Synthesis of Chiral Triazole-Based Halogen Bond Donors

Article abstract of DOI:10.1055/s-0037-1610864

The number of applications that use halogen bonding in the fields of self-assembly, supramolecular aggregation, and catalysis is growing. However, the accessibility of chiral halotriazoles shows that there is still a lot more to explore. The simple click-chemistry is applied for the straightforward synthesis of enantiomerically pure mono- and bidentate as well as multifunctional iodotriazole-based XB donors. The methodology is characterized by a wide variability due to easy access of chiral azides.

Full text of DOI:10.1055/s-0037-1610864

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2019, 51, A–H
paper
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en
M. Kaasik et al.
Paper
Synthesis
Synthesis of Chiral Triazole-Based Halogen Bond Donors
Mikk Kaasik
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functionalized
chiral azide
Sandra Kaabel
Kadri Kriis
Ivar Järving
Tõnis Kanger*
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chiral
bifunctional
XB donor
Department of Chemistry and Biotechnology,
School of Science, Tallinn University of Technology,
Akadeemia tee 15, 12618 Tallinn, Estonia
tonis.kanger@taltech.ee
XB donor unit
Received: 28.12.2018
Accepted after revision: 02.02.2019
Published online: 12.03.2019
strong XB donors, due to the strongly polarizing effect of
the carbonyl groups.8 Nitrogen-containing cycles (pyri-
dines, imidazoles, and triazoles)9 are especially valuable as
the quaternization of the nitrogen atom makes it possible to
increase the electronegativity of the core.5a,10
DOI: 10.1055/s-0037-1610864; Art ID: ss-2018-t0869-op
Abstract The number of applications that use halogen bonding in the
fields of self-assembly, supramolecular aggregation, and catalysis is
growing. However, the accessibility of chiral halotriazoles shows that
there is still a lot more to explore. The simple click-chemistry is applied
for the straightforward synthesis of enantiomerically pure mono- and
bidentate as well as multifunctional iodotriazole-based XB donors. The
methodology is characterized by a wide variability due to easy access of
chiral azides.
O
X-X
X
CF3
X
X
X
Ar
Ar
X
X
N
O
O
O
C
N
X
S
O
F2
R
R
N
R'''
X
R'''
X
R'
R'
N
N
N
N
N
X
N
X
N
N
R''''
N
R''''
N
N
Key words click chemistry, nitrogen heterocycles, halogen bonds,
hydrogen bonds, chiral compounds
Y
R''
R''
Y
Y
In this work
In this work
Figure 1 Typical examples of halogen bond donor scaffolds. Most
commonly the donor atom X in the XB donor is either iodine or
bromine
Non-covalent interactions are of importance in biology
and chemistry.1 In chemistry, self-assembly, supramolecu-
lar aggregation, and often catalysis are based on these inter-
actions. The past ten years have seen remarkable advances
in the use of halogen bonding in these fields.2 A halogen
bond (XB) is similarly to a hydrogen bond (HB) a non-cova-
lent interaction of an electrophilic atom with some Lewis
base.3 The strength of the XB depends on the structures of
both the acceptor and the donor. The donor ability is con-
nected with the polarizability of the halogen atom and
changes in the order I > Br > Cl > F.4 Electron-withdrawing
groups connected with the halogen can further polarize the
halogen atom and therefore increase its donor ability.5
Over the years the choice of XB donor scaffolds has con-
siderably expanded. The first XB donors to be described
were dihalogens and interhalogens (Figure 1).6 However, or-
ganic scaffolds offer wider opportunities to modify the XB
donor ability of the halogen atom. For example, the XB do-
nor ability increases with an increase in the s-character on
the carbon atom when comparing haloalkanes, haloarenes,
and haloalkynes.4,7 N-Haloimides have also been used as
Triazole-based XB donors are readily accessible via a
copper-catalyzed click reaction between haloalkyne and
organic azide.11 Alternatively, terminal alkynes can also be
used, in which case halogenation is carried out in situ.12 The
halotriazoles have been used in ion-pair recognition,13 as
anion receptors,10b,14 in organocatalysis,15 and in polymer
chemistry.16 Iodotriazoles as XB donors were first intro-
duced by Beer.17 In spite of a wide variety of available chiral
azides, the application of chiral triazole-based XB donors is
quite limited. The pioneering work in this field was pub-
lished by Huber et al. in 2012.15a We have recently shown
enantiodiscrimination via XBs using chiral iodotriazoles.18
Beer et al. have used chiral triazole-based rotaxanes.19
BINOL-based receptors have been designed for the enantio-
selective recognition of anions.14b,20 Interestingly, a stereo-
genic unit was also used as a bridge between two XB donor
units. In addition, a macrocyclic pseudopeptide containing
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–H

B
M. Kaasik et al.
Paper
Synthesis
three triazole cores was used as a halide receptor by Kubik
et al.14c Selected examples of chiral XB donors are depicted
in Figure 2.
The second group of XB donors contained a hydroxyl
group as the HB donor unit (compounds 5 and 6). cis-
(1S,2R)-1-Amino-2-indanol and (1S,2R)-2-amino-1,2-di-
phenylethan-1-ol were transformed into the corresponding
azides, which were then used to get XB donors 5 and 6 (85%
and 80%, respectively) and corresponding triazolium salts
(5-OTf, 6-OTf).
For the synthesis of donors 7 and 8, the second ap-
proach, converting the hydroxyl group into an azido group,
was used. The synthesis of compound 7 started from Boc-
protected (S)-prolinol. It was mesylated and treated with
sodium azide to give the azide. After the formation of the
triazole, the Boc-protecting group was removed affording
the target containing a basic amino group in 56% yield
(yield for two steps). A similar strategy was used to convert
(–)-menthol into XB donor 8 with a bulky substituent. Un-
fortunately the click reaction worked reasonably well only
N
N
N
CF3
CF3
CF3
N
Oct
N
N
N
OTf
N
I
OMe
OMe
N
CF3
2 PF6
O
I
N
I
I
Oct
N
N
N
N
H
N
O
N
N
N
N
N
N
N
I
O
I
HN
N
N
I
NH
NH
N
N
N
N
N MeO
O
N
MeO
O
I
with
tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine
HN
Boc
N
N
I
N
N
N
(TBTA) and gave the product in a lower yield (38%; for de-
tails, see Supporting Information).
N
I
I
O
N
O
N
The iodotriazoles 8 and 4b-OTf were analyzed and char-
acterized by single-crystal X-ray crystallography (Figure 3).
In the case of triazole 8, an XB formed between the iodine
atom of one donor and the nitrogen atom in the triazole
core of another molecule of 8. The distance of 2.947 Å cor-
responds to a reduction of the sum of the van der Waals ra-
dii by 16%. In the case of 4b-OTf the carbonyl oxygen acted
as an XB acceptor and the distance of 2.724 Å corresponds
to a reduction of the sum of the van der Waals radii by 22%.
Notably, in contrast to the triazolium salts previously stud-
ied,18 which formed XBs to the counter anions, the carbonyl
group of 4b-OTf outcompeted the trifluoromethanesulfon-
ate anion as an XB acceptor.
N
PF6
N
N
O
H
O
BocHN
O
Figure 2 Examples of chiral iodotriazole-based XB donors
To broaden the scope of available chiral XB donors, we
describe herein the synthesis of enantiomerically pure tri-
azole derivatives. The synthesis of mono- and bidentate as
well as multifunctional donors containing both XB and hy-
drogen bond donor moieties will be discussed.
To start with, enantiomerically pure monodentate XB
donors were synthesized from monoalkynes (iodo-
ethynyl)benzene or 1-(iodoethynyl)-3,5-bis(trifluorometh-
yl)benzene (Scheme 1). Chiral amines or alcohols were used
to obtain azides for a click reaction. Amines were directly
converted into azides by reaction with imidazole-1-sulfonyl
azide hydrochloride with the retention of the stereocenter.
Alcohols were converted into corresponding mesylates and
nucleophilic substitution resulted in azides with the inver-
sion of the stereocenter (for details, see Supporting Infor-
mation).
First, (1R,2R)-1,2-diaminocyclohexane was used as a
chiral starting compound. Monoprotection of the diamine
using phthalic anhydride, followed by acylation, then
deprotection and azidation using imidazole-1-sulfonyl
azide hydrochloride afforded azides with acyl-, benzoyl- or
pivaloyl-protected amino groups.21,22 A click reaction in the
presence of CuI and tris[(1-tert-butyl-1H-1,2,3-tri-
azolyl)methyl]amine (TTTA)11b led to triazoles 4a–c in good
yields (81–87%). The following quaternization with methyl
trifluoromethanesulfonate (MeOTf) afforded XB donors 4a-
OTf to 4c-OTf with an amide-based HB donor group.
CuI, TTTA or
CuI, TBTA
OTf
Ar
N
MeOTf
N
N
N
N
N
+
I
Ar
Q*-N3
Ar
*Q
*Q
I
I
3
1
2
3-OTf
CF3
N
N
N
N
N
N
N
N
CF3
I
Ph
Ph
5: 85%; 5-OTf: 81%
N
I
NH
R
I
OH
OH
6: 80%; 6-OTf: 78%
4a: R = Ac 81%; 4a-OTf: 20%
4b: R = Bz 87%; 4b-OTf: 60%
4c: R = Piv 81%; 4c-OTf: 88%
CF3
CF3
N
I
N
N
N
I
N
N
N
H
CF3
CF3
7: 56% (over two steps, including
8: 38%
deprotection of the pyrrolidine)
Scheme 1 Synthesis of monodentate XB donors
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–H

C
M. Kaasik et al.
Paper
Synthesis
CF3
O
B)
A)
F3C
F3C
CF3
CF3
O
N3
Cl
S
1.
NCO
O
N
NH2
O
HN
N
N
CF3
H
H
168.2o
O
170.5o
2. H+
2.947 Å
NHBoc
11
NH2
2.724 Å
12
CF3
CF3
CF3
CF3
F3C
O
O
Figure 3 Ball and stick representations of 8 (A) and 4b-OTf (B) show-
ing the angle and distances of the XB between the molecules (see Sup-
porting Information for details)
I
CF3
N
N
H
CF3
N
N
H
H
H
F3C
O
N
O
I
CF3
N3
N
13
N
Next, bidentate C2-symmetric XB donors 9 and 10 were
synthesized starting from cis-(1S,2R)-1-amino-2-indanol
and meta-bis(iodoethynyl)benzene (Scheme 2). Compound
9 was obtained by azidating the free amino group, followed
by a click reaction. On the other hand, the selective N-triflu-
oroacetylation of cis-aminoindanol allowed the transforma-
tion of the unprotected hydroxyl group into azide by the
previously described mesylation/substitution method with
inversion of the configuration. This synthon for the click re-
action differed from the synthon obtained by direct azida-
tion in the relative configuration of the substituents on the
indane ring. Also, the azido group and the respective bond
with the triazole ring changed from the first to the second
position on the indane ring. The click reaction proceeded
smoothly affording triazole 10 in an excellent yield. Com-
pounds 9 and 10 were again converted into corresponding
triazolium salts in high yields. The obtained XB donors pos-
sessed different HB moieties and formed chiral pockets for
acceptors with different geometries.
CF3
14: 90%
14-OTf: 55%
MeOTf
Scheme 3 Synthesis of urea-containing XB donor 14-OTf
Aminoindanol derivative 11 was used as a chiral linker
to connect urea and triazole moieties.23 The reaction of 3,5-
bis(trifluoromethylphenyl) isocyanate with the aromatic
amine 11 afforded after acidic deprotection urea 12 in 92%
yield. The following azidation with imidazole-1-sulfonyl
azide hydrochloride and a click reaction resulted in the for-
mation of triazole 14.
In conclusion, we have shown a straightforward ap-
proach to enantiomerically pure XB donors. A click reaction
provides a direct entry to the target compounds. Monoden-
tate, bidentate, and polyfunctional XB donors can be ob-
tained in high yields. Further studies on the applications of
these compounds are ongoing.
CF3
O
I
I
NH
N3
2
1
1
NMR spectra were measured on a Bruker Avance III 400 MHz instru-
ment. The spectra are reported in parts per million () referenced to
the residual solvent signal [CDCl3  = 7.26, CD3OD  = 3.31, DMSO-d6
 = 2.50, acetone-d6  = 2.05 (for 1H NMR); CDCl3  = 77.16, CD3OD
 = 49.00, DMSO-d6  = 39.52, acetone-d6  = 29.84 (for 13C NMR)]).
High-resolution mass spectra were recorded on an Agilent Technolo-
gies 6540 UHD Accurate-Mass Q-TOF LC/MS spectrometer by using
AJ-ESI ionization. Single crystal X-ray diffraction data was collected at
123K on Rigaku Compact HomeLab diffractometer, equipped with a
Saturn 944 HG CCD detector and Oxford Cryostream cooling system
using monochromatic Cu-K radiation (1.54178Å) from a MicroMax-
TM-003 sealed tube microfocus X-ray source. Optical rotations were
obtained using an Anton Paar GWB Polarimeter MCP 500. IR absorp-
tion frequencies in wavenumbers are listed, with the relative strength
in parentheses (w = weak, m = medium, s = strong, br = broad). Pre-
coated silica gel 60 F254 plates from Merck were used for TLC, whereas
for column chromatography, silica gel Kieselgel 40–63 m was used.
The measured melting points are uncorrected. Purchased chemicals
and solvents were used as received. CH2Cl2 was distilled over P2O5 and
2
CuI
TTTA
CuI
TTTA
N3
OH
N
N
N
N
N
N
N
N
N
N
N
N
I
I
I
I
HO
NH
HN
OH
O
CF
3 F3C
O
9: 52%
9-OTf: 86%
10: 94%
10-OTf: 97%
MeOTf
MeOTf
Scheme 2 Synthesis of bidentate XB donors
The synthetic potential of chiral azides and a click reac-
tion was further harnessed to access triazole and urea-con-
taining polyfunctional donor 14 (Scheme 3).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–H

D
M. Kaasik et al.
Paper
Synthesis
MeOH was dried by distillation over Na metal. Petroleum ether (PE)
has a boiling point of 40–60 °C. The reactions were performed with-
out additional moisture elimination, unless stated otherwise.
N-[(1R,2R)-2-(5-Iodo-4-phenyl-1H-1,2,3-triazol-1-yl)cyclo-
hexyl]benzamide (4b)
Eluent for chromatography: starting from 5% of EtOAc in CH2Cl2; col-
orless solid; yield: 0.335 g (0.709 mmol, 87%); mp 193–196 °C; []D
20
Click Reaction; General Procedure
–28.6 (c 0.30, CHCl3).
CuI (0.004 g, 0.021 mmol) and TTTA (0.010 mg, 0.023 mmol) were
dissolved in freshly distilled THF (2.3 mL, 0.2 M) under argon atmo-
sphere and stirred at r.t. for 30 min. The (iodoethynyl)benzene or 1-
(iodoethynyl)-3,5-bis(trifluoromethyl)benzene (0.45 mmol) and
azide (0.45 mmol) were added and the reaction mixture was stirred
at r.t. overnight. The mixture was concentrated, NH4OH (10 mL, 10%
w/w) was added and the aqueous phase was extracted with CH2Cl2
(3 × 10 mL). The combined organic phases were dried (anhyd Na2SO4),
concentrated, and purified by column chromatography on silica gel
(starting from 10% EtOAc in PE) to provide the triazole.
IR (KBr): 3318 (m), 3063 (w), 2940 (m), 2856 (m), 1638 (s), 1579 (w),
1543 (s), 1493 (m), 1447 (w), 1322 (s), 1286 (w), 1236 (w), 1170 (w),
983 (m), 803 (w), 769 (m), 695 cm–1 (s).
1H NMR (400 MHz, CDCl3):  = 7.85–7.79 (m, 2 H), 7.57–7.50 (m, 2 H),
7.47–7.27 (m, 6 H), 6.13 (d, J = 8.0 Hz, 1 H), 4.97 (td, J = 10.8, 4.8 Hz, 1
H), 4.66–4.43 (m, 1 H), 2.37–2.16 (m, 3 H), 2.10–1.87 (m, 3 H), 1.62–
1.47 (m, 2 H).
13C NMR (101 MHz, CDCl3):  = 167.3, 149.1 (based on HMBC), 134.6,
131.6, 130.4, 128.6, 128.6, 128.6, 127.9, 126.9, 63.2 (based on HSQC),
54.3 (based on HSQC), 32.8, 31.9, 25.1, 25.0. The iodine bonded C-
atom was not detected because of low intensity of the signal.
Conversion of Triazoles into Triazolium Salts; General Procedure
HRMS (ESI): m/z [M + H]+ calcd for C21H22IN4O: 473.0833; found:
473.0828.
The respective triazole (0.19 mmol) was dissolved in CH2Cl2 (4 mL,
0.05 M) under argon atmosphere. MeOTf (0.033 mL, 0.29 mmol) was
added dropwise and the reaction mixture was stirred at r.t. for 3 days.
Et2O was added to the mixture and the precipitate formed was fil-
tered to provide the trifluoromethanesulfonic salt.
1-[(1R,2R)-2-Benzamidocyclohexyl]-5-iodo-3-methyl-4-phenyl-
1H-1,2,3-triazol-3-ium Trifluoromethanesulfonate (4b-OTf)
The product precipitated from the reaction mixture and was recrys-
tallized from hot CH2Cl2; colorless solid; yield: 0.187 g (0.294 mmol,
60%); mp >230 °C (dec.); []D20 –5.0 (c 0.21, MeOH).
N-[(1R,2R)-2-(5-Iodo-4-phenyl-1H-1,2,3-triazol-1-yl)cyclo-
hexyl]acetamide (4a)
IR (KBr): 3304 (m), 2938 (w), 2860 (w), 1641 (s), 1580 (w), 1535 (m),
1488 (w), 1455 (w), 1323 (m), 1283 (s), 1257 (s), 1225 (w), 1155 (m),
1031 (s), 771 (w), 697 (m), 638 cm–1 (s).
1H NMR (400 MHz, CD3OD):  = 7.81–7.75 (m, 2 H), 7.70–7.53 (m, 4
H), 7.50–7.37 (m, 4 H), 4.84–4.78 (m, 1 H), 4.46 (ddd, J = 11.8, 10.1, 4.4
Hz, 1 H), 4.27 (s, 3 H), 3.35 (s, 1 H), 2.53–2.36 (m, 2 H), 2.21–1.85 (m, 4
H), 1.75–1.54 (m, 2 H).
13C NMR (101 MHz, CD3OD):  = 169.6, 147.8, 134.6, 133.2, 133.2,
131.2, 130.7, 129.6, 128.5, 124.2, 92.6, 70.3, 55.7, 39.8, 32.1, 31.9,
25.6, 25.4.
HRMS (ESI): m/z [M – CF3O3S]+ calcd for C22H25IN4O: 487.0989; found:
487.0985; m/z [OTf]– calcd for CF3O3S: 148.9526; found: 148.9529.
Colorless solid; yield: 0.145 g (0.353 mmol, 81%); mp >187 °C (dec.);
[]D20 –11.9 (c 0.43, CHCl3).
IR (KBr): 3278 (s), 3073 (w), 2928 (s), 2857 (m), 1655 (s), 1552 (s),
1447 (m), 1375 (w), 1318 (w), 1228 (w), 1173 (w), 1065 (w), 985 (m),
807 (w), 768 (m), 697 cm–1 (s).
1H NMR (400 MHz, CDCl3):  = 7.95–7.89 (m, 2 H), 7.48–7.43 (m, 2 H),
7.43–7.36 (m, 1 H), 5.57 (d, J = 8.2 Hz, 1 H), 4.77 (td, J = 10.8, 4.9 Hz, 1
H), 4.47–4.20 (m, 1 H), 2.30–2.08 (m, 3 H), 2.02–1.79 (m, 3 H), 1.76 (s,
3 H), 1.62–1.40 (m, 2 H).
13C NMR (101 MHz, CDCl3):  = 169.6, 149.0 (based on HMBC), 130.4,
128.7, 128.6, 127.9, 63.5 (based on HSQC), 53.8 (based on HSQC), 32.7,
31.9, 25.0, 24.9, 23.7. The iodine bonded C-atom was not detected be-
cause of low intensity of the signal.
HRMS (ESI): m/z [M + H]+ calcd for C16H20IN4O: 411.0676; found:
411.0674.
N-[(1R,2R)-2-(5-Iodo-4-phenyl-1H-1,2,3-triazol-1-yl)cyclo-
hexyl]pivalamide (4c)
Reaction conducted in 0.3 M solution of THF; colorless solid; yield:
20
0.108 g (0.239 mmol, 81%); mp 206–210 °C; []D +3.8 (c 0.87,
CHCl3).
1-[(1R,2R)-2-Acetamidocyclohexyl]-5-iodo-3-methyl-4-phenyl-
1H-1,2,3-triazol-3-ium Trifluoromethanesulfonate (4a-OTf)
IR (KBr): 3406 (m), 2932 (s), 2865 (w), 1650 (s), 1513 (s), 1477 (m),
1448 (m), 1317 (w), 1230 (m), 1193 (m), 1169 (w), 985 (m), 957 (w),
769 (m), 696 cm–1 (m).
1H NMR (400 MHz, CDCl3):  = 7.92–7.79 (m, 2 H), 7.49–7.42 (m, 2 H),
7.42–7.36 (m, 1 H), 5.53 (d, J = 7.9 Hz, 1 H), 4.89 (dd, J = 16.2, 10.7 Hz,
1 H), 4.46–4.18 (m, 1 H), 2.30–2.04 (m, 3 H), 2.02–1.79 (m, 3 H), 1.59–
1.42 (m, 2 H), 0.94 (s, 9 H).
13C NMR (101 MHz, CDCl3):  = 178.1, 149.1 (based on HMBC), 130.5,
128.6 (o- and m-C overlapped, based on HSQC), 127.9, 62.8 (based on
HSQC), 53.9 (based on HSQC), 38.8, 32.8, 32.0, 27.5, 25.2, 25.1. The io-
dine bonded C-atom was not detected because of low intensity of the
signal.
The product was crystallized twice; colorless solid; yield: 0.040 g
(0.070 mmol, 20%); mp 192–194 °C; []D20 +40.7 (c 0.18, MeOH).
IR (KBr): 3311 (m), 2933 (m), 2862 (w), 1651 (s), 1554 (m), 1449 (w),
1372 (w), 1285 (s), 1253 (s), 1224 (w), 1163 (m), 1030 (s), 768 (w),
707 (w), 637 cm–1 (s).
1H NMR (400 MHz, CD3OD):  = 7.81–7.48 (m, 5 H), 4.75–4.60 (m, 1
H), 4.23 (s, 3 H), 4.16 (s, 1 H), 2.44–2.27 (m, 2 H), 2.12–1.89 (m, 3 H),
1.84 (s, 3 H), 1.77–1.47 (m, 3 H).
13C NMR (101 MHz, CD3OD):  = 172.8, 147.8, 133.2, 131.3, 130.8,
124.3, 121.8 (q, J = 318.6 Hz), 92.3, 70.2, 55.2, 39.7, 32.2, 31.7, 25.4,
25.3, 22.8.
HRMS (ESI): m/z [M – CF3O3S]+ calcd for C17H23IN4O: 425.0833; found:
425.0829; m/z [OTf]– calcd for CF3O3S: 148.9526; found: 148.9529.
HRMS (ESI): m/z [M + H]+ calcd for C19H26IN4O: 453.1146; found:
453.1138.
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M. Kaasik et al.
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Synthesis
5-Iodo-3-methyl-4-phenyl-1-[(1R,2R)-2-pivalamidocyclohexyl]-
1H-1,2,3-triazol-3-ium Trifluoromethanesulfonate (4c-OTf)
13C NMR (101 MHz, CDCl3):  = 146.5, 141.3, 136.9, 132.1, 132.0 (q,
J = 33.6 Hz), 130.1, 127.6, 127.4–127.2 (m), 125.7, 124.5, 123.1 (q,
J = 272.9 Hz), 122.4–122.0 (m), 79.1, 73.8, 67.3, 40.1.
Colorless solid; yield: 0.143 g (0.232 mmol, 88%); mp 218–219 °C;
[]D20 +54.3 (c 0.20, MeOH).
HRMS (ESI): m/z [M + H]+ calcd for C19H13F6IN3O: 540.0002; found:
540.0002.
IR (KBr): 3354 (m), 2937 (m), 2865 (w), 1623 (s), 1529 (s), 1485 (m),
1455 (m), 1367 (w), 1319 (w), 1284 (s), 1223 (m), 1149 (s), 1093 (w),
1032 (s), 826 (w), 766 (w), 697 (m), 637 cm–1 (s).
4-[3,5-Bis(trifluoroomethyl)phenyl]-1-[(1S,2R)-2-hydroxy-2,3-di-
hydro-1H-inden-1-yl]-5-iodo-3-methyl-1H-1,2,3-triazol-3-ium
Trifluoromethanesulfonate (6-OTf)
1H NMR (400 MHz, CDCl3):  = 7.70–7.41 (m, 5 H), 6.55 (d, J = 8.0 Hz, 1
H), 5.08–4.87 (m, 1 H), 4.23 (s, 3 H), 4.15–4.03 (m, 1 H), 2.53–2.39 (m,
1 H), 2.25 (q, J = 12.5 Hz, 1 H), 2.11–1.75 (m, 4 H), 1.65–1.36 (m, 2 H),
1.07 (s, 9 H).
25
White solid; yield: 0.091 g (0.129 mmol, 78%); mp 176–179 °C; []D
–22.0 (c 1.10, CHCl3).
13C NMR (101 MHz, CDCl3):  = 179.3, 146.1, 132.2, 130.1, 129.9,
122.6, 89.1, 68.7, 54.7, 39.5, 38.8, 31.3, 31.1, 27.7, 24.7, 24.3.
IR (KBr): 3421 (m), 1623 (w), 1371 (m), 1283 (s), 1139 (s), 1030 (s),
911 (m), 848 (w), 757 (m), 704 (m), 680 (m), 640 cm−1 (s).
1H NMR (400 MHz, CD3OD):  = 8.40 (br s, 1 H), 8.36 (br s, 2 H), 7.53–
7.32 (m, 4 H), 6.51 (d, J = 6.3 Hz, 1 H), 5.09 (q, J = 6.7 Hz, 1 H), 4.19 (s, 3
H), 3.41 (dd, J = 16.1, 7.0 Hz, 1 H), 3.14 (dd, J = 16.2, 6.9 Hz, 1 H).
HRMS (ESI): m/z [M – CF3O3S]+ calcd for C20H29IN4O: 467.1302; found:
467.1302; m/z [OTf]– calcd for CF3O3S: 148.9526; found: 148.9529.
(1R,2S)-2-(5-Iodo-4-phenyl-1H-1,2,3-triazol-1-yl)-1,2-dipheny-
lethan-1-ol (5)
13C NMR (101 MHz, CD3OD):  = 145.5, 144.0, 136.0, 134.3 (q, J = 33.6
Hz), 132.8–132.5 (m), 132.0, 128.9, 127.8, 127.2, 127.1–126.9 (m),
126.6, 124.2 (q, J = 272.5 Hz), 94.4 (based on HMBC), 73.7, 73.2, 40.0,
39.9.
Reaction conducted in 0.3 M solution of THF; colorless solid; yield:
20
0.183 g (0.392 mmol, 85%); mp >164 °C (dec.); []D +63.1 (c 0.25,
HRMS (ESI): m/z [M – CF3O3S]+ calcd for C20H15F6IN3O: 554.0159;
CHCl3).
found: 554.0159.
IR (KBr): 3227 (br m), 2924 (m), 1604 (w), 1494 (w), 1474 (w), 1454
(m), 1322 (w), 1239 (w), 1158 (w), 1048 (s), 985 (w), 828 (m), 761
(m), 748 (s), 718 (w), 697 cm–1 (s).
1H NMR (400 MHz, CDCl3):  = 7.89–7.82 (m, 2 H), 7.47–7.22 (m, 13
H), 5.90 (dd, J = 5.5, 2.5 Hz, 1 H), 5.68 (d, J = 5.5 Hz, 1 H), 3.70 (d, J = 2.5
Hz, 1 H).
(S)-4-[3,5-Bis(trifluoromethyl)phenyl]-5-iodo-1-(pyrrolidin-2-yl-
methyl)-1H-1,2,3-triazole (7)
Triazole 7 was synthesized by the general procedure for the click reac-
tion [yield of Boc-protected 7: 0.149 g (0.252 mmol, 88%)] followed by
removal of the Boc-protecting group.
13C NMR (101 MHz, CDCl3):  = 149.4, 139.2, 133.9, 130.0, 129.2,
To a solution of tert-butyl (S)-2-[4-(3,5-bis(trifluoromethyl)phenyl]-
5-iodo-1H-1,2,3-triazol-1-yl)methyl)pyrrolidine-1-carboxylate
(0.126 g, 0.213 mmol) in CH2Cl2 (1 mL) was added TFA (0.400 mL, 5.22
mmol) at 0 °C and the reaction mixture was stirred at r.t. for 3 h. The
mixture was concentrated, triturated with Et2O, and filtered to pro-
vide the salt of 7, which was treated with sat. aq NaHCO3 (2 mL). After
stirring for 15 min, the aqueous phase was extracted with CH2Cl2
(7 × 3 mL), dried (Na2SO4), and concentrated. Removal of solvent un-
der reduced pressure afforded triazole 7 as an off-white solid; yield:
129.0, 128.8, 128.7, 128.5, 128.4, 128.4, 127.7, 126.9, 78.4, 75.6, 71.4.
HRMS (ESI): m/z [M + H]+ calcd for C22H19IN3O: 468.0567; found:
468.0562.
1-[(1S,2R)-2-Hydroxy-1,2-diphenylethyl]-5-iodo-3-methyl-4-phe-
nyl-1H-1,2,3-triazol-3-ium Trifluoromethanesulfonate (5-OTf)
Colorless solid; yield: 0.099 g (0.157 mmol, 81%); mp 188–189 °C;
[]D20 –54.8 (c 0.16, MeOH).
20
0.068 g (0.139 mmol, 65%); mp 103–104 °C; []D +11.1 (c 0.68,
MeOH).
IR (KBr): 3386 (br w), 1487 (w), 1456 (w), 1251 (s), 1165 (m), 1030
(s), 756 (w), 703 (m), 639 cm–1 (m).
1H NMR (400 MHz, CD3OD):  = 7.81–7.74 (m, 2 H), 7.70–7.58 (m, 3
H), 7.55–7.45 (m, 3 H), 7.45–7.31 (m, 7 H), 6.09 (d, J = 8.6 Hz, 1 H),
5.73 (d, J = 8.5 Hz, 1 H), 4.24 (s, 3 H).
13C NMR (101 MHz, CD3OD):  = 148.0, 141.1, 134.5, 133.3, 131.1,
131.0, 130.7, 130.7, 130.1, 130.0, 129.8, 128.0, 123.8, 93.1, 76.2, 75.5,
39.8.
IR (KBr): 2926 (m), 1620 (w), 1373 (w), 1316 (m), 1285 (s), 1183 (m),
1128 (s), 896 (m), 821 (w), 698 (w), 683 cm–1 (w).
1H NMR (400 MHz, CDCl3):  = 8.48 (br s, 2 H), 7.90 (br s, 1 H), 4.41
(qd, J = 13.7, 6.7 Hz, 2 H), 3.82 (ddd, J = 13.5, 7.4, 5.9 Hz, 1 H), 3.10–
2.93 (m, 2 H), 2.03–1.74 (m, 4 H), 1.67–1.57 (m, 1 H).
13C NMR (101 MHz, CDCl3):  = 146.7, 132.5, 132.0 (q, J = 33.5 Hz),
127.4–127.2 (m), 123.2 (q, J = 272.7 Hz), 122.2–121.8 (m), 78.6, 57.7,
55.6, 46.5, 29.3, 25.3.
HRMS (ESI): m/z [M – CF3O3S]+ calcd for C23H21IN3O: 482.0724; found:
482.0723; m/z [OTf]– calcd for CF3O3S: 148.9526; found: 148.9533.
HRMS (ESI): m/z [M + H]+ calcd for C15H14F6IN4: 491.0162; found:
(1S,2R)-1-{4-[3,5-Bis(trifluoromethyl)phenyl]-5-iodo-1H-1,2,3-
triazol-1-yl}-2,3-dihydro-1H-inden-2-ol (6)
491.0157.
Et3N (2 equiv) was used instead of TTTA; eluent for chromatography:
starting from 20% of EtOAc in PE; off-white solid; yield: 0.188 g (0.349
mmol, 80%); mp 114–116 °C; []D20 +109.3 (c 1.45, CHCl3).
4-[3,5-Bis(trifluoromethyl)phenyl]-5-iodo-1-[(1S,2S,5R)-2-isopro-
pyl-5-methylcyclohexyl]-1H-1,2,3-triazole (8)
TBTA was used instead of TTTA; eluent for chromatography: starting
from 5% CH2Cl2 in PE; colorless solid; yield: 0.048 g (0.088 mmol,
38%); mp 132–134 °C; []D20 +5.9 (c 0.04, CHCl3).
IR (KBr): 3396 (br m), 1621 (w), 1374 (w), 1307 (m), 1279 (s), 1127
(s), 897 (m), 847 (w), 809 (w), 746 (m), 699 (m), 683 cm–1 (m).
1H NMR (400 MHz, CDCl3):  = 8.42 (br s, 2 H), 7.89 (br s, 1 H), 7.46–
7.21 (m, 4 H), 6.10 (d, J = 6.4 Hz, 1 H), 4.99 (dq, J = 10.0, 6.7 Hz, 1 H),
3.40 (d, J = 6.8 Hz, 2 H), 2.93 (d, J = 10.1 Hz, 1 H).
IR (KBr): 2964 (m), 2845 (w), 1622 (w), 1462 (w), 1371 (m), 1309 (m),
1280 (s), 1243 (w), 1183 (s), 1139 (s), 898 (m), 846 (w), 809 (w), 711
(w), 700 (m), 682 cm–1 (m).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–H

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Synthesis
1H NMR (400 MHz, CDCl3):  = 8.50 (br s, 2 H), 7.89 (br s, 1 H), 5.07–
4.93 (m, 1 H), 2.38 (qd, J = 13.2, 4.0 Hz, 1 H), 2.02–1.93 (m, 1 H), 1.93–
1.76 (m, 3 H), 1.55–1.45 (m, 2 H), 1.44–1.35 (m, 1 H), 1.05 (qd,
J = 13.2, 4.2 Hz, 1 H), 0.88 (d, J = 6.5 Hz, 3 H), 0.85 (d, J = 6.4 Hz, 3 H),
0.78 (d, J = 6.5 Hz, 3 H).
13C NMR (101 MHz, CDCl3):  = 145.8, 132.8, 132.0 (q, J = 33.5 Hz),
127.7–127.4 (m), 123.4 (d, J = 274.7 Hz), 122.2–121.9 (m), 79.0, 59.6,
47.2, 40.6, 35.0, 29.0, 25.32, 25.28, 22.1, 21.5, 21.0.
IR (KBr): 3428 (br m), 3073 (w), 1713 (s), 1548 (m), 1462 (w), 1208
(s), 1166 (s), 983 (w), 929 (w), 791 (w), 750 (m), 717 cm–1 (w).
1H NMR (400 MHz, acetone-d6):  = 9.20 (d, J = 8.5 Hz, 2 H), 8.71 (t,
J = 1.8 Hz, 1 H), 8.08 (dd, J = 7.8, 1.8 Hz, 2 H), 7.68 (t, J = 7.8 Hz, 1 H),
7.46–7.26 (m, 8 H), 6.19 (t, J = 7.9 Hz, 2 H), 5.76 (td, J = 8.5, 7.3 Hz, 2
H), 3.81 (dd, J = 16.1, 8.6 Hz, 2 H), 3.70 (dd, J = 16.0, 8.3 Hz, 2 H).
13C NMR (101 MHz, acetone-d6):  = 157.91 (q, J = 37.0 Hz), 149.8,
139.8, 139.3, 132.1, 129.9, 129.8, 128.7, 128.2, 126.9, 125.8, 124.6,
116.9 (q, J = 287.9 Hz), 80.2, 67.0, 61.7, 37.9.
HRMS (ESI): m/z [M + H]+ calcd for C20H23F6IN3: 546.0835; found:
546.0841.
HRMS (ESI): m/z [M + H]+ calcd for C32H23F6I2N8O2: 918.9932; found:
918.9925.
(1S,1′S,2R,2′R)-1,1′-[1,3-Phenylenebis(5-iodo-1H-1,2,3-triazole-
4,1-diyl)]bis(2,3-dihydro-1H-inden-2-ol) (9)
4,4′-(1,3-Phenylene)bis{5-iodo-3-methyl-1-[(1S,2S)-1-(2,2,2-tri-
fluoroacetamido)-2,3-dihydro-1H-inden-2-yl]-1H-1,2,3-triazol-3-
ium} Trifluoromethanesulfonate (10-OTf)
CuI (0.10 equiv) and TTTA (0.10 equiv) were used; eluent for chroma-
tography: starting from 20% of EtOAc in PE; off-white solid; yield:
0.240 g (0.33 mmol, 52%); mp 198–203 °C; []D +23.4 (c 0.36,
20
Colorless solid; yield: 0.135 g (0.108 mmol, 97%); mp >213 °C (dec.);
MeOH).
[]D20 +21.0 (c 0.70, acetone).
IR (KBr): 3406 (br s), 2918 (w), 1610 (w), 1461 (m), 1344 (m), 1241
(m), 1215 (w), 1169 (w), 1100 (s), 985 (m), 887 (w), 796 (m), 744 (s),
718 (w), 685 cm–1 (m).
1H NMR (400 MHz, DMSO-d6):  = 8.61–8.56 (m, 1 H), 7.98 (dt, J = 7.8,
1.9 Hz, 2 H), 7.66 (t, J = 7.8 Hz, 1 H), 7.45–7.20 (m, 8 H), 6.09 (d, J = 6.5
Hz, 2 H), 5.42 (d, J = 5.9 Hz, 2 H), 4.83 (tt, J = 6.5, 6.7 Hz, 2 H), 3.23 (dd,
J = 15.6, 6.9 Hz, 2 H), 3.10 (dd, J = 15.7, 6.9 Hz, 2 H).
13C NMR (101 MHz, DMSO-d6):  = 147.1, 142.2, 138.1, 131.1, 129.1,
129.0, 126.9, 126.6, 125.9, 125.3, 125.0, 83.0, 71.9, 66.8, 66.7.
HRMS (ESI): m/z [M + H]+ calcd for C28H23I2N6O2: 728.9966; found:
728.9974.
IR (KBr): 3456 (br m), 1720 (s), 1555 (m), 1482 (w), 1251 (s), 1166 (s),
1031 (s), 757 (w), 639 (m), 518 cm–1 (w).
1H NMR (400 MHz, acetone-d6):  = 9.40 (d, J = 7.8 Hz, 2 H), 8.36–8.00
(m, 4 H), 7.56–7.22 (m, 8 H), 6.09 (dt, J = 8.8, 6.6 Hz, 2 H), 6.1–5.9 (m,
2 H), 4.44 (s, 6 H), 4.04 (dd, J = 16.7, 8.5 Hz, 2 H), 3.78 (dd, J = 16.7, 6.8
Hz, 2 H).
13C NMR (101 MHz, acetone-d6):  = 158.46 (q, J = 37.3 Hz), 147.0,
139.4, 138.2, 134.9, 133.3, 132.0, 130.4, 129.0, 125.9, 125.6, 124.8,
116.78 (q, J = 287.7 Hz), 92.8, 70.4, 62.6, 40.5, 38.0.
HRMS (ESI): m/z [M – 2 CF3O3S/2]+ calcd for C34H28F6I2N8O2/2:
474.0159; found: 474.0165; m/z [OTf]– calcd for CF3O3S: 148.9526;
found: 148.9542.
4,4′-(1,3-Phenylene)bis{1-[(1S,2R)-2-hydroxy-2,3-dihydro-1H-in-
den-1-yl]-5-iodo-3-methyl-1H-1,2,3-triazol-3-ium} Trifluoro-
methanesulfonate (9-OTf)
1-(2-{[(1R,2R)-1-Azido-2,3-dihydro-1H-inden-2-yl]oxy}-5-(triflu-
oromethyl)phenyl)-3-[3,5-bis(trifluoromethyl)phenyl]urea (13)
25
White solid; yield: 0.164 g (0.155 mmol, 86%); mp 147–150 °C; []D
The urea 12 was prepared following the literature procedure.22 Ami-
nourea 12 (0.408 g, 0.725 mmol) was dissolved in a suspension of
K2CO3 (0.151 g, 1.088 mmol) and CuSO4·5H2O (0.002 mg, 0.007 mmol)
in MeOH (10 mL). Imidazole-1-sulfonyl azide hydrochloride (0.182 g,
0.868 mmol) was added and the mixture stirred overnight at r.t. The
solvent was removed under reduced pressure, then the solid was dis-
solved in H2O (5 mL), acidified with aq HCl (10 mL, 1 M), and extract-
ed with CH2Cl2 (5 × 10 mL). The combined organic layers were dried
(MgSO4), filtered, and concentrated. The crude product was purified
by column chromatography on silica gel (starting from 5% of EtOAc in
PE) to provide the azide 13, after removal of solvent under reduced
pressure, as an off-white solid; yield: 0.297 g (0.504 mmol, 70%); mp
>205 °C (dec.); []D20 –87.0 (c 0.98, MeOH).
–8.7 (c 0.70, MeOH).
IR (KBr): 3423 (br s), 1624 (w), 1556 (w), 1479 (w), 1254 (s), 1166 (s),
1100 (m), 1029 (s), 891 (w), 815 (w), 756 (m), 696 (w), 639 cm–1 (s).
1H NMR (400 MHz, CD3OD):  = 8.09–7.98 (m, 4 H), 7.53–7.40 (m, 6
H), 7.40–7.31 (m, 2 H), 6.51 (d, J = 6.5 Hz, 2 H), 5.09 (q, J = 6.8 Hz, 2 H),
4.24 (s, 6 H), 3.40 (dd, J = 16.1, 7.0 Hz, 2 H), 3.14 (dd, J = 16.1, 6.9 Hz, 2
H).
13C NMR (101 MHz, CD3OD):  = 146.6, 144.0, 136.1, 135.1, 133.5,
132.3, 131.9, 128.8, 127.8, 126.5, 126.1, 93.9 (based on HMBC), 73.7,
73.0, 40.1, 39.9.
HRMS (ESI): m/z [M – 2 CF3O3S – CH3]+ calcd for C29H25I2N6O2:
743.0123; found: 743.0124.
IR (KBr): 3346 (m), 2103 (m), 1659 (m), 1556 (m), 1490 (m), 1447
(m), 1386 (m), 1339 (m), 1279 (s), 1181 (s), 1135 (s), 920 (w), 885
(w), 682 cm–1 (w).
1H NMR (400 MHz, DMSO-d6):  = 10.05 (s, 1 H), 8.52 (s, 1 H), 8.41 (s,
1 H), 8.06 (s, 2 H), 7.66 (s, 1 H), 7.49 (d, J = 7.1 Hz, 1 H), 7.46–7.32 (m,
5 H), 5.34 (s, 1 H), 5.31 (dd, J = 7.1, 3.8 Hz, 1 H), 3.69 (dd, J = 17.0, 7.0
Hz, 1 H), 3.11 (dd, J = 16.9, 3.7 Hz, 1 H).
13C NMR (101 MHz, DMSO-d6):  = 152.1, 148.3, 141.2, 140.0, 137.1,
130.8 (q, J = 32.8 Hz), 129.6, 129.0, 127.5, 125.4, 124.8, 124.3 (q,
J = 271.2 Hz), 123.2 (q, J = 272.8 Hz), 121.8 (q, J = 31.9 Hz), 119.8–
119.7 (m), 117.9–117.7 (m), 115.4–115.2 (m), 114.8–114.7 (m), 113.0,
83.9, 69.2, 36.6.
N,N′-{(1S,1′S,2S,2′S)-[1,3-Phenylenebis(5-iodo-1H-1,2,3-triazole-
4,1-diyl)]bis(2,3-dihydro-1H-indene-2,1-diyl)}bis(2,2,2-trifluoro-
acetamide) (10)
CuI (0.10 equiv) and TTTA (0.10 equiv) were used, 0.1 M solution. The
product was purified mostly by crystallization. The crude product
was dissolved in EtOAc (0.2 mL), then CH2Cl2 (2 mL) was added and
the fine precipitate formed was filtered to provide bistriazole 10 as
off-white crystals [yield: 0.141 g (0.154 mmol, 67%)]. The mother liq-
uid was concentrated and purified by column chromatography on sil-
ica gel (starting from 20% of acetone in PE) to provide an additional
amount of 10 as a white solid; yield: 0.057 g (0.062 mmol, 27%); total
yield: 94%; mp 172–174 °C; []D25 +31.9 (c 0.60, acetone).
HRMS (ESI): m/z [M – N2 + H]+ calcd for C25H17F9N3O2: 562.1172;
found: 562.1185.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–H

G
M. Kaasik et al.
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Synthesis
1-[3,5-Bis(trifluoromethyl)phenyl]-3-{[2-((1R,2R)-1-{4-[3,5-
bis(trifluoromethyl)phenyl]-5-iodo-1H-1,2,3-triazol-1-yl}-2,3-di-
hydro-1H-inden-2-yl)oxy]-5-(trifluoromethyl)phenyl}urea (14)
Acknowledgment
We thank Raminton Gnanagurunathan, Benjamin Schröder, Maria
Volokhova, Rudolf Ristkok, and Trine Kasemägi for their help in the
synthesis of the triazoles, and Dr. Aleksander-Mati Müürisepp for IR
and MS spectra.
Triazole 14 was synthesized by the general procedure for the click re-
action; eluent for chromatography: starting from 15% EtOAc in PE;
off-white solid; yield: 0.171 g (0.179 mmol, 90%); mp 197–199 °C;
[]D20 –69.0 (c 0.43, CHCl3).
IR (KBr): 3369 (w), 1671 (w), 1617 (w), 1547 (m), 1477 (w), 1445 (w),
1386 (m), 1338 (m), 1280 (s), 1133 (s), 899 (w), 702 (w), 683 cm–1
(w).
Supporting Information
Supporting information for this article is available online at
1H NMR (400 MHz, DMSO-d6):  = 9.98 (s, 1 H), 8.65–8.59 (m, 1 H),
8.54–8.50 (m, 1 H), 8.45 (s, 2 H), 8.25–8.15 (m, 1 H), 8.08 (s, 2 H),
7.71–7.62 (m, 1 H), 7.52–7.48 (m, 1 H), 7.45 (dd, J = 7.5 Hz, 1 H), 7.37–
7.27 (m, 1 H), 7.26–7.17 (m, 1 H), 7.17–7.08 (m, 2 H), 6.55 (d, J = 5.0
Hz, 1 H), 6.09–5.98 (m, 1 H), 3.95 (dd, J = 16.1, 7.3 Hz, 1 H), 3.43 (dd,
J = 16.4, 5.3 Hz, 1 H).
13C NMR (101 MHz, DMSO-d6):  = 151.5, 147.5, 145.5, 140.7, 139.3,
136.7, 132.3, 130.3 (q, J = 32.8 Hz), 130.2 (q, J = 33.0 Hz), 129.3, 129.1,
127.3, 126.8–126.5 (m), 124.9, 123.7, 122.7 (q, J = 272.7 Hz), 122.6 (q,
J = 273.3 Hz), 121.7, 121.5–121.4 (m), 121.8 (q, J = 31.9 Hz), 120.2 (q,
J = 270.0 Hz), 118.9, 117.5–117.2 (m), 115.0–114.6 (m), 114.3–114.1
(m), 113.8–113.7 (m), 84.0, 70.0, 36.3. The iodine bonded C-atom was
not detected because of low intensity of the signal.
https://doi.org/10.1055/s-0037-1610864.
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HRMS (ESI): m/z [M + H]+ calcd for C35H20F15IN5O2: 954.0417; found:
954.0406.
(3) Desiraju, G. R.; Ho, P. S.; Kloo, L.; Legon, A. C.; Marquardt, R.;
Metrangolo, P.; Politzer, P.; Resnati, G.; Rissanen, K. Pure Appl.
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Wu, D.; Trapp, N.; Goroff, N.; Diederich, F. Org. Lett. 2014, 16,
4722.
4-[3,5-Bis(trifluoromethyl)phenyl]-1-[(1R,2R)-2-(2-{3-[3,5-
bis(trifluoromethyl)phenyl]ureido}-4-(trifluoromethyl)phe-
noxy)-2,3-dihydro-1H-inden-1-yl]-5-iodo-3-methyl-1H-1,2,3-tri-
azol-3-ium Trifluoromethanesulfonate (14-OTf)
Colorless solid; yield: 0.068 g (0.061 mmol, 55%); mp 144–146 °C;
[]D20 –88.1 (c 0.82, MeOH).
IR (KBr): 3372 (w), 1550 (m), 1445 (w), 1387 (m), 1282 (s), 1135 (s),
1030 (m), 704 (w), 682 (w), 639 cm–1 (w).
1H NMR (400 MHz, CD3OD):  = 8.60 (d, J = 1.8 Hz, 1 H), 8.41 (s, 1 H),
8.37 (s, 2 H), 8.08 (s, 2 H), 7.61–7.50 (m, 4 H), 7.48–7.36 (m, 2 H), 7.30
(d, J = 8.6 Hz, 1 H), 6.90 (d, J = 2.7 Hz, 1 H), 5.92 (dt, J = 6.3, 2.9 Hz, 1
H), 4.24 (s, 3 H), 4.03 (dd, J = 17.3, 6.7 Hz, 1 H), 3.44 (dd, J = 17.3, 3.1
Hz, 1 H).
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(c) Sabater, P.; Zapata, F.; López, B.; Fernández, I.; Caballero, A.;
Molina, P. Dalton Trans. 2018, 47, 15941.
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Terraneoa, G.; Resnati, G. Org. Biomol. Chem. 2012, 10, 1329.
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M. S.; Decato, D. A.; Sun, J.; Massena, C. J.; Jessop, M. J.;
Berryman, O. B. Chem. Sci. 2018, 9, 5828.
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Quaedflieg, P. J. L. M.; Blaauw, R. H.; van Delft, F. L.; Rutjes, F. P. J.
T. Synlett 2005, 3059. (b) Hein, J. E.; Tripp, J. C.; Krasnova, L. B.;
Sharpless, K. B.; Fokin, V. V. Angew. Chem. Int. Ed. 2009, 48, 8018.
(c) García-Álvarez, J.; Díez, J.; Gimeno, J. Green Chem. 2010, 12,
2127. (d) Pérez, J. M.; Crosbie, P.; Lal, S.; Díez-González, S.
ChemCatChem 2016, 8, 2222.
13C NMR (101 MHz, CD3OD):  = 154.0, 149.2, 146.4, 143.8, 142.7,
135.9, 134.3 (q, J = 34.4 Hz), 133.3 (q, J = 33.1 Hz), 132.7–132.5 (m),
132.2, 130.8, 129.3, 127.3, 127.2–126.9 (m), 126.89, 126.9, 125.7 (q,
J = 273.6 Hz), 124.7 (q, J = 271.8 Hz), 124.2 (q, J = 272.5 Hz), 121.8 (q,
J = 318.5 Hz), 121.4–121.1 (m), 119.4–119.0 (m), 118.0–117.8 (m),
116.4–116.1 (m), 114.1, 94.0, 84.7, 76.5, 40.1, 38.7.
HRMS (ESI): m/z [M – CF3O3S]+ calcd for C36H22F15IN5O2: 968.0573;
found: 968.0575.
Funding Information
The authors thank the Estonian Ministry of Education and Research
(Grant Nos. IUT 19-32, IUT 19-9, and PUT1468), the Centre of Excel-
lence in Molecular Cell Engineering, and the Archimedes Foundation
(2014-2020.4.01.15-0013) for financial support.
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Paper
Synthesis
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–H