Structurally Defined α-Tetralol-Based Chiral Hypervalent Iodine Reagents

Article abstract of DOI:10.1021/acs.joc.9b01315

A novel class of chiral hypervalent iodine reagents containing an α-tetralol scaffold is introduced. Iodine triacetate is employed in a key step as a highly selective and efficient iodinating reagent for a short and convenient synthesis of iodine(III) derivatives. Solid-state X-ray analyses offer valuable structural information, while reactivities and stereoselectivities are investigated in three model reactions.

Full text of DOI:10.1021/acs.joc.9b01315

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Article
Structurally Defined #-Tetralol-Based Chiral Hypervalent Iodine Reagents
Tobias Hokamp, and Thomas Wirth
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01315 • Publication Date (Web): 09 Jun 2019
Downloaded from http://pubs.acs.org on June 10, 2019
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Structurally Defined α-Tetralol-Based Chiral Hypervalent Iodine Reagents
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Tobias Hokamp, Thomas Wirth
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Abstract
A novel class of chiral hypervalent iodine reagents containing an α-tetralol-scaffold is being
introduced. Iodine triacetate is employed in a key-step as highly selective and efficient
iodinating reagent for a short and convenient synthesis of iodine(III) derivatives. Solid state X-
ray analyses offer valuable structural information while reactivities and stereoselectivities are
investigated in three model reactions.
OAc
I
- Short synthesis route
AcO
I
OAc
OAc
5 examples
MeO
MeO
- Detailed structural information
- Application in asymmetric synthesis
OAc
O
R
O
R
Tetralol-based hypervalent iodine reagents
Introduction
Chiral hypervalent iodine compounds are powerful tools in synthetic organic chemistry as they
have contributed to a variety of novel chemical transformations.1 As mild, versatile and
environmentally benign reagents they found application in stereoselective reactions such as α-
functionalization of carbonyl compounds,2 alkene functionalization,3 phenolic oxidation,4
oxidation of sulfides5 and rearrangement reactions.6 A huge variety of chiral hypervalent
organoiodine reagents have been reported over the past two decades. Examples include the
lactic acid based reagent 17 and the amide derivative 2.4c,8 Furthermore, chirality was
introduced through the incorporation of binaphthyl backbones 39 or through a rigid spirocyclic
backbone as in 4.4a
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Previous work
AcO
R
OCOCR3
OAc
I
OAc
O
I
I
I
I
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ROC
O
COR
O
O
OAc
R
OCOCR3
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1
2
R = OCH3
R = NHMes
3
4
R = H, Et
R = H, F
This work
OMe
OMe
I(OAc)3
O
O
I(OAc)2
R
R
Scheme 1: Top: An overview of chiral hypervalent iodine reagents. Bottom: Synthesis of novel tetralol-
based chiral hypervalent iodine reagents.
This work addresses the synthesis of hypervalent iodine reagents containing a chiral α-tetralol
scaffold (Scheme 1). Here, the chiral center is located in a rigid ring system close to the iodine-
center, similar to the corresponding selenium-derivatives, which have been successfully
employed.10 As this class of hypervalent iodine reagents has not been reported so far, defined
structural information of those compounds is highly desirable in order to get insight into their
possible reactivities.
Results and Discussion
As a key step for the synthesis we aimed to apply iodine triacetate [I(OAc)3] as iodinating agent,
which has demonstrated excellent selectivities and yields in our previous studies on the direct
conversion of non-iodinated arenes into (diacetoxyiodo)arenes.11 For a selective iodination in
the 8-position, a methoxy-substituent has been implemented as a directing group in the 4-
position. This key step will reduce the number of steps for the synthesis of iodinated tetralol-
derivatives compared to know routes for similar reagents.12
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Initially, 5-methoxy-1-tetralone (5) was stereoselectively reduced to (R)-6 using a chiral
ruthenium catalyst (Scheme 2).13 Alcohol 6 was obtained in >99% ee and excellent yield (94%)
and was the starting point for the synthesis of a range of tetralol-based hypervalent iodine
reagents. The absolute configuration of 6 was determined by a solid-state x-ray structure.14 For
the first examples of hypervalent iodine compounds based on a tetralol-scaffold, different
substituents were introduced yielding 7a-c. To our delight, direct conversion to the desired
hypervalent iodine reagents 8a-c in good to excellent yield (75-90%) was achieved by simple
reaction of 7a-c with iodine triacetate.
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i) NaH, MeI
ii) NEt3, Ac2O
4-DMAP
RuCl[(R,R)-FsDPEN]
(p-cymene)
OMe
OMe
OMe
HCO2H/NEt3
iii) NEt3, Piv2O
4-DMAP
O
OH
OR
6
5
7a
7b
7c
R = Me (98%)
R = Ac (96%)
R = Piv (82%)
OMe
I(OAc)3
7
OR I(OAc)2
8a
8b
8c
R = Me (88%)
R = Ac (90%)
R = Piv (75%)
Scheme 2: Synthesis of tetralol-based hypervalent iodine reagents 8a-c by using I(OAc)3 as a key step.
The effect of amide-containing substituents was studied in the next step. As reported by
Ishihara and Muñiz,3c,4c-d the amide NH groups of 2 engage in hydrogen bonding with the
acetoxy groups located at the central iodine atom.
A convenient way for the introduction of an amide-containing substituent was the installation
of N-methylsalicylamide through a Mitsunobu reaction to reach 13 as final product after
treatment with iodine triacetate. However, an alternative pathway had to be chosen as the
direct synthesis of 13 from 12b afforded mainly 12a and minor quantities of 13. Hence, methyl
salicylate (9) was introduced first via Mitsunobu-reaction to give 10 in good yields (74%), which
was then selectively iodinated to 11 in 75% yield (Scheme 3). Amide 12a was synthesized after
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treating 11 with methylamine (79% yield) and oxidation of 12a with Selectfluor® in presence of
acetic acid provided the amide-containing tetralol-based hypervalent iodine reagent 13 in
quantitative yield.
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Scheme 3: Synthesis of the tetralol-based hypervalent iodine reagent 13.
As a next step, a pyridine-containing substituent was introduced to the chiral center. It is well
known that pyridine-derivatives are suitable ligands for iodine(III) reagents, as they have the
ability to coordinate to the iodine-center.15 Therefore, we planned to esterify 6 with picolinic
acid (17). However, as in case for the synthesis of 13, reaction of iodine triacetate with 18b led
to the formation of 18a and small amounts of 19. Hence, 6 was first protected with a
triisopropylsilyl group to give 14 in quantitative yield (Scheme 4). Iodination by using iodine
triacetate (15, 71% yield) and deprotection gave 16 in excellent yield (91%). Picolinic acid (17)
was introduced by Steglich-esterification yielding 18 (96%), which was then oxidized by
Selectfluor® in presence acetic acid to give 19 in quantitative yield.
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OMe
OMe
OMe
TIPSOTf
NEt3
I(OAc)3
TBAF
6
then: Na2S2O3
7
8
9
TIPSO
I
OH
I
(91%)
OTIPS
14
16
15
(>99%)
(71%)
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N
OMe
OMe
COOH
17
18a
Selectfluor
16
DCC, 4-DMAP
HOAc
O
R
O
I(OAc)2
N
N
O
O
19
18a
(96%; R = I)
(>99%)
[a]
18b
(rac)-
(66%; R = H)
Scheme 4: Synthesis of the pyridine-containing tetralol-based hypervalent iodine reagent 19. [a]
prepared via Steglich esterification from 6.
First structural information of this novel class of tetralol-based iodine(III) reagents was obtained
by solid state structural analysis of 8a (Figure 1).14 As expected for hypervalent iodine(III)
compounds of type ArIL2 with Ar being an aryl moiety and L a ligand containing heteroatom (O,
N, halogen), 8a has a trigonal bipyramidal geometry with the acetate ligands in the axial
position and the aryl moiety occupying the equatorial position. The two acetate ligands form,
together with the iodine atom, a nearly linear three-center-four-electron (3c-4e) hypervalent
bond with an angle of 167.3° and a distance of 2.170 Å for I(1)-O(1) and 2.144 Å for I(1)-O(3),
respectively.16 The I(1)-O(5) distance is with 3.451 Å as long as the sum of the van der Waal’s
radii of I (1.98 Å) and O (1.52 Å) and therefore no interaction between both atoms is being
observed.17 The hypervalent bond [O(1)-I(1)-O(3)] is perpendicular to the aromatic ring.
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Figure 1: X-ray structures of iodine(III) reagent 8a. Hydrogen atoms are omitted for clarity. Thermal
ellipsoids are shown at 50% probability.
By the introduction of a pivaloyl substituent as a more bulky group than a methoxy-substituent
(8c), the hypervalent I(1)-C(1) bond rotates so that the hypervalent bond [O(4)-I(1)-O(6)] is no
longer perpendicular to the aromatic ring as it was the case in 8a (Figure 2).14 The dihedral
angle in 8c between C(2)-C(1)-I(1)-O(1) is with 111.7° greater than the torsion in 8a (90.1°).
Additionally, no interaction between the iodine center and the substituent can be observed, as
the distance between I(1)-O(6) is 3.831 Å while the distance between I(1)-O(5) is 3.540 Å long.
Figure 2: X-ray structures of iodine(III) reagent 8c. Hydrogen atoms are omitted for clarity. Thermal
ellipsoids are shown at 50% probability.
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Interestingly, the introduction of an amide substituent in hypervalent iodine compound 13 did
not lead to any formation of hydrogen bonds between the acetoxy groups and the amide NH
group in the solid state but between NH and O(5) (2.004 Å, Figure 3).14
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Figure 3: X-ray structures of iodine(III) reagent 13. Hydrogen atoms are omitted for clarity with the
exception of the amide proton. Thermal ellipsoids are shown at 50% probability.
More surprisingly, in case of 19, no coordination of the pyridine nitrogen to the iodine center
can be observed (distance of N(1)-I(1): 4.766 Å) although pyridine is known for its ability to
coordinate to hypervalent iodine reagents (Figure 4).14,15
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Figure 4: X-ray structures of iodine(III) reagent 19. Hydrogen atoms are omitted for clarity. Thermal
ellipsoids are shown at 50% probability.
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Moreover, H and 13C{1H} NMR analysis for all described hypervalent iodine reagents reveals a
hindered rotation of the I(1)-C bond as the acetate protons and carbons of both ligands show
different chemical environment.
After having achieved valuable information regarding the structures of tetralol-based
hypervalent iodine reagents, the focus was directed towards the reactivity and the
stereocontrol of those reagents. Therefore, the well-known diacetoxylation of styrene 203e and
the oxidative rearrangement of 226b (Scheme 5) were carried out. Both reactions furnished
similar yields for all hypervalent iodine reagents. Diacetoxylated product (R)-21 was obtained in
65% yield using 8a and in 67% yield using 8b. Reagent 8c and 19 provided (R)-21 in very good
yield (89% and 87%, respectively), while 13 gave (S)-21 in good yield (65%). The use of all five
hypervalent iodine reagents furnished rearranged product (R)-23 in yields between 55% (using
8b) and 75% yield (using 8c). However, the stereoselectivities in the diacetoxylation of 20
remained mainly little (up to 61:39 er). Furthermore, the oxidative rearrangement provided
mainly low enantiomeric ratios between 50:50 er by the use of 8b and 57:43 er when 8a and 13
were applied. Interestingly, the enantiomeric ratio could be increased to 75:25 er in presence of
19. Thus, reagent 19 was further investigated in the α-tosylation of propiophenone 24.
However, (S)-25 was obtained in good yield (59%) but poor stereoselectivity (54:46 er). Those
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results are surprising, as hypervalent iodine reagents containing amide- or pyridine substituents
have been very successfully employed in stereoselective reactions.3c,4c-d,15g
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Scheme 5: Stereoselective diacetoxylation and rearrangement using different tetralol-based hypervalent
iodine reagents. Yields are reported and enantiomeric ratios are determined by chiral HPLC. [a] (S)-
isomer was the major isomer.
Conclusion
In summary, we have introduced a novel class of chiral hypervalent iodine reagents containing
a tetralol-scaffold, which can be directly synthesized by using iodine triacetate as iodinating
reagent. Valuable structural information was received by solid-state X-ray analysis.
Furthermore, the reactivities and stereoselectivities were investigated in three model reactions.
Experimental Section
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Reactions involving air and moisture sensitive reagents were carried out in flame dried glass
wares under a dry nitrogen. A dry, nitrogen-filled glove box from MBraun was used for the
storage of moisture sensitive hypervalent iodine reagents. Solvents used in reactions were
dried according to standard procedures. Reagents were purchased from Acros Organics, Alfa
Aesar GmbH & Co. KG, Fisher Scientific, FluoroChem, Merck KGAA and Sigma Aldrich GmbH.
Styrene was distilled prior to use by a Büchi GKR-50 Kugelrohr apparatus. All other reagents
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obtained from commercial sources were used as received. H and 13C{1H} NMR spectra were
recorded at 298 K on a Bruker DPX 300, Bruker DPX 400 or a Bruker DPX 500. All resonances are
reported relative to TMS. Spectra were calibrated relative to solvents’ residual proton and
carbon chemical shifts. Coupling constants (J) are reported in Hz. TLC was performed to monitor
the reactions using precoated aluminium sheets of Merck silica gel 60 F254 (0.20 m), and
detection of compounds was performed under UV light (254 nm) or by staining with a solution
of KMnO4. Flash column chromatography was performed using Merck silica gel 60 (40-63 µm)
to purify products applying nitrogen pressure of about 0.2 bar or on a Biotage Isolera Four using
Biotage cartridges SNAP Ultra 10 g, SNAP Ultra 25 g, SNAP Ultra 50 g and SNAP Ultra 100 g.
HRMS were measured by the EPSRC Mass Spectrometry Facility in Swansea University on a
Waters Xevo G2-S and on a Thermo Scientific LTQ Orbitrap XL or at Cardiff University on a
Waters LCT Premier XE. Ions were generated by Electrospray Ionization (ES), Electron Ionization
(EI), Nanospray Ionization (NSI), Atmospheric Sample Analysis Probe (ASAP) or Chemical
Ionization (CI). Melting points were determined with a Gallenkamp variable heater and are not
corrected. Infrared spectra were recorded on a Shimadzu FTIR Affinity-1S spectrometer. HPLC
was performed on an Agilent Technologies 1260 Infinity Quaternary LC system. Separation was
performed using Lux 5 µm Cellulose-1, LC Column (250 x 4.6 mm) or YMC Chiral Amylose-C S-
5μm (25 cm). Optical rotations were measured with a SCHMIDT + HAENSCH UniPol L
polarimeter.
Iodine triacetate I(OAc)3. Following a reported procedure,11 ground iodine (2.5 g, 10 mmol, 1.0
equiv.), acetic acid (3.5 mL, 61 mmol, 6.1 equiv.) and acetic anhydride (7.0 mL, 74 mmol,
7.4 equiv.) were added to a flame-dried Schlenk tube under nitrogen. The solution was cooled
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to –40 °C and fuming nitric acid (≥99.5%, 2.7 mL, 65 mmol, 6.5 equiv.) was added while stirring.
Afterwards, the solution was allowed to warm to room temperature and stirred for 2 hours
protected from light. All volatiles were then removed in vacuo and 4 was obtained as pale
1
yellow solid in 94% (5.60 g, 18.4 mmol) yield. H NMR (500 MHz, CDCl3): δ = 2.19 (s, 9H) ppm.
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13C{1H} NMR (75 MHz, CDCl3): δ = 180.3, 19.8 ppm. The spectroscopic data agree with the
literature.11
(R)-5-Methoxy-1,2,3,4-tetrahydro-1-naphthol (6). 5-Methoxy-1-tetralone 5 (1.76 g, 10.0 mmol)
and RuCl[(R,R)-FsDPEN](p-cymene) (356 mg, 0.450 mmol, 4.5 mol%, 90% purity) were dissolved
in dry DMF (100 mL) in a flame-dried Schlenk flask under nitrogen atmosphere. After stirring
the resulting solution for 10 minutes at room temperature, formic acid trimethylamine complex
(5:2, 4.1 mL, 50 mmol, 5.0 equiv.) was added. The reaction mixture was then stirred at room
temperature for 4 days. Afterwards, the reaction was quenched with water (150 mL) and the
mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with
brine (50 mL), dried over anhydrous MgSO4 and concentrated under vacuum. The crude
mixture was purified by flash column chromatography (n-hexane:EtOAc = 80:20) to afford 6 as
colorless solid in 94% (1.67 g, 9.40 mmol) yield. A sample was recrystallized from ethyl
acetate/n-hexane at room temperature. Colorless crystals of 6 were obtained suitable for X-ray
diffraction.14 1H NMR (500 MHz, CDCl3): δ = 7.20 (t, J = 7.9 Hz, 1H), 7.06 (d, J = 7.8 Hz, 1H), 6.76
(dd, J = 8.1, 0.7 Hz, 1H), 4.76 (t, J = 4.4 Hz, 1H), 3.83 (s, 3H), 2.80 – 2.71 (m, 1H), 2.60 – 2.51 (m,
1H), 2.00 – 1.73 (m, 5H) ppm. 13C{1H} NMR (126 MHz, CDCl3): δ = 157.1, 140.2, 126.6, 126.2,
120.7, 108.8, 68.3, 55.5, 31.8, 23.1, 18.2 ppm. The spectroscopic data agree with the
literature.18 HPLC-analysis: YMC Chiral Amylose-C S-5μm (25 cm), n-hexane/i-PrOH = 60:40,
1.0 mL/min, 254 nm tR (major) = 5.0 min, tR (minor) = 5.4 min, >99:1 er.
(R)-1,5-Dimethoxy-1,2,3,4-tetrahydronaphthalene (7a). 6 (178 mg, 1.00 mmol) was dissolved in
dry THF (8 mL) under nitrogen atmosphere. The reaction mixture was cooled to 0 °C and NaH
(80 mg, 2.0 mmol, 2.0 equiv., 60% dispersion in mineral oil) was added portionwise. After the
turbid mixture had been stirred for 1 h at 0 °C, methyl iodide (125 µL, 2.00 mmol, 2.0 equiv.)
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was added and the solution was stirred for 13 h at room temperature. The reaction mixture was
then quenched with aqueous KOH solution (10%, 10 mL). After extraction with EtOAc (3 x
10 mL), the combined organic layers were washed with brine, dried over anhydrous MgSO4 and
concentrated under vacuum. The crude mixture was purified by flash column chromatography
(n-hexane:EtOAc = 90:10) to afford 7a as colorless solid in 98% (188 mg, 0.980 mmol) yield.
1H NMR (500 MHz, CDCl3): δ = 7.17 (t, J = 7.9 Hz, 1H), 7.00 (d, J = 7.8 Hz, 1H), 6.76 (d, J = 8.1 Hz,
1H), 4.31 (t, J = 4.7 Hz, 1H), 3.82 (s, 3H), 3.45 (s, 3H), 2.76 (dt, 1H, J = 17.6, 5.7 Hz), 2.62 – 2.50
(m, 1H), 2.06 – 1.92 (m, 2H), 1.90 – 1.80 (m, 1H), 1.78 – 1.70 (m, 1H) ppm. 13C{1H} NMR
(126 MHz, CDCl3): δ = 157.2, 137.9, 126.6, 126.1, 121.6, 108.9, 76.9, 56.3, 55.5, 27.1, 23.0, 18.0
ppm. []D20 = +19.5 (c = 0.44, CHCl3). The spectroscopic data agree with the literature.19
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(R)-5-Methoxy-1,2,3,4-tetrahydronaphthalen-1-yl acetate (7b). 6 (178 mg, 1.00 mmol) was
dissolved in triethylamine (2.0 mL, 14 mmol, 14 equiv.) and acetic anhydride (284 µL,
3.00 mmol, 3.0 equiv.). 4-(Dimethylamino)-pyridine (12 mg, 0.10 mmol, 10 mol%) was then
added and the reaction mixture was stirred at room temperature for 3 h. After completion of
the reaction, the solution was diluted with methanol (10 mL) and concentrated under reduced
pressure. The residue was quenched with water (10 mL), extracted with EtOAc (3 x 10 mL),
washed with brine (10 mL), dried over anhydrous MgSO4 and concentrated under reduced
pressure. The crude product was purified by flash column chromatography (n-
1
hexane:EtOAc = 90:10) to afford 7b as colorless oil in 96% (211 mg, 0.960 mmol) yield. H NMR
(500 MHz, CDCl3): δ = 7.17 (t, J = 7.9 Hz, 1H), 6.90 (d, J = 7.8 Hz, 1H), 6.78 (d, J = 7.9 Hz, 1H), 5.99
(t, J = 4.0 Hz, 1H), 3.83 (s, 3H), 2.83 (dt, J = 9.0, 5.0 Hz, 1H), 2.58 – 2.49 (m, 1H), 2.08 (s, 3H), 2.01
– 1.88 (m, 3H), 1.87 – 1.78 (m, 1H) ppm. 13C{1H} NMR (126 MHz, CDCl3): δ = 170.9, 157.2, 135.8,
20
127.2, 126.6, 121.5, 109.3, 70.1, 55.5, 28.7, 22.9, 21.7, 18.2 ppm. []D = +121.5 (c = 0.40,
CHCl3). The spectroscopic data agree with the literature.20
(R)-5-Methoxy-1,2,3,4-tetrahydronaphthalen-1-yl pivalate (7c). 6 (232 mg, 1.30 mmol) was
dissolved in triethylamine (2.6 mL, 18 mmol, 14 equiv.) and pivalic anhydride (791 µL,
3.90 mmol, 3.0 equiv.). 4-(Dimethylamino)-pyridine (16 mg, 0.13 mmol, 10 mol%) was then
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added and the reaction mixture was stirred at room temperature for 14 h. Afterwards, the
solution was diluted with methanol (10 mL) and concentrated under reduced pressure. The
residue was quenched with water (10 mL), extracted with EtOAc (3 x 10 mL), washed with brine
(10 mL), dried over anhydrous MgSO4 and concentrated under reduced pressure. The crude
product was purified by flash column chromatography (n-hexane:EtOAc = 90:10) to afford 7c as
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colorless solid in 82% (280 mg, 1.07 mmol) yield. M.p.: 66 – 70 °C. H NMR (500 MHz, CDCl3):
δ = 7.16 (t, J = 7.9 Hz, 1H), 6.86 (d, J = 7.7 Hz, 1H), 6.78 (d, J = 8.1 Hz, 1H), 5.94 (t, J = 4.0 Hz, 1H),
3.83 (s, 3H), 2.83 – 2.78 (m, 1H), 2.61 – 2.52 (m, 1H), 2.00 – 1.78 (m, 4H), 1.21 (s, 9H) ppm.
13C{1H} NMR (126 MHz, CDCl3): δ = 178.3, 157.0, 136.2 127.1, 126.4, 121.1, 108.9, 69.8, 55.4,
38.9, 28.7, 27.2, 23.0, 18.4 ppm. HRMS (ESP): m/z = 285.1467 calcd. for C16H22O3Na+ [M+Na]+,
found: 285.1469. IR (neat): 1708, 1477, 1469, 1438, 1396, 1340, 1250, 1146, 1070, 1058, 977,
918, 777, 721, 706 cm–1. []D20 = +61.0 (c = 0.40, CHCl3).
General Procedure 1 for the Synthesis of Hypervalent Iodine Reagents 8. Iodine triacetate
(1.00 mmol, 304 mg) was dissolved in glacial acetic acid (2.0 mL). The arene (1.00 mmol,
1.0 equiv.) was added subsequently and the reaction mixture was stirred at room temperature
for 4 h. Next, all volatiles were removed and the residue was washed with dry n-hexane:Et2O
(10:1, 3 x 10 mL) to obtain the pure product.
(R)-8-(Diacetoxyiodo)-1,5-dimethoxy-1,2,3,4-tetrahydronaphthalene
(8a).
7a
(192 mg,
1.00 mmol, 1.0 equiv.) was reacted according to general procedure 1 to give 8a as colorless
solid in 88% (384 mg, 0.880 mmol) yield. A sample was recrystallized from CH2Cl2/n-hexane at -
40 °C. Colorless crystals of 8a were obtained suitable for X-ray diffraction.14 M.p.: 124 – 128 °C.
1H NMR (500 MHz, CDCl3): δ = 8.15 (d, J = 8.7 Hz, 1H), 6.79 (d, J = 8.7 Hz, 1H), 4.50 (t, J = 3.1 Hz,
1H), 3.87 (s, 3H), 3.49 (s, 3H), 2.92 – 2.84 (m, 1H), 2.46 – 2.31 (m, 2H), 2.00 (s, 3H), 1.96 (s, 3H),
1.94 – 1.86 (m, 1H), 1.83 – 1.75 (m, 1H), 1.62 (tt, J = 13.7, 3.3 Hz, 1H) ppm. 13C{1H} NMR
(126 MHz, CDCl3): δ = 176.8, 176.4, 160.5, 138.6, 137.7, 130.7, 118.4, 110.9, 76.8, 56.5, 55.8,
25.0, 23.6, 20.5, 20.4, 16.3 ppm. HRMS (EI): m/z = 376.0166 calcd. for C14H17O4I+ [M-OAc-H]+,
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found: 376.0165. IR (neat): 1641, 1566, 1458, 1360, 1339, 1252, 1188, 1078, 1047, 1007, 912,
821, 802, 665 cm–1. []D20 = –63.1 (c = 0.40, CHCl3).
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(R)-8-(Diacetoxyiodo)-5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl acetate (8b). 7b (220 mg,
1.00 mmol, 1.0 equiv.) was reacted according to general procedure 1 to give 8b as colorless
solid in 90% (418 mg, 0.880 mmol) yield. M.p.: 129 – 131 °C. 1H NMR (500 MHz, CDCl3): δ = 8.18
(d, J = 8.7 Hz, 1H), 6.84 (d, J = 8.7 Hz, 1H), 6.10 (t, J = 2.5 Hz, 1H), 3.89 (s, 3H), 3.01 – 2.92 (m,
1H), 2.50 – 2.38 (m, 1H), 2.33 – 2.23 (m, 1H), 2.06 (s, 3H), 1.96 (s, 3H), 1.96 (s, 3H), 1.92 – 1.81
(m, 3H) ppm. 13C{1H} NMR (126 MHz, CDCl3): δ = 176.5, 176.4, 169.9, 160.7, 138.1, 136.2, 131.7,
118.0, 111.7, 71.2, 56.0, 28.4, 23.6, 21.2, 20.5, 20.5, 16.8 ppm. HRMS (CI): m/z = 364.0404
calcd. for C13H19NO3I+ [M-2OAc+NH4]+, found: 364.0405. IR (neat): 1728, 1647, 1566, 1462,
1437, 1366, 1261, 1227, 1103, 1070, 1007, 984, 912, 808, 729, 667, 606 cm–1. []D20 = +9.5 (c =
0.42, CHCl3).
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(R)-8-(Diacetoxyiodo)-5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl pivalate (8c). 7c (262 mg,
1.00 mmol, 1.0 equiv.) was reacted according to general procedure 1 to give 8c as colorless
solid in 75% (380 mg, 0.750 mmol) yield. A sample was recrystallized from CH2Cl2/n-hexane at -
40 °C. Colorless crystals of 8c were obtained suitable for X-ray diffraction.14 M.p.: 124 – 128 °C.
1H NMR (500 MHz, CDCl3): δ = 8.14 (d, J = 8.1 Hz, 1H), 6.85 (d, J = 8.7 Hz, 1H), 6.08 (d, J = 2.6 Hz,
1H), 3.90 (s, 3H), 3.01 – 2.93 (m, 1H), 2.49 – 2.39 (m, 1H), 2.25 – 2.18 (m, 1H), 1.98 (s, 3H), 1.91
(s, 3H), 1.89 – 1.78 (m, 2H), 1.77 – 1.70 (m, 1H), 1.19 (s, 9H) ppm. 13C{1H} NMR (126 MHz,
CDCl3): δ = 177.4 (C), 176.6, 176.6, 160.5, 137.7, 136.3, 131.8, 117.3, 111.6, 70.0, 55.9, 39.0,
28.1, 27.1, 23.7, 20.7, 20.6, 16.6 ppm. HRMS (NSI): m/z = 447.0663 calcd. for C18H24O5I+ [M–
OAc]+, found: 447.0654. IR (neat): 1724, 1643, 1568, 1466, 1362, 1261, 1138, 1105, 1069, 1013,
978, 920, 820, 665, 615 cm–1. []D20 = –107.0 (c = 0.42, CHCl3).
Methyl (S)-2-((5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)oxy)benzoate (10). 6 (445 mg,
2.50 mmol), methyl salicylate (405 µL, 3.13 mmol, 1.3 equiv.) and triphenylphosphine (825 mg,
3.13 mmol, 1.3 equiv.) were dissolved in dry THF (7 mL) under nitrogen atmosphere. The
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reaction mixture was cooled to 0 °C and diisopropyl azodicarboxylate (652 µL, 3.13 mmol,
1.3 equiv.) was added dropwise. After 1 h at 0 °C, the mixture was warmed up to room
temperature and stirred for 18 h. The solvent was removed under reduced pressure and Et2O
(20 mL) was added. Triphenylphosphine oxide, which precipitated, was removed by filtration
and the filtrate was concentrated under vacuum. The crude mixture was purified by flash
column chromatography (n-hexane:EtOAc = 95:5) to afford 10 as white solid in 74% (578 mg,
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1.85 mmol) yield. M.p.: 48 – 52 °C. H NMR (500 MHz, CDCl3): δ = 7.76 (dd, J = 7.7, 1.8 Hz, 1H),
7.46 (ddd, J = 8.4, 7.4, 1.8 Hz, 1H), 7.16 (t, J = 8.4 Hz, 2H), 7.04 – 7.00 (m, 2H), 6.79 (d, J = 8.0 Hz,
1H), 5.39 (t, J = 5.4 Hz, 1H), 3.84 (s, 3H), 3.80 (s, 3H), 2.83 (dt, J = 17.8, 6.1 Hz, 1H), 2.63 (m, 1H),
2.17 – 2.07 (m, 2H), 2.06 – 1.97 (m, 1H), 1.85 – 1.76 (m, 1H) ppm. 13C{1H} NMR (126 MHz,
CDCl3): δ = 167.3, 157.7, 157.1, 136.8, 133.1, 131.6, 126.7, 126.2, 123.0, 121.3, 121.0, 117.0,
109.1, 76.7, 55.5, 52.1, 28.2, 23.0, 18.4 ppm. HRMS (ESP): m/z = 335.1259 calcd. for
C19H20O4Na+ [M+Na]+, found: 335.1259. IR (neat): 1728, 1597, 1450, 1300, 1240, 1182, 1163,
1128, 1080, 1012, 977, 777, 754, 729, 662 cm–1. []D20 = –29.0 (c = 0.41, CHCl3).
Methyl (S)-2-((8-iodo-5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)oxy)benzoate (11). Iodine
triacetate (1.7 mmol, 0.52 mg) was dissolved in glacial acetic acid (3.5 mL) in a flame-dried
Schlenk tube under nitrogen atmosphere. 10 (1.7 mmol, 0.53 g) was added subsequently and
the reaction mixture was stirred at room temperature for 10 h. Next, the reaction mixture was
quenched with saturated aqueous solution of Na2S2O3 (10 mL), extracted with CH2Cl2 (3 x
10 mL), washed with brine (10 mL), dried over anhydrous MgSO4 and concentrated under
reduced pressure. The crude product was purified by flash column chromatography (n-
hexane:EtOAc = 95:5) to afford 11 as pale yellow solid in 75% (559 mg, 1.28 mmol) yield. M.p.:
114 – 117 °C. 1H NMR (500 MHz, CDCl3): δ = 7.75 (dd, J = 7.7, 1.8 Hz, 1H), 7.68 (d, J = 8.6 Hz, 1H),
7.51 – 7.46 (m, 1H), 7.34 (d, J = 8.4 Hz, 1H), 6.98 (t, J = 7.5 Hz, 1H), 6.58 (d, J = 8.6 Hz, 1H), 5.52 –
5.49 (m, 1H), 3.83 (s, 3H), 3.74 (s, 3H), 2.98 (dd, J = 18.0, 5.4 Hz, 1H), 2.41 (ddd, J = 18.3, 12.4,
6.3 Hz, 1H), 2.36 – 2.29 (m, 1H), 2.12 – 2.00 (m, 1H), 1.80 – 1.72 (m, 1H), 1.66 (tt, J = 14.0,
3.2 Hz, 1H) ppm. 13C{1H} NMR (126 MHz, CDCl3): δ = 167.1, 157.6, 157.1, 137.1, 137.1, 133.0,
131.7, 130.7, 122.0, 120.2, 114.4, 111.6, 92.2, 76.2, 55.6, 51.9, 27.1, 23.6, 16.7 ppm. HRMS
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(ESP): m/z = 439.0406 calcd. for C19H20O4I+ [M+H]+, found: 439.0408. IR (neat): 1728, 1597,
1580, 1485, 1452, 1339, 1296, 1238, 1209, 1196, 1082, 1069, 981, 934, 802, 754, 731 cm–1.
[]D20 = –60.3 (c = 0.40, CHCl3).
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(S)-2-((8-iodo-5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)oxy)-N-methylbenzamide (12a). 11
(526 mg, 1.20 mmol) was dissolved in a flame-dried Schlenk tube under nitrogen atmosphere in
CH2Cl2 (2.0 mL) and methylamine (7.5 mL, 60 mmol, 50 equiv., 8 M in ethanol). The reaction
mixture was stirred at room temperature for 21 h. Afterwards, all volatiles were removed under
reduced pressure and the crude mixture was purified by flash column chromatography (n-
hexane:EtOAc = 80:20) to afford 12a as colorless solid in 79% (0.42 g, 0.95 mmol) yield. M.p.:
138 – 142 °C. 1H NMR (500 MHz, CDCl3): δ = 8.24 (dd, J = 7.8, 1.8 Hz, 1H), 7.73 (d, J = 8.6 Hz, 1H),
7.63 (br, 1H), 7.49 – 7.43 (m, 1H), 7.26 (d, J = 8.3 Hz, 1H), 7.08 (t, J = 7.5 Hz, 1H), 6.63 (d, J =
8.6 Hz, 1H), 5.58 – 5.54 (m, 1H), 3.85 (s, 3H), 3.02 – 2.95 (m, 1H), 2.73 (d, J = 4.8 Hz, 3H), 2.47 –
2.38 (m, 2H), 1.87 – 1.68 (m, 3H) ppm. 13C{1H} NMR (126 MHz, CDCl3): δ = 166.2, 157.6, 155.9,
137.6, 136.4, 132.6, 132.5, 130.6, 122.7, 121.3, 113.3, 111.9, 91.4, 77.0, 55.7, 26.9, 26.5, 23.4,
17.0 ppm. HRMS (ESP): m/z = 438.0566 calcd. for C19H21NO3I+ [M+H]+, found: 438.0572. IR
(neat): 3408, 1643, 1599, 1541, 1460, 1435, 1294, 1252, 1219, 1161, 1101, 1067, 1013, 982,
904, 804, 723, 644 cm–1. []D20 = –65.4 (c = 0.39, CHCl3).
2-((5-Methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)oxy)-N-methylbenzamide (12b). (Rac)-10
(234 mg, 0.750 mmol) was dissolved in a flame-dried Schlenk tube under nitrogen atmosphere
in CH2Cl2 (1.0 mL) and methylamine (4.7 mL, 38 mmol, 50 equiv., 8 M in ethanol). The reaction
mixture was stirred at room temperature for 21 h. Afterwards, all volatiles were removed under
reduced pressure and the crude mixture was purified by flash column chromatography (n-
hexane:EtOAc = 80:20) to afford 12b as colorless solid in 79% (184 mg, 0.590 mmol) yield. M.p.:
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99 – 103 °C. H NMR (500 MHz, CDCl3): δ = 8.25 (dd, J = 7.8, 1.8 Hz, 1H), 7.88 (br, 1H), 7.50 –
7.40 (m, 1H), 7.22 – 7.14 (m, 2H), 7.10 (t, J = 8.0 Hz, 1H), 6.95 (d, J = 7.7 Hz, 1H), 6.83 (d, J = 8.0
Hz, 1H), 5.52 (t, J = 4.8 Hz, 1H), 3.86 (s, 3H), 2.86 (dt, J = 17.8, 5.7 Hz, 1H), 2.77 (d, J = 4.8 Hz,
3H), 2.67 – 2.57 (m, 1H), 2.21 – 2.12 (m, 1H), 2.12 – 2.03 (m, 1H), 2.00 – 1.90 (m, 1H), 1.90 –
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1.80 (m, 1H) ppm. 13C{1H} NMR (126 MHz, CDCl3): δ = 166.0, 157.2, 156.5, 135.9, 132.6, 132.5,
126.8, 126.8, 123.1, 121.7, 120.9, 114.6, 109.5, 76.6, 55.5, 28.1, 26.4, 22.8, 18.5 ppm. HRMS
(ESP): m/z = 334.1419 calcd. for C19H21NO3Na+ [M+Na]+, found: 334.1427. IR (neat): 3402, 1647,
1597, 1535, 1472, 1409,1344, 1294, 1252, 1219, 1159, 1101, 1067, 1008, 976, 924, 777, 754,
727, 644 cm–1.
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(S)-8-(Diacetoxyiodo)-2-((5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)oxy)-N-
methylbenzamide (13). 12a (307 mg, 0.700 mmol) was dissolved in CH3CN (12 mL) and glacial
acetic acid (4 mL) under nitrogen atmosphere. Selectfluor® was added subsequently and the
resulting suspension was stirred at room temperature for 3 h. After completion of the reaction,
solvents were removed under vacuum and the product was dissolved in CHCl3. After filtration
under nitrogen atmosphere, the filtrate was concentrated under reduced pressure to afford 13
as yellow solid in >99% (389 mg, 0.700 mmol) yield. A sample was recrystallized from CH2Cl2/n-
hexane at -40 °C. Colorless crystals of 13 were obtained suitable for X-ray diffraction.14 M.p.:
140 – 144 °C. 1H NMR (500 MHz, CDCl3): δ = 8.22 (d, J = 8.7 Hz, 1H), 8.12 (dd, J = 7.8, 1.7 Hz, 1H),
7.57 – 7.51 (m, 1H), 7.51 – 7.45 (m, 1H), 7.27 (d, J = 8.6 Hz, 1H), 7.09 (t, J = 7.5 Hz, 1H), 6.91 (d, J
= 8.7 Hz, 1H), 6.06 – 6.02 (m, 1H), 3.95 (s, 3H), 3.02 (dd, J = 17.5, 3.2 Hz, 1H), 2.74 (d, J = 4.8 Hz,
3H), 2.51 – 2.36 (m, 2H), 1.99 (s, 3H), 1.88 – 1.74 (m, 3H), 1.72 (s, 3H) ppm. 13C{1H} NMR
(126 MHz, CDCl3): δ = 176.7, 176.2, 166.2, 160.8, 153.8, 138.1, 136.3, 133.0, 132.7, 131.4,
123.2, 122.0, 119.0, 112.9, 111.8, 73.9, 56.0, 26.7, 26.2, 23.6, 20.6, 20.0, 16.8 ppm. HRMS (NSI):
m/z = 438.0561 calcd. for C19H21NO3I+ [M–2OAc+H]+, found: 438.0553. IR (neat): 3410, 1645,
1599, 1566, 1464, 1362, 1259, 1217, 1101, 1065, 1007, 980, 932, 802, 754, 665 cm–1. []D
=
20
+25.0 (c = 0.40, CHCl3).
(R)-Triisopropyl((5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)oxy)silane (14).
6
(0.54 g,
3.0 mmol) was dissolved in a flame-dried Schlenk tube under nitrogen atmosphere in CH2Cl2
(7.0 mL) and triethylamine (0.63 mL, 4.5 mmol, 1.5 equiv.). The solution was cooled to 0 °C and
triisopropylsilyl trifluoromethanesulfonate (0.81 mL, 3.0 mmol, 1.0 equiv.) was added. The
reaction mixture was then warmed up to room temperature and stirred for 20 h. After
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(1.00 g, 3.00 mmol) yield. H NMR (500 MHz, CDCl3): δ = 7.19 – 7.11 (m, 2H), 6.72 (d, J = 7.8 Hz
1H), 4.92 (dd, J = 7.2, 4.4 Hz, 1H), 3.81 (s, 3H), 2.72 – 2.56 (m, 2H), 2.08 – 1.92 (m, 2H), 1.87 –
1.78 (m, 1H), 1.77 – 1.66 (m, 1H), 1.21 – 1.14 (m, 3H), 1.14 – 1.07 (m, 18H) ppm. 13C{1H} NMR
(126 MHz, CDCl3): δ = 157.0, 141.5, 126.0, 125.9, 120.3, 108.2, 69.7, 55.5, 32.8, 23.1, 19.0, 18.5,
18.4, 13.0 ppm. HRMS (ESP): m/z = 333.2250 calcd. for C20H33O2Si+ [M–H]+, found: 333.2263. IR
(neat): 2940, 2864, 1585, 1470, 1436, 1258, 1101, 1080, 1067, 1003, 881, 812, 772, 675,
652 cm–1. []D20 = –19.5 (c = 0.41, CHCl3).
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(R)-((8-Iodo-5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)oxy)triisopropylsilane (15). A solution
of iodine triacetate (3.0 mmol, 0.91 g) in glacial acetic acid (6.0 mL) in a flame-dried Schlenk
tube under nitrogen atmosphere was transferred to a second Schlenk tube under nitrogen
atmosphere which contained 14 (3.00 mmol, 1.00 g). The solution was stirred at room
temperature for 15 h and the reaction was then quenched by addition of saturated aqueous
solution of Na2S2O3 (10 mL). The mixture was extracted with CH2Cl2 (3 x 10 mL), washed with
brine (10 mL), dried over anhydrous MgSO4 and concentrated under reduced pressure. The
crude product was purified by flash column chromatography (n-hexane) to afford 15 as pale
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yellow solid in 71% (981 mg, 2.13 mmol) yield. M.p.: 60 – 64 °C. H NMR (500 MHz, CDCl3):
δ = 7.65 (d, J = 8.6 Hz, 1H), 6.52 (d, J = 8.6 Hz, 1H), 5.04 (t, J = 2.6 Hz, 1H), 3.80 (s, 3H), 2.90 –
2.82 (m, 1H), 2.51 (ddd, J = 17.5, 10.1, 7.2 Hz, 1H), 2.18 – 2.07 (m, 2H), 1.74 – 1.59 (m, 2H), 1.33
– 1.23 (m, 3H), 1.11 (d, J = 7.5 Hz, 9H), 1.06 (d, J = 7.5 Hz, 9H) ppm. 13C{1H} NMR (126 MHz,
CDCl3): δ = 157.6, 141.7, 137.0, 129.4, 111.2, 91.0, 72.7, 55.6, 32.0, 22.6, 18.8, 18.7, 16.3, 13.6
ppm. HRMS (ESP): m/z = 286.9933 calcd. for C11H12OI+ [M–OTIPS]+, found: 286.9940. IR (neat):
2940, 2862, 1570, 1458, 1433, 1381, 1366, 1325, 1296, 1251, 1201, 1182, 1155, 1089, 1070,
1026, 1001, 957, 883, 862, 812, 793, 716, 679, 627, 613 cm–1. []D20 = –34.8 (c = 0.39, CHCl3).
(R)-8-Iodo-5-methoxy-1,2,3,4-tetrahydronaphthalen-1-ol (16). 15 (842 mg, 1.83 mmol) was
dissolved in THF (10 mL), followed by the addition of tetrabutylammonium fluoride (5.4 mL,
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5.4 mmol, 3.0 equiv., 1 M solution in THF). The solution was stirred at room temperature for 1 h
and then concentrated in vacuo. The residue was then quenched with saturated aqueous
solution of NH4Cl (20 mL), extracted with EtOAc (3 x 20 mL), washed with brine (20 mL), dried
over anhydrous MgSO4 and concentrated under reduced pressure. The crude product was
purified by flash column chromatography (n-hexane:EtOAc = 90:10) to afford 16 as colorless
solid in 91% (508 mg, 1.67 mmol) yield. M.p.: 88 – 93 °C. 1H NMR (500 MHz, CDCl3): δ = 7.65 (d,
J = 8.6 Hz, 1H), 6.54 (d, J = 8.6 Hz, 1H), 4.83 – 4.77 (m, 1H), 3.80 (s, 3H), 2.89 (dd, J = 18.0,
5.3 Hz, 1H), 2.41 – 2.29 (m, 2H), 2.21 – 2.13 (m, 1H), 1.98 – 1.86 (m, 1H), 1.84 – 1.76 (m, 1H),
1.75 – 1.65 (m, 1H) ppm. 13C{1H} NMR (126 MHz, CDCl3): δ = 157.9, 140.3, 137.2, 129.7, 111.4,
91.0, 70.1, 55.7, 30.6, 23.7, 16.7 ppm. HRMS (CI): m/z = 302.9882 calcd. for C11H12O2I+ [M–H]+,
found: 302.9885. IR (neat): 3410, 1568, 1458, 1435, 1337, 1294, 1247, 1201, 1179, 1155, 1096,
1065, 1011, 980, 907, 799, 754, 731, 650 cm–1. []D20 = +50.3 (c = 0.40, CHCl3).
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(R)-8-Iodo-5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl picolinate (18a). 16 (456 mg,
1.50 mmol) was dissolved in a flame-dried Schlenk tube under nitrogen atmosphere in CH2Cl2
(15 mL). After cooling the solution to 0 °C, dicyclohexylcarbodiimide (400 mg, 1.94 mmol,
1.3 equiv.), 4-(dimethylamino)-pyridine (187 mg, 1.53 mmol, 1.0 equiv.) and picolinic acid
(221 mg, 1.80 mmol, 1.2 equiv.) were added. The solution was then warmed up to room
temperature and stirred for 3 h. The resulting suspension was diluted with Et2O and filtered
through celite. The filtrate was concentrated under vacuum and the crude product was purified
by flash column chromatography (n-hexane:EtOAc = 70:30) to afford 18a as colorless solid in
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96% (586 mg, 1.43 mmol) yield. M.p.: 140 – 144 °C. H NMR (500 MHz, CDCl3): δ = 8.77 (d, J =
4.6 Hz, 1H), 8.06 (d, J = 7.8 Hz, 1H), 7.78 (t, J = 7.7 Hz, 1H), 7.69 (d, J = 8.6 Hz, 1H), 7.46 – 7.42
(m, 1H), 6.60 (d, J = 8.6 Hz, 1H), 6.14 – 6.09 (m, 1H), 3.83 (s, 3H), 2.97 (m, 1H), 2.50 – 2.39 (m,
2H), 1.91 – 1.81 (m, 3H) ppm. 13C{1H} NMR (126 MHz, CDCl3): δ = 164.3, 157.6, 150.2, 148.4,
137.4, 136.9, 136.0, 131.2, 126.8, 125.3, 111.9, 91.6, 75.0, 55.7, 28.7, 23.7, 17.2 ppm. HRMS
(ESP): m/z = 410.0253 calcd. for C17H17NO3I+ [M+H]+, found: 410.0250. IR (neat): 1711, 1572,
1456, 1435, 1337, 1325, 1296, 1283, 1244, 1206, 1182, 1123, 1011, 995, 976, 895, 799, 746,
702, 681, 652, 619 cm–1. []D20 = +81.5 (c = 0.27, CHCl3).
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5-Methoxy-1,2,3,4-tetrahydronaphthalen-1-yl picolinate (18b). (Rac)-6 (267 mg, 1.50 mmol) was
dissolved in a flame-dried Schlenk tube under nitrogen atmosphere in CH2Cl2 (15 mL). After
cooling the solution to 0 °C, dicyclohexylcarbodiimide (400 mg, 1.94 mmol, 1.3 equiv.), 4-
(dimethylamino)-pyridine (187 mg, 1.53 mmol, 1.0 equiv.) and picolinic acid (221 mg,
1.80 mmol, 1.2 equiv.) were added. The solution was then warmed up to room temperature
and stirred for 3 h. The resulting suspension was diluted with Et2O and filtered through celite.
The filtrate was concentrated under vacuum and the crude product was purified by flash
column chromatography (n-hexane:EtOAc = 70:30) to afford 18b colorless solid in 74% (315 mg,
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1.11 mmol) yield. M.p.: 48 – 52 °C. H NMR (500 MHz, CDCl3): δ = 8.78 – 8.75 (m, 1H), 8.10 –
8.05 (m, 1H), 7.79 (td, J = 7.7, 1.6 Hz, 1H), 7.46 – 7.41 (m, 1H), 7.16 (t, J = 7.9 Hz, 1H), 7.00 (d, J =
7.8 Hz, 1H), 6.78 (d, J = 8.1 Hz, 1H), 6.33 (t, J = 4.5 Hz, 1H), 3.83 (s, 3H), 2.86 (dt, J = 17.9, 5.3 Hz,
1H), 2.66 – 2.54 (m, 1H), 2.20 – 1.98 (m, 3H), 1.95 – 1.84 (m, 1H) ppm. 13C{1H} NMR (126 MHz,
CDCl3): δ = 164.8, 157.2, 150.2, 148.6, 137.0, 135.4, 127.3, 126.8, 126.6, 125.3, 121.6, 109.4,
+
71.8, 55.5, 28.8, 22.9, 18.5 ppm. HRMS (ESP): m/z = 284.1287 calcd. for C17H18NO3 [M+H]+,
found: 284.1297. IR (neat): 1705, 1585, 1472, 1437, 1351, 1302, 1287, 1263, 1244, 1180, 1125,
1103, 1065, 885, 877, 792, 777, 750, 705, 640, 617 cm–1.
(R)-8-(Diacetoxyiodo)-5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl picolinate (19). 18a
(450 mg, 1.10 mmol) was dissolved in CH3CN (20 mL) and glacial acetic acid (6.6 mL) under
nitrogen atmosphere. Selectfluor® was added subsequently and the resulting suspension was
stirred at room temperature for 4 h. After completion of the reaction, solvents were removed
under vacuum and the product was dissolved in CHCl3. After filtration under nitrogen
atmosphere, the filtrate was concentrated under reduced pressure to afford 19 as yellow solid
in >99% (580 mg, 1.10 mmol) yield. A sample was recrystallized from CH2Cl2/n-hexane at -40 °C.
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Colorless crystals of 8a were obtained suitable for X-ray diffraction.14 M.p.: 62 – 66 °C. H NMR
(500 MHz, CDCl3): δ = 8.75 (ddd, J = 4.7, 1.8, 0.9 Hz, 1H), 8.17 (d, J = 8.7 Hz, 1H), 8.14 (dt, J = 7.9,
1.1 Hz, 1H), 7.79 (td, J = 7.7, 1.8 Hz, 1H), 7.44 (ddd, J = 7.6, 4.7, 1.2 Hz, 1H), 6.85 (d, J = 8.7 Hz,
1H), 6.50 (t, J = 2.8 Hz, 1H), 3.91 (s, 3H), 3.07 – 2.97 (m, 1H), 2.57 – 2.40 (m, 2H), 1.97 (s, 3H),
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2.02 – 1.82 (m, 3H), 1.43 (s, 3H) ppm. 13C{1H} NMR (126 MHz, CDCl3): δ = 176.4, 176.1, 164.0,
160.7, 150.0, 148.1, 138.1, 137.0, 135.9, 132.0, 127.0, 125.7, 118.4, 111.8, 72.7, 56.0, 28.6,
23.7, 20.5, 19.8, 16.9 ppm. HRMS (CI): m/z = 468.0302 calcd. for C19H19NO5I+ [M-OAc]+, found:
468.0304. IR (neat): 1717, 1647, 1568, 1464, 1437,1362, 1287, 1263, 1125, 1069, 978, 916, 812,
731, 667 cm–1. []D20 = –56.3 (c = 0.40, CHCl3).
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General Procedure 2 for the Stereoselective Diacetoxylation of Styrene 20. In analogy to a
procedure of Fujita et al.,3e the hypervalent iodine reagent (0.200 mmol, 1.25 equiv.) and
styrene 20 (18 µL, 0.16 mmol) were dissolved in CH2Cl2 (1.6 mL) in the presence of glacial acetic
acid (80 µL) and trimethylsilyl acetate (80 µL, 0.53 mmol, 3.3 equiv.) in a flame-dried Schlenk
tube under nitrogen atmosphere. The solution was cooled to –78 °C. Boron trifluoride diethyl
etherate (40 µL, 0.32 mmol, 2.0 equiv.) was added to the solution, which was then warmed up
to room temperature over 10 h. H2O (5 mL) was added and the resulting mixture was extracted
with CH2Cl2 (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried
over anhydrous MgSO4 and concentrated under vacuum. The crude mixture was purified by
flash column chromatography (n-hexane:EtOAc = 90:10).
(R)-1-Phenylethane-1,2-diyl diacetate ((R)-21). 7a (87 mg, 0.200 mmol, 1.3 equiv.) was reacted
according to general procedure 2 to give (R)-21 as pale yellow oil in 65% (23 mg, 0.10 mmol)
yield. 7b (93 mg, 0.200 mmol, 1.3 equiv.) was reacted according to general procedure 2 to give
(R)-21 as pale yellow oil in 67% (24 mg, 0.11 mmol) yield. 7c (101 mg, 0.200 mmol, 1.3 equiv.)
was reacted according to general procedure 2 to give (R)-21 as pale yellow oil in 89% (32 mg,
0.14 mmol) yield. 19 (105 mg, 0.200 mmol, 1.3 equiv.) was reacted according to general
procedure 2 to give (R)-21 as pale yellow oil in 87% (31 mg, 0.14 mmol) yield. In order to
determine the enantiomeric ratio of 21, the products were converted into the corresponding
diols. HPLC-analysis: Lux® 5 µm Cellulose-1, LC Column (250 x 4.6 mm), n-hexane/i-PrOH = 95:5,
0.7 mL/min, 209 nm, tR (major) = 29.4 min, tR (minor) = 32.5 min, up to 61:39 er.
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(S)-1-Phenylethane-1,2-diyl diacetate ((S)-21). 13 (111 mg, 0.200 mmol, 1.3 equiv.) was reacted
according to general procedure 2 to give (S)-21 as pale yellow oil in 65% (23 mg, 0.10 mmol)
yield. 1H NMR (500 MHz, CDCl3): δ = 7.38 – 7.30 (m, 5H), 6.02 (dd, J = 8.0, 3.9 Hz, 1H), 4.33 (dd, J
= 11.9, 3.9 Hz, 1H), 4.29 (dd, J = 11.9, 8.0 Hz, 1H), 2.12 (s, 3H), 2.06 (s, 3H) ppm. 13C{1H} NMR
(126 MHz, CDCl3): δ = 170.8, 170.2, 136.6, 128.8, 128.7, 126.8, 73.5, 66.2, 21.2, 20.9 ppm. The
spectroscopic data agree with the literature.3c In order to determine the enantiomeric ratio of
21, the products were converted into the corresponding diols. HPLC-analysis: Lux® 5 µm
Cellulose-1, LC Column (250 x 4.6 mm), n-hexane/i-PrOH = 95:5, 0.7 mL/min, 209 nm, tR (minor)
= 28.9 min, tR (major) = 33.5 min, 57:43 er.
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General Procedure 3 for the Oxidative Rearrangement of 22. The hypervalent iodine reagent
(0.20 mmol, 1.2 equiv.) was dissolved in CH2Cl2:trifluoroethanol (10:1 v/v, 1.5 mL) and
methanol (24 µL, 0.60 mmol, 3.3 equiv.). The solution was cooled to -78 °C, 1,1-
diphenylpentane 22 (40 mg, 0.18 mmol) and TsOH • H2O (48 mg, 0.25 mmol, 1.3 equiv.) were
added subsequently and the reaction mixture was stirred at -78 °C for 2 h. The reaction was
then quenched with aqueous saturated Na2S2O3 (5 mL) and the resulting mixture was extracted
with CH2Cl2 (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried
over anhydrous MgSO4 and concentrated under vacuum. The crude mixture was purified by
flash column chromatography (n-hexane:EtOAc = 90:10).
(R)-1,2-Diphenyl-1-pentanone ((R)-23). 7a (87 mg, 0.20 mmol, 1.2 equiv.) was reacted according
to general procedure 3 to give (R)-23 as colorless solid in 60% (26 mg, 0.12 mmol) yield. 7b
(93 mg, 0.20 mmol, 1.2 equiv.) was reacted according to general procedure 3 to give (R)-23 as
colorless solid in 55% (24 mg, 0.10 mmol) yield. 7c (101 mg, 0.200 mmol, 1.2 equiv.) was
reacted according to general procedure 3 to give (R)-23 as colorless solid in 75% (32 mg,
0.14 mmol) yield. 19 (105 mg, 0.200 mmol, 1.2 equiv.) was reacted according to general
procedure 3 to give (R)-23 as colorless solid in 74% (32 mg, 0.13 mmol) yield. HPLC-analysis:
YMC Chiral Amylose-C S-5μm (25 cm), n-hexane/i-PrOH = 99.5:0.5, 1.0 mL/min, 243 nm tR
(minor) = 9.1 min, tR (major) = 12.7 min, up to 75:25 er.
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(S)-1,2-Diphenyl-1-pentanone ((S)-23). 13 (111 mg, 0.200 mmol, 1.2 equiv.) was reacted
according to general procedure 3 to give (S)-23 as colorless solid in 71% (31 mg, 0.13 mmol)
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yield. H NMR (500 MHz, CDCl3): δ = 7.88 (d, J = 7.9 Hz, 2H), 7.39 (t, J = 7.3 Hz, 1H), 7.30 (t, J =
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7.6 Hz, 2H), 7.26 – 7.16 (m, 4H), 7.11 (t, J = 7.0 Hz, 1H), 4.48 (t, J = 7.2 Hz, 1H), 2.14 – 2.03 (m,
1H), 1.79 – 1.68 (m, 1H), 1.32 – 1.11 (m, 2H), 0.84 (t, J = 7.3 Hz, 3H) ppm. 13C{1H} NMR
(126 MHz, CDCl3): δ = 200.2, 140.0, 137.2, 132.9, 129.0, 128.8, 128.6, 128.4, 127.1, 53.6, 36.3,
21.0, 14.2 ppm. The spectroscopic data agree with the literature.6b HPLC-analysis: YMC Chiral
Amylose-C S-5μm (25 cm), n-hexane/i-PrOH = 99.5:0.5, 1.0 mL/min, 243 nm tR (major) =
8.4 min, tR (minor) = 10.4 min, 57:43 er.
(2S)-2-[(4-Methylbenzenesulfonyl)oxy]-1-phenylpropan-1-one ((S)-25). 19 (105 mg, 0.200 mmol,
1.3 equiv.) and p-TsOH • H2O (95 mg, 0.40 mmol, 2.5 equiv.) were dissolved in CH2Cl2 (2 mL)
and the resulting solution was stirred for 30 minutes. Afterwards, the solution was cooled to -
40 °C and propiophenone 24 (21 µL, 0.16 mmol) was added. After having stirred at this
temperature for 3 h, the solution was warmed up to room temperature over 10 h. The reaction
was then quenched with aqueous saturated Na2S2O3 (5 mL) and the resulting mixture was
extracted with CH2Cl2 (3 x 10 mL). The combined organic layers were washed with brine
(10 mL), dried over anhydrous MgSO4 and concentrated under vacuum. The crude mixture was
purified by flash column chromatography (n-hexane:EtOAc = 90:10) to give (S)-25 as colorless
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oil in 59% (29 mg, 0.094 mmol) yield. H NMR (400 MHz, CDCl3): δ = 7.90 – 7.85 (m, 2H), 7.77 –
7.72 (m, 2H), 7.62 – 7.56 (m, 1H), 7.49 – 7.42 (m, 2H), 7.29 – 7.25 (m, 2H), 5.78 (q, J = 6.9 Hz,
1H), 2.41 (s, 3H), 1.60 (d, J = 6.9 Hz, 3H) ppm. 13C{1H} NMR (101 MHz, CDCl3): δ = 195.0, 145.1,
134.0, 133.8, 133.6, 129.9, 128.9, 128.9, 128.1, 77.5, 21.8, 18.9 ppm. The spectroscopic data
agree with the literature.21 HPLC-analysis: YMC Chiral Amylose-C S-5μm (25 cm), n-hexane/i-
PrOH = 85:15, 0.7 mL/min, 226 nm tR (minor) = 15.8 min, tR (major) = 17.5 min, 54:46 er.
Supporting Information
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Copies of 1H and 13C NMR spectra for all synthesized compounds 6-8, 10-16, 18, 19, 21, 23 and
25; chiral HPLC chromatograms of 6, 21, 23 and 25; X-ray crystal data of compounds 6, 8a, 8c,
13 and 19.
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Acknowledgments
We thank the Fonds der Chemischen Industrie (TH) and the School of Chemistry, Cardiff
University for financial support.
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(e) Guilbault, A.; Legault, C. Y. Drastic Enhancement of Activity in Iodane-Based α-Tosylation of
Ketones: Iodine(III) Does the Hypervalent Twist. ACS Catal. 2012, 2, 219-222. (f) Levitre, G. ;
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