Design and synthesis of a chiral halogen-bond donor with a sp3-hybridized carbon-iodine moiety in a chiral fluorobissulfonyl scaffold

Article abstract of DOI:10.3390/molecules25194539

The first example of a chiral halogen-bond donor with a sp3-hybridized carbon-iodine moiety in a fluorobissulfonyl scaffold is described. The binaphthyl backbone was designed as a chiral source and the chiral halogen-bond donor (R)-1 was synthesized from

Full text of DOI:10.3390/molecules25194539

molecules
Article
Design and Synthesis of a Chiral Halogen-Bond
Donor with a Sp3-Hybridized Carbon–Iodine Moiety
in a Chiral Fluorobissulfonyl Scaffold
Hiroto Uno 1, Kohei Matsuzaki 1, Motoo Shiro 2 and Norio Shibata 1,3,
*
1
Department of Nanopharmaceutical Sciences, Nagoya, Institute of Technology, Gokiso, Showa-ku,
Nagoya 466-8555, Japan; h.uno.844@stn.nitech.ac.jp (H.U.); kohei-matsuzaki@oat-agrio.co.jp (K.M.)
Rigaku Corporation, 3-9-12, Matsubara-cho, Akishima-shi, Tokyo 196-8666, Japan; msshiro@nyc.odn.ne.jp
Institute of Advanced Fluorine-Containing Materials, Zhejiang Normal University, 688 Yingbin Avenue,
Jinhua 321004, China
2
3
*
Correspondence: nozshiba@nitech.ac.jp; Tel./Fax: +81-52-735-7543
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
Academic Editor: Derek J. McPhee
Received: 11 September 2020; Accepted: 1 October 2020; Published: 3 October 2020
ꢀꢁꢂꢃꢄꢅꢆ
Abstract: The first example of a chiral halogen-bond donor with a sp3-hybridized carbon–iodine
moiety in a fluorobissulfonyl scaffold is described. The binaphthyl backbone was designed as
a chiral source and the chiral halogen-bond donor (R)-
11 steps. An NMR titration experiment demonstrated that (R)-
1
was synthesized from (R)-1,10-binaphthol in
worked as a halogen-bond donor.
1
The Mukaiyama aldol reaction and quinoline reduction were examined using (R)-1 as a catalyst to
evaluate the asymmetric induction.
Keywords: halogen-bond; chiral halogen-bond donor; Lewis acid; organo-catalyst
1. Introduction
Halogen-bonds (XBs) are one type of non-covalent interactions between an electrophilic region
associated with a halogen atom and a Lewis base [ ]. The strength of halogen bonding interactions
1,2
is similar to those of hydrogen bonds (HBs), encouraging us to investigate XBs as a new driving
force for organic reactions. Recently, reactions using halogen-bond donors as catalysts have been
reported [3,4], for example, reduction reaction [5], halide abstraction [6,7], Diels-Alder [8,9], and Michael
addition [10]. Our group also reported that FBDT-I (2-fluoro-1,3-benzodithiole-1,1,3,3-tetraoxy-2-iodide),
a halogen-bond donor with a sp3-hybridized carbon–iodine moiety, catalyzed the Mukaiyama aldol
reaction and reduction of quinolines [11]. Increasing attention has been paid to achiral reactions as
well as the application of XBs in asymmetric synthesis [12–15]. The strong directionality of XBs can be
considered more advantageous than HBs, which have been extensively used in asymmetric catalysis.
This property makes it possible to form rigid asymmetric environments around substrates activated by
XBs. Thus, chiral XB donors have good potential as asymmetric catalysts. In 2004, Tang et al. synthesized
chiral cationic imidazolium XB donors, which catalyzed hydrogen transfer reactions to C=N bonds (but
no asymmetric induction) [16]. Arai et al. accomplished halogen-bond-assisted asymmetric Mannich
reactions using chiral XB catalysts derived from cinchona alkaloids (Figure 1a) [17
,18]. Although four
more chiral XB catalysts were reported afterwards [19 23], all the structures of chiral XB catalysts are
–
limited to those containing a sp2-hybridized carbon–iodine (Csp2–I) moiety. Besides, the current chiral
XB catalysts are based on very few core structures, resulting in less developed asymmetric reactions,
and thus a need for novel motifs. In this context, we were interested in the novel chiral XB catalysts
containing a sp3-hybridized carbon–iodine (Csp3–I) moiety. A Csp3–I moiety in chiral XB catalysts would
construct an asymmetric carbon center directly attached to iodine. The sp3-hybridized carbon–iodine
Molecules 2020, 25, 4539; doi:10.3390/molecules25194539
www.mdpi.com/journal/molecules

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chiral center should be advantageous for creating complex three-dimensional environments around
the iodine, which play a critical role for XB. However, the chiral XB catalysts containing a Csp3–I moiety
have yet to be reported. Herein, we report a novel chiral halogen-bond donor with a Csp3–I moiety in
a chiral fluorobissulfonyl scaffold, and its attempt to use the Mukaiyama aldol reaction and quinoline
reduction for evaluation of its catalytic activity (Figure 1b).
Figure 1. The use of chiral halogen-bond donors as organo-catalysts: (a) previous work, (b) this work.
2. Results and Discussion
We recently reported the development of new halogen-bond donors with fluorobissulfonyl
scaffolds and their application as a Lewis-acid catalyst in the Mukaiyama aldol reaction [11].
Our designed halogen-bond donor, FBDT-I, can be synthesized easily, which makes it possible
to design its chiral derivatives. Thus, as an extension of our halogen-bond chemistry, we wanted
to develop a new chiral halogen-bond donor. In our previous report [11], we disclosed that FBDT-I
catalyzed the reduction reaction of quinolines with the Hantzsch ester. An asymmetric path to
achieving this type of reduction using chiral phosphoric acid catalysts, which have binaphthyl moieties,
was reported by Rueping et al. [24]. List et al. also reported the enantioselective reduction of imines
using chiral disulfonimide as a Brønsted acid catalyst [25]. These facts encouraged us to assume that
a fuluorobissulfonyl halogen-bond donor, which has a chiral binaphthyl moiety, could also work as
an asymmetric catalyst. Thus, we designed a fluorobissulfonyl halogen-bond donor
binaphthyl backbone (Figure 2).
1 with a chiral

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Figure 2. Design of a chiral halogen-bond donor (R)-1 with a sp3-hybridized carbon–iodine moiety.
The synthetic route of the chiral binaphthyl halogen-bond donor (R)-1 is shown in Scheme 1.
3,30-Phenyl-substituted binaphthol 1-I was synthesized from (R)-1,10-binaphthol according to a reported
procedure [26]. Then, carbamoylation of the hydroxy group gave 1-II, and a Newman-Kwart
rearrangement afforded thiocarbamate 1-III in 85% yield. Next, reduction using LiAlH4 gave dithiol
1-IV, alkylation of thiol with dimethoxymethane afforded cyclic sulfide 1-V, and bissulfonylmethane
1-VI was synthesized by mCPBA (m-chloroperoxybenzoic acid) oxidation in 80% yield within three
steps. The fluorination of 1-VI with SelectfluorTM and iodination of 1-VII under basic conditions gave
product (R)-
preparation of (R)-
1
in good yield (69%, 89%) (see Supplementary Materials). Although the total yield for the
was good (16% for 11 steps), the synthesis of this catalyst having a Csp3–I moiety
1
was rather complicated for the preparation of other chiral XB catalysts with a Csp2–I moiety [17–23].
Scheme 1. Synthesis of chiral halogen-bond donor (R)-1.

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The structure of (R)-
recrystallization of (R)-
a = 10.6720(2), b = 10.9407(2), c = 13.7402(3),
1
was determined by X-ray analysis of a single crystal of (R)-
1
from the
1
in CH2Cl2 (1,2-dichloroethane)/hexane (Figure 3A, unit cell parameters:
= 90, = 106.390(8), = 90). The length of carbon–iodine
α
β
γ
was 2.130 Å, corresponding to the general Csp3–I bond length (2.13 Å). For future design, we assumed
that the longer substituted groups at 3,30-position of binaphthyl might be better for asymmetric
induction, because the XB-activated substrates could not be positioned near the chiral environment of
the catalyst due to the long distance of Csp3–I. In a previous report [11], we revealed that intermolecular
halogen bonding between the iodine atom and the oxygen atom of the sulfonyl group was formed in
FBDT-I. However, in this chiral (R)-
We believe that it was due to the steric repulsion of (R)-
in the solution state. Figure 3C shows the result of the NMR titration experiments on (R)-
tetrabutylammonium chloride (nBu4NCl) in chloroform-d (CDCl3) (Figure 3C). After titration, the 19
NMR signals were upshifted ( 4.40 ppm), corresponding with our previous report [11]. This result
indicates that the iodine atom of (R)- interacts with the chloride anion of nBu4NCl. Thus, it was
demonstrated that (R)-1 works as a halogen-bond donor.
1
, intermolecular halogen bonding was not observed (Figure 3B).
. Next, we tried to observe the halogen-bond
with
1
1
F
−
1
Figure 3.
atoms and solvent were omitted for clarity. Selected bond distances (Å): C1–I1, 2.130 (4), C1–F1,
1.370 (5). ( ) X-ray packing structure of (R)- with ellipsoid at 50% probability. The hydrogen atoms
and solvent were omitted for clarity. (C) 19F NMR titration of (R)-1 with nBu4NCl in CDCl3.
(A) X-ray structure of (R)-1 with ellipsoid at 50% probability (CCDC 2031026). The hydrogen
B
1
Encouraged by this potential of (R)-1, we examined (R)-1 as a catalyst in the Mukaiyama aldol
reaction with dimethyl-substituted silyl ketene acetal 3a, as in our previous report [11]. Surprisingly,
only trace amounts of product 4a were formed in the reaction (Scheme 2(1)). We assumed that the steric
repulsion between (R)-
the reaction with less steric non-substituted silyl ketene acetal 3b, and product 4b was successfully
obtained in 77% yield. However, HPLC analysis of desilylated revealed that stereoselectivity was not
observed (Scheme 2(2)). Next, reduction of quinoline with a catalytic amount of (R)- was examined,
and product 8 was obtained in 98% yield, but the product was racemic (Scheme 2(3)).
1 and 3a inhibited the nucleophilic attack on aldehyde 2. Thus, we attempted
5
6
1
Scheme 2. Mukaiyama aldol reaction (Equations (1) and (2)) and reduction of quinoline (Equation (3))
with (R)-1.

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A plausible reaction mechanism is shown in Scheme 3. In the initial step, the halogen-bond donor
works as a Lewis acid to activate the carbonyl group of aldehyde or the nitrogen atom of
quinolone . The nucleophile 3b or hydride can then attack substrates to form the desired products
4b (Scheme 3). The lack of asymmetric induction suggests that the monodentate structure of is not
(R)-
1
2
6
2/6
/
8
1
suitable for asymmetric catalysis.
Scheme 3. A plausible reaction mechanism for the transformation from
2 or 6 into 4b or 8 using (R)-1.
3. Materials and Methods
3.1. General Information
All reactions were performed in oven-dried glassware under a positive pressure of nitrogen.
Solvents were transferred via syringe and were introduced into the reaction vessels through a rubber
septum. Chemicals were purchased and used without further purification unless otherwise noted.
All of the reactions were monitored by thin-layer chromatography (TLC) carried out on a 0.25 mm
Merck silica gel (60-F254) (Kenilworth, NJ, USA). TLC plates were visualized with UV light and
7% phosphomolybdic acid or KMnO4 in water/heat. Column chromatography was carried out on
a column packed with silica gel (60 N spherical neutral size 50–60 µm) supplied by Kanto Chemical
Co., Inc. (Tokyo, Japan). The 1H-NMR (300 MHz), 19F-NMR (282 MHz), and 13C-NMR (126 MHz)
spectra for each solution in CDCl3 were recorded on Varian Mercury 300 (Agilent Technologies,
Palo Alto, CA, USA) and Avance 500 (Bruker, Billerica, MA, USA) NMR spectrometers. Chemical
shifts (
δ
) are expressed in ppm downfield from TMS (
δ
= 0.00) or C6F6 (
δ
=
−
162.2 (CDCl3)) as
an internal standard. Mass spectra were recorded on a SHIMADZU GCMS-QP5050A (EI-MS) and
SHIMAZU LCMS-2020 (ESI-MS) (Shimadzu Corporation, Kyoto, Japan). Melting points were recorded
on Buchi M-565. Infrared spectra were recorded on a JASCO FT/IR-4100 spectrometer. Chemicals
were purchased and used without further purification unless otherwise noted. CH2Cl2 was dried
and distilled before use. X-ray measurements were carried out on a Rigaku R-AXIS RAPID or Rigaku
Mercury70 diffractometer with graphite monochromated Mo K
α
radiation at
100 ◦C. The crystal
−
structure was solved by the direct method (SIR2004) and refined by the full-matric least-square
technique (SHELXL97). The non-hydrogen atoms were refined anisotropically. Hydrogen atoms were
refined by the riding model using the appropriate HFIX command in SHELXL97. All calculations were
performed with the CrystalStructure software package.
3.2. Synthesis of the Chiral Halogen-Bond Donor (R)-1
(R)-O,O’-(3,30-Diphenyl-[1,10-binaphthalene]-2,20-diyl) bis(dimethylcarbamothioate) (1-II)
(R)-3,30-diphenyl-BINOL (1-I) was prepared according to published literature [26].
1-II was prepared according to published literature [27].
To a solution of (R)-3,30-diphenyl-BINOL (2.71 g, 6.18 mmol, 1.0 equiv.) in N,N-dimethylformamide
(DMF) (20 mL) cooled by ice/water bath, dropwise a suspension of sodium hydride (NaH) was added
(60% oil suspension, 1.04 g, 26.0 mmol, 4.2 equiv.) in DMF (7.0 mL) and the mixture was stirred at
0 ◦C for 10 min. A solution of dimethylthiocarbamoyl chloride (2.80 g, 26.0 mmol, 4.2 equiv.) in DMF
(7.0 mL) was added, and the mixture was allowed to warm to room temperature over 1 h and then
stirred at 85 ◦C for 43 h. After cooling to room temperature, aqueous 3% KOH solution (56 mL) was
added, and the resulting precipitate was filtered and washed with H2O. The precipitate was dissolved

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into CH2Cl2, and the solution was washed with H2O and brine, dried over Na2SO4, and concentrated
under reduced pressure. The crude product was purified by column chromatography on silica gel
(CHCl3) to give product 1-II (3.14 g, 83% yield) as a white solid.
Several peak sets were observed due to the rotamers of the title compound. All peaks are given below:
mp = 138.7–139.7 ◦C (CHCl3); MS (ESI, m/z) 623 [(M + Na)+]; HRMS (ESI) calcd. for C38H32N2NaO2S2
[(M + Na)+]: 635.1803 found 635.1815; 1H NMR (CDCl3, 500 MHz):
δ
= 2.04 (s, 6H rotamer), 2.68 (s, 6H
rotamer), 2.73 (s, 6H rotamer), 2.82 (s, 6H rotamer), 2.87 (s, 6H rotamer), 3.03 (s, 6H rotamer), 7.21–8.07
(m, 20H); 13C NMR (CDCl3, 126 MHz):
= 37.0, 37.9, 39.0, 42.2, 42.6, 125.0, 125.7, 125.8, 125.9, 126.05,
δ
126.08, 126.2, 126.5, 127.0, 127.19, 127.25, 127.3, 127.6, 127.9, 127.99, 128.02, 128.1, 128.4, 128.5, 129.3,
129.46, 129.49, 129.7, 130.1, 130.4, 131.6 131.7, 132.5, 132.7, 133.4, 134.9, 135.4, 136.5, 138.33, 138.36, 139.0,
147.4, 147.5, 148.1, 184.7, 185.4, 185.7; IR (KBr) 699, 732, 756, 789, 892, 910, 1119, 1137, 1152, 1184, 1243,
1286, 1359, 1392, 1420, 1451, 1497, 1530, 2935, 3053 cm−1
.
(R)- S,S’-(3,30-Diphenyl-[1,10-binaphthalene]-2,20-diyl) bis(dimethylcarbamothioate) (1-III)
1-III was prepared according to published literature [27].
A test tube equipped with rubber septa and magnetic stir bar was charged with 1-II (1.5 g, 2.45 mmol,
1.0 equiv.). The tube was degassed by vacuum evacuation and backfilled with argon. The tube
was placed into a preheated (250 ◦C) sand bath and stirred at 250 ◦C for 2 h. After cooling to room
temperature, CHCl3 was added, and the crude was purified by column chromatography on silica gel
(CHCl3) to give the desired product 1-III (1.27 g 85% yield) as a slightly yellow solid.
Several peak sets were observed due to the rotamers of the title compound. All peaks are given below:
mp = 243.6–244.3 ◦C (CHCl3); MS (ESI, m/z) 613 [(M + Na)+]; HRMS (ESI) calcd. for C38H32N2NaO2S2
[(M + Na)+]: 635.1803 found 635.1803; 1H NMR (CDCl3, 300 MHz):
7.59–7.63 (m, 4H), 7.88 (d, J = 8.1 Hz, 2H), 7.96 (s, 2H); 13C NMR (CDCl3, 126 MHz):
δ
= 2.42 (s, 12H), 7.22–7.49 (m, 12H),
= 38.6, 126.1,
δ
126.8, 127.1, 127.2, 127.5, 127.9, 128.1, 129.4, 130.2, 132.4, 133.5, 142.0, 144.1, 144.3, 165.5; IR (KBr) 527,
606, 653, 682, 700, 751, 783, 907, 1027, 1090, 1259, 1359, 1403, 1444, 1492, 1666, 2927, 3026, 3052 cm−1
.
(R)-2,6-Diphenyl-4H-dinaphtho [2,1-d:10,20-f][1,3]dithiepine 3,3,5,5-tetraoxide (1-VI)
1-VI was prepared according to published literature [27].
Step 1:
To a solution of 1-III (1.25 g, 2.04 mmol, 1.0 equiv.) in tetrahydrofuran (THF) (30 mL), portionwise
lithium aluminum hydride (543 mg, 14.3 mmol, 7.0 equiv.) was added and the mixture was stirred at
reflux (80 ◦C) for 24 h. After cooling to room temperature, the reaction was quenched by aqueous 10%
HCl solution (60 mL) and extracted with CH2Cl2. The combined organic layer was dried over Na2SO4
and concentrated under reduced pressure. The crude product 1-IV (836 mg, 87% yield, slightly yellow
solid) was used in the next reaction without further purification.
Step 2:
To a solution of 1-IV (836 mg, 1.78 mmol, 1.0 equiv.) and dimethoxymethane (0.173 mL, 1.96 mmol, 1.1
equiv.) in CH2Cl2 (8.9 mL), boron trifluoride diethyl etherate (BF3 OEt2) (0.470 mL, 3.74 mmol, 2.1
·
equiv.) was added and the mixture was stirred at room temperature for 9 h. After completing the
reaction, the solution was diluted with CH2Cl2, washed with aqueous 2% KOH solution (4 × 50 mL),
dried over Na2SO4, and concentrated under reduced pressure. The crude product 1-V (859 mg, >99%
yield, yellow solid) was used in the next reaction without further purification.
Step 3:
mCPBA (assume 65%, 14.2 mmol, 8.0 equiv.) was dried in vacuo at room temperature for 1 h before the
addition of CH2Cl2 (60 mL), and the solution was cooled to 0 ◦C. A solution of 1-V (859 mg, 1.78 mmol,
1.0 equiv.) in CH2Cl2 (10 mL) was added, and the mixture was stirred at room temperature for 24 h.
After completing the reaction, the solution was washed with aqueous 2% KOH solution (3
×
25 mL),
dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by
column chromatography on silica gel (n-hexane/CH2Cl2 = 1/4) to give product 1-VI (895 mg, 80% yield
for 3 steps) solid.

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Several peak sets were observed due to the rotamers of the title compound. All peaks are given below:
mp = 322.4–333.5 ◦C (CHCl3); MS (ESI, m/z) 545 [(M H)−]; HRMS (ESI) calcd. for C33H22NaO4S2
[(M + Na)+]: 569.0857 found 569.0863; 1H NMR (CDCl3, 500 MHz):
= 4.59 (s, 2H), 7.09–7.11 (m 2H),
7.39–7.55 (m, 12H), 7.68–7.71 (m, 2H), 8.00 (d, J = 8.5 Hz, 2H), 8.06 (s, 2H); 13C NMR (CDCl3, 126 MHz):
= 83.9, 127.1, 127.7, 127.8, 128.0, 128.29, 128.35, 130.1, 130.6, 131.3, 132.3, 133.8, 134.8, 138.1, 139.2,
139.5; IR (KBr) 506, 539, 650, 700, 728, 764, 779, 810, 828, 906, 1099, 1130, 1148, 1170, 1213, 1340, 1396,
1493, 1575, 2913, 2977, 3024, 3063 cm−1
−
δ
δ
.
(R)-4-Fluoro-2,6-diphenyl-4H-dinaphtho[2,1-d:10,20-f][1,3]dithiepine 3,3,5,5-tetraoxide (1-VII)
To a suspension of NaH (60% oil suspension, 66.4 mg, 1.05 equiv.) in THF (1.5 mL) cooled in an ice/water
bath, a solution of bis(phenylsulfonyl)methane 1-VI (863 mg, 1.58 mmol, 1.0 equiv.) in THF (9.5 mL)
was added portion-wise and the mixture was stirred for 30 min at room temperature. The resulting
mixture was added to a suspension of selectfluor® (588 mg, 1.66 mmol, 1.05 equiv.) in acetonitrile
(MeCN) (3.3 mL) at 0 ◦C and the residue was rinsed with THF (5.0 mL). The mixture was allowed
to warm to room temperature and stirred for 10 h. After completing the reaction, the solvents were
removed under reduced pressure, and the residue was diluted with H2O and extracted with CH2Cl2.
The combined organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated
under reduced pressure. The crude product was purified by column chromatography on silica gel
(n-hexane/CH2Cl2 = 2/3 to 1/9) to give product 1-VII (613 mg, 69% yield) as a white solid.
Several peak sets were observed due to the rotamers of the title compound. All peaks are given below:
mp = 300.6–301.6 ◦C (CHCl3); MS (ESI, m/z) 587 [(M + Na)+]; HRMS (ESI) calcd. for C33H21FNaO4S2
[(M + Na)+]: 587.0763 found 587.0757; 1H NMR (CDCl3, 500 MHz):
δ
= 5.56 (d, J = 46.0 Hz, 2H), 7.11
(d, J = 8.8 Hz, 2H), 7.41–7.54 (m, 12H), 7.70–7.74 (m, 2H), 7.99–8.01 (m, 2H), 8.08 (d, J = 8.0 Hz, 2H),
8.06 (s, 2H); 13C NMR (CDCl3, 126 MHz):
= 112.9 (d, J = 271.1 Hz), 127.0, 127.1, 127.75, 127.78, 127.80,
127.9, 128.1, 128.3, 128.41, 128.43, 128.45, 128.49, 128.6, 130.48, 130.50, 130.6, 131.2, 132.1, 132.2, 133.9,
134.0, 135.08, 135.12, 139.0, 139.06, 139.09, 139.4, 139.8, 141.0; 19F NMR (CDCl3, 282 MHz):
173.2
(d, J = 46.0 Hz, 1F); IR (KBr) 531, 541, 650, 699, 730, 752, 769, 795, 905, 1097, 1128, 1146, 1173, 1189, 1353,
1396, 1445, 1492, 1574, 2923, 3028, 3055 cm−1
δ
δ
=
−
.
(R)-4-Fluoro-4-iodo-2,6-diphenyl-4H-dinaphtho[2,1-d:10,20-f][1,3]dithiepine 3,3,5,5-tetraoxide ((R)-1)
To a solution of 1-VII (595 mg, 1.05 mmol, 1.0 equiv.) in MeCN (7.9 mL), cesium carbonate (Cs2CO3)
(411 mg, 1.26 mmol, 1.2 equiv.) was added and the mixture was stirred at room temperature for
15 min. Iodine (I2) (348 mg, 1.37 mmol, 1.3 equiv.) was added to the mixture and stirred at room
temperature for 4 h. After completing the reaction, the solvent was removed under reduced pressure
and the residue was dissolved in CH2Cl2/H2O. The aqueous layer was discarded, and the organic
layer was washed with saturated aqueous Na2S2O3 solution and brine, dried over anhydrous Na2SO4,
and concentrated under reduced pressure. The crude product was purified by column chromatography
on silica gel (n-hexane/CH2Cl2 = 2/3) to afford halogenated product (R)-1 (643 mg, 89% yield) as
a slightly yellow solid.
mp = 217.8–218.7 ◦C (CHCl3); MS (ESI, m/z) 713 [(M + Na)+]; HRMS (ESI) calcd. for C33H20FINaO4S2
[(M + Na)+]: 712.9729 found 712.9725; 1H NMR (CDCl3, 500 MHz):
(m, 11H), 7.69–7.73 (m, 3H), 7.99 (d, J = 8.0 Hz, 2H), 8.04–8.06 (m, 2H); 13C NMR (CDCl3, 126 MHz):
= 114.6 (d, J = 339.7 Hz), 125.7, 126.7, 126.8, 126.9, 127.76, 127.82, 127.9, 128.0, 128.1, 128.36, 128.44,
128.5, 128.6, 130.2, 130.5, 130.7, 131.6, 132.1, 132.2, 133.9, 134.1, 135.0, 135.2, 139.00, 139.02, 139.9, 140.19,
δ = 7.12–7.20 (m 2H), 7.40–7.50
δ
140.22, 141.4; 19F NMR (CDCl3, 282 MHz):
δ
= 112.7 (s, 1F); IR (KBr) 517, 532, 545, 577, 588, 630, 642,
−
700, 730, 762, 778, 904, 1138, 1158, 1170, 1356, 1395, 1444, 1492, 1573, 3024, 3055 cm−1
.
3.3. Experimental Procedure of 19F NMR Titration of (R)-1 with nBu4NCl in CDCl3
To a solution of (R)-
(1.5 M in CDCl3) was added and 19F NMR of the mixture was taken when the added nBu4NCl solution
was 0, 0.5, 1.0, and 2.0, equivalent to (R)- . Chemical shifts ( ) are recorded in ppm downfield from
C6F6 (δ = −162.2 (CDCl3)) as an internal standard.
1 (20.7 mg, 0.03 mmol) in CDCl3 (0.6 mL) in an NMR tube, a solution of nBu4NCl
1
δ

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3.4. General Procedure of Mukaiyama Aldol with (R)-1
Silyl ketene acetals 3 were prepared according to published literature [28].
To a solution of (R)-
1
(3.5 mg, 0.005 mmol, 10 mol%) and aldehyde
2 (0.05 mmol, 1.0 equiv.) in CH2Cl2
(0.05 mL), silyl ketene acetal
3
(0.075 mmol, 1.5 equiv.) was added and the mixture was stirred at room
temperature for 12 h. After completing the reaction, the mixture was filtered through a pad of silica
gel, and the filtrate was concentrated under reduced pressure. The crude product was purified by
column chromatography on silica gel to give the desired product 4. Next, to a solution of 4 in THF
(0.25 mL), tetrabutylammonium fluoride (TBAF) (1.0 M in THF, 1.0 equiv.) was added and the mixture
was stirred at room temperature for 1 h. The crude product was purified by column chromatography
on silica gel to give desilylated product 5.
Methyl 3-((tert-butyldimethylsilyl)oxy)-3-(naphthalen-2-yl)propanoate (4b)
Following the general procedure, (R)-1 (3.5 mg, 0.005 mmol, 10 mol%), aldehyde 2 (7.8 mg, 0.05 mmol,
1.0 equiv.), and silyl ketene acetal 3b (14.1 mg, 0.0075 mmol, 1.5 equiv.) were used in CH2Cl2 (0.05 mL)
at room temperature for 12 h. The crude product was purified by column chromatography on silica gel
(n-hexane/EtOAc = 97/3) to give product 4b (13.3 mg, 77% yield) as a white solid.
The 1H NMR spectrum matched the one reported by B. List et al. [29].
MS (ESI, m/z) 367 [(M + Na)+]; 1H NMR (CDCl3, 300 MHz):
2.63 (dd, J = 4.1, 14.7 Hz, 1H), 2.82 (dd, J = 9.3, 14.7 Hz, 1H), 3.69 (s, 3H), 5.33 (dd, J = 4.1, 9.3 Hz, 1H),
δ
= 0.17 (s, 3H), 0.04 (s, 3H), 0.86 (s, 9H),
−
7.46–7.52 (m, 3H), 7.77–7.84 (m, 4H).
Methyl 3-hydroxy-3-(naphthalen-2-yl)propanoate (5)
The 1H NMR spectrum matched the one reported by Denmark et al. [30].
MS (ESI, m/z) 253 [(M + Na)+]; 1H NMR (CDCl3, 300 MHz):
δ = 2.78–2.88 (m, 2H), 3.32–3.33 (d, J = 2.7 Hz,
1H), 3.73 (s, 3H), 5.30–5.32 (m, 1H), 7.44–7.51 (m, 3H), 7.83–7.84 (m, 4H).
3.5. General Procedure of Reduction of Quinoline with (R)-1
Quinoline 6 was prepared according to published literature [31].
To a mixture of (R)-
1
(6.9 mg, 0.01 mmol, 10 mol%), quinoline
6 (20.5 mg, 0.1 mmol, 1.0 equiv.)
and Hantzsch ester
7
(55.7 mg, 0.220 mmol, 2.2 equiv.) were added in CH2Cl2 (1.4 mL) at room
temperature for 24 h. The crude product was purified by column chromatography on silica gel
(n-hexane/EtOAc = 97/3) to give product 8 (20.5 mg, 98% yield) as a yellow oil.
The 1H NMR spectrum matched the one reported by Lacôte et al. [32].
MS (ESI, m/z) 210 [(M + H)+]; 1H NMR (CDCl3, 300 MHz):
δ = 1.93–2.15 (m, 2H), 2.69–2.78 (m, 1H),
2.87–2.98 (m, 1H), 4.03 (brs, 1H), 4.44 (dd, J = 3.0, 9.0 Hz, 1H), 6.53 (d, J = 7.5 Hz, 1H), 6.65 (t, J = 7.5 Hz,
1H), 7.01 (t, J = 7.2 Hz, 2H), 7.25–7.40 (m, 5H).
4. Conclusions
In summary, we have described the synthesis of a new chiral halogen-bond donor, which has
a fluorobissulfonyl scaffold with a chiral binaphthyl backbone, and its application as a Lewis acid catalyst.
A chiral halogen-bond donor (R)-
16% total yield in 11 steps. The use of a catalytic amount of (R)-
1
was synthesized from commercially available (R)-1,10-binaphthol in
1
in the Mukaiyama aldol reaction and
quinoline reduction afforded the products in high yield. As far as we know, these are the first examples
of chiral XB catalysts containing a sp3-hybridized carbon–iodine moiety. While enantioselectivity
could not be induced by (R)-1 in the attempted reactions, the results should be useful for the new
design of effective chiral XB catalysts containing a sp3-hybridized carbon–iodine moiety, such as
bidentate-type catalysts, but not monodentate-type catalysts, as one example. Further investigation
into these possibilities is ongoing in our laboratory.

Molecules 2020, 25, 4539
9 of 10
Supplementary Materials: The Supplementary Materials are available online, that contains 1H, 13C, and 19F-NMR
spectra or IR spectra of and . Crystallographic data of (R)- is also available from the Cambridge
Crystallographic Database as file numbers CCDC 2031026.
1,
4,
5
8
1
Author Contributions: N.S. conceived the concept; H.U. and K.M. optimized the synthetic routes and reaction
conditions; N.S. directed the project; H.U. and M.S. analyzed X-ray data; N.S. and H.U. prepared the manuscript.
All authors have read and agreed to the published version of the manuscript.
Funding: This work was supported by the Society of Iodine Science (SIS) and JSPS KAKENHI grants JP 18H02553
(KIBAN B, NS).
Conflicts of Interest: The authors declare no conflict of interest.
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Sample Availability: Samples of the compounds are not available from the authors.
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2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
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