12d). The minor stereoisomers, resulting from the
cyclisation of 8c and 8d, have aryl rings in a relative trans-
configuration (Figure 2). Cyclisation of 10 proceeded with lower
diastereoselectivity (when compared to 8) provided cyclobutane
14 with a syn orientation of the phenyl substituents as the major
product (Figure 2).
Table 2. Substrate scope of [2+2] photocycloaddition mediated by 1.
Entry
Diene
Product
Conv.
[%][a]
Yield
[%][b]
d.r.[c]
1
a: Ar = Ph, X = N+(CH3)2
b: Ar = Ph, X = N-Ac
quant.
quant.
quant.
quant.
88
70
92
80
>10:1
>10:1
6:1
2
3[d]
4
c: Ar = Ph, X = N-Boc
d: Ar = 4-MeOPh, X = N-Boc
3:1
Figure 2. Stereoisomers formed by [2+2] cycloaddition.
5
6
a: X = N+(CH3)2
b: X = N-Ac
quant.
90
55
53
-
-
Experiments with dienes 8–11 confirmed the usability of the
alloxazine 1 photocatalyst for the synthesis of 6,7-(12), 1,5-(13)
and 1,6-diphenyl (14), and 1-phenylbicyclo[3.2.0]heptanes (15),
which were previously not prepared photochemically (with the
exception of 12, X = NTs). To illustrate the facile overall
synthetic approach towards bicyclic compounds 12-15, the
synthesis of diene precursors 8–11 is depicted as a general
retrosynthetic scheme (see Scheme 2; for details see
Supporting Information). The synthesis starts from readily
available allylbromides[21] and Boc-protected cinnamylamine.[22]
7
a: X = N+(CH3)2
b: X = N-Ac
quant.
25
60
3:1
-
8[d]
n.d.[e]
9
a: X = N+(CH3)2
b: X = N-Ac
quant.
33
55
-
-
10
n.d.[e]
11
a: X = S, b: X = SO, c: S+CH3
d: X = SO2
0
-
-
12[d]
90
51
>10:1
Scheme 2. General scheme of the synthesis of dienes 8-11. For details, see
Supporting Information).
[a] Conversion based on 1H NMR data from experiments on analytical
scale after 40 min of irradiation: c(substrate) = 20 mM, c(1) = 0.5 mM, r.t.,
V = 1 mL. [b] Isolated yields from the experiments on semipreparative
scale (0.06-0.4 mmol, see Experimental). [c] Based on 1H NMR data. [d]
10 mol-% of the catalyst. [e] Not determined.
Next, we studied the cycloaddition of sulfur containing
dienes 16 (prepared according to a literature procedure[23]; see
Supporting Information). Thia-derivative 16a, analogously to free
amines, did not cyclise under our photocatalytic conditions (entry
11, Table 2). Our attempt to force dienes 16 towards the [2+2]
cycloaddition by changing the sulfur oxidation state showed that
the sulfone 16d and not the sulfoxide 16b afforded the bicyclic
product 17. Per analogy to the nitrogen derivatives, we also tried
observed for the Boc-derivatives (entries 1–4). The cycloaddition
reactions of 9–11 were tested and the derivatives with the
spacer containing an ammonium or acetamido group found to be
superior among derivatives 6 and 8. While the quaternary salts
afforded products with quantitative conversion, the acetyl
derivatives reacted more slowly (entries 5–10). Notably, the
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10.1002/ejoc.201601377
European Journal of Organic Chemistry
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to use the sulfonium salt 16c but we did not observe its
cyclization under our reaction conditions.
As regards the “central” atom connecting both unsaturated
parts of the dienes, we showed our approach using
photocatalyst 1 was useful in the cycloaddition of carba-, oxa-,
aza- and thia-derivatives (for a summary, see Table 3). The
As it is important from the point of view of potential practical
applications, regardless of the “central” atom, all the
photocyclisations exhibited high diastereoselectivity preferring
the exo-configuration (Table 3). In the case of both major and
minor products, the cis-annulated five-membered ring was
observed with the only exception being derivative 18, which was
latter two need “protection” either by transformation to the amide, previously shown to be formed as a mixture of diastereoisomers
quaternary salt or sulfone as free sulfides[24a] (Eox = 1.5 V vs
SCE, value for dibutyl sulfide) and amines[24b] (Eox = 0.78–1.39 V
vs SCE, values for aliphatic amines) easily undergo single
containing the rare (but not unknown[25]
) trans-annulated
bicyclo[3.2.0]heptane. Its formation can be attributed to the
bulkiness of the sulfone group.[26]
electron transfer oxidation by an excited alloxazine[12] (E*red
=
To demonstrate usefulness of our method for practical
applications, we applied it towards the synthesis of compound
22, which is a possible precursor used in the synthesis of the
D4/5-HT2A receptor antagonist rac-2a (Scheme 3). We used
Boc as an easily removable group to protect 19. To our delight,
cyclisation of diene 20 afforded the cyclobutane product 21 with
high diastereoselectivity (>10:1). Deprotection of 21 with
trifluoroacetic acid gave 22 in good yield (see Experimental for
details).
1.68 V) thus quenching its excited state[23a,24] (for example of
quenching experiments of with 16a, see Supporting
1
Information). This undesired process hampers the cycloaddition
reaction. However one should take in mind that bicyclo-product
formation could be also influenced by protecting group type
which can affect conformation possibilities of diene.
Table 3. Substrate scope of visible-light [2+2] photocycloaddition mediated
by 1.
Major
Minor
X
With 1
Literature
product
product
N+(CH3)2 (Ar = Ph)
N-Ac (Ar = Ph)
N-Boc (Ar = Ph)
N-Ts (Ar = Ph)
CH2 (Ar = Ph)
O (Ar = 4-MeOPh)
N+(CH3)2
N-Ac
>10:1
>10:1
6:1
-
-
-
-
>10:1[a]
-
7:1[c]
7:3
>10:1
>10:1
10:1
6:1
-
-
Scheme 3. Application of flavin 1-mediated photocycloaddition in the
synthesis of biologically active compound rac-2a.
N-Cbz
10:1[b]
N-Boc
6:1[b]
Cycloaddition of quaternary salts with 1 takes place as readily as
it even allows double-cyclisation of derivative 23 with four
cinnamyl groups thus providing chiral compound 24 (Scheme 4).
This is an evidence that our approach can be applied for the
synthesis of spiro quaternary ammonium systems which are of
great interest because of numerous applications, e.g. in
asymmetric phase transfer catalysis[27] or as electrolytes.[28]
CH2
7:1[c]
>10:1
-
-
N-Boc
-
N-Ts
>10:1[a]
>10:1[a]
-
-
O
>10:1[c]
>10:1
SO2
Ar = 4-MePh
8:1[d]
-
18
[a] With iridium catalyst.[10] [b] UV light-promoted cycloaddition in the presence
of acetophenone sensitizer.[18a] [c] ref.[12]. [d] ref.[26]
Scheme 4. Application of flavin 1-mediated photocycloaddition in the
synthesis of chiral aza-spiro compound rac-24.
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10.1002/ejoc.201601377
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The observed E/Z isomerisation in the case of some
nitrogen-containing derivatives under the cycloaddition
conditions prompted us to test our photocatalyst 1 in the
production of a mixture enriched with the Z-isomer from a pure
E-isomer. This approach could be used for the preparation of the
Z-isomer, which is usually hard to achieve by convenient
approaches. A similar method for Z-isomer generation has been
reported using riboflavin but is limited to -disubstituted
acrylates.[29] Our screening showed 1 was suitable for the
isomerisation of electron-rich cinnamyl derivatives 25 thus being
complementary to riboflavin from the point of view of the
substrate scope (Scheme 5). Possible isolation of Z-isomer from
the mixture by column chromatography was documented on the
derivative 25 (X = H, R = NHBoc) (see Experimental and
Supporting Information).
organocatalysis.[30] Our application reveals alloxazines to be
useful also in photocatalysis.
Experimental Section
General: NMR spectra were measure on Agilent 400 MR DDR2 (399.94
MHz for 1H, 100.58 MHz for 13C and 376.29 MHz for 19F), Varian Mercury
Plus 300 (299.97 MHz for 1H, 75.48 MHz for 13C and 282.23 MHz for 19F),
Bruker Avance DRX 500 (500.13 MHz for 1H and 125.77 MHz for 13C)
or Bruker 600 Avance III (600.13 MHz for 1H and 150.90 MHz for 13C)
spectrometers. In 1H and 13C NMR spectra, chemical shifts are given in
ppm referenced relative to residual peaks: δH = 7.26 ppm (CHCl3) and δC
= 77.16 ppm (CDCl3) in chloroform-d; in δH = 2.50 ppm (CHD2SOCD3)
and δC = 39.52 ppm (CD3SOCD3) in DMSO-d6. Abbreviation of signals
characteristics and multiplicities are: b = broad, s = singlet, d = doublet, t
= triplet, q = quartet, dd = doublet of doublets, ddd = doublet of doublet of
doublets, dddd = doublet of doublet of doublet of doublets, dt = doublet of
1
triplets, m = multiplets. Where indicated, signals in H and 13C NMR are
assigned unambiguously based on analysis of 1H-1H-COSY; 1H-13C-
HSQC; 1H-13C-HMBC; 13C-APT; 1H-1H-NOESY and 1D 1H-1H-NOESY. In
case signals are ambiguous and/or difficult to distinguish, signals are
marked with all possible allocation indicated by conjunction “or”.
Accuracy of 13C spectra assignments (compounds 7, 12, 13-15 and 21)
were checked by CSEARCH Robot Referee.[31] Numbering (see
supporting Information) of characterized compounds is arbitrarily chosen,
however considering IUPAC recommendations. Mass spectrometry
analysis was performed on LTQ Orbitrap Velos (Thermo Fisher
Scientific). Photoreactions were performed in Schlenk tube irradiated with
high power LED emitor LED Engin LZC-70UA00. TLC analyses were
carried out on a DC Alufolien Kieselgel 60 F254 (Merck). Preparative
column chromatography separations were performed on a silica gel
Kieselgel 60 (0.040–0.063 mm) (Merck). Starting materials, reagents and
deuterated solvents were obtained from commercial suppliers and used
without further purification. Dry solvents were purified and dried using
standard procedures. For synthesis of dienes 5, 6, 8-11, 16, 19, 20 and
23 see Supporting Information. Catalyst 1 was prepared as we described
previously.[12]
Scheme 5. Application of flavin 1 in photochemical isomerisation of alkenes.
Conclusions
In summary, photocycloaddition reactions mediated by flavin 1
and visible light have been shown to be an efficient method for
the cyclisation of nitrogen- and sulfur-containing aryl-dienes to
the corresponding aryl-bicyclo[3.2.0]heptanes. The efficiency
and stereoselectivity of the cyclisation procedure depends on
the heteroatom character and the position of the aryl ring. Free
heteroatom-containing dienes do not cyclise; on the other hand,
protection by transformation to the amide, quaternary salt or
sulfone allows the intermolecular [2+2] cycloaddition reaction to
proceed (analogously to oxa- and carba-derivatives[12]).
Cyclisation of the quaternary salts seems to be superior among
the nitrogen-containing dienes both from the point of view of
Preparative [2+2] cycloadditions – general procedure: Diene (0.05 -
0.4 mmol) and 1 (2.5 mol-% unless otherwise stated) were placed in
Schlenk tube followed by acetonitrile. Reaction mixture was degassed by
freeze-thaw-pump procedure and irradiated by 400 nm LED for 40 min.
Acetonitrile was removed on rotatory evaporator and crude product was
purified by column chromatography.
efficiency and diastereoselectivity allowing
a
variety of
Rel-(1S,5R,6S)-3,3-dimethyl-6-phenyl-3-azabicyclo[3.2.0]heptan-3-
ium trifluoromethanesulfonate (7a): Prepared by general procedure
from N-allyl-N,N-dimethylcinnamylammonium trifluoromethanesulfonate
(6a) (70 mg, 0.2 mmol) in acetonitrile (20 mL). Purified by column
chromatography (CH2Cl2:MeOH 10:1). Product 7a was obtained as a
single diastereomer (d.r. > 10: 1) as a white solid (55 mg, 0.15 mmol,
78%). 1H NMR (400 MHz, CDCl3) δ = 7.36 – 7.16 (m, 5H, H-C(Ar)), 4.02
– 3.85 (m, 1H, aH-C(4)), 4.02 – 3.85 (m, 1H, aH-C(2)), 3.75 (ddd, J = 12.1,
phenylcyclobutanes to be prepared. Interestingly to the best of
our knowledge, quaternary salts have never been used directly
for [2+2] photocycloadditions, although some quaternary salts
derived from 3-azabicyclo[3.2.0]heptanes[15] show biological
activity.
The substrates studied in our paper do not absorb light
above 300 nm (see Supporting Information), which means the
use of strong UV light is required to achieve their
photocycloaddition, which is similar to that found when
acetophenone is used as a sensitiser. Our method allows the
use of visible light, which is available in most laboratories.
Importantly, our flavin catalyst 1 is readily available[12] and
considerably cheaper when compared to ruthenium- or iridium-
based photocatalysts. Flavin derivatives with an alloxazine core
analogous to 1 have still been used exclusively in “dark”
b
b
7.1, 4.4 Hz, 1H, H-C(4)), 3.75 (ddd, J = 12.1, 7.1, 4.4 Hz, 1H, H-C(2)),
3.69 (td, J = 8.7, 4.6 Hz, 1H, H-C(6)), 3.43 (s, 3H, H-C(9)), 3.32 – 3.22 (m,
1H, H-C(5)), 3.28 – 3.20 (m, 1H, H-C(1)), 2.97 (s, 3H, H-C(8)), 2.50 –
2.35 (m, 2H, H-C(7)). 13C NMR (101 MHz, CDCl3) δ = 143.2 (C(1‘)),
128.9 (C(3‘) and C(5‘)), 126.9 (C(4‘)), 126.6 (C(2‘) and C(6‘)), 120.8 (q, J
= 320 Hz, CF3SO3), 72.0 (C(4)), 71.2 (C(2)), 52.1 (C(9)), 51.6 (C(8)),
43.8 (C(5)), 42.9 (C(6)), 33.4 (C(1)), 29.3 (C(7)). HRMS (ESI) m/z: [(M-
-
CF3SO3 )+] (C14H20N) calculated: 202.15903, found: 202.15912.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201601377
European Journal of Organic Chemistry
FULL PAPER
Rel-(1S,5R,6S)-3-acetyl-6-phenyl-3-azabicyclo[3.2.0]heptane
(7b):
6.4 Hz, 4H, H-C(3‘) and H-C(5‘)), 7.04 – 6.95 (m, 2H, H-C(4‘)), 6.92 –
6.83 (m, 4H, H-C(2‘) and H-C(6‘)), 4.10 (d, J = 3.2 Hz, 2H, H-C(1)), 4.02
(dd, J = 13.1, 6.9 Hz, 2H, aH-C(3)), 3.93 (dd, J = 12.4, 6.0 Hz, 2H, bH-
C(3)), 3.63 – 6.56 (m, 2H, H-C(2)), 3.46 (s, 3H, H-C(6)), 3.08 (s, 3H, H-
C(5)). 13C NMR (101 MHz, CDCl3) δ = 138.5 (C(1‘)), 128.2 (C(3‘) and
C(5‘)), 128.0 (C(2‘) and C(6‘)), 126.5 (C(4‘)), 120.9 (q, J = 320 Hz,
Prepared by general procedure from N-Allyl-N-cinnamylacetamide (6b)
(80 mg, 0.4 mmol) in acetonitrile (20 mL). Purified by column
chromatography (hexane:ethyl acetate 5:1). Product 7b was obtained as
a single diastereomer (d.r. > 10: 1) as a colorless oil (75 mg, 0.15 mmol,
1
94%). H NMR (400 MHz, CDCl3) and 13C NMR (100 MHz, CDCl3) were
-
in agreement with literature showing pure two rotamers in ratio 1:1 of exo
diastereomer.[18a] 1H NMR (400 MHz, CDCl3) δ = 7.39 – 7.18 (m, 10H),
4.00 (d, J = 12.6 Hz, 1H), 3.93 – 3.82 (m, 1H), 3.65 – 3.60 (m, 2H), 3.58
– 3.51 (m, 1H), 3.47 (dd, J = 11.1, 6.2 Hz, 1H), 3.31 – 3.19 (m, 4H), 3.09
(d, J = 7.0 Hz, 1H), 3.06 (d, J = 6.4 Hz, 1H), 3.03 – 2.89 (m, 3H), 2.45 –
2.30 (m, 2H), 2.21 – 2.16 (m, 2H), 2.16 (s, 3H), 2.14 (s, 3H). 13C NMR
(75 MHz, CDCl3) δ = 170.01, 169.96, 144.8, 144.6, 128.6, 128.5, 127.3,
126.4, 126.3, 54.4, 54.0, 52.2, 51.9, 46.6, 45.4, 42.8, 34.8, 33.2, 32.4,
32.2, 23.0, 22.9. HRMS (ESI) m/z: [(M+Na+)+] (C14H17NONa) calculated:
238.12024, found: 238.12067.
CF3SO3 ), 71.6 (C(3)), 52.2 (C(6)), 52.0 (C(5)), 46.5 (C(1)), 39.5 (C(2)).
- +
HRMS (ESI) m/z: [(M-CF3SO3 ) ] (C20H24N) calculated: 278.19033, found:
278.19056.
Rel-1-((1R,5S,6R,7S)-3-acetyl-6,7-diphenyl-3-
azabicyclo[3.2.0]heptane (12b): Prepared by general procedure from N-
dicinnamylacetamide (8b) (25 mg, 0.09 mmol) in acetonitrile (10 mL).
Purified by column chromatography (hexane:ethyl acetate 4:1). Product
12b was obtained as a single diastereomer (d.r. > 10:1) as a white solid
(17 mg, 0.06 mmol, 70%). 1H NMR (400 MHz, CDCl3) δ = 7.12 – 7.06 (m,
4H, H-C(3‘), H-C(5‘), H-C(3‘‘) and H-C(5‘‘)), 7.05 – 6.99 (m, 2H, H-C(4‘)
and H-C(4‘‘)), 6.95 – 6.88 (m, 4H, H-C(2‘), H-C(6‘), H-C(2‘‘) and H-C(6‘‘)),
4.10 (dd, J = 12.9, 2.0 Hz, 1H, H-C(2)), 3.82 – 3.77 (m, 1H, H-C(7)), 3.77
– 3.74 (m, 1H, H-C(4)), 3.73 – 3.70 (m, 1H, H-C(6)), 3.73 – 3.68 (m, 1H,
H-C(4)), 3.62 (dd, J = 13.0, 7.9 Hz, 1H, H-C(2)), 3.49 – 3.42 (m, 1H, H-
C(1)), 3.34 – 3.27 (m, 1H, H-C(5)), 2.18 (s, 3H, H-C(9)). 13C NMR (75
MHz, CDCl3) δ = 170.0 (C(8)), 140.2 (C(1‘) or (C(1‘‘)), 139.9 (C(1‘) or
C(1‘‘)), 128.1 (C(3‘) or C(5‘) or C(3‘‘) or C(5‘)), 127.99 (C(3‘) or C(5‘) or
C(3‘‘) or C(5‘)), 127.98 (C(2‘) or C(6‘) or C(2‘‘) or C(6‘)), 127.95 (C(2‘) or
C(6‘) or C(2‘‘) or C(6‘)), 126.09 (C(4‘) or C(4‘‘)), 126.04 (C(4‘) or C(4‘‘)),
54.1 (C(4)), 52.1 (C(2)), 48.6 (C(6)), 47.9 (C(7)), 41.7 (C(1)), 40.1 (C(5)),
23.1 (C(9)). HRMS (ESI) m/z: [(M+H+)+] (C20H22NO) calculated:
292.16959, found: 292.16970.
Rel-(1S,5R,6S)-tert-butyl
6-phenyl-3-azabicyclo[3.2.0]heptane-3-
carboxylate (7c): Prepared by general procedure from tert-butyl N-allyl-
N-(cinnamyl)carbamate (6c) (117 mg, 0.4 mmol) using 10% of 1 in
acetonitrile (20 mL). Purified by column chromatography (hexane:ethyl
acetate 5:1). Product 7c was obtained as mixture of diastereomers (d.r. =
6:1) as a colorless oil (94 mg, 0.34 mmol, 80%). NMR data were in
agreement with those reported[18a] except of assignment of carbon atoms
1
C(5) and C(6) which we corrected: H NMR (400 MHz, DMSO-d6, 80°C)
δ = 7.39 – 7.14 (m, 5H, H-C(Ar‘)), 3.59 (d, J = 11.6 Hz, 1H, aH-C(2)), 3.56
(dd, J = 11.9, 2.1 Hz, 1H, aH-C(4)), 3.38 (dd, J = 11.5, 7.5 Hz, 1H, bH-
b
C(2)), 3.24 (dd, J = 11.4, 5.9 Hz, 1H, H-C(4)), 3.20 (dd, J = 7.1, 3.2 Hz,
1H, H-C(6)), 2.96 – 2.89 (m, 2H, H-C(1) and H-C(5)), 2.32 – 2.24 (m, 1H,
H-C(7)), 2.12 (ddd, J = 11.9, 9.7, 2.6 Hz, 1H, H-C(7)), 1.46 (s, 9H, H-
C(10)). 13C NMR (101 MHz, DMSO-d6, 80°C) δ = 153.9 (C(8)), 144.6
(C(1‘)), 127.8 (C(2‘) and C(6‘)), 125.7 (C(3‘) and C(5‘)), 125.4 (C(4‘)),
77.9 (C(9)), 51.9 (C(4)), 51.8 (C(2)), 45.2 (C(5)), 41.9 (C(6)), 33.2 (C(1)),
31.2 (C(7)), 27.9 (C(10)). HRMS (ESI) m/z: [(M+Na+)+] (C17H23NO2Na)
calculated: 296.16210, found: 296.16241.
Rel-(1R,5S,6R,7S)-tert-butyl
6,7-Diphenyl-3-
azabicyclo[3.2.0]heptane-3-carboxylate (12c): Prepared by general
procedure from tert-butyl N,N-dicinnamylcarbamate (8c) (35 mg, 0.1
mmol) using 10% of 1 in acetonitrile (10 mL). Purified by column
chromatography (hexane:ethyl acetate 5:1). Product 12c was obtained
as a mixture of diastereomers (d.r. = 6:1) as a colorless oil (32 mg, 0.1
mmol, 92%). 1H NMR (400 MHz, DMSO-d6, 70°C) δ = 7.10 – 7.03 (m, 4H,
H-C(3‘) and H-C(5‘)), 7.01 – 6.93 (m, 6H, H-C(2‘) and H-C(4‘) and H-
C(6‘)), 3.73 (d, J = 3.9 Hz, 2H, H-C(3)), 3.67 (d, J = 11.7 Hz, 2H, H-C(1)),
3.51 – 3.44 (m, 2H, H-C(1)), 3.32 – 3.24 (m, 2H, H-C(2)), 1.47 (s, 9H, H-
C(6)). 13C NMR (101 MHz, CD3SOCD3, 70°C) δ = 153.9 (C(4)), 140.2
(C(1‘)), 127.5 (C(2‘) and C(6‘)), 127.2 (C(3‘) and C(5‘)), 125.1 (C(4‘)),
78.1 (C(5)), 51.8 (C(1)), 47.2 (C(3)), 39.5 (C(2)), 27.9 (C(6)). HRMS (ESI)
m/z: [(M+Na+)+] (C23H27NO2Na) calculated: 372.19340, found: 372.19441.
Rel-(1S,5R,6S)-benzyl
6-phenyl-3-azabicyclo[3.2.0]heptane-3-
carboxylate (7d): Prepared by general procedure from benzyl N-allyl-N-
(cinnamyl)carbamate (6d) (55 mg, 0.18 mmol) in acetonitrile (20 mL).
Purified by column chromatography (hexane:ethyl acetate 10:1). Product
7d was obtained as mixture of diastereomers (10:1) as a colorless oil (50
mg, 0.16 mmol, 91%). NMR data of 7d was reported at 100°C in
C6D5NO2 in literature.[18a] We decided to record NMR data and assign
peaks in DMSO at 80°C as a common NMR solvent. 80°C was sufficient
temperature to obtain sharp signals. 1H NMR (400 MHz, DMSO-d6,
80°C) δ = 7.43 – 7.06 (m, 10H, H-C(Ar)), 5.15 (s, 2H, H-C(9)), 3.69 (d, J
Rel-(1R,5S,6R,7S)-tert-butyl 6,7-bis(4-methoxyphenyl)-3-azabicyclo-
[3.2.0]heptane-3-carboxylate (12d): Prepared by general procedure
from tert-butyl N,N-bis(4-methoxycinnamyl)carbamate (8d) (25 mg, 0.06
mmol) in acetonitrile (6 mL). Purified by column chromatography
(hexane:ethyl acetate 10:1). Product 12d was obtained accompanied
with minor diastereomer (d.r. = 3:1) as a white solid (20 mg, 0.04 mmol,
80%). 1H NMR (400 MHz, DMSO-d6, 70°C) δ = 6.89 (d, J = 8.7 Hz, 4H,
H-C(3‘) and H-C(5‘)), 6.65 (d, J = 8.6 Hz, 4H, H-C(2‘) and H-C(6‘)), 3.63
(s, 6H, H-C(7)), 3.62 (d, J = 11.6 Hz, 2H, H-C(3)), 3.61 (s, 2H, H-C(1)),
3.44 (dd, J = 11.5, 6.6 Hz, 2H, H-C(3)), 3.22 – 3.18 (m, 2H, H-C(2)), 1.44
(s, 9H, H-C(6)). 13C NMR (101 MHz, DMSO-d6, 70°C) δ = 156.9 (C(4‘)),
153.9 (C(4)), 132.3 (C(1‘)), 128.5 (C(2‘) and C(6')), 112.9 (C(3‘) and
C(5‘)), 78.1 (C(5)), 54.6 (C(7)), 51.8 (C(3)), 46.5 (C(1)), 40.2 (C(2)), 27.9
(C(6)). HRMS (ESI) m/z: [(M+Na+)+] (C25H31NO4Na) calculated:
432.21453, found: 432.21460.
a
= 11.7 Hz, 1H, aH-C(4)), 3.65 (d, J = 12.1 Hz, 1H, H-C(2)), 3.49 (dd, J =
b
b
11.4, 7.3 Hz, 1H, H-C(2)), 3.34 (dd, J = 11.5, 5.7 Hz, 1H, H-C(4)), 3.23
(dd, J = 11.2, 6.6 Hz, 1H, H-C(6)), 2.99 – 2.94 (m, 1H, H-C(1)), 2.97 –
2.92 (m, 1H, H-C(5)), 2.29 (dt, J = 12.0, 8.4 Hz, 1H, H-C(6)), 2.18 – 2.07
(m, 1H, H-C(7)). 13C NMR (101 MHz, CD3SOCD3, 70°C) δ = 154.2 (C(8)),
144.5 (C(1‘)), 136.9 (C(1‘‘)), 127.87 (C(3‘,5‘) or C(3‘‘,5‘‘)), 127.84 (C(3‘,5‘)
or C(3‘‘,5‘‘)), 127.2 (C(4‘) or C(4‘‘)), 126.9 (C(2‘‘) and C(6‘‘)), 125.8 (C(2‘)
and C(6‘‘)), 125.4 (C(4‘) or C(4‘‘)), 65.5 (C(9)), 52.1 (C(2)), 51.9 (C(4)),
45.2 (C(5)), 41.8 (C(6)), 33.2 (C(1)), 31.2 (C(7)). HRMS (ESI) m/z:
[(M+Na+)+] (C20H21NO2Na) calculated: 330.14645, found: 330.14721.
Rel-(1R,5S,6R,7S)-3,3-dimethyl-6,7-diphenyl-3-azabicyclo[3.2.0]-
heptan-3-ium trifluoromethanesulfonate (12a): Prepared by general
procedure
from
N,N-dicinnamyl-N,N-dimethylammonium
trifluoromethanesulfonate (8a) (25 mg, 0.05 mmol) in acetonitrile (5 mL).
Purified by column chromatography (CH2Cl2:MeOH 10:1). Product 12a
was obtained as a single diastereomer (d.r. > 10:1) as a colorless oil (22
mg, 0.044 mmol, 88%). 1H NMR (400 MHz, CDCl3) δ = 7.06 (dd, J = 8.1,
Meso-3,3-dimethyl-1,5-diphenyl-3-azabicyclo[3.2.0]heptan-3-ium
trifluoromethanesulfonate (13a): Prepared by general procedure from
N-(2-phenylprope-2-en-1-yl)-N,N-dimethyl-2-phenylprope-2-en-1-
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10.1002/ejoc.201601377
European Journal of Organic Chemistry
FULL PAPER
ammonium trifluoromethanesulfonate (9a) (50 mg, 0.12 mmol) in
acetonitrile (20 mL). Purified by column chromatography (CH2Cl2:MeOH
10:1). Product 13a was obtained as a white solid (28 mg, 0.07 mmol,
55%). 1H NMR (400 MHz, CDCl3) δ = 7.40 – 7.31 (m, 2H, H-C(4‘)), 7.19
– 7.09 (m, 4H, H-C(3‘) and H-C(5‘)), 6.89 – 6.82 (m, 4H, H-C(2‘) and H-
C(6‘)), 4.38 (d, J = 13.4 Hz, 2H, bH-C(3)), 4.14 (d, J = 13.3 Hz, 2H,
aH-C(3)), 3.77 (s, 3H, H-C(5)), 3.47 (s, 3H, H-C(4)), 2.86 – 2.63 (m, 4H,
H-C(1)). 13C NMR (101 MHz, CDCl3) δ = 140.2 (C(1‘)), 128.6 (C(3‘) and
C(5‘)), 127.3 (C(4‘)), 127.1 (C(2‘) and C(6‘)), 120.8 (q, J = 320 Hz,
= 7.43 – 7.36 (m, 2H, H-C(3‘) and H-C(5‘)), 7.35 – 7.27 (m, 3H, H-C(2‘)
and H-C(4‘) and H-C(6‘)), 4.19 (d, J = 12.5 Hz, 1H, bH-C(2)), 4.13 (ddd, J
= 12.2, 8.1, 1.9 Hz, 1H, aH-C(4)), 4.08 (dd, J = 12.5, 1.8 Hz, 1H, aH-C(2)),
3.90 (dd, J = 12.3, 7.0 Hz, 1H, bH-C(4)), 3.64 (qd, J = 8.0, 4.4 Hz, 1H, H-
C(5)), 3.51 (s, 3H, H-C(9)), 2.88 (s, 3H, H-C(8)), 2.74 (ddd, J = 12.5, 9.5,
7.0 Hz, 1H, bH-C(7)), 2.47 (dddd, J = 12.7, 10.4, 8.8, 6.9 Hz, 1H, aH-C(6)),
2.29 (dddd, J = 12.2, 10.5, 5.7, 1.5 Hz, 1H, aH-C(7)), 2.08 (dddd, J = 13.6,
9.7, 5.6, 4.3 Hz, 1H, bH-C(6)). 13C NMR (101 MHz, CDCl3): δ = 143.7
(C(1‘)), 129.6 (C(3‘) and C(5‘)), 127.6 (C(4‘)), 125.0 (C(2‘) and C(6‘)),
-
-
CF3SO3 ), 78.1 (C(3)), 58.2 (C(4)), 57.7 (C(2)), 54.3 (C(5)), 30.2 (C(1)).
120.8 (q, J = 320 Hz, CF3SO3 ), 77.3 (C(2)), 72.3 (C(4)), 53.1 (C(9)), 52.8
- +
HRMS (ESI) m/z: [(M-CF3SO3 ) ] (C20H24N) calculated: 278.19033, found:
(C(8)), 52.3 (C(1)), 40.4 (C(5)), 34.3 (C(7)), 20.5 (C(6)). HRMS (ESI) m/z:
- +
278.19040.
[(M-CF3SO3 ) ] (C14H20N1) calculated: 202.15903, found: 202.15925.
Meso-3-acetyl-1-(1,5-diphenyl-3-azabicyclo[3.2.0]heptane
(13b):
Rel-(1R,5R,7R)-6,6-Dimethyl-7-phenyl-3λ⁶-thiabicyclo[3.2.0]heptane-
3,3-dione (17): Prepared by general procedure from [(1E)-3-(3-
methylbut-2-ene-1-sulfonyl)prop-1-en-1-yl]benzene (16c) (101 mg, 0.40
mmol) in acetonitrile (20 mL). Purified by flash chromatography
(hexane:ethyl acetate 3:1) and crystallization from hexane. Product 17
was obtained as a white crystals as a pure diastereomer (51 mg, 0.2
mmol, 51%). M. p. 97–99 °C. 1H NMR (400 MHz, CDCl3) δ = 7.37–7.21
(m, 3H, H-C(3‘), H-C(4‘) and H-C(5‘)), 7.09 (d, J = 7.4 Hz, 2H, H-C(2‘)
and H-C(6‘)), 3.56 (qd, J = 9.1, 3.1 Hz, 1H, H-C(5)), 3.41 (d, J = 9.6 Hz,
1H, H-C(6)), 3.36–3.20 (m, 3H, H-C(4) and H2C(2)), 3.00 (dd, J = 13.8,
3.1 Hz, 1H, H-C(4)), 2.75 (q, J = 8.7 Hz, 1H, H-C(1)), 1.21 (s, 3H, H-C(9)),
0.87 (s, 3H, H-C(8)). 13C NMR (101 MHz, CDCl3) δ = 138.2 (C(1’)), 128.6
(C(3’) and C(5’)), 127.2 (C(2’) and C(6’)), 127.0 (C(4’)), 54.8 (C(4)), 53.9
(C(6)), 51.2 (C(2)), 41.6 (C(1)), 39.9 (C(7)), 31.5 (C(5)), 25.2 (H-C(9)),
25.0 (H-C(8)). HR-MS (ESI) (m/z): [M+Na]+ (C14H18O2SNa) calc.:
273.0920, found: 273.0922.
Prepared by general procedure from N,N-bis(2-phenylallyl)acetamide
(9b) (95 mg, 0.33 mmol) in acetonitrile (20 mL). Purified by sublimation.
Product 13b was obtained as a white solid (50 mg, 0.17 mmol, 53%). 1H
NMR (400 MHz, CDCl3) δ = 7.19 – 7.03 (m, 6H, H-C(3‘), H-C(4‘), H-C(5‘),
H-C(3‘‘), H-C(4‘‘) and H-C(5‘‘)), 6.98 – 6.88 (m, 4H, H-C(2‘), H-C(6‘), H-
b
C(2‘‘) and H-C(6‘‘), 4.50 (d, J = 12.3 Hz, 1H, H-C(2)), 4.03 (d, J = 11.3
Hz, 1H, bH-C(4)), 3.86 (d, J = 11.3 Hz, 1H, aH-C(4)), 3.72 (d, J = 12.4 Hz,
1H, aH-C(2)), 2.76 – 2.62 (m, 1H, aH-C(6)), 2.57 – 2.44 (m, 1H, aH-C(7)),
2.39 – 2.28 (m, 2H, bH-C(7) and bH-C(6)), 2.22 (s, 3H, H-C(9)). 13C NMR
(101 MHz, CDCl3) δ = 169.5 (C(8)), 142.60 (C(1‘)), 142.65 (C(1‘‘)),
128.05 (C(2‘) and C(6‘)), 127.98 (C(2‘‘) and C(6‘‘)), 126.8 (C(3‘) and
C(5‘)), 126.7 (C(3‘‘) and C(5‘‘)), 126.2 (C(4‘)), 126.1 (C(4‘‘)), 62.3 (C(4)),
58.4 (C(2)), 57.1 (C(5)), 55.9 (C(1)), 30.0 (C(7)), 29.5 (C(6)), 22.6 (C(9)).
HRMS (ESI) m/z: [(M+H+)+] (C20H22NO) calculated: 292.16959, found:
292.16993.
Rel-(1R,5S,6R)-3,3-dimethyl-1,6-diphenyl-3-azabicyclo[3.2.0]heptan-
3-ium trifluoromethanesulfonate (14a): Prepared by general procedure
from N-cinnamyl-N,N-dimethyl-2-phenylprop-2-en-1-ammonium trifluoro-
methanesulfonate (10a) (25 mg, 0.05 mmol) in acetonitrile (5 mL).
Purified by column chromatography (CH2Cl2:MeOH 10:1). Product 14a
was obtained as a white solid as a mixture of diastereomers (d.r. = 3:1)
(18 mg, 0.04 mmol, 70%). Major diastereomer: 1H NMR (400 MHz,
CDCl3) δ = 7.51 – 7.05 (m, 10H, H-C(Ar‘) and H-C(Ar‘‘)), 4.38 (d, J = 12.6
Hz, 1H, bH-C(2)), 4.29 (d, J = 12.6 Hz, 1H, aH-C(2)), 4.09 (d, J = 11.2 Hz,
Tert-butyl
rel-(1S,5R,6S)-6-(4-fluorophenyl)-3-azabicyclo[3.2.0]-
heptane-3-carboxylate (21): Prepared by general procedure from 20 (70
mg, 0.24 mmol) in acetonitrile (20 mL). Purified by column
chromatography (hexane:ethyl acetate 3:1). Product 21 was obtained as
1
colourless oil as a pure diastereomer (45 mg, 0.16 mmol, 65%). H NMR
(400 MHz, DMSO-d6, 70°C) δ = 7.29 (ddt, J = 8.5, 5.4, 3.1 Hz, 2H, H-
C(2‘) and H-C(6‘)), 7.15 – 7.04 (m, 2H, H-C(3‘) and H-C(5‘)), 3.58 (d, J =
11.6 Hz, 1H, H-C(4)), 3.54 (d, J = 11.6 Hz, 1H, H-C(2)), 3.37 (dd, J =
11.7, 7.1 Hz, 1H, H-C(2)), 3.22 (dd, J = 10.5, 4.9 Hz, 1H, H-C(4)), 3.26 –
3.15 (m, 1H, H-C(6)), 2.94 – 2.86 (m, 2H, H-C(1) and H-C(5)), 2.29 –
2.20 (m, 1H, H-C(7)), 2.11 (ddd, J = 11.9, 9.6, 2.6 Hz, 1H, H-C(7)), 1.45
(s, 9H, H-C(10)). 13C NMR (101 MHz, DMSO-d6, 70°C) δ = 160.4 (d, J =
241.8 Hz, C(4‘)), 153.9 (C(8)), 140.8 (d, J = 3.0 Hz, C(1‘)), 127.7 (d, J =
7.9 Hz, C(2‘) and C(6‘)), 114.5 (d, J = 21.0 Hz, C(3‘) and C(5‘)), 78.0
(C(9)), 52.0 (C(2)), 51.7 (C(4)), 45.4 (C(5)), 41.2 (C(6)), 33.1 (C(1)), 31.5
(C(7)), 27.9 (C(10)). HRMS (ESI) m/z: [M+Na+]+ (C17H22NFO2Na)
calculated: 314.15268, found: 314.15278.
b
a
1H, H-C(4)), 4.01 (d, J = 11.2 Hz, 1H, H-C(4)), 3.84 – 3.74 (m, 2H, H-
C(6) and H-C(5)), 3.52 (s, 3H, H-C(9)), 3.03 (dd, J = 12.3, 8.0 Hz, 1H, bH-
a
C(7)), 2.83 (s, 3H, H-C(8)), 2.29 (dd, J = 12.2, 8.1 Hz, 1H, H-C(7)). 13C
NMR (101 MHz, CDCl3) δ = 143.6 (C(1‘)), 142.5 (C(1‘‘)), 129.8 (C(3‘) and
C(5‘)), 128.9 (C(3‘‘) and C(5‘‘)), 127.7 (C(4‘‘)), 127.1 (C(4‘)), 126.8 (C(2‘)
and C(6‘)), 125.1 (C(2‘‘) and C(6‘‘)), 120.7 ( 76.4 (C(2)), 72.7 (C(4)), 54.2
(C(8)), 53.9 (C(9)), 49.9 (C(1)), 48.0 (C(5)), 41.0 (C(6)), 40.5 (C(7)).
Minor diastereomer: 1H NMR (400 MHz, CDCl3) δ = 7.49 – 7.11 (m, 10H,
H-C(Ar‘) and H-C(Ar‘‘)), 4.14 – 4.05 (m, 2H, H-C(4)), 4.01 (d, J = 11.5 Hz,
b
a
1H, H-C(2)), 3.90 (d, J = 11.5 Hz, 1H, H-C(2)), 3.48 – 3.38 (m, 1H, H-
C(5)), 3.29 (s, 3H, H-C(9)), 3.14 (dd, J = 12.1, 10.0 Hz, 1H, bH-C(7)),
2.95 (s, 3H, H-C(8)), 2.83 – 2.78 (m, 1H, aH-C(7)). 13C NMR (101 MHz,
CDCl3) δ = 142.5 (C(1‘)), 139.3 (C(1‘‘)), 129.8 (C(3‘) and C(5‘)), 129.1
(C(3‘‘) and C(5‘‘)), 127.9 (C(4‘‘)), 127.2 (C(4‘)), 126.7 (C(2‘) and C(6‘)),
Rel-(1S,5R,6S)-6-(4-fluorophenyl)-3-azabicyclo[3.2.0]heptane
(22):
Compound 21 (35 mg, 0.12 mmol) was dissolved in dry CH2Cl2 (10 mL)
and TFA (5 mL) was dropwise added. Reaction mixture was stirred for
2 h and then quenched by NaOH solution until basic pH was reached.
Mixture was extracted with additional CH2Cl2 (2 x 20 mL). Organic
phases were joined, dried by MgSO4 and volatilities were removed on
rotatory evaporator to obtain 22 (20 mg, 0.10 mmol, 87 %) as a
colourless oil. 1H NMR (401 MHz, CDCl3) δ = 7.25 – 7.16 (m, 2H, H-C(2‘)
and H-C(6‘)), 7.04 – 6.94 (m, 2H, H-C(3‘) and H-C(5‘)), 3.27 (m, 2H, H-
C(6), H-N(3)), 3.10 (d, J = 11.3 Hz, 1H, H-C(2) or H-C(4)), 3.06 (d, J =
10.8 Hz, 1H, H-C(4) or H-C(2)), 2.92 – 2.84 (m, 3H, H-C(4) or H-C(2) and
H-C(1) and H-C(5)), 2.79 (dd, J = 11.4, 4.8 Hz, 1H, H-C(2) or H-C(4)),
2.27 (dddd, J = 12.5, 9.6, 5.8, 1.4 Hz, 1H, H-C(7)), 2.08 (ddd, J = 13.2,
9.7, 3.4 Hz, 1H, H-C(7)). 13C NMR (101 MHz, CDCl3) δ = 161.3 (d, J =
243.6 Hz, C(4‘)), 142.2 (d, J = 3.1 Hz, C(1‘)), 127.9 (d, J = 7.8 Hz, C(2‘)
and C(6‘)), 115.2 (d, J = 21.1 Hz, C(3‘) and C(5‘)), 53.7 (C(4) and C(2)),
-
125.5, (C(2‘‘) and C(6‘‘)), 120.7 (q, J = 320 Hz, CF3SO3 ), 78.6 (C(2)),
67.6 (C(4)), 52.9 (C(9)), 52.2 (C(8)), 48.7 (C(1)), 45.2 (C(6)), 40.6 (C(7)),
- +
33.1 (C(5)). HRMS (ESI) m/z: [(M-CF3SO3 ) ] (C20H24N) calculated:
278.19033, found: 278.19072.
Rel-(1R,5S)-3,3-dimethyl-1-phenyl-3-azabicyclo[3.2.0]heptan-3-ium
trifluoromethanesulfonate (15a): Prepared by general procedure from
N-allyl-N,N-dimethyl-2-phenylprope-2-en-1-ammonium trifluoromethane-
sulfonate (11) (90 mg, 0.26 mmol) in acetonitrile (20 mL). Purified by
column chromatography (CH2Cl2:MeOH 10:1). Product 15a was obtained
as a whites solid (50 mg, 0.14 mmol, 55%). 1H NMR (400 MHz, CDCl3): δ
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47.1 (C(5) or C(6)), 41.4 (C(6) or C(5)), 34.8 (C(1)), 32.0 (C(7)). HRMS
(ESI) m/z: [M+H+]+ (C12H15NF) calculated: 192.11830, found: 192.11830.
14605; i) M. A. Ischay, M. E. Anzovino, J. Du, T. P. Yoon, J. Am. Chem.
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Rel-(1S,3S,5R,6S,6'S,7R,7'R)-6,6',7,7'-tetraphenyl-3-azonia-3,3'-
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a
11.1, 7.8, 1.7 Hz, 2H, H-C(2) or aH-C(4), 4.80 (dd, J = 12.0, 7.8 Hz, 2H,
bH-C(2) or bH-C(4)), 4.43 (dd, J = 9.8, 5.4 Hz, 2H, H-C(6) or H-C(7)), 4.25
(dd, J = 10.2, 4.5 Hz, 2H, bH-C(4) or bH-C(2)), 4.24 (dd, J = 11.0, 6.6 Hz,
2H, H-C(7) or H-C(6)), 3.98 (ddd, J = 11.6, 7.8, 1.7 Hz, 2H, aH-C(4) or
aH-C(2)), 3.64 – 3.55 (m, 2H, H-C(1) or H-C(5)), 3.57 (dddd, J = 17.3, 9.5,
7.5, 4.5 Hz, 2H, H-C(5) or H-C(1)). 13C NMR (151 MHz, CDCl3) δ 138.82
(C(Ar), 138.76 (C(Ar), 128.14 (C(Ar)), 128.12 (C(Ar)), 128.1 (C(Ar)),
128.0 (C(Ar)), 126.41 (C(Ar)), 126.39 (C(Ar)), 68.2 (C(4) or C(2)), 67.7
(C(2) or C(4)), 46.5 (C(6) or C(7)), 46.1 (C(7) or C(6)), 39.8 (C(5) or C(1)),
39.4 (C(1) or C(5)). HRMS (ESI) m/z: [M-B-r]+ (C36H36N+) calculated:
482.28423, found:482.28432.
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Acknowledgements
This project was supported by the Czech Science Foundation
(Grant No. 14-09190S). Authors thanks the German National
Science Foundation (GRK 1626 „Chemical Photocatalysis“).
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Keywords: Cycloaddition • Photocatalysis • Flavin • Nitrogen
and Sulfur heterocycles • Ammonium salts
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Robot
Referee”:
N.
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W.
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http://nmrpredict.orc.univie.ac.at/c13robot/robot.php.
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Entry for the Table of Contents (Please choose one layout)
Layout 2:
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Visible-Light Photocycloaddition
M. Jirásek, K. Straková, T. Neveselý, E.
Svobodová, Z. Rottnerová, and R.
Cibulka*
Page No. – Page No.
Photoorganocatalytic [2+2] cycloaddition mediated by flavin derivative 1 and visible
light affords variety of aza- and thia-analogues of bicyclo[3.2.0]heptanes with high
diastereoselectivities.
Flavin-Mediated Visible Light [2+2]
Photocycloadditon of Nitrogen and
Sulfur-Containing Dienes
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