Synthesis of Chiral Thiourea-Thioxanthone Hybrids

Article abstract of DOI:10.1055/s-0036-1590931

Four different 1-aminocyclohexanes bearing a tethered thioxanthone group in the 2-position were prepared. The synthesis commenced with the respective N-protected β-amino acids, the carboxyl group of which was employed for the introduction of the thioxanthone moiety. After construction of the thioxanthone and protecting group removal, the conversion of the amino group into the respective thiourea was accomplished by treatment with N -3,5-bis(trifluoromethyl)phenyl isothiocyanate and yielded the title compounds in which the thioxanthone resides in different spatial positions relative to the thiourea motif. Overall yields varied between 20-35%.

Full text of DOI:10.1055/s-0036-1590931

SYNTHESIS
0
0
3
9
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7
8
8
1
1
4
3
7
-
2
1
0
X
Georg Thieme Verlag Stuttgart · New York
2017, 49, A–M
paper
A
en
F. Mayr et al.
Paper
Synthesis
Synthesis of Chiral Thiourea-Thioxanthone Hybrids
Florian Mayr
Ar
site for substrate coordination
F3C
Ar =
CF3
N
N
H
H
Lisa-Marie Mohr
Elsa Rodriguez
Thorsten Bach*
S
O
S
sensitizer
0
0
0
0
0-
0
0
2
1-
3
4
2
0-
2
0
2
Y
X
X = spacer, Y = H, CH2
Department Chemie and Catalysis Research Center (CRC),
Technische Universität München, Lichtenbergstr. 4,
85747 Garching, Germany
thorsten.bach@ch.tum.de
Received: 10.08.2017
Accepted: 12.09.2017
Published online: 19.10.2017
DOI: 10.1055/s-0036-1590931; Art ID: ss-2017-n0521-op
alyst for the enantioselective (86–92% ee) intramolecular
[2+2] photocycloaddition10 of 4-alkenylcoumarins.10,11
Three hydrogen bonding interactions were invoked to ex-
plain the stereochemical outcome and to account for the
bathochromic absorption shift that is responsible for the se-
lective excitation of the catalyst-substrate complex. In addi-
tional work, it was discovered that the racemic intermolec-
ular [2+2] photocycloaddition of coumarins can be mediat-
ed by achiral thiourea catalysts.12 The Beeler group
developed a bisthiourea, which is capable of binding a cin-
namate at each of its binding sites, and thus increases the
regioselectivity of the cinnamate [2+2] photodimeriza-
tion.13
License terms:
Abstract Four different 1-aminocyclohexanes bearing a tethered thi-
oxanthone group in the 2-position were prepared. The synthesis com-
menced with the respective N-protected β-amino acids, the carboxyl
group of which was employed for the introduction of the thioxanthone
moiety. After construction of the thioxanthone and protecting group
removal, the conversion of the amino group into the respective
thiourea was accomplished by treatment with N-3,5-bis(trifluorometh-
yl)phenyl isothiocyanate and yielded the title compounds in which the
thioxanthone resides in different spatial positions relative to the
thiourea motif. Overall yields varied between 20–35%.
The stoichiometric use of a chiral thiourea was found by
our group to induce a notable enantioselectivity (75% ee) in
the intramolecular thioxanthone-sensitized [2+2] photocy-
cloaddition of a 2,3-dihydropyridone-5-carboxylate.3g In
particular, the last result triggered synthetic efforts aiming
at a covalent linkage between a chiral thiourea entity and a
thioxanthone and we herein report on the synthesis of such
thiourea-thioxanthone hybrids.
The choice of compounds depicted in Figure 1 was in-
spired by the idea to make a set of chiral 1,2-disubstituted
cyclohexanes available in which the thiourea and the thiox-
anthone unit would be oriented in varying spatial arrange-
ments. Compound 1 bears both units in equatorial positions
of a cyclohexane chair while a boat conformation of the cy-
clohexane is enforced in compound 2 with the thioxan-
thone and thiourea both located in a pseudoequatorial (exo)
position. In compound 3, either thiourea or thioxanthone
could be axially positioned with the other substituent being
equatorial. Since there was evidence (vide infra) that the
thioxanthone was equatorial in 3, a fourth cyclohexane de-
rivative 4 was designed in which the thioxanthone unit
would definitely be axial but the thiourea equatorial. In all
catalysts 1–4, the aryl substituent was selected to be the
privileged 3,5-bis(trifluoromethyl)phenyl group.14
Key words amino acids, chiral pool, esterification, indium, oxazoles,
photochemistry, thiourea, thioxanthone
Thioxanthone (9H-thioxanthen-9-one) exhibits its lon-
gest wavelength absorption maximum at λ = 376 nm (ε =
6200 M–1 cm–1) and its triplet energy has been determined
as 265 kJ mol–1.1 The triplet state is populated by direct irra-
diation with a quantum yield of 0.85 in benzene2 and thiox-
anthone has consequently been employed as a triplet sensi-
tizer for several applications.3 Recent interest in visible-
light-induced enantioselective transformations4 has led to
the development of thioxanthone derivatives in which the
chromophore is linked to a chiral backbone. In our group,
the linkage was achieved via oxazole annulation to a chiral
1,5,7-trimethyl-3-azabicyclo[3.3.1]nonan-2-one scaffold.
The chiral sensitizer was shown to catalyze inter- and intra-
molecular [2+2] photocycloaddition reactions in a highly
enantioselective fashion.5,6 The Xiao group developed a bi-
functional photocatalyst for an enantioselective aerobic ox-
idation in which the thioxanthone unit is connected to chi-
ral bisoxazoline complexes by a conformationally flexible
ester linkage.7
In light of the spectacular success the thiourea binding
motif has encountered in organocatalysis,8,9 it seems
tempting to employ it also in photochemistry to exert che-
mo- and stereoselectivity control. The group of Sivaguru
showed that a thiourea, which is linked at position C2 to an
axially chiral 2′-hydroxy-1,1′-binaphthyl, is an effective cat-
Taking compound 1 as an example, a few retrosynthetic
considerations are illustrated in Scheme 1. Primary amine 5
was chosen as an immediate precursor for the thiourea
since it was expected that treatment with 3,5-bis(trifluoro-
Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–M

B
F. Mayr et al.
Paper
Synthesis
spective ester A was achieved. The reduction could, howev-
er, not be performed.
Ar
Ar
F3C
Ar =
CF3
S
N
S
N
H
H
Similar issues were initially encountered with the N-
phthaloyl derivative 7, which was readily accessible from
acid 6 by treatment with phthalic anhydride (8) and tri-
ethylamine in benzene (Scheme 3).17 Ester formation pro-
ceeded smoothly after activation via the acid chloride and
reaction with thioxanthone 9.5a Attempted reduction of
compound 10 with tin(II) chloride or by Pd-catalyzed trans-
fer hydrogenation18 remained unsuccessful. Gratifyingly, it
N
O
N
O
H
N
H
N
O
O
S
S
1
2
Ar
N
Ar
N
S
S
H
H
N
O
N
H
N
H
NH2
O
NR2
O
N
1
O
COOH
O
S
S
6
7
R2 = H2
R2 = Phth
5
3
4
S
Figure 1 Structure of target compounds 1–4 in which a chiral thiourea
is linked with a photochemically active thioxanthone via an annulated
oxazole or an ethynyl group
Scheme 1 Retrosynthetic considerations for the construction of
thiourea-thioxanthone hybrids (Phth = phthaloyl)
methyl)phenyl isothiocyanate15 would not interfere with
the thioxanthone functionality. In previous work on chiral
templates and catalysts for enantioselective reactions, the
oxazole group was identified as a reliable linker to be annu-
lated to a given arene.16 Formation of the oxazole requires a
carboxylic acid precursor and it was expected that the
amine group had to be protected prior to the annulation.
The arene is normally introduced as its ortho-nitro-substi-
tuted aryl ester that upon reduction rearranges to the re-
spective ortho-hydroxy-substituted amide (Scheme 2). For
the desired thioxanthone annulation the starting material
was thus 3-hydroxy-2-nitrothioxanthone,5a which was to
be linked to an appropriately N-protected carboxylic acid
derived from enantiopure compound 6. Initial attempts to
O
O
SnCl2
SOCl2, py
O
NO2
OH
65 °C (THF)
90 °C (PhH)
N
O
HN
O
S
S
S
O
O
A
B
C
Scheme 2 Synthetic access to oxazole-annulated thioxanthones C
starting with (2-nitrothioxanthone-3-yl) ester A
O
1. (COCl)2 [DMF] (CH2Cl2)
O
2.
O
8
O
NEt3 [DMAP]
0 °C → rt
O2N
HO
employ
a benzyloxycarbonyl or tert-butyloxycarbonyl
NEt3, 100 °C
(PhMe)
9
amine protecting group revealed that they were incompati-
ble with the formation of the aryl ester bond or the subse-
quent reduction step. Likewise the immediate formation of
the thiourea prior to the oxazole annulation was not viable.
In most instances, not even the required ester A (Scheme 2)
could be formed in useful yields. The phthaloyl protecting
group (Phth) was thus selected as a putatively more robust
protecting group with compound 7 being the desired start-
ing material.
In previous work, the introduction of the thioxanthone
had been achieved by reduction of the nitro group with
tin(II) chloride in refluxing THF.5a The cyclization of amide
B to the desired oxazole C was performed with thionyl chlo-
ride/pyridine (py) in refluxing benzene. When attempting
to apply these conditions to the synthesis of N-substituted
ester derivatives of acid 6, there was either no reaction or
the formation of decomposition products was observed.
The most promising route was the immediate use of the re-
spective thiourea with which a moderate yield of the re-
(CH2Cl2)
S
6
7
95%
99%
NPhth
NPhth
O
Ar1
S
In, HCl, 80 °C
(THF/H2O)
O
O
O
HN
81%
O2N
HO
11
S
O
Ar2
10
NPhth
1. N2H4 (MeOH)
2.
CF3
N
13
(THF)
O
PPh3, DIAD
(THF)
O
SCN
CF3
1
S
83%
32%
12
Scheme 3 Synthesis of thiourea-thioxanthone hybrid 1 starting from
β-amino acid 6
Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–M

C
F. Mayr et al.
Paper
Synthesis
was found that the nitro group could be reduced smoothly
with indium in an acidic THF/water mixture.19 In the event,
the acyl group underwent the expected O–N migration and
amide 11 was isolated in 81% yield. The cyclization to the
oxazole ring was achieved under Mitsunobu conditions20
while the use of SOCl2 and POCl3 as dehydrating agents
failed. Oxazole 12 was obtained in 83% yield and the remov-
al of the phthaloyl protecting group was accomplished by
hydrazinolysis.21 Eventually, the desired thiourea was pre-
pared by treatment of amine 5 with 3,5-bis(trifluorometh-
yl)phenyl isothiocyanate (13). The relatively low overall
yield is likely due to material loss in the hydrazinolysis reac-
tion (vide infra).
8, NEt3
100 °C
(PhMe)
H2 [Pd/C]
(EtOAc)
NPhth
NH2
NPhth
COOH
90%
98%
COOH
COOH
14
15
16 (98% ee)
NPhth
O
NPhth
O
1. (COCl)2 [DMF] (CH2Cl2)
2. 9, NEt3 [DMAP] 0 °C → rt
(CH2Cl2)
In, HCl, 80 °C
(THF/H2O)
OAr1
NHAr2
99%
87%
17
18
NPhth
For the synthesis of compound 2, access to enantiopure
β-amino acid 1422 was required (Scheme 4). This goal was
accomplished by applying a known enantiotopos-differen-
tiating methanolysis reaction to the respective succinic an-
hydride.23 Curtius rearrangement, reduction, and ester hy-
drolysis (100 °C in 1,4-dioxane/water) led to the desired
compound, which was converted into the phthaloyl deriva-
tive 15 by treatment with phthalic anhydride. Hydrogena-
tion of the endocyclic double bond furnished carboxylic
acid 16, the enantiomeric excess (ee) of which was deter-
mined by chiral HPLC analysis to be 98%. The remaining se-
quence followed the route developed for compound 1. After
formation of ester 17, the reduction of the nitro arene with
indium and the concomitant rearrangement led to amide
18, which was further transformed under Mitsunobu con-
ditions into thioxanthone 19. In this instance, the attempt-
ed removal of the phthaloyl group by hydrazinolysis was
not successful but led only to decomposition. Methyl-
amine24 led to the cleavage of one imide N–C bond but the
reaction remained stalled at the stage of the amide. The
best result was achieved by treating phthalimide 19 with
ethylenediamine (EDA) at 50 °C.25 The protecting group was
completely removed and the resulting primary amine was
immediately converted into the desired thiourea 2.
1. EDA, 50 °C
N
O
O
PPh3, DIAD
(THF)
(EtOH/CH2Cl2)
2. 13 (THF)
2
S
88%
39%
19
Scheme 4 Synthesis of thiourea-thioxanthone hybrid 2 starting from
β-amino acid 14
8, NEt3
HCl, 120 °C
100 °C
NPhth
COOH
NHBz
NH2⋅HCl
(H2O)
(PhMe)
quant.
96%
COOH
COOH
20
21
22
NPhth
O
NPhth
O
1. (COCl)2 [DMF] (CH2Cl2)
2. 9, NEt3 [DMAP] 0 °C → rt
(CH2Cl2)
In, HCl, 80 °C
(THF/H2O)
OAr1
NHAr2
97%
91%
23
24
NPhth
N
O
1. EDA, 50 °C
O
PPh3, DIAD
(THF)
(EtOH/CH2Cl2)
2. 13 (THF)
While the thiourea and the thioxanthone are locked by
the rigid norbornane ring in 2, a conformationally more
flexible cis-substitution at the cyclohexane ring was ex-
pected for thiourea 3. The synthesis (Scheme 5) com-
menced with commercially available N-benzoyl (Bz)-pro-
tected amino acid 20, which was converted via free acid hy-
drochloride 2126,27 into the N-phthaloyl-protected amino
acid 22. The subsequent sequence of esterification, reduc-
tion/rearrangement, and oxazole ring closure proved its re-
liability and efficiency by providing the respective interme-
diates 23, 24, and 25 in excellent yields (89–97%). Treat-
ment with EDA turned out to be also in this case the
preferred method for phthaloyl removal and delivered the
primary amine for immediate conversion into thiourea 3.
The overall yield for the six-step synthesis was 35%.
3
S
89%
46%
25
Scheme 5 Synthesis of thiourea-thioxanthone hybrid 3 starting from
N-benzoyl-protected β-amino acid 20
The proton at carbon atom C1 (Scheme 6) is expected to ex-
hibit in conformation 3′ one large coupling constant due to
the axial-axial coupling (3Jaa) and two small coupling con-
stants due the axial-equatorial coupling (3Jae).28 Indeed, its
precursor 25 showed exactly this pattern with 3Jaa = 13.2 Hz
and 3Jae = 5.2 Hz and 3Jae = 3.6 Hz. The proton at C2 appeared
3
as a virtual quartet with an average coupling constant of J
≅ 5.2 Hz. Related 1H NMR data were recorded for com-
pounds 23 and 24. However, the situation was different for
compound 3. The 1H NMR spectrum revealed for H1 a signal
that appeared as virtual tt with two coupling constants of 3J
The conformational preference of compound 3 was
1
studied by H NMR spectroscopy at ambient temperature.
Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–M

D
F. Mayr et al.
Paper
Synthesis
≅ 8.3 Hz and 3J ≅ 4.0 Hz. While one of the larger signal split-
tings is due to the coupling to NH, the remaining coupling
pattern (3J = 8.3, 4.0, 4.0 Hz) results from coupling to vicinal
protons. Likewise, the proton H2 changed its signal pattern
and appeared as a virtual dt with 3J = 7.4 Hz and 3J ≅ 4.3 Hz.
Boc2O, NEt3
(CH2Cl2)
Swern oxidation
NH2
OH
NHBoc
OH
–78 °C → rt
92%
94%
26
27
O
S
Br
N2
PO(OMe)2
H
1
S
30
NHBoc
Ar
NHBoc
O
[Pd(PPh3)4/CuI]
KOtBu (THF)
–78 °C → rt
N
N
H
H
H
2
60 °C (NEt3/THF)
H
H
O
H
N
O
N
78%
67%
H
28
29
O
S
NH
S
H
1
S
NH
NHPG
S
O
Ar
Ar
3''
3'
N
N
H
O
S
H
H
2
H
3J = 12.4 Hz
Scheme 6 Equilibrium between conformations 3′ and 3′′ of com-
pound 3 as suggested by the 1H NMR data for the indicated proton (see
narrative)
TFA
(CH2Cl2)
O
PG = Boc 31
PG = H 32
13 (THF)
4'
S
78%
4
74%
Apparently there is no clear preference for either con-
former 3′ or 3′′ and neither proton H1 nor H2 has a clear
preference for the axial position. Rather it seems as if an
equilibrium was established at ambient temperature most
likely due to the fact that the two substituents at C1 and C2
are similar in size. In order to establish a less ambiguous
conformational situation within the cis-substituted cyclo-
hexane ring, a thiourea-thioxanthone hybrid 4 was devised
in which the thioxanthone was linked to the cyclohexane
ring by the linear, sterically unencumbered29 ethynyl group.
The synthesis of this compound started from hydrochloride
21, which was reduced with LiAlH4 in THF to furnish amino
alcohol 26 in 93% yield (Scheme 7). Upon tert-butoxycar-
bonyl (Boc) protection of the amino group, alcohol 2730 was
subjected to a Swern oxidation.31 The resulting aldehyde 28
was converted into the terminal alkyne 29 by Seyferth–Gil-
bert homologization.32 Sonogashira cross-coupling33 with
the known 2-bromothioxanthone (30)34 gave the 2-substi-
tuted thioxanthone 31, which could be readily deprotected
with trifluoroacetic acid (TFA) to give the desired amine 32.
As in the previous syntheses, the desired thiourea was gen-
erated by treatment of the amine with 3,5-bis(trifluoro-
methyl)phenyl isothiocyanate (13).
Scheme 7 Preferred conformation 4′ and synthesis of thiourea-thiox-
anthone hybrid 4 starting from β-amino alcohol 26
of compound 4 is representatively shown in Figure 2. The
long-wavelength absorption between 370 and 420 nm with
a λmax = 392 nm (ε = 3340 M–1 cm–1) is likely due to the thi-
oxanthone chromophore while the strong absorptions set-
ting in below 320 nm are attributed to allowed transitions
of the thiourea and the thioxanthone. In line with their
UV/Vis spectra, the compounds are yellow-colored solids.
Phosphorescence data have not yet been obtained but it
was expected that the compounds will act as triplet sensi-
tizers in the same fashion as does the parent thioxanthone.
As expected, compound 4 displays preferred conforma-
tion 4′ in which the tethered thioxanthone is axially posi-
tioned. The 1H NMR coupling pattern of proton H1 is a vir-
tual ddt with coupling constants of 3J = 12.4 Hz, 3J = 8.5 Hz,
3
3
and J ≅ 3.9 Hz. Since the coupling constant of J = 8.5 Hz
could be clearly assigned to the vicinal CH–NH coupling the
other coupling constants are due to vicinal CH–CH coupling
with 3Jaa = 12.4 Hz and 3Jae ≅ 3.9 Hz. Likewise, the equatorial
Figure 2 UV/Vis spectrum of thiourea-thioxanthone hybrid 4 in CH2Cl2
solution (c = 0.1 mM)
In preliminary and non-optimized experiments, it was
probed whether the thiourea-thioxanthone hybrids would
act as catalysts of visible-light-induced reactions. Along
these lines, catalyst 4 was employed in the photocyclization
of 2-aryloxycyclohex-2-enones,35 which has recently
3
3
proton H2 shows a virtual quartet with the Jae ≅ Jee = 3.6
Hz.
The UV/Vis spectra of the new thioxanthones are all
similar (see the Supporting Information) and the spectrum
Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–M

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F. Mayr et al.
Paper
Synthesis
received increasing attention.3h,36 Gratifyingly, we found that
the reaction of compound 33, which does not proceed at λ =
419 nm in the absence of a sensitizer could be successfully
promoted by catalyst 4 (Scheme 8). Although the yield and
enantioselectivity of product 34 was low, the experiment
demonstrates that the thiourea-thioxanthone hybrids are
catalytically active and that an asymmetric binding event at
the NH-hydrogen atoms of the thiourea is likely to occur.
ments were performed on a Bellingham + Stanley ADP400+ with a
0.05 dm cuvette at λ = 589 nm (Na D-line) at room temperature. The
specific rotation is given in 10–1 grad cm2 g–1, the concentration is giv-
en in g/100 mL. Analytical HPLC was performed using a chiral station-
ary phase (flow rate: 1.0 mL/min, column type and eluent are given
for the corresponding compounds) and UV detection (λ = 210 nm or
254 nm) at 20 °C.
(1R,2R)-2-(1′,3′-Dioxoisoindolin-2′-yl)cyclohexane-1-carboxylic
Acid (7)
O
O
hν (λ = 419 nm)
10 mol% 4
Amino acid 6 (200 mg, 1.40 mmol, 1.00 equiv) was dissolved in anhyd
toluene (20 mL). Subsequently, phthalic anhydride (218 mg,
1.47 mmol, 1.05 equiv) and NEt3 (283 mg, 0.38 mL, 2.80 mmol,
2.00 equiv) were added. The mixture was stirred at 100 °C. After 18 h,
the solution was cooled to rt and washed with aq 3 M HCl (100 mL).
The aqueous layer was extracted with CH2Cl2 (3 × 100 mL). The com-
bined organic layers were dried (Na2SO4), filtered and the solvent was
removed under reduced pressure. The desired product was obtained
as a colorless solid (363 mg, 1.33 mmol, 95%) and was used in the
H
O
O
rt (PhCF3)
Br
Br
26%
(49% conv.)
33
34 (12% ee)
Scheme 8 Sensitized photocyclization of 2-(4-bromophenoxy)-3,5,5-
trimethylcyclohex-2-enone (33)
20
next step without purification; mp 138–140 °C; [α]D –10 (c = 1.00,
CH2Cl2).
In summary, we have successfully synthesized four
thiourea-thioxanthone hybrid compounds from the respec-
tive β-amino acids. For the attachment of the thioxanthone
by oxazole annulation we have devised a generally applica-
ble and mild reaction sequence. The compounds exhibit a
two-point hydrogen bonding site at the thiourea and it is
expected that the thioxanthone will act as a sensitizer to
promote photochemical reactions of bound substrates in
the respective 1:1 complexes. Work along these lines is cur-
rently underway in our laboratories and will be reported in
due course.
IR (ATR): 3514 (m, OH), 3369 (w, OH), 2936 (m, CHsp3), 2861 (m,
CHsp3), 1740 (m), 1697 (s, C=O), 1376 (m), 1330 (m), 1204 (w), 1077
(m), 718 cm–1 (m).
1H NMR (400 MHz, CDCl3): δ = 1.28–1.60 (m, 3 H, H-5, H-6), 1.69–1.90
(m, 3 H, H-3, H-4), 1.99–2.20 (m, 2 H, H-3, H-6), 3.43 (virt. td, 3J ≅
3J = 12.1 Hz, 3J = 3.7 Hz, 1 H, H-1), 4.28 (ddd, 3J = 12.1, 11.3, 4.0 Hz, 1
H, H-2), 7.67 (dd, 3J = 5.5 Hz, 4J = 3.0 Hz, 2 H, H-5′, H-6′), 7.78 (dd,
3J = 5.5 Hz, 4J = 3.0 Hz, 2 H, H-4′, H-7′), 10.40 (br s, 1 H, OH).
13C NMR (101 MHz, CDCl3): δ = 24.7 (t, C-5), 25.3 (t, C-4), 29.7 (t, C-6),
29.8 (t, C-3), 44.7 (d, C-1), 51.0 (d, C-2), 123.4 (d, 2 C, C-4′, C-7′), 131.9
(s, 2 C, C-3a′, C-7a′), 134.0 (d, 2 C, C-5′, C-6′), 168.2 (s, 2 C, C-1′, C-3′),
179.2 (s, COOH).
MS (EI, 70 eV): m/z (%) = 273 (8, [M]+), 227 (12, [M – CH3]+), 186 (15),
All reactions involving moisture-sensitive chemicals were carried out
in flame-dried glassware under positive pressure of argon with mag-
netic stirring. THF, CH2Cl2, and Et2O were purified using a SPS-800
solvent purification system (M. Braun). TLC was performed on silica-
coated glass plates (silica gel 60 F254) with detection by UV (λ = 254
nm), cerium ammonium molybdate (CAM) or KMnO4 (0.5% in H2O)
with subsequent heating. Flash chromatography was performed on
silica gel 60 (Merck, 230–400 mesh) with the indicated eluent. Com-
mon solvents for chromatography [pentane (Pn), cyclohexane (Chx),
EtOAc, CH2Cl2, Et2O, MeOH] were distilled prior to use. Solutions refer
to sat. aq solutions, unless otherwise stated. IR spectra were recorded
on a JASCO IR-4100 (ATR). MS/HRMS measurements were performed
on a Finnigan MAT 8200 or Thermo Fisher DFS (EI)/Finnigan LSQ clas-
sic or Thermo Fisher LTY Orbitrap XL (ESI). 1H and 13C NMR spectra
were recorded in CDCl3 or DMSO-d6 at 300 K on a Bruker AV-360,
Bruker AVHD-400, Bruker AV-500, or a Bruker AVHD-500 instrument.
Chemical shifts are reported relative to CHCl3 (δ = 7.26) or DMSO-d5
(δ = 2.50). Apparent multiplets that occur as a result of the accidental
equality of coupling constants to those of magnetically non-equiva-
lent protons are marked as virtual (virt.). The multiplicities of the
13C NMR signals were determined by DEPT-edited phase sensitive
HSQC experiments. Assignments are based on COSY, HMBC, HSQC,
and NOESY experiments. Signals that could not be assigned unambig-
uously are marked with an asterisk (*). UV/Vis Spectroscopy was per-
formed on a PerkinElmer Lambda 35 UV/Vis spektometer. Unless oth-
erwise mentioned, UV spectra were recorded using a Hellma preci-
sion cell made of quartz with a pathway of 1 mm. Solvents and
concentrations are given for each spectrum. Rotation value measure-
160 (63), 148 (20, [C8H6NO2]+), 91 (100, [C7H7]+).
HRMS (EI): m/z [M]+ calcd for C15H15NO4: 273.1001; found: 273.0996.
2′-Nitro-9′-oxo-9′H-thioxanthen-3′-yl (1R,2R)-2-(1′′,3′′-Dioxoiso-
indolin-2′′-yl)cyclohexane-1-carboxylate (10)
The protected amino acid 7 (666 mg, 2.34 mmol, 1.10 equiv) was dis-
solved in anhyd CH2Cl2 (33 mL). Oxalyl chloride (297 mg, 0.20 mL,
2.34 mmol, 1.10 equiv) and a catalytic amount of DMF (7 drops) was
added at rt. The mixture was stirred at rt for 3 h. In parallel, thioxan-
thone 9 (581 mg, 2.13 mmol, 1.00 equiv) and a catalytic amount of 4-
dimethylaminopyridine (10 crystals) was dissolved in anhyd CH2Cl2
(33 mL) and cooled to 0 °C. At this temperature, NEt3 (647 mg,
0.89 mL, 6.39 mmol, 3.00 equiv) was added. Subsequently, the previ-
ously prepared solution of acid chloride was added slowly. The mix-
ture was warmed to rt and stirred overnight. After 18 h, aq NH4Cl
(100 mL) was added and the layers were separated. The aqueous layer
was extracted with CH2Cl2 (3 × 150 mL) and the combined organic
layers were washed with aq 2 M NaOH (200 mL), dried (Na2SO4), and
filtered. The solvent was evaporated and the desired product was ob-
tained without further purification as a yellowish solid (1.11 g,
2.11 mmol, 99%); mp 202–205 °C; Rf = 0.89 (CH2Cl2/MeOH 98:2) [UV,
KMnO4]; [α]D20 –92 (c = 1.00, CH2Cl2).
IR (ATR): 3086 (w, CHsp2), 3036 (w, CHsp2), 2933 (m, CHsp3), 2864 (m,
CHsp3), 1766 (s, C=O), 1708 (s, C=O), 1635 (s), 1605 (s), 1519 (m,
C=Csp2), 1379 (m), 1341 (s), 1293 (m), 1108 (m), 1077 (m), 1025 (m),
717 cm–1 (m).
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1H NMR (400 MHz, CDCl3): δ = 1.50–1.56 (m, 2 H, H-4, H-5), 1.78 (virt.
td, 3J ≅ 3J = 12.8 Hz, 3J = 3.4 Hz, 1 H, H-4), 1.90–1.99 (m, 3 H, H-3, H-5,
H-6), 2.30 (virt. qd, 3J ≅ 3J = 12.4 Hz, 3J = 2.8 Hz, 1 H, H-6), 2.49 (virt.
td, 3J ≅ 3J = 13.7 Hz, 3J = 1.8 Hz, 1 H, H-3), 3.84 (ddd, 3J = 12.3 Hz,
11.3 Hz, 3.7 Hz, 1 H, H-1), 4.55 (ddd, 3J = 12.3 Hz, 11.3 Hz, 4.0 Hz, 1 H,
H-2), 7.17 (s, 1 H, H-4′), 7.54–7.58 (m, 2 H, H-5′, H-7′), 7.69 (ddd,
2-{(1R,2R)-2-(10′-Oxo-10′H-thioxantheno[2′,3′-d]oxazol-2′-yl)-
cyclohexyl}isoindoline-1′′,3′′-dione (12)
The synthesized amide 11 (275 mg, 552 μmol, 1.00 equiv) was dis-
solved in anhyd THF (26 mL). At rt, PPh3 (318 mg, 1.21 mmol,
2.20 equiv) and diisopropyl azodicarboxylate (245 mg, 0.24 mL,
1.21 mmol, 2.20 equiv) were added. The mixture was stirred at rt and
after 4 h, the solvent was evaporated. The crude product was purified
by flash chromatography (4 × 25 cm, CH2Cl2/MeOH 98:2). The desired
product was obtained as a yellow solid (220 mg, 458 μmol, 83%); mp
4
3
4
3J = 8.3, 7.0 Hz, J = 1.6 Hz, 1 H, H-6′), 7.74 (dd, J = 5.5 Hz, J = 3.1 Hz,
2 H, H-5′′, H-6′′), 7.87 (dd, 3J = 5.5 Hz, 4J = 3.1 Hz, 2 H, H-4′′, H-7′′),
8.54–8.60 (m, 1 H, H-8′), 9.20 (s, 1 H, H-1′).
20
13C NMR (100 MHz, CDCl3): δ = 24.6 (t, C-4), 25.4 (t, C-5), 29.5 (t, C-6),
29.6 (t, C-3), 45.4 (d, C-1), 51.1 (d, C-2), 122.0 (d, C-4′), 123.4 (d, 2 C,
C-4′′, C-7′′), 126.3 (d, C-5′), 127.1 (s, C-9a′), 127.8 (d, C-7′), 128.3 (d, C-
1′), 128.5 (s, C-8a′), 130.3 (d, C-8′), 132.0 (s, 2 C, C-3a′′, 7a′′), 133.4 (d,
C-6′), 134.2 (d, 2 C, C-5′′, C-6′′), 135.7 (s, C-4b′), 140.2 (s, C-3′), 144.1
(s, C-4a′), 145.9 (s, C-2′), 168.3 (s, 2 C, C-1′′, C-3′′), 170.9 (s, COO),
177.9 (s, C-9′).
225–227 °C; Rf = 0.50 (CH2Cl2/MeOH 98:2) [UV, KMnO4]; [α]D –152
(c = 1.00, CH2Cl2).
IR (ATR): 3071 (w, CHsp2), 2952 (m, CHsp3), 2921 (m, CHsp3), 2864 (w,
CHsp3), 1764 (m, C=O), 1701 (s, C=O), 1643 (m), 1620 (s), 1435 (m,
CHsp3), 1394 (m), 1373 (m), 1293 (m), 1244 (w), 1155 (w), 1077 (m),
1023 (m), 719 cm–1 (m, CHsp2).
1H NMR (400 MHz, CDCl3): δ = 1.49–1.65 (m, 2 H, H-4, H-5), 1.82–2.07
MS (EI, 70 eV): m/z (%) = 528 (3, [M]+), 273 (29, [C13H7NO4S]+), 256
(m, 4 H, H-3, H-4, H-5, H-6), 2.29–2.45 (m, 2 H, H-3, H-6), 4.12 (ddd,
(100, [C15H14NO3]+), 148 (79, [C8H6NO2]+).
3
3
3J = 12.3 Hz, 11.4 Hz, 3.6 Hz, 1 H, H-2), 4.57 (virt. td, J ≅ J = 11.7 Hz,
3J = 3.8 Hz, 1 H, H-1), 7.44 (ddd, 3J = 8.2 Hz, 6.9 Hz, 4J = 1.3 Hz, 1 H, H-
8′), 7.48–7.52 (m, 2 H, H-4′, H-6′), 7.57 (ddd, 3J = 8.3 Hz, 6.9 Hz,
4J = 1.5 Hz, 1 H, H-7′), 7.64 (dd, 3J = 5.5 Hz, 4J = 3.0 Hz, 2 H, H-5′′, H-6′′),
7.74 (dd, 3J = 5.5 Hz, 4J = 3.0 Hz, 2 H, H-4′′, H-7′′), 8.55 (dd, 3J = 8.2 Hz,
4J = 1.5 Hz, 1 H, H-9′), 8.76 (s, 1 H, H-11′).
HRMS (EI): m/z [M]+ calcd for C28H20N2O7S: 528.0991; found:
528.0995.
(1R,2R)-2-(1′′,3′′-Dioxoisoindolin-2′′-yl)-N-(3′-hydroxy-9′-oxo-9′H-
thioxanthen-2′-yl)cyclohexane-1-carboxamide (11)
13C NMR (101 MHz, CDCl3): δ = 24.8 (t, C-4), 25.5 (t, C-5), 29.9 (t, C-3),
30.7 (t, C-6), 40.0 (d, C-2), 52.5 (d, C-1), 106.3 (d, C-4′), 122.0 (d, C-
11′), 123.4 (d, 2 C, C-4′′, C-7′′), 125.7 (d, C-6′), 126.4 (d, C-8′), 126.5 (s,
C-4a′), 128.7 (s, C-9a′), 130.0 (d, C-9′), 131.8 (s, 2 C, C-3a′′, C-7a′′),
132.3 (d, C-7′), 134.1 (d, 2 C, C-5′′, C-6′′), 134.2 (s, C-10a′), 137.0 (s, C-
5a′), 141.0 (s, C-3a′), 153.0 (s, C-11a′), 168.2 (s, 2 C, C-1′′, C-3′′), 168.9
(s, C-2′), 179.8 (s, C-10′).
Ester 10 (406 mg, 768 μmol, 1.00 equiv) was dissolved in THF (27 mL)
and H2O (27 mL) was added. To this solution In (441 mg, 3.84 mmol,
5.00 equiv) and concd HCl (0.75 mL) were added. The mixture was
stirred at 80 °C for 18 h. After this time, the solution was cooled to rt
and CH2Cl2 (50 mL) was added. The mixture was filtered over Celite
and washed with aq NaHCO3 (100 mL). The aqueous layer was ex-
tracted with CH2Cl2 (3 × 100 mL). The combined organic layers were
dried (Na2SO4), filtered, and the solvent was removed under reduced
pressure. Purification by flash chromatography (4 × 20 cm, CH2Cl2/
MeOH 95:5) furnished the title compound as an orange-colored solid
(310 mg, 622 μmol, 81%); mp 150–154 °C; Rf = 0.51 (CH2Cl2/MeOH
95:5) [UV, KMnO4]; [α]D20 +46 (c = 1.00, CH2Cl2).
HRMS (ESI): m/z [M + H]+ calcd for C28H20N2O4S: 481.1217; found:
481.1217.
1-[3′′,5′′-Bis(trifluoromethyl)phenyl]-3-{(1R,2R)-2-(10′-oxo-10′H-
thioxantheno[2′,3′-d]oxazol-2′-yl)cyclohexyl}thiourea (1)
IR (ATR): 3296 (w, NH), 3066 (w, OH), 2931 (m, CHsp3), 2857 (m,
CHsp3), 1766 (w), 1700 (s, C=O), 1588 (m, C=Csp2), 1517 (m, C=Csp2),
1438 (m, CHsp3), 1369 (m), 1294 (w), 1262 (w), 1077 (m), 717 cm–1
(m, CHsp2).
Oxazole 12 (70.0 mg, 146 μmol, 1.00 equiv) was dissolved in anhyd
MeOH (13 mL). Hydrazine hydrate (364 mg, 0.36 mL, 7.29 mmol,
50.0 equiv) was added and the mixture was stirred at rt for 24 h.
Upon removal of the solvent, the residue was dissolved in CH2Cl2 and
filtered over SiO2 (1 × 2 cm, CH2Cl2/MeOH 95:5). After evaporation of
the solvent, the crude material was used in the next step without fur-
ther purification. The crude material was dissolved in anhyd THF
(10 mL) and 3,5-bis(trifluoromethyl)phenyl isothiocyanate (83.1 mg,
0.06 mL, 307 μmol, 2.10 equiv) was added. The reaction mixture was
stirred at rt and after 18 h, the solvent was evaporated. Purification by
flash chromatography (2 × 7 cm, CH2Cl2/MeOH 99:1) afforded the de-
sired thiourea as a yellow solid (29.0 mg, 46.7 μmol, 32% over two
steps); mp 124–126 °C; Rf = 0.20 (CH2Cl2/MeOH 99:1) [UV, KMnO4];
[α]D20 +80 (c = 1.00, CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 1.00–1.17 (m, 1 H, H-5), 1.42–1.54 (m,
1 H, H-4), 1.63–1.82 (m, 4 H, H-3, H-4, H-5, H-6), 2.00 (virt. dq,
3J = 12.7 Hz, 3J ≅ 3J = 3.6 Hz, 1 H, H-3), 2.06–2.18 (m, 1 H, H-6), 3.82
(virt. td, 3J ≅ 3J = 11.8 Hz, 3J = 3.7 Hz, 1 H, H-1), 4.53 (virt. td, 3J ≅
3
3J = 11.8 Hz, J = 4.0 Hz, 1 H, H-2), 6.99 (s, 1 H, H-4′), 7.44–7.48 (m, 2
H, H-7′, H-5′), 7.53–7.56 (m,
1
H, H-6′), 7.59 (dd, 3J = 5.5 Hz,
4J = 3.0 Hz, 2 H, H-5′′, H-6′′), 7.73 (dd, 3J = 5.5 Hz, 4J = 3.0 Hz, 2 H, H-4′′,
H-7′′), 8.47 (s, 1 H, H-1′), 8.61 (dd, 3J = 8.4 Hz, 4J = 1.6 Hz, 1 H, H-8′),
9.33 (s, 1 H, NH), 10.81 (s, 1 H, OH).
13C NMR (101 MHz, CDCl3): δ = 24.7 (t, C-5), 25.2 (t, C-4), 29.8 (t, C-3),
30.9 (t, C-6), 47.4 (d, C-1), 51.8 (d, C-2), 114.6 (d, C-4′), 121.9 (s, C-4a′),
123.4 (d, 2 C, C-4′′, C-7′′), 123.7 (d, C-1′), 126.0 (d, C-7′), 126.4 (d, C-
5′), 126.9 (s, C-3′), 128.6 (s, C-8a′), 130.0 (d, C-8′), 131.8 (s, 2 C, C-3a′′,
C-7a′′), 132.2 (d, C-6′), 134.1 (d, 2 C, C-5′′, C-6′′), 136.6 (s, C-9a′), 137.5
(s, C-4b′), 153.8 (s, C-2′), 168.5 (s, 2 C, C-1′′, C-3′′), 175.2 (s, CON),
179.3 (s, C-9′).
IR (ATR): 3327 (w, NH), 2956 (w, CHsp3), 2929 (w, CHsp3), 2852 (w,
CHsp3), 1701 (m, C=O), 1625 (m, C=Csp2), 1438 (m, CHsp3), 1277 (m),
1028 (m), 910 (m), 749 cm–1 (m, CHsp2).
1H NMR (400 MHz, CDCl3): δ = 1.55–1.79 (m, 4 H, H-4, H-5), 1.93–2.00
(m, 2 H, H-3, H-6), 2.08–2.17 (m, 1 H, H-6), 2.37–2.41 (m, 1 H, H-3),
3.73 (br s 1 H, H-2), 4.96–5.16 (m, 1 H, H-1), 7.41–7.68 (m, 5 H, H-4′,
H-6′, H-7′, H-8′, H-4′′), 7.95 (s, 2 H, H-2′′), 8.15 (br s, 1 H, NH), 8.50 (d,
3J = 8.1 Hz, 1 H, H-9′), 8.68 (s, 1 H, H-11′), 9.01 (br s, 1 H, NH).
MS (EI, 70 eV): m/z (%) = 498 (1, [M]+), 480 (10 [M – H2O]+), 333 (100,
[C20H15NO2S]+), 280 (10), 170 (3), 71 (10).
13C NMR (101 MHz, CDCl3): δ = 21.2 (t, C-4*), 22.0 (t, C-5*), 28.3 (t, C-
6), 39.3 (t, C-3), 54.0 (d, C-2), 60.6 (d, C-1), 106.8 (d, C-4′), 118.7 (d, C-
4′′), 119.0 (s, C-1′′), 121.3 (d, C-11′), 122.5 (q, JC,F = 165 Hz, 2 C, CF3),
HRMS (EI): m/z [M]+ calcd for C28H22N2O5S: 498.1249; found:
498.1248.
1
Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–M

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F. Mayr et al.
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Synthesis
123.8 (d, 2 C, C-2′′), 125.9 (d, C-6′*), 126.3 (d, C-7′*), 128.2 (s, C-4a′),
129.9 (d, C-8′), 132.4 (q, 2J = 33.6 Hz, 2 C, C-3′′), 132.8 (d, C-9′), 134.9
(s, C-9a′), 137.4 (s, C-5a′), 139.9 (s, C-10a′), 140.0 (s, C-3a′), 152.5 (s,
C-11a′), 169.3 (s, C-2′), 180.0 (s, C-10′), 180.3 (s, NCSN).
13C NMR (101 MHz, CDCl3): δ = 28.0 (t, C-6), 29.8 (t, C-5), 37.8 (t, C-7),
40.1 (d, C-1*), 40.2 (d, C-4*), 53.1 (d, C-2), 57.5 (d, C-3), 123.3 (d, 2 C,
C-4′, C-7′), 132.0 (s, 2 C, C-3a′, C-7a′), 134.0 (d, 2 C, C-5′, C-6′), 168.7 (s,
2 C, C-1′, C-3′), 175.1 (s, COOH).
HRMS (ESI): m/z [M + H]+ calcd for C29H21F6N3O2S2: 622.1052; found:
MS (EI, 70 eV): m/z (%) = 185 (1, [M]+), 94 (21), 78 (9), 66 (100), 40
622.1047.
(10).
HRMS (EI): m/z [M]+ calcd for C16H15NO4: 285.0996; found: 285.1000.
(1S,2S,3R,4R)-3-(1′,3′-Dioxoisoindolin-2′-yl)bicyclo[2.2.1]hept-5-
ene-2-carboxylic Acid (15)
2′-Nitro-9′-oxo-9′H-thioxanthen-3′-yl (1R,2S,3R,4S)-3-(1′′,3′′-Dioxo-
isoindolin-2′′-yl)bicyclo[2.2.1]heptane-2-carboxylate (17)
Amino acid 14 (962 mg, 6.28 mmol, 1.00 equiv) was dissolved in an-
hyd toluene (150 mL). Subsequently, phthalic anhydride (978 mg,
6.60 mmol, 1.05 equiv) and NEt3 (1.26 g, 1.74 mL, 12.6 mmol,
2.00 equiv) were added. The mixture was stirred at 100 °C. After 18 h,
the solution was cooled to rt and washed with aq 3 M HCl (150 mL).
The aqueous layer was extracted with CH2Cl2 (3 × 150 mL). The com-
bined organic layers were dried (Na2SO4), filtered, and the solvent was
removed under reduced pressure. The desired product was obtained
The protected amino acid 16 (870 mg, 3.05 mmol, 1.10 equiv) was
dissolved in anhyd CH2Cl2 (30 mL), and oxalyl chloride (387 mg,
0.26 mL, 3.05 mmol, 1.10 equiv) and a catalytic amount of DMF (5
drops) was added. The mixture was stirred at rt for 3 h. Meanwhile
thioxanthone 9 (757 mg, 2.77 mmol, 1.00 equiv) was dissolved in an-
hyd CH2Cl2 (65 mL) and cooled to 0 °C. At this temperature, NEt3
(854 mg, 1.17 mL, 8.31 mmol, 3.00 equiv) and a catalytic amount of
4-dimethylaminopyridine (5 crystals) was added. At 0 °C the freshly
prepared solution of acid chloride was added slowly. After addition,
the mixture was slowly warmed to rt and stirred overnight. After 18
h, the reaction was stopped with aq NH4Cl (100 mL) and extracted
with CH2Cl2 (3 × 100 mL). The combined organic layers were washed
with aq 2 M NaOH (150 mL), dried (Na2SO4), and filtered. The solvent
was evaporated under reduced pressure and the product was ob-
tained as a yellow solid (1.48 g, 2.74 mmol, 99%); mp 202–206 °C;
20
as a brown viscous oil (1.60 g, 5.65 mmol, 90%); [α]D +64 (c = 1.00,
CH2Cl2).
IR (ATR): 3227 (m, OH), 3059 (w, CHsp2), 2983 (w, CHsp3), 2952 (w,
CHsp3), 1770 (m), 1703 (s, C=O), 1402 (m), 1367 (s), 1329 (s), 1178
(m), 1158 (m), 872 (m), 714 (s), 695 (s), 662 cm–1 (m).
1H NMR (300 MHz, CDCl3): δ = 1.75 (virt. dt, 2J = 9.3 Hz, 3J ≅
3J = 1.9 Hz, 1 H, H-7), 2.63 (virt. dt, 2J = 9.3 Hz, 3J ≅ 3J = 1.9 Hz, 1 H, H-
7), 2.77 (dd, 3J = 8.6 Hz, 4J = 1.8 Hz, 1 H, H-2), 3.18 (virt. t, 3J ≅
3J = 1.9 Hz, 1 H, H-4), 3.42 (d, 3J = 1.9 Hz, 1 H, H-1), 4.28 (dd,
20
Rf = 0.83 (CH2Cl2/MeOH 98:2) [UV, KMnO4]; [α]D –92 (c = 1.00,
CH2Cl2).
4
3
3
3J = 8.6 Hz, J = 1.8 Hz, 1 H, H-3), 6.22 (dd, J = 5.6 Hz, J = 2.9 Hz, 1 H,
H-6), 6.31 (dd, 3J = 5.6 Hz, 3J = 3.1 Hz, 1 H, H-5), 7.64–7.70 (m, 2 H, H-
5′, H-6′), 7.74–7.81 (m, 2 H, H-4′, H-7′).
IR (ATR): 3089 (w, CHsp2), 2956 (w, CHsp3), 2880 (w, CHsp3), 1759 (s,
C=O), 1702 (s, C=O), 1640 (s, C=Csp2), 1338 (s, N=O), 1105 (s, C–O), 730
cm–1 (m, C–S).
13C NMR (75 MHz, CDCl3): δ = 45.3 (d, C-1), 45.6 (d, C-2), 45.9 (d, C-4),
47.8 (t, C-7), 55.6 (d, C-3), 123.2 (d, 2 C, C-4′, C-7′), 132.0 (s, 2 C, C-3a′,
C-7a′), 134.0 (d, 2 C, C-5′, C-6′), 138.3 (d, C-5), 138.8 (d, C-6), 168.9 (s,
2 C, C-1′, C-3′), 176.9 (s, COOH).
1H NMR (400 MHz, CDCl3): δ = 1.45 (d, 3J = 2.3 Hz, 1 H, H-6ax), 1.47 (d,
3J = 2.3 Hz, 1 H, H-5ax), 1.52–1.55 (m, 1 H, H-7), 1.71–1.86 (m, 2 H, H-
5eq, H-6eq), 2.72 (virt. dt, 2J = 10.9 Hz, 3J ≅ 3J = 2.0 Hz, 1 H, H-7), 2.94 (s,
1 H, H-1*), 3.01 (s, 1 H, H-4*), 3.31 (dd, 3J = 9.1 Hz, 4J = 1.6 Hz, 1 H, H-
2), 4.53 (dd, 3J = 9.1 Hz, 4J = 1.5 Hz, 1 H, H-3), 7.05 (s, 1 H, H-4′), 7.50–
7.57 (m, 2 H, H-5′, H-7′), 7.64–7.74 (m, 3 H, H-6′, H-5′′, H-6′′), 7.84
(dd, 3J = 5.4 Hz, 4J = 3.0 Hz, 2 H, H-4′′, H-7′′), 8.55 (dd, 3J = 8.0 Hz,
4J = 1.5 Hz, 1 H, H-8′), 9.19 (s, 1 H, H-1′).
13C NMR (101 MHz, CDCl3): δ = 28.4 (t, C-6), 29.6 (t, C-5), 37.9 (t, C-7),
40.1 (d, C-1*), 40.5 (d, C-4*), 53.6 (d, C-2), 58.0 (d, C-3), 122.0 (d, C-4′),
123.4 (d, 2 C, C-4′′, C-7′′), 126.2 (d, C-5′), 127.0 (s, C-9a′), 127.8 (d, C-
7′), 128.3 (d, C-1′), 128.5 (s, C-8a′), 130.3 (d, C-8′), 132.0 (s, 2 C, C-3a′′,
C-7a′′), 133.4 (d, C-6′), 134.3 (d, 2 C, C-5′′, C-6′′), 135.7 (s, C-4b′), 140.1
(s, C-3′), 144.1 (s, C-4a′), 146.0 (s, C-2′), 168.7 (s, 2 C, C-1′′, C-3′′), 169.0
(s, COO), 177.9 (s, C-9′).
MS (EI, 70 eV): m/z (%) = 92 (60, [C7H8]+), 91 (100), 65 (13), 40 (12,
[C3H4]+).
HRMS (EI): m/z [M]+ calcd for C16H13NO4: 283.0845; found: 283.0836.
(1R,2S,3R,4S)-3-(1′,3′-Dioxoisoindolin-2′-yl)bicyclo[2.2.1]heptane-
2-carboxylic Acid (16)
The protected amino acid 15 (1.53 g, 5.42 mmol, 1.00 equiv) was dis-
solved in EtOAc (92 mL) and Pd/C (10% w/w, 181 mg) was added. The
mixture was stirred under H2 atmosphere (balloon) at rt. After 18 h,
the mixture was filtered over Celite and washed with CH2Cl2
(150 mL). The solvent was evaporated under reduced pressure. The
product was isolated as a colorless solid (1.51 g, 5.31 mmol, 98%); mp
75–78 °C; [α]D20 +36 (c = 1.00, CH2Cl2).
MS (EI, 70 eV): m/z (%) = 268 (24), 239 (100), 211 (65), 200 (40), 186
(25), 148 (28), 92 (26), 57 (23).
HRMS (EI): m/z [M]+ calcd for C29H20N2O7S: 540.0986; found:
540.0993.
Chiral HPLC (OD-RH, 150 × 4.6 mm, MeCN/H2O (2:10), 1 mL/min,
λ = 210 nm, 254 nm): tR1 = 11.1 min, tR2 = 12.9 min.
IR (ATR): 3258 (m, OH), 2959 (m, CHsp3), 2874 (m, CHsp3), 1731 (s,
C=O), 1453 (w), 1373 (w), 1286 (m), 1107 (m), 1073 (w), 719 cm–1 (s).
(1R,2S,3R,4S)-3-(1′′,3′′-Dioxoisoindolin-2′′-yl)-N-(3′-hydroxy-9′-
oxo-9′H-thioxanthen-2′-yl)bicyclo[2.2.1]heptane-2-carboxamide
(18)
1H NMR (400 MHz, CDCl3): δ = 1.24–1.38 (m, 3 H, H-5ax, H-6ax, H-7),
1.60–1.71 (m, 2 H, H-5eq, H-6eq), 2.61 (virt. dt, 2J = 10.8 Hz, 3J ≅
3J = 2.1 Hz, 1 H, H-7), 2.67 (d, 3J = 3.7 Hz, 1 H, H-1*), 2.77 (d,
3J = 3.4 Hz, 1 H, H-4*), 2.86 (dd, 3J = 9.3 Hz, 4J = 1.7 Hz, 1 H, H-2), 4.38
(dd, 3J = 9.3 Hz, 4J = 1.5 Hz, 1 H, H-3), 7.69 (dd, 3J = 5.5 Hz, 4J = 3.0 Hz, 2
H, H-5′, H-6′), 7.80 (dd, 3J = 5.5 Hz, 4J = 3.0 Hz, 2 H, H-4′, H-7′).
The ester 17 (400 mg, 741 μmol, 1.00 equiv) was dissolved in THF
(26 mL) and H2O (26 mL) was added. In (425 mg, 3.70 mmol,
5.00 equiv) and concd HCl (0.72 mL) were added. The mixture was
heated to 80 °C and stirred for 20 h. After cooling to rt, CH2Cl2
(100 mL) was added and the mixture was filtered over Celite. The
mixture was washed with aq NaHCO3 (150 mL) and extracted with
CH2Cl2 (3 × 100 mL). The combined organic layers were dried
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F. Mayr et al.
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Synthesis
(Na2SO4), filtered, and evaporated. The crude material was purified by
flash column chromatography (4 × 20 cm, CH2Cl2/MeOH 95:5) and
the product was isolated as an orange solid (328 mg, 642 μmol, 87%);
mp 166–169 °C; Rf = 0.44 (CH2Cl2/MeOH 95:5) [UV, KMnO4]; [α]D
–144 (c = 1.00, CH2Cl2).
HR-MS (EI): m/z [M]+ calcd for C29H20NO4S: 492.1144; found:
492.1143.
20
1-[3′′,5′′-Bis(trifluoromethyl)phenyl]-3-{(1S,2R,3S,4R)-3-(10′-oxo-
10′H-thioxantheno[2′,3′-d]oxazol-2′-yl)bicyclo[2.2.1]heptan-2-
yl}thiourea (2)
IR (ATR): 3248 (m, OH), 3141 (m, NH), 2967 (w, CHsp3), 2872 (w,
CHsp3), 1697 (s, C=O), 1583 (s, C=Csp2), 1304 (s, C–N), 718 cm–1 (s, C–S).
The oxazole 19 (70.0 mg, 142 μmol, 1.00 equiv) was suspended in an-
hyd EtOH (4.5 mL), and anhyd CH2Cl2 (4.5 mL) was added. To the solu-
tion ethylenediamine (85.0 mg, 0.10 mL, 1.42 mmol, 10.0 equiv) was
added. The mixture was warmed to 50 °C and stirred for 20 h. After
cooling, the solvent was evaporated and the crude material was fil-
tered by short flash column chromatography (1 × 2 cm, CH2Cl2/MeOH
95:5). The isolated product was used in the next step without further
purification. The readily prepared amine was dissolved in anhyd THF
(8 mL) and isothiocyanate 13 (80.8 mg, 54.0 μL, 298 μmol, 2.10 equiv)
was added. The mixture was stirred at rt. After 18 h, the solvent was
evaporated and the crude material was purified by flash column chro-
matography (1 × 5 cm, CH2Cl2/MeOH 99:1). The product was isolated
1H NMR (400 MHz, CDCl3): δ = 1.18–1.38 (m, 2 H, H-5ax, H-6ax), 1.54–
1.60 (m, 1 H, H-7), 1.65–1.80 (m, 2 H, H-5eq, H-6eq), 2.68 (s, 1 H, H-1),
2.85 (d, 2J = 11.1 Hz, 1 H, H-7), 3.08–3.15 (m, 2 H, H-2, H-4), 4.44 (dd,
3J = 8.6 Hz, 4J = 1.6 Hz, 1 H, H-3), 6.94 (s, 1 H, H-4′), 7.44–7.55 (m, 2 H,
3
H-5′, H-7′), 7.55–7.62 (m, 3 H, H-6′, H-5′′, H-6′′), 7.76 (dd, J = 5.4 Hz,
4J = 3.1 Hz, 2 H, H-4′′, H-7′′), 8.26 (s, 1 H, H-1′), 8.47 (s, 1 H, OH), 8.65
(dd, 3J = 8.2 Hz, 4J = 1.5 Hz, 1 H, H-8′), 10.11 (s, 1 H, NH).
13C NMR (101 MHz, CDCl3): δ = 28.8 (t, C-5), 29.3 (t, C-6), 38.4 (t, C-7),
38.7 (d, C-4), 40.9 (d, C-1), 56.0 (d, C-2), 60.0 (d, C-3), 115.2 (d, C-4′),
122.2 (s, C-4a′), 123.5 (d, 2 C, C-4′′, C-7′′), 123.9 (d, C-1′), 126.3 (d, C-
7′), 126.3 (d, C-5′), 127.3 (s, C-3′), 128.8 (s, C-8a′), 129.9 (d, C-8′),
131.6 (s, 2 C, C-3a′′, C-7a′′), 132.2 (d, C-6′), 134.2 (d, 2 C, C-5′′, C-6′′),
136.7 (s, C-9a′), 137.4 (s, C-4b′), 153.9 (s, C-2′), 169.6 (s, 2 C, C-1′′, C-
3′′), 173.3 (s, CON), 179.0 (s, C-9′).
as a yellow solid (35.1 mg, 55.4 μmol, 39% over 2 steps); mp 202–
20
204 °C; Rf = 0.21 (CH2Cl2/MeOH 99:1) [UV, KMnO4]; [α]D
(c = 1.00, CH2Cl2).
–40
IR (ATR): 3281 (m, NH), 3063 (w, CHsp2), 2960 (w, CHsp3), 2925 (w,
CHsp3), 2876 (w, CHsp3), 1766 (w), 1719 (s, C=O), 1637 (m), 1618 (s,
C=N), 1591 (m), 1435 (s), 1370 (m), 1275 (s, C=S), 1173 (m), 1132 (s),
1110 (m), 715 cm–1 (m, C–S).
1H NMR (400 MHz, CDCl3): δ = 1.60–1.79 (m, 5 H, H-5, H-6, H-7), 1.94
(d, 2J = 11.4 Hz, 1 H, H-7), 2.58 (s, 1 H, H-4), 3.13 (s, 1 H, H-1), 3.37 (s,
1 H, H-3), 4.32 (s, 1 H, H-2), 6.67 (s, 1 H, NH), 7.52 (ddd, 3J = 8.2 Hz,
MS (EI, 70 eV): m/z (%) = 205 (25), 91 (28, [C6H3O]+), 72 (45), 71 (49,
[C3H2NO]+), 42 (100).
HRMS (EI): m/z [M]+ calcd for C29H22N2O5S: 510.1249; found:
510.1244.
2-{(1S,2R,3S,4R)-3-(10′-Oxo-10′H-thioxantheno[2′,3′-d]oxazol-2´-
yl)bicyclo[2.2.1]heptan-2-yl}isoindoline-1′′,3′′-dione (19)
4
3
4
7.0 Hz, J = 1.3 Hz, 1 H, H-8′), 7.58 (dd, J = 7.8 Hz, J = 1.3 Hz, 1 H, H-
6′), 7.62–7.68 (m, 1 H, H-7′), 7.67 (s, 1 H, H-4′), 7.76 (s, 1 H, H-4′′), 8.23
(s, 2 H, H-2′′), 8.67 (dd, 3J = 8.2 Hz, 4J = 1.4 Hz, 1 H, H-9′), 8.92 (s, 1 H,
H-11′), 10.40 (s, 1 H, NH).
The amide 18 (523 mg, 1.03 mmol, 1.00 equiv) was dissolved in an-
hyd THF (73 mL), and PPh3 (323 mg, 1.23 mmol, 1.20 equiv) and di-
isopropyl azodicarboxylate (249 mg, 0.24 mL, 1.23 mmol, 1.20 equiv)
were added. The mixture was stirred at rt. After 4 h, the solvent was
evaporated and the crude material was purified by flash column chro-
matography (4 × 25 cm, CH2Cl2/MeOH 98:2). The product was isolat-
ed as a yellow solid (444 mg, 902 μmol, 88%); mp 223–226 °C;
13C NMR (126 MHz, CDCl3): δ = 28.8 (t, C-5), 29.5 (t, C-6), 29.9 (t, C-7),
37.5 (d, C-4), 43.6 (d, C-1), 61.3 (d, C-3), 63.3 (d, C-2), 107.4 (d, C-4′′),
116.5 (d, C-4′), 118.9 (s, C-1′′), 121.4 (d, C-11′), 124.0 (d, 2 C, C-2′′),
1
124.3 (s, 2 C, C-3′′), 125.8 (d, C-8′), 126.6 (q, JC,F = 211 Hz, 2 C, CF3),
20
Rf = 0.47 (CH2Cl2/MeOH 98:2) [UV, KMnO4]; [α]D +30 (c = 1.00,
126.8 (d, C-7′*), 127.4 (s, C-4a′), 128.8 (d, C-9′), 130.4 (s, C-9a′), 132.7
(d, C-6′*), 136.7 (s, C-5a′), 139.0 (s, C-10a′), 141.0 (s, C-3a′), 153.4 (s,
C-11a′), 170.3 (s, C-2′), 182.9 (s, C-10′), 186.6 (s, NCSN).
MS (EI, 70 eV): m/z (%) = 633 (1, [M]+), 362 (12), 345 (39, [C21H15NO2S]+),
317 (52, [C19H11NO2S]+), 271 (100, [C9H4F6NS]+), 229 (18), 213 (24),
163 (13).
CH2Cl2).
IR (ATR): 3059 (w, CHsp2), 2991 (w, CHsp3), 2948 (w, CHsp3), 2876 (w,
CHsp3), 1766 (m), 1707 (s, CO), 1618 (s, C=N), 1590 (m, C=Csp2), 1435
(s), 1293 (s), 1100 (m), 743 (m), 714 cm–1 (s, C–S).
1H NMR (400 MHz, CDCl3): δ = 1.51 (d, 3J = 2.3 Hz, 1 H, H-5), 1.52–
1.54 (m, 1 H, H-6), 1.61 (virt. dt, 2J = 10.7 Hz, 3J ≅ 3J = 1.6 Hz, 1 H, H-7),
1.77–1.90 (m, 2 H, H-5eq, H-6eq), 2.87 (virt. dt, 2J = 10.7 Hz, 3J ≅
3J = 2.0 Hz, 1 H, H-7), 2.96 (d, 3J = 3.6 Hz, 1 H, H-4), 3.01 (d, 3J = 2.4 Hz,
1 H, H-1), 3.61 (dd, 3J = 8.8 Hz, 4J = 1.5 Hz, 1 H, H-3), 4.61 (dd,
3J = 8.8 Hz, 4J = 1.5 Hz, 1 H, H-2), 7.39 (s, 1 H, H-4′), 7.43 (dd,
HRMS (ESI): m/z [M + H]+ calcd for C30H22F6N3O2S2: 634.1052; found:
634.1047.
(1R,2S)-2-Aminocyclohexane-1-carboxylic Acid Hydrochloride
(21)
3J = 8.2 Hz, 7.0 Hz, 4J = 1.3 Hz,
1
H, H-8′), 7.50 (dd, 3J = 8.1 Hz,
4J = 1.5 Hz, 1 H, H-6′), 7.54–7.61 (m, 3 H, H-7′, H-5′′, H-6′′), 7.63–7.67
(m, 2 H, H-4′′, H-7′′), 8.51–8.56 (m, 1 H, H-9′), 8.59 (s, 1 H, H-11′).
Amino acid 20 (3.00 g, 12.1 mmol, 1.00 equiv) was dissolved in aq 6 N
HCl (150 mL). The mixture was stirred at 120 °C for 48 h. After this
time, the solvent was evaporated and the product was obtained as a
colorless solid (2.15 g, 12.0 mmol, 99%); mp 198–220 °C.
13C NMR (101 MHz, CDCl3): δ = 28.5 (t, C-5), 30.0 (t, C-6), 38.0 (t, C-7),
39.8 (d, C-4), 41.3 (d, C-1), 49.1 (d, C-3), 58.8 (d, C-2), 106.3 (d, C-4′),
121.8 (d, C-11′), 123.1 (d, 2 C, C-4′′, C-7′′), 125.6 (d, C-6′), 126.4 (d, C-
8′), 126.4 (s, C-4a′), 128.7 (s, C-9a′), 130.0 (s, C-9′), 131.8 (s, 2 C, C-3a′′,
C-7a′′), 132.3 (d, C-7′), 134.0 (d, 2 C, C-5′′, C-6′′), 137.0 (s, C-5a′), 137.3
(s, C-10a′), 141.1 (s, C-3a′), 152.6 (s, C-11a′), 167.2 (s, 2 C, C-1′′, C-3′′),
168.6 (s, C-2′), 179.8 (s, C-10′).
1H NMR (400 MHz, DMSO-d6): δ = 1.11–2.06 (m, 8 H, H-3, H-4, H-5,
3
3
H-6), 2.89 (virt. q, J ≅ J = 4.4 Hz, 1 H, H-1), 3.08–3.41 (m, 1 H, H-2),
8.06 (s, 3 H, NH3), 12.90 (s, 1 H, COOH).
13C NMR (101 MHz, DMSO-d6): δ = 22.0 (t, C-4), 22.2 (t, C-5), 25.5 (t,
C-6), 27.0 (t, C-3), 41.8 (d, C-1), 48.8 (d, C-2), 174.0 (s, COOH).
MS (EI, 70 eV): m/z (%) = 492 (1, [M]+), 345 (36, [C21H15NO2S]+), 317
The analytical data are in accordance with the literature.27
(100, [C19H11NO2S]+), 289 (8), 260 (5), 219 (5), 170 (6).
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Synthesis
(1R,2S)-2-(1′,3′-Dioxoisoindolin-2′-yl)cyclohexane-1-carboxylic
Acid (22)
3J = 12.8 Hz. 3J ≅ J = 3.2 Hz, 1 H, H-3), 3.38 (virt. q, 3J ≅ 3J = 4.2 Hz, 1 H,
H-1), 4.48 (ddd, 3J = 12.8 Hz, 5.1 Hz, 3.5 Hz, 1 H, H-2), 7.57 (ddd,
3J = 8.2 Hz. 7.1 Hz, 4J = 1.2 Hz, 1 H, H-7′), 7.60–7.63 (m, 2 H, H-4′, H-
5′), 7.69–7.74 (m, 3 H, H-6′, H-5′′, H-6′′), 7.86 (dd, 3J = 5.4 Hz,
4J = 3.0 Hz, 2 H, H-4′′, H-7′′), 8.60 (dd, 3J = 8.2 Hz, 4J = 1.5 Hz, 1 H, H-8′),
9.24 (s, 1 H, H-1′).
13C NMR (101 MHz, CDCl3): δ = 21.0 (t, C-4), 26.0 (t, C-5), 26.2 (t, C-3),
27.9 (t, C-6), 44.0 (d, C-1), 52.7 (d, C-2), 122.7 (d, C-4′), 123.4 (d, 2 C,
C-4′′, C-7′′), 126.3 (d, C-5′), 127.0 (s, C-9′), 127.7 (d, C-7′), 128.3 (d, C-
1′), 128.6 (s, C-8a′), 130.3 (d, C-8′), 132.0 (s, 2 C, C-3a′′, C-7a′′), 133.4
(d, C-6′), 134.4, (d, 2 C, C-5′′, C-6′′) 136.0 (s, C-4b′), 140.2 (s, C-3′),
144.2 (s, C-4a′), 146.2 (s, C-2′), 168.8 (s, 2 C, C-1′′, C-3′′), 170.3 (s,
COO), 178.0 (s, C-9′).
Hydrochloride 21 (493 mg, 2.75 mmol, 1.00 equiv) was dissolved in
anhyd toluene (50 mL). Subsequently phthalic anhydride (427 mg,
2.88 mmol, 1.05 equiv) and NEt3 (556 mg, 0.76 mL, 5.49 mmol,
2.00 equiv) were added. The mixture was stirred at 100 °C. After 18 h,
the solution was cooled and washed with aq 3 M HCl (150 mL). The
aqueous layer was extracted with CH2Cl2 (3 × 150 mL). The combined
organic layers were dried (Na2SO4) and filtered. The solvent was re-
moved under reduced pressure. The desired product was obtained as
20
a colorless solid (743 mg, 2.72 mmol, 99%); mp 144–146 °C; [α]D
–52 (c = 1.00, CH2Cl2).
IR (ATR): 3285 (m, OH), 2960 (m, CHsp3), 2925 (w, CHsp3), 2868 (m,
CHsp3), 1719 (s, C=O), 1690 (s, C=O), 1405 (m), 1372 (s, C–N), 1331
(m), 1184 (m), 1082 (m), 1018 (m), 713 cm–1 (m, CHsp2).
MS (EI, 70 eV): m/z (%) = 528 (1, [M]+), 273 (32, [C13H7NO4S]+), 256
(100, [C15H14NO3]+), 148 (75, [C8H6NO2]+).
1H NMR (400 MHz, CDCl3): δ = 1.33–1.44 (m, 1 H, H-5), 1.55 (virt. dt,
3J = 13.8 Hz, 3J ≅ 3J = 4.0 Hz, 1 H, H-6), 1.66 (virt. ddt, 3J = 13.8 Hz,
12.4 Hz, 3J ≅ 3J = 4.6 Hz, 1 H, H-5), 1.77 (dd, 3J = 13.2 Hz. 3.6 Hz, 1 H, H-
4), 1.90–2.01 (m, 2 H, H-6, H-3), 2.15 (virt. dt, 3J = 13.8 Hz, 3J ≅
3J = 2.8 Hz, 1 H, H-4), 2.82 (virt. dq, 3J = 12.7 Hz, 3J ≅ 3J = 3.4 Hz, 1 H, H-
3), 3.00 (virt. q, 3J ≅ 3J = 2.9 Hz, 1 H, H-1), 4.33 (ddd, 3J = 12.7 Hz,
5.3 Hz, 3.5 Hz, 1 H, H-2), 7.66 (dd, 3J = 5.5 Hz, 4J = 3.0 Hz, 2 H, H-5′, H-
6′), 7.77 (dd, 3J = 5.5 Hz, 4J = 3.0 Hz, 2 H, H-4′, H-7′), 8.42 (br s, 1 H,
COOH).
13C NMR (101 MHz, CDCl3): δ = 21.6 (t, C-5), 26.0 (t, C-6), 26.1 (t, C-4),
27.5 (t, C-3), 42.9 (d, C-1), 52.8 (d, C-2), 123.8 (d, 2 C, C-4′, C-7′), 132.0
(s, 2 C, C-3a′, C-7a′), 134.0 (d, 2 C, C-5′, C-6′), 168.7 (s, 2 C, C-1′, C-3′),
178.0 (s, COOH).
HRMS (EI): m/z [M]+ calcd for C28H20N2O7S: 528.0991; found:
528.0992.
(1R,2S)-2-(1′,3′-Dioxoisoindolin-2′-yl)-N-(3′′-hydroxy-9′′-oxo-9′′H-
thioxanthen-2′′-yl)cyclohexane-1-carboxamide (24)
Ester 23 (699 mg, 1.36 mmol, 1.00 equiv) was dissolved in THF
(40 mL) and H2O (40 mL) was added. To this solution In (780 mg,
6.80 mmol, 5.00 equiv) and concd HCl (1.12 mL) were added. The
mixture was stirred at 80 °C and after 18 h, the solution was cooled to
rt and CH2Cl2 (50 mL) was added. The mixture was filtered over Celite
and washed with aq NaHCO3 (100 mL). The aqueous layer was ex-
tracted with CH2Cl2 (3 × 150 mL). The combined organic layers were
dried (Na2SO4), filtered, and the solvent was removed under reduced
pressure. Purification by flash chromatography (4 × 20 cm, CH2Cl2/
MeOH 95:5) afforded the title product as an orange solid (597 mg,
1.24 mmol, 91%); mp 136–138 °C; Rf = 0.59 (CH2Cl2/MeOH 95:5) [UV,
KMnO4]; [α]D20 –4 (c = 1.00, CH2Cl2).
MS (EI, 70 eV): m/z (%) = 273 (12, [M]+), 256 (25, [C15H13NO3]+), 227
(15), 186 (23), 148 (33, [C8H6NO2]+), 91 (100).
HRMS (EI): m/z [M]+ calcd for C15H15NO4: 273.1001; found: 273.0996.
IR (ATR): 3262 (w, OH), 2933 (w, CHsp3), 2851 (w, CHsp3), 2552 (w,
CONH), 1769 (m, C=O), 1708 (s, C=O), 1658 (m, CONH), 1607 (s,
CHsp2), 1589 (s, CHsp2), 1523 (s, CONH), 1490 (s), 1437 (s), 1077 (s),
1016 (s), 742 (CHsp2), 707 cm–1 (s, CHsp2).
2′-Nitro-9′-oxo-9′H-thioxanthen-3′-yl (1R,2S)-2-(1′′,3′′-Dioxoisoin-
dolin-2´´-yl)cyclohexane-1-carboxylate (23)
The protected amino acid 22 (450 mg, 1.65 mmol, 1.10 equiv) was
dissolved in anhyd CH2Cl2 (20 mL) and oxalyl chloride (209 mg,
0.14 mL, 1.65 mmol, 1.10 equiv) and a catalytic amount of DMF (5
drops) was added at rt. The mixture was stirred at rt for 3 h. Mean-
while thioxanthone 9 (388 mg, 1.50 mmol, 1.00 equiv) and a catalytic
amount of 4-dimethylaminopyridine (5 crystals) was dissolved in an-
hyd CH2Cl2 (45 mL) and cooled to 0 °C. At this temperature, NEt3
(456 mg, 0.63 mL, 4.50 mmol, 3.00 equiv) was added. At 0 °C the
readily prepared solution of acid chloride was added slowly. The mix-
ture was warmed to rt and stirred overnight. After 18 h, aq NH4Cl
(80 mL) was added and the layers were separated. The aqueous layer
was extracted with CH2Cl2 (3 × 100 mL) and the combined organic
layers were washed with aq 2 M NaOH (150 mL), dried (Na2SO4), and
filtered. The solvent was evaporated and the desired product was ob-
tained without further purification as a yellowish solid (768 mg,
1.46 mmol, 97%); mp 188–190 °C; Rf = 0.86 (CH2Cl2/MeOH 98:2) [UV,
KMnO4]; [α]D20 –216 (c = 1.00, CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 1.38–1.49 (m, 1 H, H-4), 1.57–1.62 (m,
1 H, H-5), 1.70 (virt. dt, 3J = 13.3 Hz, 3J ≅ 3J ≅ 4.2 Hz, 1 H, H-3), 1.78
3
3
3
(virt. dt, J = 13.1 Hz, J ≅ J ≅ 4.6 Hz, 1 H, H-6), 1.99–2.08 (m, 1 H, H-
4), 2.08–2.22 (m, 1 H, H-5), 2.24–2.31 (m, 1 H, H-6), 2.97 (virt. dq
3J = 12.4 Hz, 3J ≅ 3J = 3.7 Hz, 1 H, H-3), 3.17 (virt. q, 3J ≅ 3J = 4.5 Hz, 1 H,
H-1), 4.35 (ddd, 3J = 12.4 Hz, 5.1 Hz, 3.8 Hz, 1 H, H-2), 7.15 (s, 1 H, H-
4′), 7.48 (ddd, 3J = 8.2 Hz, 6.7 Hz, 4J = 1.5 Hz, 1 H, H-7′), 7.52–7.65 (m,
5 H, H-4′′, H-5′′, H-6′′, H-7′′, H-5′), 7.62 (ddd, 3J = 8.2 Hz, 6.7 Hz,
4J = 1.5 Hz, 1 H, H-6′), 7.88 (s, 1 H, H-1′), 8.42 (dd, 3J = 8.2 Hz,
4J = 1.5 Hz, 1 H, H-8′), 9.14 (s, 1 H, OH), 10.65 (s, 1 H, NH).
13C NMR (101 MHz, CDCl3): δ = 21.2 (t, C-5), 25.8 (t, C-4), 25.9 (t, C-3),
28.9 (t, C-6), 45.0 (d, C-1), 52.6 (d, C-2), 115.4 (d, C-4′), 122.0 (s, C-4a′),
123.4 (d, 2 C, C-4′′, C-7′′), 124.1 (d, C-1′), 126.2 (d, C-7′), 126.3 (d, C-
5′), 127.0 (s, C-3′), 128.7 (s, C-8a′), 129.4 (d, C-8′), 131.4 (s, 2 C, C-3a′′,
C-7a′′), 132.3 (d, C-6′), 134.2 (d, 2 C, C-5′′, C-6′′), 137.0 (s, C-9a′), 137.7
(s, C-4b′), 154.7 (s, C-2′), 168.6 (s, 2 C, C-1′′, C-3′′), 175.3 (s, CONH),
179.5 (s, C-9′).
IR (ATR): 2948 (w, CHsp3), 2887 (w, CHsp3), 2847 (w, CHsp3), 1779 (s,
C=O), 1709 (s, C=O), 1644 (s, C=O), 1592 (s, CHsp2), 1522 (s, NO2), 1340
(s, NO2), 1077 (s), 1049 (s), 1017 (s), 743 (s, CHsp2), 723 (s, CHsp2), 693
cm–1 (C–S–C).
MS (EI, 70 eV): m/z (%) = 498 (5, [M]+), 256 (30, [C15H14NO3]+), 227 (38,
[C14H13NO2]+), 148 (43, [C8H4NO2]+), 111 (55).
1H NMR (400 MHz, CDCl3): δ = 1.50 (virt. dt, 3J ≅ 3J = 13.3 Hz, 3.9 Hz, 1
H, H-5), 1.66–1.70 (m, 1 H, H-4), 1.79–1.89 (m, 2 H, H-3, H-6), 1.97–
2.06 (m, 2 H, H-4, H-5), 2.40 (d, 3J = 14.7 Hz, 1 H, H-6), 2.91 (virt. dq,
HRMS (ESI): m/z [M + H]+ calcd for C28H22N2O5S: 499.1322; found:
499.1322.
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Synthesis
2-{(1S,2R)-2-(10′-Oxo-10′H-thioxantheno[2′,3′-d]oxazol-2′-yl)cy-
clohexyl}isoindoline-1′′,3′′-dione (25)
7.70–7.84 (m, 2 H, H-6′, H-7′), 8.07 (d, 3J = 8.6 Hz, 1 H, NH), 8.16 (s, 1
H, H-4′′), 8.20 (s, 2 H, H-2′′), 8.49 (dd, 3J = 8.2 Hz, 4J = 1.4 Hz, 1 H, H-9′),
8.73 (s, 1 H, H-11′), 9.97 (s, 1 H, NH).
13C NMR (101 MHz, DMSO-d6): δ = 22.1 (t, C-4*), 22.4 (t, C-5*), 25.9 (t,
C-3), 28.3 (t, C-6), 38.8 (d, C-2), 52.0 (d, C-1), 107.7 (d, C-4′′), 116.1 (d,
C-4′), 116.2 (s, C-1′′), 120.0 (d, C-11′) 120.9 (q, 1JC,F = 183 Hz, 2 C, CF3),
121.8 (d, 2 C, C-2′′), 126.1 (q, 2JC,F = 109 Hz, 2 C, C-3′′), 126.2 (d, C-7′*),
126.7 (d, C-8′), 127.7 (s, C-4a′), 129.1 (d, C-9′), 132.9 (d, C-6′*), 133.5
(s, C-9a′), 136.5 (s, C-5a′), 140.7 (s, C-10a′), 141.6 (s, C-3a′), 152.6 (s,
C-11a′), 169.1 (s, C-2′), 178.6 (s, NCSN), 179.9 (s, C-10′).
The synthesized amide 24 (575 mg, 1.15 mmol, 1.00 equiv) was dis-
solved in anhyd THF (55 mL). At rt, PPh3 (666 mg, 2.54 mmol,
2.20 equiv) and diisopropyl azodicarboxylate (513 mg, 0.50 mL,
2.54 mmol, 2.20 equiv) were added. The mixture was stirred at rt for
4 h. After this time, the solvent was evaporated. The crude product
was purified by flash chromatography (4 × 25 cm, CH2Cl2/MeOH
98:2). The desired product was obtained as a yellow solid (510 mg,
1.06 mmol, 89%); mp 95–98 °C; Rf = 0.64 (CH2Cl2/MeOH 98:2) [UV,
KMnO4]; [α]D20 –176 (c = 1.00, CH2Cl2).
MS (EI, 70 eV): m/z (%) = 621 (1, [M]+), 578 (2, [C29H19F6N3O2S]+), 392
(15, [C16H12F6N3S]+), 333 (63, [C10H18F3N3O2S2]+), 271 (100,
[C9H4F6NS]+), 229 (67, [C8H5F6N]+).
IR (ATR): 2932 (w, CHsp3), 2357 (w), 1708 (s, C=O), 1637 (m, C=N),
1619 (s, C=Csp2), 1436 (s, CHsp3), 1366 (s, CHsp3), 1292 (s), 1108 (m),
740 (s, CHsp2), 716 (s, CHsp2), 698 cm–1 (m, C–S–C).
HRMS (ESI): m/z [M + H]+ calcd for C29H21F6N3O2S2: 622.1052; found:
1H NMR (500 MHz, CDCl3): δ = 1.56 (virt. ddt, 3J = 13.6 Hz, 9.6 Hz, 3J ≅
3J = 4.7 Hz, 1 H, H-5), 1.71–1.80 (m, 2 H, H-4, H-6), 1.98–2.06 (m, 1 H,
H-3), 2.13–2.16 (m, 1 H, H-5), 2.30–2.34 (m, 1 H, H-3), 2.37 (virt. dt,
3J = 13.4 Hz, 3J ≅ 3J = 4.1 Hz, 1 H, H-4), 2.88 (virt. dq, 3J = 13.2 Hz, 3J ≅
3J = 3.6 Hz, 1 H, H-6), 3.69–3.71 (m, 1 H, H-2), 4.59 (ddd, 3J = 13.2 Hz,
5.3 Hz, 3.6 Hz, 1 H, H-1), 7.49 (ddd, 3J = 8.1 Hz, 6.9 Hz, 4J = 1.4 Hz, 1 H,
H-8′), 7.57 (dd, 3J = 8.2 Hz, 4J = 1.3 Hz, 1 H, H-6′), 7.60 (s, 1 H, H-4′),
7.63 (ddd, 3J = 8.2 Hz, 6.9 Hz, 4J = 1.4 Hz, 1 H, H-7′), 7.67–7.73 (m, 4 H,
H-4′′, H-5′′, H-6′′, H-7′′), 8.63 (dd, 3J = 8.1 Hz, 4J = 1.4 Hz, 1 H, H-9′),
8.89 (s, 1 H, H-11′).
13C NMR (101 MHz, CDCl3): δ = 21.3 (t, C-5), 25.6 (t, C-6), 26.4 (t, C-4),
28.5 (t, C-3), 39.1 (d, C-2), 53.2 (d, C-1), 106.6 (d, C-4′), 122.0 (d, C-
11′), 123.4 (d, 2 C, C-4′′, C-7′′), 125.7 (d, C-6′), 126.4 (d, C-8′), 126.7 (s,
C-4a′), 128.9 (s, C-9a′), 130.1 (d, C-9′), 131.9 (s, 2 C, C-3a′′, C-7a′′),
132.4 (d, C-7′), 134.2 (d, 2 C, C-5′′, C-6′′), 137.2 (s, C-5a′), 137.8 (s, C-
10a′), 141.1 (s, C-3a′), 153.4 (s, C-11a′), 168.4 (s, 2 C, C-1′′, C-3′′), 168.6
(s, C-2′), 180.0 (s, C-10′).
622.1045.
tert-Butyl [(1S,2R)-2-(Hydroxymethyl)cyclohexyl]carbamate (27)
To a solution of [(1S,2R)-2-aminocyclohexyl]methanol (26; 130 mg,
1.01 mmol, 1.00 equiv) in CH2Cl2 (2 mL) was added Et3N (280 μL,
203 mg, 2.01 mmol, 2.00 equiv). The solution was cooled to 0 °C and
Boc2O (230 mg, 1.06 mmol, 1.05 equiv) was added. The solution was
stirred and allowed to warm to rt overnight. The reaction was
quenched by the addition of aq 1 M HCl. The layers were separated
and the aqueous layer was extracted with CH2Cl2 (2 × 5 mL). The or-
ganic layers were combined and successively washed with aq NaHCO3
(2 × 15 mL) and brine (2 × 15 mL), and dried (Na2SO4). The solvent was
removed under reduced pressure and the residue was purified by
flash chromatography (3 × 10 cm, Chx/EtOAc 9:1 → 4:1). Product 27
was obtained as a yellow oil (213 mg, 928 μmol, 92%); Rf = 0.17
(Chx/EtOAc 4:1) [UV, KMnO4]; [α]D20 –30 (c = 1.00, CH2Cl2).
1H NMR (500 MHz, CDCl3): δ = 0.86–0.98 (m, 1 H, H-5), 1.14–1.36 (m,
3 H, H-3, H-4, H-6), 1.45 [s, 9 H, C(CH3)3], 1.52–1.83 (m, 5 H, H-2, H-3,
H-5, H-6, OH), 3.21 (virt. t, 3J ≅ 3J = 11.4 Hz, 1 H, CHHOH), 3.34 (dd, 2J =
11.9 Hz, 3J = 4.7 Hz, 1 H, CHHOH), 4.04–4.07 (m, 1 H, H-1), 4.77 (d, 3J =
9.0 Hz, 1 H, NH).
MS (EI, 70 eV): m/z (%) = 480 (3, [M]+), 333 (100, [C20H15NO3S]+).
HRMS (ESI): m/z [M + H]+ calcd for C28H20N2O4S: 481.1217; found:
481.1217.
1-[3′′,5′′-Bis(trifluoromethyl)phenyl]-3-{(1S,2R)-2-(10′-oxo-10′H-
thioxantheno[2′,3′-d]oxazol-2′-yl)cyclohexyl}thiourea (3)
13C NMR (126 MHz, CDCl3): δ = 21.0 (t, C-5), 23.1 (t, C-4), 24.9 (t, C-3),
28.2 (q, CH3), 30.3 (t, C-6), 43.1 (d, C-2), 45.1 (d, C-1), 63.9 (t, CH2OH),
80.0 [s, C(CH3)3], 157.2 (s, NHCO).
To a solution of oxazole 25 (510 mg, 1.06 mmol, 1.00 equiv) in anhyd
EtOH (35 mL) were added anhyd CH2Cl2 (35 mL) and ethylenediamine
(638 mg, 0.71 mL, 10.6 mmol, 10.0 equiv) and the mixture was
stirred at 50 °C for 24 h. After this time, the solvent was evaporated,
diluted with CH2Cl2, and filtered over SiO2. After evaporation of the
solvent, the crude material was used in the next step without further
purification. The crude material was dissolved in anhyd THF (70 mL)
and 1-isothioxyanato-3,5-bis(trifluoromethyl)benzene (575 mg,
0.39 mL, 2.12 mmol, 2.00 equiv) was added. The reaction mixture
was stirred at rt and after 18 h, the solvent was evaporated. Purifica-
tion by flash chromatography (2 × 15 cm, Pn/EtOAc 4:1) afforded the
final thiourea as a yellow solid (300 mg, 0.48 mmol, 46% over 2 steps);
The spectroscopic data match the literature values.30a
tert-Butyl [(1S,2R)-2-Formylcyclohexyl]carbamate (28)
A solution of oxalyl chloride (0.55 mL, 824 mg, 6.50 mmol, 1.00 equiv)
in CH2Cl2 (16 mL) was cooled to –78 °C, before a solution of DMSO
(1.38 mL, 1.52 g, 19.5 mmol, 3.00 equiv) in CH2Cl2 (2 mL) was added
dropwise. The solution was stirred for 1 h at –78 °C. Subsequently, a
solution of carbamate 27 (1.49 g, 6.50 mmol, 1.00 equiv) in CH2Cl2 (7
mL) was added slowly over 10 min. After an additional 10 min, NEt3
(4.50 mL, 3.30 g, 32.5 mmol, 5.00 equiv) was added. The reaction mix-
ture was stirred for an additional 15 min at –78 °C and then allowed
to warm to rt. The reaction was quenched by the addition of H2O (20
mL). The layers were separated and the aqueous layer was extracted
with CH2Cl2 (2 × 20 mL). The combined organic layers were washed
successively with aq NH4Cl (1 × 60 mL) and brine (1 × 60 mL), dried
(Na2SO4), and filtered. All volatiles were removed under reduced pres-
sure and the product 28 was obtained as a brownish solid (1.39 g,
6.12 mmol, 94%) and used in the next step without further purifica-
tion; mp 23–25 °C; [α]D20 +82.4 (c = 0.17, CH2Cl2).
20
mp 126–128 °C; Rf = 0.22 (Pn/EtOAc 4:1) [UV, KMnO4]; [α]D –216
(c = 1.00, CH2Cl2).
IR (ATR): 2936 (w, CHsp3), 1711 (s, C=O), 1607 (m, C=Csp2), 1589 (m,
C=Csp2), 1520 (s, C=Csp2), 1436 (s, CHp3), 1383 (s), 1274 (s), 1174 (s),
1129 (s), 743 (s, CHp3), 698 cm–1 (m, C–S–C).
1H NMR (400 MHz, DMSO-d6): δ = 1.51–1.89 (m , 6 H, H-3, H-4, H-5,
H-6), 1.99–2.15 (m, 2 H, H-3, H-6), 3.79 (virt. td, 3J ≅ 3J = 7.4 Hz,
3J = 4.3 Hz, 1 H, H-2), 4.99 (virt. tt, 3J ≅ 3J = 8.3 Hz, 4.0 Hz, 1 H, H-1),
7.58 (ddd, 3J = 8.2, 6.8 Hz, 4J = 1.5 Hz, 1 H, H-8′), 7.62 (s, 1 H, H-4′),
Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–M

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Synthesis
1H NMR (300 MHz, CDCl3): δ = 1.19–1.38 (m, 1 H, H-5), 1.43 [s, 9 H,
C(CH3)3], 1.53–1.77 (m, 6 H, H-3, H-4, H-5, H-6), 1.91–2.01 (m, 1 H, H-
3), 2.71 (virt. q, 3J ≅ 3J = 4.6 Hz, 1 H, H-2), 3.97 (virt. tt, 3J ≅ 9.1, 4.1 Hz,
1 H, H-1), 5.15–5.31 (m, 1 H, NH), 9.70 (d, 3J = 4.2 Hz, 1 H, CHO).
13C NMR (126 MHz, CDCl3): δ = 22.9 (t, C-3), 23.7 (t, C-5), 23.9 (t, C-4),
28.5 (q, CH3), 29.8 (t, C-6), 48.2 (d, C-1), 52.1 (d, C-2), 79.6 [s, C(CH3)3],
155.5 (s, NHCO), 204.8 (s, CHO).
(2 × 20 cm, Chx/EtOAc 50:1 → 20:1 → 5:1) to give the title compound
as a bright yellow solid (121 mg, 280 μmol, 78%); mp 185–187 °C; Rf =
0.16 (Chx/EtOAc 20:1) [UV, KMnO4]; [α]D20 –154 (c = 1.00, CH2Cl2).
IR (ATR): 3364 (w, N–H), 3058 (w, ArH), 2973 (w, CH3), 2934 (w, CH2),
2859 (w, C–H), 2221 (w, C≡C), 1681 (m, C=O), 1642 (m, C=O), 1438 (m,
N–H), 1248 (m), 1162 (m), 894 (w), 825 (w), 743 (m), 620 cm–1 (w).
1H NMR (400 MHz, CDCl3): δ = 1.32–1.40 (m, 1 H, H-5), 1.47 [s, 9 H,
C(CH3)3], 1.57–1.71 (m, 4 H, H-3, H-4, H-6), 1.75–1.81 (m, 2 H, H-5, H-
6), 1.93–2.02 (m, 1 H, H-3), 3.18–3.26 (m, 1 H, H-2), 3.62–3.72 (m, 1
H, H-1), 4.85 (d, 3J = 9.5 Hz, 1 H, NH), 7.53 (dd, 3J = 7.2 Hz, 4J = 1.4 Hz, 1
H, H-4′), 7.55 (d, 3J = 8.4 Hz, 1 H, H-7′), 7.61 (dd, 3J = 8.1 Hz, 4J = 1.4 Hz
1 H, H-5′), 7.64–7.66 (m, 2 H, H-3′, H-6′), 8.63 (dd, 3J = 8.1 Hz, 4J = 1.5
Hz, 1 H, H-8′), 8.66 (d, 4J = 1.8 Hz, 1 H, H-1′).
13C NMR (101 MHz, CDCl3): δ = 21.2 (t, C-4), 25.2 (t, C-5), 28.6 (q,
CH3), 29.5 (t, C-6), 30.6 (t, C-3), 34.4 (d, C-2), 51.0 (d, C-1), 79.6 [s,
OC(CH3)3], 83.2 (s, CHC≡CAr), 91.3 (s, CHC≡CAr), 122.0 (s, C-2′), 126.1
(d, C-5′), 126.2 (d, C-4′), 126.7 (d, C-7′), 128.8 (s, C-8a′), 129.2 (s, C-
1a′), 130.1 (d, C-8′), 132.6 (d, C-6′), 133.1 (d, C-1′), 135.1 (d, C-3′),
136.8 (s, C-4a′), 137.1 (s, C-5a′), 155.3 (s, NHCO), 179.5 (s, C=O).
The spectroscopic data match the literature values.30a
tert-Butyl [(1S,2S)-2-Ethynylcyclohexyl]carbamate (29)
A solution of dimethyl(diazomethyl)phosphonate (1.90 g, 12.6 mmol,
2.05 equiv) in THF (15 mL) was cooled to –78 °C. KOtBu (1.45 g,
12.9 mmol, 2.10 equiv) was added and the solution was stirred for 1
h. Subsequently, a solution of aldehyde 28 (1.39 g, 6.16 mmol, 1.00
equiv) in THF (190 mL) was added slowly. The reaction mixture was
stirred for 15 h and was allowed to warm to rt during that time. The
reaction was quenched by the addition of aq NH4Cl (80 mL). The lay-
ers were separated and the aqueous layer was extracted with EtOAc
(3 × 80 mL). The combined organic layers were successively washed
with aq NH4Cl (2 × 250 mL) and brine (2 × 250 mL), dried (Na2SO4),
and all the volatiles were removed under reduced pressure. The crude
product was purified by flash chromatography (4 × 20 cm,
Chx/EtOAc 10:1) to afford 29 as a colorless solid (0.91 g, 4.07 mmol,
MS (EI, 70 eV): m/z (%) = 333 (100, [M – CO2t-Bu]+), 290 (89,
[C19H14OS]+), 237 (92, [C15H9OS]+), 139 (11, [C7H7OS]+).
HRMS (ESI): m/z [M + H]+ calcd for C26H28NO3S: 434.1784; found:
434.1784.
20
67%); mp 50 °C; Rf = 0.64 (Chx/EtOAc 4:1) [UV, KMnO4]; [α]D −24
(c = 1.00, CH2Cl2).
2′-{[(1S,2S)-2-Aminocyclohexyl]ethynyl}-9′H-thioxanthen-9′-one
(32)
IR (ATR): 3437 (w, N–H), 3309 (w, C–H), 2977 (w, CH3), 2934 (m, CH2),
2860 (w, C–H), 2111 (w, C≡C), 1702 (s, C=O), 1497 (s, N–H), 1365 (m),
1245 (m), 1165 (s), 944 (w), 864 (w), 779 (w), 626 cm–1 (m).
1H NMR (400 MHz, CDCl3): δ = 1.22–1.34 (m, 1 H, H-5), 1.44 [s, 9 H,
C(CH3)3], 1.48–1.66 (m, 4 H, H-3, H-4, H-6), 1.67–1.76 (m, 2 H, H-5, H-
6), 1.80–1.89 (m, 1 H, H-3), 2.11 (d, 4J = 2.5 Hz, 1 H, C≡CH), 2.96 (br s, 1
H, H-2), 3.56 (virt. ddt, 3J = 13.1 Hz, 8.6 Hz, 3J ≅ 3J = 4.0 Hz, 1 H, H-1),
4.80 (d, 3J = 9.4 Hz, 1 H, NH).
Boc-protected amine 31 (75 mg, 173 μmol, 1.00 equiv) was dissolved
in CH2Cl2 (2 mL) and cooled to 0 °C. TFA (132 μL, 197 mg, 1.73 mmol,
10.0 equiv) was slowly added and the solution was stirred at rt for 2 h.
The reaction was quenched by the addition of H2O (5 mL) and the lay-
ers were separated. The aqueous layer was extracted with CH2Cl2 (2 ×
5 mL). The combined organic layers were successively washed with aq
NaHCO3 (2 × 15 mL) and brine (1 × 15 mL), dried (Na2SO4), and the
volatiles were removed under reduced pressure. The crude product
was purified by flash column chromatography (2 × 20 cm, CH2-
Cl2/MeOH 19:1 + 1 vol% NH3) to give the title compound as a slowly
crystallizing yellow oil (43.3 mg, 130 μmol, 78%); Rf = 0.54 (CH2-
13C NMR (126 MHz, CDCl3): δ = 20.8 (t, C-4), 25.1 (t, C-5), 28.6 (q,
CH3), 29.0 (t, C-6), 30.2 (t, C-3), 33.4 (d, C-2), 50.5 (d, C-1), 71.9 (d,
C≡CH), 79.4 [s, C(CH3)3], 84.1 (s, C≡CH), 155.2 (s, NHCO).
MS (EI, 70 eV): m/z (%) = 167 (30, [C9H13NO2]+), 123 (27, [C9H13N]+),
20
Cl2/MeOH 9:1 + 1 vol% NH3) [UV, KMnO4]; [α]D –66 (c = 1.00, CH2-
106 (27, [C8H10]+), 57 (100, [C4H8]+).
Cl2).
HRMS (ESI): m/z [M + H]+ calcd for C13H22NO2: 224.1645; found:
224.1645.
IR (ATR): 3360 (w, N–H), 3058 (w, ArH), 2929 (m, CH2), 2855 (w, C–H),
2222 (w, C≡C), 1639 (m, C=O), 1591 (m, N–H), 1461 (m), 1438 (m),
1397 (m), 1326 (m), 1079 (w), 917 (w), 742 (m), 635 cm–1 (w).
1H NMR (400 MHz, CDCl3): δ = 1.27–1.36 (m, 1 H, H-5), 1.46–1.78 (m,
8 H, H-3, H-4, H-5, H-6, NH2), 1.92–2.00 (m, 1 H, H-6), 2.83 (virt. dt,
3J = 10.2 Hz, 3J ≅ 3J = 3.9 Hz, 1 H, H-2), 3.04 (virt. q, 3J ≅ 3J = 4.1 Hz, 1 H,
H-1), 7.45–7.51 (m, 2 H, H-7′, H-4′), 7.55 (d, 3J = 7.7 Hz, 1 H, H-5′),
7.59–7.64 (m, 2 H, H-6′, H-3′), 8.60 (dd, 3J = 8.1 Hz, 4J = 1.5 Hz, 1 H, H-
8′), 8.64 (d, 4J = 1.7 Hz, 1 H, H-1′).
13C NMR (101 MHz, CDCl3): δ = 21.8 (t, C-5), 24.6 (t, C-4), 30.2 (t, C-6),
32.7 (t, C-3), 37.5 (d, C-1), 51.9 (d, C-2), 83.2 (s, CHC≡C), 92.0 (s,
CHC≡C), 122.2 (s, C-2′), 126.1 (d, C-5′), 126.2 (d, C-4′), 126.6 (d, C-7′),
129.1 (s, C-8a′), 129.2 (s, C-1a′), 130.1 (d, C-8′), 132.5 (d, C-6′), 133.0
(d, C-1′), 135.0 (d, C-3′), 136.6 (s, C-4a′), 137.0 (s, C-5a′), 179.5 (s,
C=O).
tert-Butyl {(1S,2S)-2-[(9′-Oxo-9′H-thioxanthen-2′-yl)-ethynyl]cy-
clohexyl}carbamate (31)
Alkyne 29 (80 mg, 360 μmol, 1.00 equiv) and bromothioxanthone
3034 (114 mg, 394 μmol, 1.10 equiv) were dissolved in anhyd THF (18
mL) and freshly distilled NEt3 (18 mL). The solution was degassed
three times by the freeze-pump-thaw37 method. Subsequently,
Pd(PPh3)4 (41.4 mg, 35.8 μmol, 0.10 equiv) and CuI (13.6 mg, 71.6
μmol, 0.20 equiv) were added and the mixture was again degassed
four times by the freeze-pump-thaw method. The mixture was heat-
ed to 60 °C for 16 h in a sealed tube. After cooling to rt, the volatiles
were removed under reduced pressure. The black residue was dis-
solved in CH2Cl2 (20 mL) and the organic layer was washed succes-
sively with aq NH4Cl (2 × 20 mL) and brine (2 × 20 mL). The organic
layer was dried (Na2SO4) and the solvent was removed under reduced
pressure. The crude product was purified by flash chromatography
MS (EI, 70 eV): m/z (%) = 333 (100 [M]+), 290 (89, [C19H14OS]+), 237
(89, [C15H9OS]+), 139 (11, [C7H7OS]+).
HRMS (ESI): m/z [M + H]+ calcd for C21H20NOS: 334.1260; found:
334.1259.
Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–M

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Synthesis
1-[3′′,5′′-Bis(trifluoromethyl)phenyl]-3-{(1S,2S)-2-[(9′-oxo-9′H-
thioxanthen-2′-yl)ethynyl]cyclohexyl}thiourea (4)
Funding Information
Financial support by the European Research Council under the Euro-
pean Union’s Horizon 2020 research and innovation programme
(grant agreement No 665951 – ELICOS) and the Alexander von
Humboldt-Stiftung (postdoctoral fellowship to E. R.) is gratefully
To a solution of amine 32 (240 mg, 730 μmol, 1.00 equiv) in THF (11
mL) was added isothiocyanate 13 (145 μL, 214 mg, 791 μmol, 1.10
equiv) and the reaction mixture was stirred for 16 h at rt. Then, the
solvent was removed under reduced pressure and the crude product
was purified by flash chromatography (3 × 15 cm, Chx/EtOAc 9:1 →
4:1). The product 4 was isolated as a bright yellow solid (330 mg, 550
μmol, 74%); mp 201–202 °C; Rf = 0. 43 (Chx/EtOAc 4:1) [UV, KMnO4];
[α]D20 –104 (c = 1.00, CH2Cl2).
acknowledged.
E
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Supporting Information
IR (ATR): 3327 (br w, N–H), 3061 (w, ArH), 2934 (w, CH2), 2858 (w, C–
H), 2223 (w, C≡C), 1618 (m, C=O), 1585 (m, N–H), 1523 (m, N–H),
1276 (m, C–F), 1172 (s, C=S), 1128 (s), 986 (m), 884 (m), 744 (m), 681
cm–1 (m).
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1590931.
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1H NMR (500 MHz, CDCl3): δ = 1.40–1.50 (m, 1 H, H-5), 1.59–1.67 (m,
2 H, H-4), 1.67–1.73 (m, 1 H, H-3), 1.77 (td, 3J = 12.4 Hz, 3.8 Hz, 1 H, H-
6), 1.82–1.88 (m, 1 H, H-5), 1.95–2.01 (m, 1 H, H-3), 2.06–2.12 (m, 1
H, H-6), 3.48 (virt. q, 3J ≅ 3J = 4.0 Hz, 1 H, H-2), 4.65 (virt. ddt, 3J = 11.8
Hz, 7.7 Hz, 3J ≅ 3J = 3.5 Hz, 1 H, H-1), 7.04 (d, 3J = 7.7 Hz, 1 H, H-3′),
7.12 (d, 3J = 8.3 Hz, 1 H, H-4′), 7.38 (d, 3J = 8.7 Hz, 1 H, cyclohexyl-
NHCS), 7.49–7.54 (m, 2 H, H-5′, H-4′′), 7.58 (dd, 3J = 8.1 Hz, 4J = 0.7 Hz,
1 H, H-7′), 7.66 (ddd, 3J = 8.3 Hz, 7.0 Hz, 1.3 Hz, 1 H, H-6′), 7.99 (br s, 2
H, H-2′′, H-6′′), 8.32 (d, 4J = 1.6 Hz, 1 H, H-1′), 8.50 (dd, 3J = 8.2 Hz, 4J =
1.3 Hz, 1 H, H-8′), 9.11 (s, 1 H, Ar-NHCS).
13C NMR (101 MHz, CDCl3): δ = 21.1 (t, C-4), 25.1 (t, C-5), 28.6 (t, C-6),
30.3 (t, C-3), 33.5 (d, C-2), 54.9 (d, C-1), 83.2 (s, CHC≡C), 91.4 (s,
CHC≡C), 118.4 (d, C-4′′), 121.7 (s, C-2′), 123.7 (d, C-2′′), 123.8 (d, C-6′′),
124.5 (s, CF3), 125.7 (d, C-4′), 126.3 (d, C-7′), 127.0 (d, C-5′), 128.3 (s,
C-1a′), 128.6 (s, C-8a′), 129.8 (d, C-8′), 131.6 (s, C-3′′), 132.0 (s, CF3),
132.3 (s, C-5′′), 132.5 (d, C-1′), 133.1 (d, C-6′), 134.8 (d, C-3′), 137.0 (s,
C-4a′), 137.6 (s, C-5a′), 140.4 (s, C-1′′), 180.0 (s, C=S), 180.3 (s, C=O).
Primary Data
for this article are available online at https://doi.org/10.1055/s-0036-
1590931 and can be cited using the following DOI: 10.4125/pd0096th.
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The spectroscopic data match the literature values.3h
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Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–M