A Chiral Thiourea as a Template for Enantioselective Intramolecular [2 + 2] Photocycloaddition Reactions

Article abstract of DOI:10.1021/acs.joc.6b01039

A chiral (1R,2R)-diaminocyclohexane-derived bisthiourea was found to exhibit a significant asymmetric induction in the intramolecular [2 + 2] photocycloaddition of 2,3-dihydropyridone-5-carboxylates. Under optimized conditions, the reaction was performed with visible light employing 10 mol % of thioxanthone as triplet sensitizer. Due to the different electronic properties of its carbonyl oxygen atoms, a directed binding of the substrate to the template is possible, which in turn enables an efficient enantioface differentiation.

Full text of DOI:10.1021/acs.joc.6b01039

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Brief Communication
A Chiral Thiourea as Template for Enantioselective
Intramolecular [2+2] Photocycloaddition Reactions
Florian Mayr, Richard Brimioulle, and Thorsten Bach
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01039 • Publication Date (Web): 03 Jun 2016
Downloaded from http://pubs.acs.org on June 3, 2016
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Upon absorption of a photon, substrates of a photochemical reaction undergo rapid bond
formation requiring little if any further activation. UV/Vis irradiation initiates the reaction but
does not induce a significant asymmetric induction, even if used in circularly polarized form.1 If
photochemical reactions are to be performed enantioselectively, stoichiometric templates have
been shown to be powerful tools.2 Among several templates3 which operate via hydrogen
bonding,4 lactam 15 has turned out to be very useful for several transformations, including [2+2]
photocycloaddition reactions.6 The combination of an adjacent hydrogen bond donor (NH) and a
hydrogen bond acceptor (CO) enables an unambiguous directionality of the binding event
(Scheme 1).
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S
CHEME 1. High Directionality in the Binding of Lactam 1 to a Photochemical Substrate, e.g.
1(2H)ꢀIsoquinolone
Although chiral thioureas have found widespread use as organocatalysts in thermal reactions7
applications in photocycloaddition chemistry are rare. The two hydrogen bond donors (NH) at the
thiourea core offer limited directionality and are in thermal reactions often combined with a third
site for reagent activation, e.g. in Takemoto’s catalyst.8 Thiourea 2 (Figure 1) as developed by the
Sivaguru group exhibits an additional hydroxy group at the naphthalene and was used as a
catalyst for enantioselective [2+2] photocycloaddition reaction of coumarins.9,10 Bisthiourea 3
was shown by the Beeler group to bind a cinnamate at each of the two thiourea binding sites and
thus increased the regioselectivity of the cinnamate [2+2] photodimerization.11
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F
IGURE 1. Structure of Thioureas 2 and 3 Employed as Catalysts or Templates in [2+2]
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Photocycloaddition Reactions
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Although it was shown already in the seminal study by Schreiner and Wittkopp on thiourea
catalysis that binding to a dicarbonyl compound is not necessarily symmetrical12 we are not
aware of a thiourea, which was used as a chiral template in [2+2] photocycloaddition reactions of
1,3ꢀdicarbonyl compounds.13 In this communication, we present a preliminary study on the
intramolecular [2+2] photocycloaddition of 2,3ꢀdihydropyridoneꢀ5ꢀcarboxylates.14
SCHEME 2. Synthesis of Bisthioureas 5 from (1R,2R)ꢀDiaminocyclohexane (4)
The study commenced with the synthesis of various chiral bisthioureas derived from
commercially available (1R,2R)ꢀdiaminocyclohexane (4) (Scheme 2). Simple addition of the
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respective aryl isothiocyanate (two equiv.) delivered the desired products 5 in high yields, some
of which (5a,15a 5d,15b 5k,15c) have been previously reported.
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It was speculated that dihydropyridone substrate 6 (Table 1) would bind to either thiourea unit of
the bisthiourea or potentially that two molecules would bind to both thiourea units
simultaneously. In any case, only 50 mol% of the template should be sufficient to achieve a
significant asymmetric induction. In an initial screening performed at room temperature,
bisthioureas were indeed found to be superior to any other class of thioureas (see Supporting
Information for further details). In further experiments, the intramolecular [2+2]
photocycloaddition to products 7 and entꢀ7 was performed at λ = 366 nm in toluene at −70 °C
and at a concentration of c = 20 mM (Table 1). Gratifyingly, we found that bisthiourea 5k16
resulted in a significant enantiomeric excess in favor of one enantiomeric product. Other
bisthioureas 5eꢀ5j, 5l, which carry an electron deficient aryl group resulted also in a notable
enantioselectivity but were inferior to template 5k.
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T
ABLE 1. Evaluation of Bisthioureas 5 as Chiral Complexing Agents in the Intramolecular [2+2]
Photocycloaddition of Dihydropyridone 6
a
Thiourea 5l was not fully soluble in toluene solution. The reaction mixture remained heterogenous.
It was confirmed that toluene was the best solvent for direct irradiation by performing the
reactions also in other solvents (see SI). In addition, it could be shown that neither a decrease nor
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a significant increase in template concentration led to an improved enantioselectivity. With 10
mol% 5k, the reaction proceeded in 74% yield but the ee dropped to 4%. With 2.3 equiv. (230
mol%) of 5k, the reaction slowed and a yield of 71% was recorded after an irradiation time of 18
hours (23% ee). Although an increase in substrate concentration helped to improve the
enantioselecitivity (64% ee at c = 100 mM), the improvement was again at the expense of an
extended reaction time and a decreased overall yield (see SI).
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In parallel to the optimization experiments, we found that the intramolecular [2+2]
photocycloaddition of substrate 6 could be performed with visible light, if thioxanthone (8) was
employed as a triplet sensitizer.17 A 1:2 (v/v) mixture of these solvents had earlier been found to
be suitable for low temperature irradiation experiments due its low melting point. Remarkably,
the enantioselectivity of the [2+2] photocycloaddition improved significantly under sensitized
conditions (Table 2). With 50 mol% thioxanthone the reaction remained incomplete after four
hours (entry 1) but the enantioselectivity was promising (76% ee). Upon prolonged irradiation,
there was no change in enantioselectivity and the reaction went to completion (entry 2) delivering
94% of product. A simultaneous decrease of the loading in template and sensitizer, did not alter
the yield but the enantioselectivity decreased as it had done in the direct irradiation experiments
(entry 3). Indeed, with 10 mol% of template 5k a maximum of 20% of substrate can be bound
and can thus react enantioselectively. If the template amount was increased to 50 mol%, the
enantioselectivity increased as expected while the reaction rate and the yield remained
satisfactorily high (entry 4).
T
ABLE 2. Sensitization of the Enantioselective Intramolecular [2+2] Photocycloaddition 6 → 7
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yieldb
[%]
eec
[%]
entry 5k [mol%] 8 [mol%] t [h]a
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a Irradiation time at the indicated conditions. b Yield of isolated product after purification by chromatography. c The
enantiomeric excess was determined by chiral HPLC or GLC analysis.
Structure 7 was assigned to the major photocycloaddition enantiomer based on comparison of the
chiroptical data of its decarboxylation product with those of a known photocycloaddition product
(see SI for further details).18 The intramolecular approach of the tethered olefin on carbon atom
C6 of the dihydropyridone must thus have occurred from the si face. This preference is suggested
if coordination of the substrate to the thiourea occurs as shown in Figure 2 for complex 8 and if
the other thiourea moiety (in grey) shields the re face. Support of a nonꢀsymmetric binding was
found when determining the chemical shift changes upon mixing substrate 6 and thiourea 5k in
benzeneꢀd6. The 13CꢀNMR chemical shift of carbonyl carbon atom C4 is most extensive while
there is very little changes observed for the other two carbonyl groups (see SI for further details).
If instead of the methyl carboxylate 6, the respective ethyl carboxylate was employed, there was
little change in the reaction outcome (73% yield, 72% ee). However, substrate 9 with a second
basic carbonyl oxygen atom gave no enantioselectivity.
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F
IGURE 2. Structure 8 of the putative complex between substrate(s) 6 and bisthiourea 5k,
structure of photocycloaddition precursor 9, and structure of monothiourea 10
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The second thiourea unit in 5k can be replaced by a tertꢀbutoxycarbonyl (Boc) protecting group.
Thiourea 1019 was tested only under conditions of direct irradiation under which it delivered the
same major product enantiomer as template 5k (see SI) supporting the hypothesis of an
association mode as given for 8. An intriguing conclusion can be drawn from the increased
enantioselectivity observed in the sensitized reactions (Table 2) as compared to the direct
irradiation reaction (Table 1). It is conceivable that the increase is due to the thioxanthone acting
simultaneously as a sensitizer and a steric shield. This hypothesis is currently further studied in
our laboratories and results will be reported in due course.
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EXPERIMENTAL SECTION
General Methods:
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All reactions sensitive to air or moisture were carried out in flameꢀdried glassware under a
positive pressure of argon using standard Schlenk techniques. Dry tetrahydrofuran (THF),
dichloromethane (CH2Cl2), and diethylether (Et2O) were obtained from a solvent purification
system. Other dry solvents were obtained in the highest purity available and used without further
purification. Technical solvents used for aqueous workup and for column chromatography [nꢀ
pentane (pentane), ethyl acetate (EtOAc), diethyl ether (Et2O), dichloromethane (CH2Cl2),
methanol (MeOH)] were distilled prior to use. Photochemical experiments were performed in
Duran tubes (diameter: 1.2 cm, volume 10 mL or 20 mL each; diameter 2.0 cm, volume 60 mL)
in a photochemical reactor equipped with 16 fluorescence lamps: (λ = 366 nm, λ = 419 nm).20
Prior to irradiation, the mixture was deoxygenated by purging with argon in an ultrasonicating
bath for 15 minutes. Flash chromatography was performed on silica gel 60 (230ꢀ240 mesh) with
the eluent mixtures given in the corresponding procedures. Thinꢀlayer chromatography (TLC)
was performed on silicaꢀcoated glass plates (silica gel 60 F 254). Compounds were detected by
UV (λ = 254 nm, 366 nm) and CAM (cerium ammonium molybdate) solution. All solvents for
chromatography were distilled prior to use. Analytical HPLC was performed using a chiral
stationary phase (flow rate: 1.0 mL/min, column type and eluent is given for the corresponding
compounds) and UV detection (λ = 210 nm or 254 nm) at 20 °C. IR spectra were recorded by the
attenuated total reflection (ATR) technique. 1HꢀNMR and 13CꢀNMR spectra were recorded at
300 K. Chemical shifts are reported as parts per million (ppm) relative to residual CHCl3
(δH = 7.26 ppm and δC = 77.0 ppm) or DMSOꢀδ5 (δH = 2.50 ppm and δC = 39.5 ppm). All
coupling constants (J) are reported in Hertz (Hz). Apparent multiplets that occur as a result of
accidental equality of coupling constants those of magnetically nonꢀequivalent protons are
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marked as virtual (virt.). The relative configuration of chiral products and the multiplicity of the
13CꢀNMR signals were determined by twoꢀdimensional NMR experiments (COSY, NOESY,
HSQC, HMBC). Mass spectra were measured with a mass selective quadrupole detector (EI, 70
eV) or with an ion trap mass spectrometer (ESI). HRMS data were determined at a doubleꢀ
focussing magnetic sector instrument (EI, 70 eV) or at a linear ion trap with a Fourier transform
ion cyclotron resonance detector (ESI).
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General Procedure for the Synthesis of Thioureas 5. To a solution of (1R,2R)ꢀ
diaminocyclohexane (1.0 eq) in THF (50 mM) was added the corresponding isothiocyanate (2.1
eq) at room temperature. The mixture was stirred at room temperature for 18 hours. After
evaporation of the sovent the crude mixture was purified by column chromatography. Specific
conditions and yields are given for each thiourea below.
1,1'ꢀ[(1R,2R)ꢀCyclohexaneꢀ1,2ꢀdiyl]bis(3ꢀmesitylthiourea) (5b). (1R,2R)ꢀDiaminocyclohexane
(50.0 mg, 0.44 mmol, 1.0 eq) was dissolved in THF and 2ꢀisothiocyanatoꢀ1,3,5ꢀtrimethylbenzene
(163 mg, 0.92 mmol, 2.1 eq) was added. The crude material was purified by column
chromatography (pentane:EtOAc = 4:1). The product (77.5 mg, 0.17 mmol, 38%) was isolated as
a white solid. m.p.: 197ꢀ201 °C. TLC (pentane:EtOAc = 4:1): Rf = 0.17 [UV, KMnO4]. IR (ATR):
ν̃
(cmꢀ1) = 3174, 2924, 2854, 1529, 1489, 1230, 850. 1H NMR (250 MHz, CDCl3): δ (ppm) =
1.20ꢀ1.38 (m, 6H), 1.68 (d, 3J = 8.7 Hz, 2H), 2.15 (s, 6H), 2.22 (s, 2H), 2.30 (s, 12H), 4.21 (s,
2H), 6.00 (s, 2H), 6.79ꢀ7.16 (m, 4H), 13C{1H}ꢀNMR (CDCl3 91 MHz): δ (ppm) = 18.0 (q), 18.6
(q), 21.1 (q), 24.7 (t), 32.6 (t), 58.7 (d), 129.6 (s), 130.0 (s), 136.5 (s), 137.6 (d), 138.9 (s), 180.6
(s). [α]D20 = +141.4 (c = 0.3, CHCl3). MS (EI, 70 EV): m/z (%) = 468 (1), 177 (100)
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[(C10H11NS)+], 144 (39), 119 (16) [(C9H11)+], 91 (14), 49 (8). HRMS (EI): Calculated for
C26H36N4S2 [M+] = 468.2381. Found = 468.2354.
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1,1'ꢀ[(1R,2R)ꢀCyclohexaneꢀ1,2ꢀdiyl]bis[3ꢀ(3,5ꢀdimethoxyphenyl)thiourea] (5c). (1R,2R)ꢀ
Diaminocyclohexane (50.0 mg, 0.44 mmol, 1.0 eq) was dissolved in THF and 1ꢀisothiocyanatoꢀ
3,5ꢀdimethoxybenzene (180 mg, 0.92 mmol, 2.1 eq) was added. The crude material was purified
by column chromatography (pentane:EtOAc = 4:1). The product (218 mg, 0.43 mmol, 99 %) was
isolated as a white solid. m.p.: 149ꢀ152 °C. TLC (pentane:EtOAc = 4:1): Rf = 0.36 [UV, KMnO4].
IR (ATR): ν̃
(cmꢀ1) = 3213, 2935, 2854, 1598, 1510, 1451, 1329, 1257, 1202, 1153, 1122, 1038,
836. 1H NMR (400 MHz, CDCl3): δ (ppm) = 1.23ꢀ1.34 (m, 4H), 1.74 (d, 3J = 7.5 Hz, 2H), 2.15
(d, 3J = 10.3 Hz, 2H), 3.79 (s, 12H), 4.39ꢀ4.43 (m, 2H), 6.36 (virt. t, 4J ≅ 4J ≅ 2.2 Hz, 2H), 6.41
(d, 4J = 2.2 Hz, 4H), 6.65 (d, 3J = 7.0 Hz, 2H), 7.62 (s, 2H). 13C{1H}ꢀNMR (CDCl3, 101 MHz): δ
(ppm) = 24.6 (t), 32.3 (t), 55.8 (q), 59.3 (d), 99.5 (s), 103.5 (d), 137.6 (s), 161.9 (d), 180.2 (s).
[α]D20 = + 4.1 (c = 1.0, CHCl3). MS (EI, 70 EV): m/z (%) =322 (8), 207 (26), 195 (54)
[(C9H9NO2S)+], 189 (27), 153 (17), 97 (22), 71 (45), 57 (86), 43 (100). HRMS (EI): Calculated
for C24H32N4O4S2 [M+] = 504.1865. Found = 504.1861.
1,1'ꢀ[(1R,2R)ꢀCyclohexaneꢀ1,2ꢀdiyl]bis[3ꢀ(2,6ꢀdifluorophenyl)thiourea] (5e). (1R,2R)ꢀ
Diaminocyclohexane (50.0 mg, 0.44 mmol, 1.0 eq) was dissolved in THF and 1,3ꢀdifluoroꢀ2ꢀ
isothiocyanatobenzene (157 mg, 0.92 mmol, 2.1 eq) was added. The crude material was purified
by column chromatography (pentane: EtOAc = 4:1). The product (199 mg, 0.44 mmol, 99%) was
isolated as a white solid. m.p.: 133ꢀ137 °C. TLC (pentane:EtOAc = 4:1): Rf = 0.10 [UV, KMnO4].
IR (ATR): ν̃
(cmꢀ1) = 3206, 3040, 2937, 2857, 1598, 1527, 1509, 1470, 1449, 1296, 1240, 1186,
1123, 1002, 776. 1H NMR (400 MHz, CDCl3): δ (ppm) = 1.24ꢀ1.32 (m, 4H), 1.75 (d, 3J = 7.4 Hz,
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2H), 2.27ꢀ2.31 (m, 2H), 4.27 (brs, 2H), 6.93ꢀ6.97 (m, 6H), 7.23ꢀ7.27 (m, 2H), 7.40 (brs, 2H).
13C{1H}ꢀNMR (CDCl3, 101 MHz): δ (ppm) = 24.7 (t), 32.0 (t), 59.8 (d), 112.5 (dd, 2JCF = 22.3
Hz), 113.8 (t, 2JCF = 16.4 Hz), 129.2 (dt, 3JCF = 9.4 Hz), 158.4 (d, 1JCF = 253 Hz), 181.5 (s). [α]D
= +113.8 (c = 1.0, CHCl3). MS (EI, 70 EV): m/z (%) = 171 (45) [(C7H4F2NS)+], 129 (12), 97
(12), 70 (16), 61 (27), 43 (100). HRMS (EI): Calculated for C20H20F4N4S2 [M+] = 456.1066.
Found = 456.1050.
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1,1'ꢀ[(1R,2R)ꢀCyclohexaneꢀ1,2ꢀdiyl]bis[3ꢀ(2,4,6ꢀtrifluorophenyl)thiourea] (5f). (1R,2R)ꢀ
Diaminocyclohexane (50.0 mg, 0.44 mmol, 1.0 eq) was dissolved in THF and 1,3,5ꢀtrifluoroꢀ2ꢀ
isothiocyanatobenzene (174 mg, 0.92 mmol, 2.1 eq) was added. The crude material was purified
by column chromatography (pentane:EtOAc = 4:1). The product (210 mg, 0.43 mmol, 98%) was
isolated as a white solid. m.p.: 162ꢀ165 °C. TLC (pentane:EtOAc = 4:1): Rf = 0.25 [UV, KMnO4].
IR (ATR): ν̃
(cmꢀ1) = 3209, 3035, 2944, 2864, 1602, 1512, 1449, 1341, 1240, 1175, 1123, 1040,
998, 842. 1H NMR (400 MHz, DMSOꢀd6): δ (ppm) = 1.22ꢀ1.23 (m, 4H), 1.65ꢀ1.67 (m, 2H),
2.14ꢀ2.16 (m, 2H), 4.14 (brs, 2H), 7.20 (t, 3J = 8.8 Hz, 4H), 7.97 (brs, 2H), 8.99 (brs, 2H).
13C{1H}ꢀNMR (DMSOꢀd6, 101 MHz): δ (ppm) = 24.3 (t), 31.4 (t), 57.8 (d), 100.8 (dt, 3JCF = 26.1
Hz), 112 (s), 159.0 (ddd, 1JCF = 250 Hz, 3JCF = 15.9 Hz, 7.0 Hz), 160.4 (d, 1JCF = 246 Hz), 182.0
(s). [α]D20 = +105.0 (c = 0.5, CHCl3). MS (EI, 70 EV): m/z (%) = 269 (100), 226 (38), 189 (40)
[(C7H2F3NS)+], 172 (25), 147 (22), 81 (29), 56 (30). HRMS (EI): Calculated for C20H18F6N4S2
[M+] = 492.0877. Found = 492.0854.
1,1'ꢀ[(1R,2R)ꢀCyclohexaneꢀ1,2ꢀdiyl]bis[3ꢀ(2,3,4,5ꢀtetrafluorophenyl)thiourea] (5g) (1R,2R)ꢀ
Diaminocyclohexane (100 mg, 0.88 mmol, 1.0 eq) was dissolved in THF and 1,2,3,4ꢀtetrafluoroꢀ
5ꢀisothiocyanatobenzene (383 mg, 1.85 mmol, 2.1 eq) was added. The crude material was
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[UV, KMnO4]. IR (ATR): ν̃
(cmꢀ1) = 3220, 3044, 2939, 2860, 1519, 1491, 1333, 1313, 1273,
1257, 1220, 1200, 1060, 969, 951, 849, 711. 1H NMR (400 MHz, CDCl3): δ (ppm) = 1.38ꢀ1.42
(m, 4H), 1.85ꢀ1.87 (m, 2H), 2.27ꢀ2.30 (m, 2H), 4.34ꢀ4.39 (m, 2H), 7.19 (br s, 2H), 7.23ꢀ7.30 (m,
2H), 7.54 (br s, 2H). 13C{1H}ꢀNMR (CDCl3, 126 MHz): δ (ppm) = 24.7 (t), 32.0 (t), 59.9 (d),
110.1 (dd, 2JCF = 21.5 Hz), 120.9 (s), 139.7 (d, 1JCF = 240.3 Hz), 141.7 (d, 1JCF = 239.6 Hz),
143.0 (dd, 1JCF = 246.9 Hz, 2JCF = 9.4 Hz), 146.8 (dd, 1JCF = 248.5 Hz, 2JCF = 10.2 Hz), 181.3 (s).
[α]D20 = + 42.9 (c = 1.0, CHCl3). MS (EI, 70 EV): m/z (%) = 206 (6) [(C7HF4NS)+] , 94 (100), 66
(26), 57 (20) [(CNS)2+] . HRMS (EI): Calculated for C20H16F8N4S2 [M+] = 528.0689. Found =
528.0721.
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The isothiocyanate was prepared as follows: Sodiumcarbonate (2.04 g, 24.2 mmol, 4.0 eq) was
dissolved in water (8 mL). The mixture was stirred for 10 minutes and dichloromethane (8 mL)
was added, followed by 2,3,4,5ꢀtetrafluoroaniline (1.0 g, 6.06 mmol, 1.0 eq). The mixture was
cooled to 0 °C and thiophosgene (0.70 mL, 1.04 g, 9.08 mmol, 1.5 eq) was added dropwise via
syringe over a period of 20 minutes. The mixture was allowed to warm slowly to room
temperature and it was strirred for one hour at room temperature. The mixture was washed with
brine (50 mL). The aqueous layer was extracted with dichloromethane (3 × 50 mL). The
combined organic layers were dried over Na2SO4, filtered and the solvent was removed under
reduced pressure. The crude material was purified by chromatography through a short column
(pentane:EtOAc = 4:1). 1,2,3,4ꢀTetrafluoroꢀ5ꢀisothiocyanatobenzene was used in the next step
without further purification (vide infra).
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1,1'ꢀ[(1R,2R)ꢀCyclohexaneꢀ1,2ꢀdiyl]bis[3ꢀ(perfluorophenyl)thiourea] (5h) (1R,2R)ꢀ
Diaminocyclohexane (50.0 mg, 0.44 mmol, 1.0 eq) was dissolved in THF and 1,2,3,4,5ꢀ
pentafluoroꢀ6ꢀisothiocyanatobenzene (207 mg, 0.92 mmol, 2.1 eq) was added. The crude material
was purified by column chromatography (pentane:EtOAc = 4:1). The product (246 mg, 0.44
mmol, 99%) was isolated as a white solid. m.p.: 207ꢀ211 °C. TLC (pentane:EtOAc = 4:1): Rf =
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0.41 [UV, KMnO4]. IR (ATR): ν̃
(cmꢀ1) = 3212, 3044, 2941, 2860, 1552, 1518, 1510, 1467, 1341,
1314, 1274, 1227, 987. 1H NMR (400 MHz, CDCl3): δ (ppm) = 1.14ꢀ1.48 (m, 4H), 1.87 (d, 3J =
6.4 Hz, 2H), 2.37 (d, 3J = 9.9 Hz, 2H), 4.22 (brs, 2H), 7.77 (brs, 2H), 7.86 (brs, 2H). 13C{1H}ꢀ
NMR (CDCl3, 101 MHz): δ (ppm) = 24.7 (t), 31.8 (t), 60.5 (d), 112.3 (dt, 2JCF = 12.9 Hz, 3JCF
2.1 Hz), 138.1 (d, 1JCF = 254 Hz), 141.2 (d, 1JCF = 256 Hz), 144.2 (ddd, 1JCF = 254 Hz, 2JCF
=
=
10.7 Hz, 3JCF = 2.7 Hz), 182.0 (s). [α]D20 = +106.3 (c = 1.0, CHCl3). MS (EI, 70 EV): m/z (%) =
225 (100) [(C7F5NS)+], 193 (26), 183 (42) [(C6HF5N)+], 167 (8) [(C6F5)+] 117 (23). HRMS (EI):
Calculated for C20H14F10N4S2 [M+] = 564.0500. Found = 564.0489.
1,1'ꢀ[(1R,2R)ꢀCyclohexaneꢀ1,2ꢀdiyl]bis{3ꢀ[2ꢀ(trifluoromethyl)phenyl]thiourea} (5i) (1R,2R)ꢀ
Diaminocyclohexane (50.0 mg, 0.44 mmol, 1.0 eq) was dissolved in THF and 1ꢀisothiocyanatoꢀ
2ꢀ(trifluoromethyl)benzene (187 mg, 0.92 mmol, 2.1 eq) was added. The crude material was
purified by column chromatography (pentane: EtOAc = 4:1). The product (214 mg, 0.41 mmol,
94%) was isolated as a white solid. m.p.: 180ꢀ182 °C. TLC (pentane:EtOAc = 4:1): Rf = 0.18
[UV, KMnO4]. IR (ATR): ν̃
(cmꢀ1) = 3246, 3176, 3017, 2937, 2860, 1602, 1538, 1522, 1504,
1458, 1322, 1282, 1238, 1173, 1158, 1136, 1123, 1058, 1037, 758. 1H NMR (400 MHz, CDCl3):
δ (ppm) = 1.15ꢀ1.36 (m, 4H), 1.67ꢀ1.81 (m, 2H), 2.18 (d, 3J = 12.7 Hz, 2H), 4.31ꢀ4.36 (m, 2H),
6.61 (br s, 2H), 7.41ꢀ7.50 (m, 6H), 7.64 (virt. t, 3J ≅ 3J ≅ 7.7 Hz, 2H), 7.72 (d, 3J = 7.8 Hz, 2H).
13C{1H}ꢀNMR (CDCl3, 101 MHz): δ (ppm) = 24.7 (t), 32.0 (t), 59.5 (d), 123.3 (q, 1JCF = 273.4
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Hz), 126.8 (q, 2JCF = 30.2 Hz), 127.5 (dq, 3JCF = 5.0 Hz), 128.1 (d), 129.6 (d), 133.7 (d), 133.8
(s), 181.2 (s). [α]D20 = + 71.6 (c = 1.0, CHCl3). MS (EI, 70 EV): m/z (%) = 203 (100)
[(C8H4F3NS)+], 161 (55) [(C7H5F3N)+] , 114 (56), 43 (45). [(C6HF5N)+], 116 (23). HRMS (EI):
Calculated for C22H22F6N4S2 [M+] = 520.1190. Found = 520.1177.
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1,1'ꢀ[(1R,2R)ꢀCyclohexaneꢀ1,2ꢀdiyl]bis{3ꢀ[3ꢀ(trifluoromethyl)phenyl]thiourea} (5j) (1R,2R)ꢀ
Diaminocyclohexane (50.0 mg, 0.44 mmol, 1.0 eq) was dissolved in THF and 1ꢀisothiocyanatoꢀ
3ꢀ(trifluoromethyl)benzene (187 mg, 0.92 mmol, 2.1 eq) was added. The crude material was
purified by column chromatography (pentane:EtOAc = 4:1). The product (217 mg, 0.42 mmol,
95%) was isolated as a white solid. m.p.: 154ꢀ156 °C. TLC (pentane:EtOAc = 4:1): Rf = 0.23
[UV, KMnO4]. IR (ATR): ν̃
(cmꢀ1) = 3296, 3246, 3147, 3063, 2956, 2031, 1552, 1457, 1327,
1270, 1167, 792, 693. 1H NMR (400 MHz, CDCl3): δ (ppm) = 1.21ꢀ1.31 (m, 4H), 1.73 (br s, 2H),
2.13ꢀ2.14 (m, 2H), 4.33ꢀ4.37 (m, 2H), 6.88 (br s, 2H), 7.40ꢀ7.52 (m, 8H), 8.31 (s, 2H). 13C{1H}ꢀ
NMR (CDCl3, 101 MHz): δ (ppm) = 24.6 (t), 32.0 (t), 59.2 (d), 121.6 (dq, 3JCF = 4.0 Hz), 123.4
(dq, 3JCF = 3.7 Hz), 123.6 (q, 1JCF = 272.6 Hz), 128.1 (d), 130.5 (d), 132.2 (q, 2JCF = 32.8 Hz),
137.3 (s), 180.3 (s). [α]D20 = +11.0 (c = 0.5, CHCl3). MS (EI, 70 EV): m/z (%) = 203 (100)
[(C8H4F3NS)+], 145 (48) [(C7H4F3)+] , 95 (26), 75 (17) [(CH3N2S)+], 57 (25). HRMS (EI):
Calculated for C22H22F6N4S2 [M+] = 520.1190. Found = 520.1198.
1,1'ꢀ[(1R,2R)ꢀCyclohexaneꢀ1,2ꢀdiyl]bis[3ꢀ(3ꢀnitrophenyl)thiourea] (5l) (1R,2R)ꢀ
Diaminocyclohexane (50.0 mg, 0.44 mmol, 1.0 eq) was dissolved in THF and 1ꢀisothiocyanatoꢀ
3ꢀnitrobenzene (166 mg, 0.92 mmol, 2.1 eq) was added. The crude material was purified by
column chromatography (pentane:EtOAc = 4:1). The product (193 mg, 0.41 mmol, 93%) was
isolated as a yellowish solid. m.p.: 206ꢀ208 °C. TLC (pentane:EtOAc = 4:1): Rf = 0.45 [UV,
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KMnO4]. IR (ATR): ν
̃
(cmꢀ1) = 3266, 3098, 2948, 2860, 1522, 1346, 1266, 1212, 730. 1H NMR
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(400 MHz, DMSOꢀd6): δ (ppm) = 1.28ꢀ1.35 (m, 4H), 1.70ꢀ1.72 (m, 2H), 2.17ꢀ2.20 (m, 2H), 4.33
(br s, 2H), 7.53 (virt. t, 3J ≅ 3J ≅ 8.2 Hz, 2H), 7.77 (d, 3J = 7.77 Hz, 2H), 7.89 (dd, 3J = 7.9 Hz, 4J
= 2.2 Hz, 2H), 8.04ꢀ8.05 (m, 2H), 8.57 (br s, 2H), 9.99 (br s, 2H). 13C{1H}ꢀNMR (DMSOꢀd6,
101 MHz): δ (ppm) = 24.2 (t), 31.3 (t), 56.6 (d), 116.5 (d), 118.0 (d), 128.3 (d), 129.7 (d), 140.8
(s), 147.5 (s), 180.0 (s). [α]D20 = + 3.1 (c = 0.3, CHCl3). MS (ESI): m/z (%) = 475.1 (100)
[M+H+],. HRMS (ESI): Calculated for C20H23N6O4S2 [M+H+] = 475.1217. Found = 475.1216.
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Methyl 4ꢀoxoꢀ1ꢀ(pentꢀ4ꢀenoyl)ꢀ1,4,5,6ꢀtetrahydropyridineꢀ3ꢀcarboxylate (6). To a solution of
pentꢀ4ꢀenoic acid (0.56 mL, 5.50 mmol, 1.1 eq) in dichloromethane (10 mL) oxalylic chloride
(0.47 mL, 5.50 mmol, 1.1 eq) and a few drops of DMF were added at room temperature. The
mixture was stirred at room temperature for two hours. In a second flask 3ꢀ(methoxycarbonyl)ꢀ4ꢀ
oxopiperidinꢀ1ꢀium chloride (0.97 g, 5.00 mmol, 1.0 eq) was dissolved in dichloromethane (10
mL). Triethylamine (2.77 mL, 20.0 mmol, 4.0 eq) and two grains of DMAP were added. The
mixture was cooled to 0 °C and the in situ formed pentꢀ4ꢀenoyl chloride was subsequently added
slowly over the course of 10 minutes. The resulting mixture was allowed to warm to room
temperature and stirred overnight. The reaction was quenched with aqueous HCl (1 M) (10 mL).
The organic layer was separated and the aqueous layer was extracted three times with EtOAc (3 ×
60 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4 and
filtered. After evaporation the crude material was filtered through a short silica column. The
crude material was taken into the next step without further purification. A fraction of the crude
product (510 mg, 2.12 mmol, 1.00 eq) was suspended in dry 1,4ꢀdioxane (16 mL). To this
mixture 2,3ꢀdichloroꢀ5,6ꢀdicyanoꢀ1,4ꢀbenzoquinone (550 mg, 2.44 mmol, 1.15 eq) was added at
room temperature. The mixture was stirred at room temperature for five hours. Subsequently, the
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reaction was quenched by addition of an aqueous saturated NaHCO3ꢀsolution (10 mL). The
mixture was extracted three times with CH2Cl2 (3 × 30 mL) The combined organic layers were
washed with brine (50 mL), dried over Na2SO4 and filtered. After evaporation the crude material
was purified by column chromatography (pentane:EtOAc = 1:1). The product (292 mg, 1.23
mmol, 58 % over 2 steps) was isolated as a yellowish solid. m.p.: 88ꢀ90 °C. TLC (EtOAc): Rf =
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0.55 [UV, KMnO4]. IR (ATR): ν̃
(cmꢀ1) = 3073, 2952, 2913, 1715, 1574, 1128, 918. 1H NMR
(360 MHz, CDCl3): δ (ppm) = 2.49 (dtt, 3J = 7.6 Hz, 6.6 Hz, 4J = 1.2 Hz, 2H), 2.63 (t, 3J = 7.6
Hz, 2H), 2.78 (t, 3J = 7.5 Hz, 2H), 3.83 (s, 3H), 4.08 (t, 3J = 7.5 Hz, 2H), 5.07 (virt. dq, 3J = 10.3
Hz, 2J ≅ 4J ≅ 1.3 Hz, 1H), 5.12 (virt. dq, 3J = 17.0 Hz, 2J ≅ 4J ≅ 1.6 Hz, 1H), 5.85 (ddt, 3J = 17.0
Hz, 10.3 Hz, 6.6 Hz, 1H), 8.72 (s, 1H). 13C{1H} NMR (90 MHz, CDCl3): δ (ppm) = 28.5 (t), 32.8
(t), 36.2 (t), 41.6 (t), 52.3 (q), 108.8 (s), 116.7 (t), 135.9 (d), 149.9 (d), 164.7 (s), 171. (s), 188.3
(s). MS (EI, 70 EV): m/z (%) = 153 (40) [(C7H7NO3)+], 121 (34), 84 (30) [(C5H7O)+], 55 (40), 43
(100). HRMS (EI): Calculated for C12H15NO4 [M+] = 237.1001. Found = 237.0998.
Ethylꢀ4ꢀoxoꢀ1ꢀ(pentꢀ4ꢀenoyl)ꢀ1,4,5,6ꢀtetrahydropyridineꢀ3ꢀcarboxylate. In analogy to the
procedure for the preparation of methyl ester 6 the corresponding ethyl ester was synthesized
from 3ꢀ(ethoxycarbonyl)ꢀ4ꢀoxopiperidinꢀ1ꢀium chloride (765 mg, 3.68 mmol). The desired
product (483 mg, 1.84 mmol, 50%) was isolated over two steps as a yellowish solid. m.p.: 58ꢀ60
°C. TLC (pentane:EtOAc = 1:1): Rf = 0.20 [UV, KMnO4]. IR (ATR): ν̃
(cmꢀ1) = 3524, 3077,
2979, 2930, 1739, 1691, 1577, 1308, 1220, 1132, 909. 1HꢀNMR (360 MHz, CDCl3): δ (ppm) =
1.34 (t, 3J = 7.1 Hz, 3H), 2.33ꢀ2.55 (m, 2H), 2.61 (t, 3J = 7.4 Hz, 2H), 2.77 (t, 3J = 7.3 Hz, 2H),
4.07 (t, 3J = 7.3 Hz, 2H), 4.28 (q, 3J = 7.1 Hz, 2H), 5.06 (virt. dq, 3J = 10.3 Hz, 4J ≅ 2J ≅ 1.2 Hz,
1H), 5.12 (virt. dq, 3J = 17.1 Hz, 4J ≅ 2J ≅ 1.6 Hz, 1H), 5.83 (ddt, 3J = 17.1 Hz, 10.3 Hz, 6.6 Hz,
1H), 8.70 (s, 1H), 13C{1H}ꢀNMR (90 MHz, CDCl3): δ (ppm) = 14.4 (q), 28.5 (t), 32.8 (t), 36.3 (t),
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41.6 (t), 61.1 (t), 109.1 (s), 116.6 (t), 135.9 (d), 149.5 (d), 164.0 (s), 171.4 (s), 188.4 (s). MS (EI,
70 EV): m/z (%) = 251 (4) [M+], 166 (15) [(C8H8NO3)+], 124 (21) [(C6H6NO2)+], 83 (21)
[(C5H7O)+], 55 (100), 43 (65). HRMS (EI): Calculated for C13H17NO4 [M+] = 251.1158. Found =
251.1149.
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General procedure for racemic photoreactions. The solution of the corresponding substrate (c
= 20 mM) was purged with argon in an ultrasonicating bath for 10 minutes. The mixture was
irradiated at room temperature at λ = 366 nm until the reaction was complete. The solvent was
removed under reduced pressure and the crude material was purified by column chromatography
using an appropriate solvent system, as described in the individual procedure.
General procedure for enantioselective photoreactions at λ = 366 nm. A solution of the
corresponding substrate and thiourea (50 mol%) in toluene (c = 20 mM) was purged with argon
in an ultrasonicating bath for 10 minutes. The mixture was irradiated at −70 °C at λ = 366 nm for
four hours. The solvent was removed under reduced pressure and the crude material was purified
by column chromatography using an appropriate system, as described in the individual
procedure.
General procedure for sensitized enantioselective photoreactions at λ = 419 nm. A solution
of the corresponding substrate, thiourea (50 mol%) and thioxanthone (10 mol%) in a mixture of
trifluorotoluene and hexafluoroxylene (1:2, c = 5 mM) was purged with argon in an
ultrasonicating bath for 10 minutes. The mixture was irradiated at −65 °C at λ = 419 nm for 16
hours. The solvent was removed under reduced pressure and the crude material was purified by
column chromatography using an appropriate system, as described in the individual procedure.
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Methyl (4´S,7aS,8aS)ꢀ3,7ꢀdioxohexahydroꢀ1H,5Hꢀcyclobutanequinolizineꢀ7a(4´H)ꢀ
carboxylate (7) A solution of ester 6 (11.5 mg, 0.05 mmol, 1.0 eq) was irradiated in the
corresponding solvent (see Tables 1 and 2). After irradiation the solvent was removed under
reduced pressure and the crude material was purified by column chromatography (EtOAc).
Yields for the individual reactions are given in Tables 1 and 2. In the racemic reaction, which was
performed in toluene, the product racꢀ7 (11.4 mg, 0.05 mmol, 99%) was isolated as a colorless
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oil. TLC (EtOAc): Rf = 0.34 [KMnO4]. IR (ATR): ν̃
(cmꢀ1) = 2953, 2361, 1733, 1709, 1643,
1433, 1355, 1244, 1160, 1088, 945. 1H NMR (300 MHz, CDCl3): δ (ppm) = 1.49ꢀ1.63 (m, 1H),
2.05ꢀ2.21 (m, 2H), 2.33 (dd, 2J = 12.7 Hz, 3J = 7.2 Hz, 1H), 2.37ꢀ2.45 (m, 1H), 2.57ꢀ2.76 (m,
2H), 2.79ꢀ2.93 (m 1H), 2.98 (ddd, 2J = 12.7 Hz, 3J = 9.0 Hz, 4J = 1.9 Hz, 1H), 3.10 (ddd, 2J =
13.5 Hz, 3J = 10.3 Hz, 6.7 Hz, 1H), 3.79 (s, 3H), 4.44 (virt. dq, 3J ≅ 8.1 Hz, 4J ≅ 1.8 Hz, 1H), 4.79
(ddd, 2J = 13.5 Hz, 3J = 6.8 Hz, 2.7 Hz, 1H). 13C{1H}ꢀNMR (CDCl3, 75 MHz): δ (ppm) = 26.8
(t), 28.9 (d), 31.3 (t), 33.3 (t), 38.3 (t), 38.3 (t), 53.4 (q), 54.6 (s), 58.7 (d), 170.0 (s), 170.6 (s),
204.8 (s). [α]D20 = −36.5 (c = 0.8, CHCl3) [75% ee]. MS (EI, 70 EV): m/z (%) = 237 (20) [M+],
164 (27), 140 (45), 110 (62), 98 (83), 96 (100), 82 (54), 55 (35). HRMS (EI): Calculated for
C12H15NO4 [M+] = 237.1001. Found = 237.0994. Chiral HPLC (ADꢀH, 250 × 4.6 mm, nꢀ
hexane/iꢀPrOH = 90:10, 1 mL/min, λ = 210 nm, 254 nm): tR [racemate] = 16.9 min, 22.1 min; tR
[7] = 18.1 min, 23.1 min. Chiral GLC: tR1 = 556 min, tR2 = 558 min [60 °C (1 min), 150 °C (0.16
°C/min), 150 °C (10 min), 220 °C (10 °C/min), 220 °C (5 min)].
Ethyl (4aS,7aS,8aS)ꢀ3,7ꢀdioxohexahydroꢀ1H,5Hꢀcyclobutanequinolizineꢀ7a(4aH)ꢀ
carboxylate According to the general procedure for racemic photoreactions, a solution of the
ethyl ester (25.1 mg, 0.10 mmol, 1.0 eq) in toluene was irradiated. After complete conversion the
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solvent was removed under reduced pressure and the crude material was purified by column
chromatography (EtOAc). The product (19.6 mg, 0.08 mmol, 78%) was isolated as a colorless
oil.
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According to the general procedure for sensitized enantioselective photoreactions at λ = 419 nm,
a solution of ethylester (12.7 mg, 0.05 mmol, 1.0 eq), thiourea 5k (50 mol%) and thioxanthone
(8) (10 mol%) in a mixture of trifluorotoluene and hexafluoroxylene was irradiated. After 16
hours the solvent was removed under reduced pressure and the crude material was purified by
column chromatography (EtOAc). The product (9.30 mg, 0.04 mmol, 73%) was isolated as a
colorless oil (72% ee). TLC (EtOAc): Rf = 0.39 [KMnO4]. IR (ATR): ν̃
(cmꢀ1) = 2948, 2871,
1737, 1707, 1656, 1462, 1425, 1241, 1203, 1160, 1089. 1HꢀNMR (400 MHz, CDCl3): δ (ppm) =
1.29 (t, 3J = 7.1 Hz, 3H), 1.51ꢀ1.61 (m, 1H), 2.04ꢀ2.20 (m, 2H), 2.31 (dd, 2J = 12.7 Hz, 3J = 6.5
Hz, 1H), 2.37ꢀ2.44 (m, 1H), 2.59ꢀ2.74 (m, 2H), 2.80ꢀ2.90 (m, 1H), 2.98 (ddd, 2J = 12.7 Hz, 3J =
9.0 Hz, 4J = 1.8 Hz, 1H), 3.11 (ddd, 2J = 13.5 Hz, 3J = 10.7 Hz, 6.2 Hz, 1H), 4.25 (qd, 3J = 7.1
Hz, 2J = 1.7 Hz, 2H), 4.43 (d, 3J = 8.9 Hz, 1H), 4.79 (ddd, 2J = 13.5 Hz, 3J = 7.1 Hz, 2.3 Hz, 1H).
13C{1H}ꢀNMR (CDCl3, 91 MHz): δ (ppm) = 14.2 (q), 26.9 (t), 28.9 (d), 31.4 (t), 33.1 (t), 38.3 (t),
38.3 (t), 54.7 (s), 58.8 (d), 62.6 (t), 169.5 (s), 170.6 (s), 204.9 (s). [α]D20 = −29.1 (c = 0.8, CHCl3)
[70% ee]. MS (EI, 70 EV): m/z (%) = 251 (11) [M+], 206 (16) [(C11H12NO3)+], 167 (27), 164
(76), 149 (100) [(C8H7NO2)+] , 139 (17), 124 (25), 121 (30), 109 (81) [(C6H7NO)+], 96 (94)
[(C6H8O)+], 82 (51), 69 (25), 55 (55), 41 (27). HRMS (EI): Calculated for C13H17NO4 [M+] =
251.1158. Found = 251.1154. Chiral HPLC (ADꢀH, 250 × 4.6 mm, nꢀheptane/iꢀPrOH = 90:10,
1mL/min, λ = 210 nm, 254 nm): tR [racemate] = 13.7 min, 16.4 min; tR [enantioenriched product]
= 14.0 min, 16.4 min.
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1ꢀ(Pentꢀ4ꢀenoyl)ꢀ5ꢀ(pyrrolidineꢀ1ꢀcarbonyl)ꢀ2,3ꢀdihydropyridinꢀ4(1H)ꢀone (9)
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Borontrichloride (11.4 mL, 1M, 11.4 mmol, 1.1 eq) was added to a solution of pyrrolidine (6.00
7
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mL, 5.21 g, 73.3 mmol, 7.1 eq) in dichloromethane (15 mL). The mixture was stirred at 0 °C for
one hour. Meanwhile methyl 4ꢀoxoꢀ1ꢀ(pentꢀ4ꢀenoyl)ꢀpiperidineꢀ3ꢀcarboxylate (2.47 g, 10.3
mmol, 1.0 eq), as described in the procedure for ester 6, was dissolved in dichloromethane (10
mL) and the solution was added to the mixture slowly at 0 °C by syringe. After two hours the
mixture was acidified with concentrated HCl to pH = 1 and saturated with NaCl. The mixture
was extracted twice with dichloromethane (2 × 100 mL), dried over Na2SO4, filtered and
evaporated. After a short filtration over SiO2 (EtOAc) the crude material was used without further
purification. The crude material (1.95 g, 7.01 mmol, 1.0 eq) was dissolved in THF (10 mL) and
added slowly to a mixture of NaH (364 mg, 60%, 9.11 mmol, 1.3 eq) in THF (40 mL) at 0 °C.
After 45 minutes of stirring at 0 °C the mixture was cooled to −78 °C and a solution of
phenylselenyl bromide (1.98 g, 8.41 mmol, 1.2 eq) in THF (10 mL) was added slowly. The
mixture was stirred at −78 °C for one hour and subsequently warmed to room temperature. After
two hours at room temperature, a saturated aqueous solution of NaHCO3 (100 mL) was added.
The mixture was extracted with EtOAC (100 mL) and three times with dichloromethane (3 × 100
mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The residue
was dissolved in dichloromethane (30 mL) and cooled to 0 °C. Water (8 mL) and aqueous
hydrogenperoxide (36%, 30 mL) were added. The mixture was stirred at 0 °C for one hour. A
saturated aqueous solution of NaHCO3 (70 mL) was added and the mixture was extracted four
times with dichloromethane (4 × 100 mL). The combined organic layers were dried over Na2SO4
and filtered. The solvent was removed under reduced pressure. The crude material was
recrystallized from cyclohexane:EtOAc (30 mL:6 mL). The product (471 mg, 1.70 mmol, 17%)
was isolated as a yellowish solid. m.p.: 97ꢀ100 °C. TLC (CH2Cl2:MeOH = 95:5): Rf = 0.45 [UV,
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KMnO4]. IR (ATR): ν
̃
(cmꢀ1) = 3208, 2967, 2872, 1667, 1598, 1509, 1448, 1294, 1187, 1160,
5
6
7
8
1122, 1038, 999, 906, 837. 1H NMR (400 MHz, CDCl3): δ (ppm) = 1.81ꢀ1.94 (m, 4H), 2.45 (dtt,
3J = 8.2 Hz, 6.8 Hz, 4J = 1.4 Hz, 2H), 2.58 (t, 3J = 8.2 Hz, 2H), 2.70 (t, 3J = 7.4 Hz, 2H), 3.35 (t,
3J = 6.6 Hz, 2H), 3.53 (t, 3J = 6.6 Hz, 2H), 4.07 (t, 3J = 7.4 Hz, 2H), 5.03 (virt. dq 3J = 10.2 Hz, 4J
≅ 2J ≅ 1.3 Hz, 1H), 5.08 (virt. dq, 3J = 17.1 Hz, 4J ≅ 2J ≅ 1.6 Hz, 1H), 5.82 (ddt, 3J = 17.1 Hz,
10.2 Hz, 6.8 Hz, 1H), 8.15 (s, 1H). 13C{1H} NMR (101 MHz, CDCl3): δ (ppm) =24.5 (t), 26.2 (t),
28.5 (t), 32.7 (t), 35.7 (t), 46.4(t), 48.3 (t), 115.6 (s), 116.4 (d), 136.1 (d), 164.2 (s) 171.3 (s),
188.7 (s). MS (EI, 70 EV): m/z (%) = 255 (4), 168 (6), 149 (5), 98 (55) [(C5H8NO)+], 85 (30), 70
(100) [(C7H8N)+], 55 (54). HRMS (EI): Calculated for C15H20N2O3 [M+] = 276.1474. Found =
276.1465.
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Intramolecular [2+2] photocycloaddition of 9: (4aSR,7aSR,8aSR)ꢀ8aꢀ(Pyrrolidineꢀ1ꢀ
carbonyl)octahydroꢀ1H,5Hꢀcyclobutanequinolizineꢀ1,5ꢀdione. According to the general
procedure for racemic photoreactions, a solution of amide 9 (27.5 mg, 0.10 mmol, 1.0 eq) in
acetonitrile was irradiated. After complete conversion the solvent was removed under reduced
pressure and the crude material was purified by column chromatography (CH2Cl2:MeOH = 95:5).
The product (23.4 mg, 0.08 mmol, 85%) was isolated as a colorless oil.
According to the general procedure for sensitized enantioselective photoreactions at λ = 419 nm,
a solution of amide 9 (13.8 mg, 0.05 mmol, 1.0 eq), thiourea 5k (50 mol%) and thioxanthone (8)
(10 mol%) in a mixture of trifluorotoluene and hexafluoroxylene was irradiated. After 16 hours
the solvent was removed under reduced pressure and the crude material was purified by column
chromatography (CH2Cl2:MeOH = 95:5). The product (12.8 mg, 0.05 mmol, 93%) was isolated
as a colorless oil in racemic form. TLC (CH2Cl2:MeOH = 95:5): Rf = 0.19 [UV, KMnO4]. IR
(ATR): ν
̃
(cmꢀ1) = 3185, 3025, 2945, 1633, 1514, 1415, 1323, 1247, 1120, 1036, 998. 1HꢀNMR
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(300 MHz, CDCl3): δ (ppm) = 1.40ꢀ1.54 (m, 1H), 1.76ꢀ1.88 (m, 4H), 2.95ꢀ2.17 (m, 2H), 2.33 (dt,
2J = 15.4 Hz, 3J = 3.1 Hz, 1H), 2.48ꢀ2.74 (m, 5H), 3.09ꢀ3.17 (m, 1H), 3.34ꢀ3.57 (m, 4H), 4.64
(ddd, 2J = 13.3 Hz, 3J = 9.0 Hz, 1.7 Hz, 1H), 4.95 (d, 3J = 8.2 Hz, 1H). 13C{1H}ꢀNMR (CDCl3, 75
MHz): δ (ppm) = 23.7 (t), 26.4 (t), 27.4 (t), 28.7 (d), 31.7 (t), 32.0 (t), 38.4 (t), 38.6 (t), 46.2 (t),
47.3 (s), 58.1 (t), 58.7 (d), 165.6 (s), 170.6 (s), 205.3 (s). MS (EI, 70 EV): m/z (%) = 108 (15)
[(C6H6NO)2+], 92 (57), 91 (100), 79 (17), 77 (13), 51 (7). HRMS (EI): Calculated for C15H20N2O3
[M+] = 276.1474. Found = 276.1464. Chiral HPLC (ADꢀH, 250 × 4.6 mm, nꢀheptane/iꢀPrOH =
80:20, 1 mL/min, λ = 210 nm, 254 nm): tR [racemate] = 12.0 min, 13.4 min..
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Decarboxylation of Photoproduct 7. Photoproduct 7 (6.00 mg, 25.3 µmol, 1.0eq) was dissolved
in THF/water (1.0 mL/ 0.5 mL) and lithium hydroxide monohydrate (1.60 mg, 37.9 µmol, 1.5 eq)
was added. The mixture was stirred at room temperature for two hours. Subsequently the mixture
was acidified with HCl (2 ) and extracted three times with dichloromethane (3 × 10 mL). The
M
combined organic layers were dried over Na2SO4, filtered and the solvent was removed under
reduced pressure. The crude material was purified by column chromatography (EtOAc) to give
the product (4.0 mg, 21.8 µmol, 86%) as a colorless oil. [α]D20 = −49.8 (c = 0.4 CH2Cl2).
The enantiomer of this compound is known and shows a positive specific rotation. The analytical
data were in accordance with the reported values.18a
tertꢀButyl [(1R,2R)ꢀ2ꢀ{3ꢀ[3,5ꢀbis(trifluoromethyl)phenyl]thioureido}cyclohexyl]carbamate
(10) (1R,2R)ꢀDiaminocyclohexane (150 mg, 1.31 mmol, 1.0 eq) was dissolved in 1,4ꢀdioxane (9
mL). In an additional flask diꢀtertꢀbutyldicarbonate (315 mg, 1.44 mmol, 1.1 eq) was dissolved in
1,4ꢀdioxane (15 mL). This mixture was added slowly to the stirring mixture by syringe. The
reaction was stirred over night at room temperature and the solvent was evaporated under
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reduced pressure. The crude material was dissolved in THF (25 mL) and 1ꢀisothiocyanatoꢀ3,5ꢀ
bis(trifluoromethyl)benzene (390 mg, 0.26 mL, 1.44 mmol, 1.1 eq) was added at room
temperature. The mixture was stirred at room temperature overnight. The solvent was removed
under reduced pressure. The crude material was purified by column chromatography (pentane:
EtOAc = 4:1). Product 1019 (467 mg 0.91 mmol, 73%) was isolated as a white solid. m.p.: 96ꢀ99
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°C. TLC (pentane:EtOAc = 4:1): Rf = 0.43 [UV, KMnO4]. IR (ATR): ν̃
(cmꢀ1) = 3292, 2979,
2937, 2860, 1671, 1527, 1384, 1275, 1170, 1130, 681. 1H NMR (400 MHz, CDCl3): δ (ppm) =
1.07ꢀ1.21 (m, 2H), 1.42 (s, 12 H), 1.69ꢀ1.72 (m, 1H), 2.00 (d, 3J = 12 Hz, 1H), 2.21ꢀ2.24 (m, 1H),
3.24ꢀ3.27 (m, 1H), 4.40 (br s, 1H), 4.92 (d, 3J = 6.8 Hz, 1H), 7.07 (br s, 1H), 7.68 (s, 1H), 7.83 (s,
2H), 8.09 (br s, 1H). 13C{1H}ꢀNMR (CDCl3, 101 MHz): δ (ppm) = 25.0 (t), 28.5 (q), 33.1 (t),
55.3 (d), 79.5 (d), 119.6 (d), 120.6 (q, 1JCF = 200.7 Hz), 124.3 (d), 132.8 (q, 2JCF = 33.5 Hz),
139.1 (s), 156.7 (s), 181.0 (s). [α]D20 = +20.6 (c = 1.0, CHCl3). MS (EI, 70 EV): m/z (%) = 271
(4) [(C9H3F6NS)+], 202 (6), 197 (16) [(C11H19NO2)+], 141 (62), 97 (100), 57 (93). HRMS (EI):
Calculated for C20H25F6N3O2S2 [M+] = 485.1566. Found = 485.1556.
ACKNOWLEDGEMENT
Financial support by the European Research Council under the European Union’s Horizon 2020
research and innovation programme (grant agreement No 665951 − ELICOS), the Deutsche
Forschungsgemeinschaft (Reinhart Koselleck program), and by the Fonds der Chemischen
Industrie (Ph.D. scholarship to R. B.) is gratefully acknowledged.
SUPPORTING INFORMATION
1Hꢀ and 13CꢀNMR spectra of all compounds reported in the Experimental Section, HPLC and
GLC traces of representative products. This information is available free of charge via the
Internet at http://pubs.acs.org.
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REFERENCES
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(a) Bach, T.; Bergmann, H.; Harms, K. Angew. Chem. Int. Ed. 2000, 39, 2302ꢀ2304. (b) Bach,
T.; Bergmann, H.; Grosch, B.; Harms, K. J. Am. Chem. Soc. 2002, 124, 7982ꢀ7990. (c)
Bakowski, A.; Dressel, M.; Bauer, A.; Bach, T. Org. Biomol. Chem. 2011, 9, 3516ꢀ3529. (d)
Coote, S. C.; Bach, T. J. Am. Chem. Soc. 2013, 135, 14948ꢀ14951.
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Recent review on [2+2] photocycloaddition reactions: Poplata, S.; Tröster, A.; Zou, Y.ꢀQ.;
Bach, T. Chem. Rev. 2016, 116, in press, doi: 10.1021/acs.chemrev.5b00723.
7
(a) Hof, K.; Lippert, K. M.; Schreiner, P. R. in Science of Synthesis: Asymmetric
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Schreiner, P. R. in Hydrogen Bonding in Organic Synthesis (ed. P. M. Pihko), WileyꢀVCH,
Weinheim, 2009, pp. 141ꢀ251; (c) Connon, S. J. Chem. Eur. J. 2006, 12, 5418ꢀ5427; (d) Taylor,
M. S.; Jacobsen, E. N. Angew. Chem. Int. Ed. 2006, 45, 1520ꢀ1543.
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8 Takemoto, Y. Chem. Pharm. Bull. 2010, 58, 593ꢀ601.
9 (a) Vallavoju, N.; Selvakumar, S.; Jockusch, S.; Sibi, M. P.; Sivaguru, J. Angew. Chem. Int. Ed.
2014, 53, 5604ꢀ5608. (b) Vallavoju, N.; Selvakumar, S.; Jockusch, S.; Prabhakaran, M. T.; Sibi,
M. P.; Sivaguru, J. Adv. Synth. Catal. 2014, 356, 2763ꢀ2768.
10
For a recent mechanistic study, see: Vallavoju, N.; Selvakumar, S.; Pemberton, B. C.;
Jockusch, S.; Sibi, M. P.; Sivaguru, J. Angew. Chem. Int. Ed. 2016, 55, 5446ꢀ5451.
11 Telmesani, R.; Park, S. H.; LynchꢀColameta, T.; Beeler, A. B. Angew. Chem. Int. Ed. 2015, 54,
11521ꢀ11525.
12 Schreiner, P. R.; Wittkopp, A. Org. Lett. 2002, 4, 217ꢀ220.
13 Examples in thermal reactions: (a) Hoashi, Y.; Okino, T.; Takemoto, Y. Angew. Chem. Int. Ed.
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132, 2775ꢀ2783. (d) Molleti, N.; Allu, S.; Ray, S. K.; Singh, V. K. Tetrahedron Lett. 2013, 54,
3241ꢀ3244.
14
For intermolecular [2+2] photocycloaddition reactions of 2,3ꢀdihydropyridones, see: (a)
Guerry, P.; Neier, R.; Chimia 1987, 41, 341ꢀ342. (b) Guerry, P.; Neier, R. J. Chem. Soc., Chem.
Commun. 1989, 1727ꢀ1728. (c) Aeby, D.; Eichenberger, E.; Haselbach, E.; Suppan, P.; Guerry,
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Pasteris, O.; Neier, R. Helv. Chim. Acta 1991, 74, 163ꢀ178.
15
(a) Tommasino, M. L.; Thomazeau, C.; Touchard, F.; Lemaire M. Tetrahedron: Asymmetry
1999, 10, 1813ꢀ1819. (b) Costero, A. M.; Llaosa, U.; Gil, S.; Parra, M.; Colera, M. Tetrahedron:
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Asymmetry 2009, 20, 1468ꢀ1471. (c) Sohtome, Y.; Tanatani, A.; Hashimoto, Y.; Nagasawa, K.
Tetrahedron Lett. 2004, 45, 5589ꢀ5592.
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16 For a study on the privileged 3,5ꢀbis(trifluoromethyl)phenyl group, see: Lippert, K. M.; Hof, K.
Gerbig, D.; Ley, D.; Hausmann, H.; Guenther, S.; Schreiner, P. R. Eur. J. Org. Chem. 2012,
5919ꢀ5927.
17 Maturi, M. M.; Bach, T. Angew. Chem. Int. Ed. 2014, 53, 7661ꢀ7664.
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(a) Brimioulle, R.; Bach, T. Science 2013, 342, 840ꢀ843. (b) Brimioulle, R.; Bauer, A.; Bach,
T. J. Am. Chem. Soc. 2015, 137, 5170ꢀ5176.
19 Yu, L.; Li, P. Tetrahedron Lett. 2014, 55, 3697ꢀ3700.
20
For emission spectra, see: (a) λ = 366 nm: Maturi, M. M.; Wenninger, M.; Alonso, R.; Bauer,
A.; Pöthig, A.; Riedle, E.; Bach, T. Chem. Eur. J. 2013, 19, 7461ꢀ7472. (b) λ = 419 nm: Alonso,
R.; Bach, T. Angew. Chem. Int. Ed. 2014, 53, 4368ꢀ4371.
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