Electron-Deficient Chiral Lactic Acid-Based Hypervalent Iodine Reagents

Article abstract of DOI:10.1021/acs.joc.7b01571

Novel electron-deficient chiral hypervalent iodine reagents were prepared in good overall yields. The reactivity and stereoselectivity of these reagents in oxidative rearrangements of alkenes to α-aryl ketones were investigated. The results show that the new reagents have good reactivity and generate products with high enantiomeric excess.

Full text of DOI:10.1021/acs.joc.7b01571

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Note
Electron-deficient Chiral Lactic Acid-based Hypervalent Iodine Reagents
Jihan Qurban, Mohamed Elsherbini, and Thomas Wirth
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01571 • Publication Date (Web): 20 Jul 2017
Downloaded from http://pubs.acs.org on July 20, 2017
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Electron-deficient Chiral Lactic Acid-based Hypervalent Iodine Reagents
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Jihan Quarban, Mohamed Elsherbini, Thomas Wirth*
School of Chemistry, Cardiff University, Park Place, Cardiff, CF10 3AT, UK
wirth@cf.ac.uk
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O
I(OAc)2
O
O
O
O
TsOH•H2O, MeOH
R
R
Ph
+
Ph
CH2Cl2 / CF3CH2OH
Ph
Ph
CF3
Abstract:
Novel electronꢀdeficient chiral hypervalent iodine reagents were prepared in good overall yields.
The reactivity and stereoselectivity of these reagents in oxidative rearrangements of alkenes to αꢀ
aryl ketones was investigated. The results show that the new reagents have good reactivity and
generate products with high enantiomeric excess.
The chemistry of hypervalent iodine reagents has witnessed a massive growth and
development in the 21st century. The extensive interest in hypervalent iodine reagents is
attributed to their powerful oxidizing properties, along with their easy handling, commercial
availability and benign environmental impact. Their synthetic applications include oxidation,
halogenation, amination, C–C bond formation, heterocyclization and rearrangement
reactions.1,2,3
Recently, many efforts were devoted to the development of hypervalent iodine catalyzed
chemical transformations.4 The catalytic cycle relies on the re-oxidation of an iodine(I)
species, mainly iodoarenes, into the corresponding hypervalent iodine compounds in the
presence of a stoichiometric oxidant. Hydrogen peroxide, oxone, m-chloroperbenzoic acid,
sodium perborate, and Selectfluor® are commonly used terminal oxidants in such catalytic
transformations. The utilization of chiral iodoarenes as organocatalysts for different
enantioselective transformations is a fast-growing research area and several approaches have
been published recently.5
Chiral hypervalent iodine(III) reagents have been very successfully used in stereoselective
synthesis and received much attention.6 Fujita7 and Ishihara8 initially published the synthesis
and use of chiral hypervalent iodine reagents based on lactic acid. Many reactions have been
investigated using these chiral reagents and in some of them very high stereoselectivities
have been obtained. We also have contributed to that development and published highly
stereoselective oxyaminations9 and also the first stereoselective rearrangements based on
chiral, lactic acid-based iodine(III) reagents.10 The investigation of more recent
rearrangements employing additional orthoesters to generate
α-aryl esters as reaction
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products proved to be less efficient with the known lactic acid-based iodine(III) reagents. We
therefore decided to prepare more reactive versions of the reagents 1 by the attachment of an
electron-withdrawing group such as a trifluoromethyl substituent (R = CF3) in the para-
position to the iodine (Figure 1). This should enhance the electrophilicity of the hypervalent
iodine reagents 2 (R = CF3) as compared to the unsubstituted reagents 2 (R = H). With other
hypervalent iodine(III) derivatives we have already shown that the addition of CF3 groups in
para position to the iodine(III) moiety enhances their reactivity.11
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O
I
O
O
L
I
L
O
oxidation
O
O
O
O
R'
R'
R'
R'
R
R
1
2
Figure 1: Lactic acid-based hypervalent iodine reagents 2
Such reagents have been prepared by the route shown below starting from the commercially
available 3ꢀnitroꢀ5ꢀ(trifluoromethyl)phenol 3 (Scheme 1), through which the novel key building
block, 2ꢀiodoꢀ5ꢀ(trifluoromethyl)benzeneꢀ1,3ꢀdiol 6 was accessed. Reduction of the nitro group in 3
to the corresponding amino derivative, 3ꢀaminoꢀ5ꢀ(trifluoromethyl)phenol 4 was achieved in 97%
yield with disodium sulfide in ethanol. Diazotation of 4 was followed by treatment with a saturated
aqueous solution of copper sulfate leading to the formation of 5ꢀ(trifluoromethyl)benzeneꢀ1,3ꢀdiol 5
in 73% yield. The desired iodoarene 6 was obtained in 39% yield via the reaction of diol 5 with
elemental iodine.12
I
I2, NaHCO3
H2O/THF
(i) H2SO4/H2O
(ii) NaNO3/H2O
(i) Na2S/EtOH
(ii) NaOH/EtOH
H2N
OH
O2N
OH
HO
OH
HO
OH
39%
(iii) urea
(iv) CuSO4/H2O
73 %
EtOH
97 %
CF3
CF3
CF3
CF3
3
4
5
6
Scheme 1: Synthesis of 2ꢀiodoꢀ5ꢀ(trifluoromethyl)benzeneꢀ1,3ꢀdiol 6
Having the key intermediate 6 in our hands, we could proceed to achieve the synthesis of the target
hypervalent iodine reagents of type 2. Following literature procedures, the iodoarene 6 was
transformed into the lactate based chiral iodoarene derivative 1a in 98% yield under Mitsunobu
reaction conditions. Basic hydrolysis of the diester 1a afforded the dicarboxylic acid 1b in 80%
yield. Activation of the dicarboxylic acid 1b followed by the reaction with 2,6ꢀdiisopropylaniline
and 2,4,6ꢀtrimethylaniline afforded the amides 1c in 71% and 1d in 83% yield, respectively
(Scheme 2). Finally, the chiral iodoarenes were oxidized to the corresponding hypervalent iodine
reagents 2a and 2c using Selectflour® in a mixture of acetonitrile and acetic acid. The iodine
compound 2d could not be isolated despite many attempts.
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O
O
I
O
O
I
O
PPh3, DIAD
THF
HO
NaOH
MeOH/THF
OMe
O
O
O
O
MeO
OMe
R
R
5
6
+
80%
98%
7
8
9
6
CF3
CF3
1a
1b R = OH
(i) oxalylchloride, then RNH2
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Selectfluor R
CH3COOH
CH3CN
1c R = 2,6-(iPr)2C6H3-NH 71%
1d R = 2,4,6-Me3C6H2-NH 83%
(ii) SelectfluorR, CH3COOH
CH3CN
97%
O
O
I(OAc)2
O
O
O
I(OAc)2
O
O
O
R
MeO
OMe
R
CF3
CF3
2c R = 2,6-(iPr)2C6H3-NH 78%
2d R = 2,4,6-Me3C6H2-NH 0%
2a
Scheme 2: Synthesis of chiral iodine(III) reagents 2a and 2c
Several efficient methods for the synthesis of αꢀaryl substituted carbonyl compounds through metalꢀ
catalyzed cross coupling reactions of ketones are known.13 We have reported an efficient metalꢀfree
method for synthesizing αꢀarylated carbonyl compounds via an enantioselective oxidative
rearrangement of alkenes using stoichiometric chiral hypervalent iodine reagents (Scheme 3).14
Based on this reaction we have now developed new chiral iodoarenes for accessing αꢀaryl carbonyl
compounds.
O
iodine(III) (1.2 eq)
MeOH
Ar
R
R
Ar
Ar'
Ar'
Scheme 3: Rearrangement of alkenes to αꢀarylated ketones
Initially, we explored the oxidative rearrangement of alkene 7 using different chiral iodine(III)
reagents as stoichiometric oxidants (1.2 eq). To evaluate the reactivity of the newly prepared
hypervalent iodine reagents 2a and 2c, we studied the oxidative rearrangement of the alkene 7 by
reagents 2a, 2c and the previously reported reagents 2e – 2g (Table 1).8 Reagent 2a (Table 1, entry
1) with the trifluoromethyl substituent showed comparable reactivity and similar enantioselectivity
to the previously reported reagents with either a methyl substituent 2e or without substituent 2f
(Table 1, entries 2 and 3). Yields range between 45 and 50% while the enantiomeric excess is
between 87 and 92%. All reagents produce the same enantiomer of 8 (Rꢀconfiguration), but in each
reaction a small amount (5ꢀ15%) of ketone 9 is detected as a side product. Reagents 2c and 2g with
amide functionalities in the side chain showed much lower reactivity (Table 1, entries 4 and 5),
while the enantioselectivity is almost identical.
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ArI(III) (1.2 eq)
MeOH, (3 eq)
p-TsOH•H2O (1.2 eq)
O
O
Ph
Ph
Ph
Ph
–78 ºC, 4 h, then rt, 8 h
CH2Cl2/TFE (10:1)
Ph
Ph
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Entry ArI(III)
8 yield [%] 8 ee [%]
9 yield [%]
(absolute
configuration)
91 (R)
O
I(OAc)2
O
O
O
O
1
50
45
5
O
O
MeO
OMe
OMe
OMe
CF3
2a
O
I(OAc)2
O
2
87 (R)
5
MeO
2e
O
I(OAc)2
O
3
49
5
92 (R)
78 (R)
10
10
O
O
MeO
2f
iPr
iPr
iPr
I(OAc)2
O
O
4
O
N
H
N
H
iPr
CF3
2c
O
I(OAc)2
O
5
15
92 (R)
15
O
O
N
H
N
H
2g
Table 1: Different iodine(III) reagents 2 in the rearrangement of alkene 7
Furthermore, the potential of the oxidative rearrangement of alkene 7 using different iodoarene
catalysts (20 mol%) in presence of a stoichiometric oxidant was investigated. The catalytic
reactions had to be performed at a higher reaction temperature as the oxidation to iodine(III) is too
slow at low temperature. Initially, several iodoarenes were screened in the presence of one
equivalent mꢀchloroperbenzoic acid (mCPBA). Substantial amounts of 9 were generated while the
overall yield was very low. Enantioselectivities were also low (45ꢀ76% ee, see supporting
information). Different oxidants were also investigated. Although Selectfluor® showed reasonable
reactivity, fluorinated byꢀproducts 11a and 11b were always produced by direct reaction with the
alkene. Some selected reaction conditions are summarized in Scheme 4.
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oxidant
ArI (0.2 eq)
MeOH (8 eq)
O
O
OR
Ph
p-TsOH•H2O (1.5 eq)
Ph
O
Ph
Ph
Ph
Ph
5
6
Ph
Ph
0 ºC, 4 h, then rt, 8 h
CH2Cl2/TFE (10:1)
Ph
F
Ph
7
8
7
ArI
1a
1f
1f
1f
oxidant
8
9
10
-
-
-
3%
-
11a R = Me, 11b R = H
-
-
11a: 20%, 11b: 27%
-
11a: 30%, 11b: 10%
mCPBA (1 eq)
mCPBA (1 eq)
6%, 70% ee
16%, 70% ee
54%
21%
2%
62%
1%
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Selectfluor R (1 eq) 19%, 67% ee
mCPBA (5 eq)
13%, 76% ee
1f
Selectflour R (5 eq) 19%, 67% ee
Scheme 4. Rearrangement with chiral iodoarene catalysts.
Yields of the rearranged reaction product 8 never exceeded 20%, so no catalytic conversion was
achieved. Moreover, if the reaction is performed without iodoarene using 1 eq. mCPBA, only
compound 9 was formed in 71% yield indicating a strong background reaction under the reaction
conditions. Further details are found in the supporting information.
In summary, we have synthesized new trifluoromethylꢀsubstituted lactic acidꢀbased hypervalent
iodine derivatives, which showed similar behaviour and unfortunately no advantage to the
unsubstituted reagents with regards to the stereoselective rearrangement investigated here.
Experimental Section:
All starting materials were purchased from commercial suppliers and used without further
purification and all solvents used were dried and purified by standard techniques. Reactions
requiring the exclusion of moisture were carried out under an atmosphere of argon or nitrogen in
ovenꢀdried glassware. Flash chromatography was carried out using Merck silica gel (35ꢀ70 ꢁm) or
on a Biotage Isolera Four platform using SNAP Ultra (25 ꢁm) cartridges. Melting points were
recorded on a Gallenkamp MPD350 apparatus. IR measurements were taken using a PerkinꢀElmer
1600 FTIR spectrometer. NMR spectra were recorded on Bruker DPX 300, Bruker DPX 400, or
Bruker DPX 500. H NMR spectra were measured at 300, 400 and 500 MHz. 13C {1H} NMR
spectra were measured at 75, 100, and 125 MHz using CDCl as the solvent and internal reference.
1
3
Coupling constants J are given in Hz. Multiplicity as follows: s = singlet, d = doublet, t = triplet, q
= quartet, sext = sextet, sept = septet, m = multiplet, br = broad. High Resolution Mass
Spectrometry (HRMS) was carried out using a Waters LCT Premier XE mass spectrometer using
Electrospray Ionisation (ESI). Optical rotations were measured with a UniPol L polarimeter. Highꢀ
performance liquid chromatography (HPLC) analysis was conducted using Shimadzu LCꢀ10 AD
coupled diode arrayꢀdetector SPDꢀMAꢀ10AꢀVP.
3ꢀAminoꢀ5ꢀhydroxybenzotrifluoride 412
3ꢀNitroꢀ5ꢀhydroxybenzotrifluoride (5 g, 24.1 mmol) dissolved in ethanol (25 mL) was gently
refluxed during the gradual addition of a solution of disodium sulfide (25 g, 104 mmol) in alcohol
(100 mL). After 1.5 h, hot 10% ethanolic sodium hydroxide solution (12.5 mL) was added,
refluxing continued for 1 hour, then the alcohol removed under reduced pressure. The residue was
acidified with hydrochloric acid (2 M) and then neutralised by the addition of sodium hydrogen
carbonate solution, and extracted with ether (4 x 50 mL). The combined organic layers were dried
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over anhydrous MgSO4, filtered, and concentrated under reduced pressure affording 3ꢀaminoꢀ5ꢀ
hydroxybenzotrifluoride 4 as a red solid (4.15 g, 97%).
m.p.: 83 – 85 ºC; 1H NMR (400 MHz, CDCl3): δ = 6.49 (s, 1H), 6.45 (s, 1H), 6.29 (s, 1H), 4.98 (br
s, 1H), 3.84 (s, 2H) ppm.
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9
3,5ꢀDihydroxybenzotrifluoride 512
3ꢀAminoꢀ5ꢀhydroxybenzotrifluoride 4 (3.98 g, 22.47 mmol), dissolved in a mixture of water (14
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o
mL) and concentrated sulphuric acid (16 mL). After cooling to 0 C, a solution of sodium nitrite
(1.5 g) in water (8 ml), was added slowly, after 15 minutes, the excess nitrous acid was destroyed
by addition of urea. Then the cooled solution was added to a refluxing saturated solution of copper
sulfate (200 mL). Then left to cool down to the room temperature and extracted with ether (4 x 50
ml), the combined extracts were dried over anhydrous MgSO4, filtered, and concentrated under
reduced pressure affording 3,5ꢀdihydroxybenzotrifluoride 5 as a red solid (2.93 g, 73%).
m.p.: 87 – 89 ºC; 1H NMR (400 MHz, CDCl3): δ = 6.66 (s, 2H), 6.50 (s, 1H), 5.32 (br s, 2H) ppm.
2ꢀIodoꢀ5ꢀ(trifluoromethyl)benzeneꢀ1,3ꢀdiol 615
3,5ꢀDihydroxybenzotrifluoride 5 (2.14 g, 12 mmol) was dissolved in H2O/THF (1:1) (250 mL).
After cooling to 0 ºC, iodine (3.12 g, 12.6 mmol) was added followed by slow addition of NaHCO3
(1.108 g, 13.2 mmol). The resulting reaction mixture was stirred for 10 min at 0 ºC, then allowed to
warm to room temperature and stirred for 40 min. The reaction was then quenched by the addition
of a saturated aqueous Na2S2O3 solution (10 mL). After extraction with EtOAc (4 x 40 ml), the
combined organic phases were dried over anhydrous MgSO4 and concentrated under reduced
pressure. Purification by flash column chromatography (8:2 Hex/EtOAc) afforded the pure product
6 as a yellow solid (1.37 g, 39%).
o
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m.p.: 91 – 92 C; IR (solid) υ/cmꢀ1: 3277, 1250, 1010; H NMR (300 MHz, CDCl3): δ = 6.80 (s,
2H), 5.55 (s, 2H) ppm; 13C {1H} NMR (126 MHz, CDCl3): δ = 156.2, 133.2 (q, J = 33.3 Hz), 123.4
(q, J = 272.5 Hz), 104.4, 81.6 ppm; 19FꢀNMR (471 MHz, CDCl3): δ = –63.32 ppm; HRMS (ESIꢀ
TOF) m/z: [MꢀH] calculated for C7H3F3IO2 = 302.9130; found: 302.9134.
Dimethyl 2,2'ꢀ((2ꢀiodoꢀ5ꢀ(trifluoromethyl)ꢀ1,3ꢀphenylene)bis(oxy))(2R,2'R)ꢀdipropionate 1a15
2ꢀIodoꢀ5ꢀ(trifluoromethyl)benzeneꢀ1,3ꢀdiol 6 (1.3 g, 4.27 mmol), was dissolved in dry THF (25
mL) under an argon atmosphere. After addition of methyl (S)ꢀlactate (0.897 g, 9.4 mmol),
triphenylphosphine (2.6 g, 9.83 mmol) and diisopropyl azodicarboxylate (2 g, 10.26 mmol), the
reaction mixture was stirred for 16 h at room temperature and then concentrated under reduced
pressure. Purification by flash column chromatography (8:2 Hexane/EtOAc) afforded the pure
product 1a as a colourless solid (1.96 g, 98%).
o
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m.p.: 69 – 71 C; [α]D20: –90.5o (c = 0.243, CHCl3); IR (solid) υ/cmꢀ1: 1739, 1244, 1109; HꢀNMR
(500 MHz, CDCl3): δ = 6.58 (s, 2H), 4.83 (q, J = 6.8 Hz, 2H), 3.77 (s, 6H), 1.73 (d, J = 6.8 Hz, 6H)
ppm; 13Cꢀ{1H} NMR (126 MHz, CDCl3): δ = 171.6, 158.7, 132.3 (q, J = 33.6 Hz), 123.6 (q, J =
19
273.2 Hz), 103.6, 85.3, 74.5, 52.7, 18.6 ppm; FꢀNMR (471 MHz, CDCl3): δ –62.94 ppm; HRMS
(ESIꢀTOF) m/z: [M+Na]+ calculated for C15H16F3IO6Na = 498.9841; found: 498.9847.
(2R,2'R)ꢀ2,2'ꢀ((2ꢀIodoꢀ5ꢀ(trifluoromethyl)ꢀ1,3ꢀphenylene)bis(oxy))dipropionic acid 1b15
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Dimethyl 2,2'ꢀ((2ꢀiodoꢀ5ꢀ(trifluoromethyl)ꢀ1,3ꢀphenylene)bis(oxy))(2R,2'R)ꢀdipropionate 1a (1.683
g, 3.534 mmol) was dissolved in THF/MeOH (1:1) (20 mL). After addition of aqueous NaOH (2 M,
10 ml, 20 mmol, 5.6 eq) the reaction mixture was stirred for 6 h at room temperature and then
acidified with aqueous HCl (3 M). After extraction with EtOAc (4 x 40 ml), the combined organic
phases were washed with brine, dried over anhydrous MgSO4 and concentrated under reduced
pressure, affording product 1b as a colourless solid (1.265 g, 80%).
9
m.p.: 127 – 128 C; IR (solid) υ/cmꢀ1: 2991, 1705, 1242, 1110; HꢀNMR (500 MHz, DMSO): δ
=13.18 (s, 2H), 6.74 (s, 2H), 5.11 (q, J = 6.7 Hz, 2H), 1.57 (d, J = 6.7 Hz, 6H) ppm; 13C {1H} NMR
(126 MHz, CD3OD): δ = 174.6, 160.3, 132.8 (q, J = 32.8 Hz), 125.2 (q, J = 271.2 Hz), 103.9, 85.4,
75.2, 18.8 ppm; 19FꢀNMR (471 MHz, DMSO): δ = –61.34 ppm; HRMS (ESIꢀTOF) m/z: [MꢀH]
calculated for C13H11F3IO6 = 446.9553; found: 446.9569.
o
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(2R,2'R)ꢀ2,2'ꢀ((2ꢀIodoꢀ5ꢀ(trifluoromethyl)ꢀ1,3ꢀphenylene)bis(oxy))bis(Nꢀ(2,6ꢀdiisopropylꢀ
phenyl)propanamide) 1c15
(2R,2'R)ꢀ2,2'ꢀ((2ꢀIodoꢀ5ꢀ(trifluoromethyl)ꢀ1,3ꢀphenylene)bis(oxy))dipropionic acid 1b (1.344 g, 3
mmol) was suspended in dry CH2Cl2 (30 mL) under an argon atmosphere. After addition of oxalyl
chloride (1.33 g, 10.5 mmol, 3.5 eq) and a catalytic amount of DMF the reaction mixture was
stirred for 3 h at room temperature and then concentrated in vacuum. The crude product was reꢀ
dissolved in dry CH2Cl2 (16 mL) under an argon atmosphere and 2,6ꢀdiisopropylaniline (2.632 g,
15 mmol, 5 eq) as well as pyridine (0.95 g, 12 mmol) were added. The reaction mixture was stirred
for 16 h at room temperature and quenched by the addition of aqueous HCl (3 M). After extraction
with CH2Cl2, the combined organic phases were dried over anhydrous MgSO4 and concentrated
under reduced pressure. purification by flash column chromatography (8:2→2:2 Hex/EtOAc)
afforded 1c as a yellow solid (1.639 g, 71%).
m.p.: 230 – 233 ºC; [α]D20: –503 (c = 0.286, CHCl3); IR (solid) υ/cmꢀ1: 3203, 1660, 1249, 1101; 1H
NMR (300 MHz, CDCl3): δ = 7.83 (s, 2H), 7.32 (t, J = 7.7 Hz, 2H), 7.18 (d, J = 7.7 Hz, 4H), 6.92
(s, 2H), 5.10 (q, J = 6.6 Hz, 2H), 3.0ꢀ2.85 (m, 4H), 1.82 (d, J = 6.5 Hz, 6H), 1.20 (d, J = 6.8 Hz,
12H), 1.15ꢀ1.0 (m, 12H) ppm; 13C {1H} NMR (126 MHz, CDCl3): δ = 169.9, 157.4, 146.1, 133.3
(q, J = 33 Hz), 129.9, 128.9, 123.6, 123.0, 103.6, 84.6, 76.6, 28.8, 22.5, 18.7 ppm; 19F NMR (471
MHz, CDCl3): δ = –62.9 ppm; HRMS (ESIꢀTOF) m/z: [M+H]+ calculated for C37H47F3IN2O4 =
767.2527; found: 767.2521.
(2R,2'R)ꢀ2,2'ꢀ((2ꢀIodoꢀ5ꢀ(trifluoromethyl)ꢀ1,3ꢀphenylene)bis(oxy))bis(Nꢀmesitylpropanamide)
1d15
(2R,2'R)ꢀ2,2'ꢀ((2ꢀIodoꢀ5ꢀ(trifluoromethyl)ꢀ1,3ꢀphenylene)bis(oxy))dipropionic acid 1c (1.286 g,
2.87 mmol) was suspended in dry CH2Cl2 (29 mL) under an argon atmosphere. After addition of
oxalyl chloride (1.276 g, 10 mmol) and a catalytic amount of DMF the reaction mixture was stirred
for 3 h at room temperature and then concentrated in vacuo. The crude product was reꢀdissolved in
dry CH2Cl2 (4 mL) under an argon atmosphere and 2,4,6ꢀtrimethylaniline (1.54 g, 11.39 mmol, 5
eq) as well as pyridine (0.882 g, 11.16 mmol) were added. The reaction mixture was stirred for 16 h
at room temperature and quenched by addition of aqueous HCl (3 M, 10 mL). After extraction with
CH2Cl2, the combined organic phases were dried over anhydrous MgSO4 and concentrated under
reduced pressure. purification by flash column chromatography (8:2 → 2:2 Hex/EtOAc) afforded
pure 1d as a yellow solid (1.621 g, 83%).
1
m.p.: 293 – 297 ºC; [α]D20: –740 (c = 1.0, CHCl3); IR (solid) υ/cmꢀ1: 3257,1670, 1250, 1150; H
NMR (300 MHz, CDCl3): δ = 7.89 (s, 2H), 6.91 (s, 4H), 6.87 (s, 2H), 5.05 (q, J = 6.7 Hz, 2H), 2.27
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(s, 6H), 2.16 (s, 12H), 1.82 (d, J = 6.7 Hz, 6H) ppm; 13C {1H} NMR (126 MHz, CDCl3): δ = 168.9,
157.5, 137.4, 135.1, 129.9, 129.1, 128.8, 122.0, 103.9, 85.0, 76.7, 20.9, 18.8, 18.3 ppm; 19F NMR
(471 MHz, CDCl3): δ = –63.00 ppm; HRMS (ESIꢀTOF) m/z: [M+H]+ calculated for C31H35F3IN2O4
= 683.1588; found: 683.1594.
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Dimethyl 2,2'ꢀ((2ꢀ(diacetoxyꢀλ3ꢀiodanyl)ꢀ5ꢀ(trifluoromethyl)ꢀ1,3ꢀphenylene)bis(oxy)) (2R,2'R)ꢀ
dipropionate 2a8
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Dimethyl 2,2'ꢀ((2ꢀiodoꢀ5ꢀ(trifluoromethyl)ꢀ1,3ꢀphenylene)bis(oxy))(2R,2'R)ꢀdipropionate 1a (0.238
g, 0.5 mmol) and Selectfluor® (0.885 g, 2.5 mmol) were dissolved in CH3CN (16 mL) and glacial
acetic acid (5 mL) under N2. The reaction mixture was stirred at room temperature overnight. The
reaction mixture was concentrated under vacuum then water (25 mL) was added to the residue, and
extracted with CH2Cl2 (3 × 20 mL). The combined organic layers were dried over anhydrous
MgSO4, filtered, and concentrated under reduced pressure, to give 2a as a yellowish solid (0.288 g,
97%).
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m.p.: 195 – 197 ºC; [α]D20: –65 (c = 0.4, CHCl3); H NMR (300 MHz, CDCl3): δ = 6.78 (s, 2H),
4.93 (q, J = 6.8 Hz, 2H), 3.77 (s, 6H), 1.98 (s, 6H), 1.70 (d, J = 6.8 Hz, 6H);13C {1H} NMR (126
MHz, CDCl3): δ = 177.25, 170.76, 157.08, 137.08 (q, J = 33.2 Hz), 122.91 (q, J = 273.6 Hz),
110.43, 103.41, 74.90, 52.84, 20.46, 18.35 ppm;
19F NMR (471 MHz, CDCl3): δ = –63.7 ppm.
(2R,2'R)ꢀ2,2'ꢀ((2ꢀ(Diacetoxyꢀλ3ꢀiodanyl)ꢀ5ꢀ(trifluoromethyl)ꢀ1,3ꢀphenylene)bis(oxy))bis(Nꢀ(2,6ꢀ
diisopropylphenyl)propanamide) 2c8
(2R,2'R)ꢀ2,2'ꢀ((2ꢀiodoꢀ5ꢀ(trifluoromethyl)ꢀ1,3ꢀphenylene)bis(oxy))bis(Nꢀ(2,6ꢀdiisopropylphenyl)
propanamide) 1c (191.7 mg, 0.25 mmol), Selectfluor® (885 mg, 2.5 mmol).
Yield: 78%; m.p.: 220 – 222 ºC; [α]D20: –60 (c = 0.167, CHCl3); 1HꢀNMR (400 MHz, CDCl3): δ =
8.16 (s, 2H), 7.33ꢀ7.2 (m, 2H), 7.18 (s, 2H), 7.11 (sbr, 4H), 5.21 (q, J = 6.7 Hz, 2H), 2.98 (m, 4H),
1.91 (d, J = 6.6 Hz, 6H), 1.44 (s, 6H), 1.3ꢀ0.8 (m, 24H) ppm; 13C {1H} NMR (101 MHz, CDCl3): δ
= 176.8, 169.7, 156.4, 146.1, 129.7, 129.0, 123.6, 103.0, 77.2, 76.9, 28.6, 23.4, 19.5, 19.3 ppm (2
signals (CꢀCF3) did not appear in the NMR spectrum). 19FꢀNMR (471 MHz, CDCl3): δ = –63.05
ppm.
Compounds 2e, 2f and 2g were prepared following the same procedure as compounds 2a and 2c.
Their spectral data are in agreement with literature.8
Dimethyl2,2'ꢀ((2ꢀ(diacetoxyꢀλ3ꢀiodanyl)ꢀ5ꢀmethylꢀ1,3ꢀphenylene)bis(oxy))(2R,2'R)ꢀ
dipropionate 2e8
1H NMR (400 MHz, CDCl3): δ = 6.37 (s, 2H), 4.86 (q, J = 6.8 Hz, 2H), 3.77 (s, 6H), 2.36 (s, 3H),
1.98 (s, 6H), 1.68 (d, J = 6.8 Hz, 6H) ppm.
Dimethyl2,2'ꢀ((2ꢀ(diacetoxyꢀλ3ꢀiodanyl)ꢀ5ꢀmethylꢀ1,3ꢀphenylene)bis(oxy))(2R,2'R)ꢀ
dipropionate 2f8
1H NMR (400 MHz, CDCl3): δ = 7.39 (t, J = 8.4 Hz, 1H), 6.57 (d, J = 8.4 Hz, 2H), 4.87 (q, J = 6.8
Hz, 2H), 3.75 (s, 6H), 1.98 (s, 6H), 1.68 (d, J = 6.8 Hz, 6H) ppm.
(2,6ꢀBis(((R)ꢀ1ꢀ(mesitylamino)ꢀ1ꢀoxopropanꢀ2ꢀyl)oxy)phenyl)ꢀ λ3ꢀiodanediyl diacetate 2g8
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1H NMR (400 MHz, CDCl3): δ = 8.35 (s, 2H), 7.58 (t, J = 8.4 Hz, 1H), 6.93 (d, J = 8.4, 2H), 6.8 (s,
4H), 5.15 (q, J = 6.6 Hz, 2H), 2.20 (s, 6H), 1.95 – 1.78 (m, 12H), 1.89 (d, J = 6.6 Hz, 6H), 1.49 (s,
6H) ppm.
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General procedure for catalytic oxidative rearrangement for 1,1-diphenyl-1-pentene
by chiral iodine reagents:
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To the solution of 1,1ꢀdiphenylꢀ1ꢀpentene (1.0 eq.), iodine reagent (0.2 eq.), mCPBA (1.0 eq.),
methanol (8.0 eq.) in CH2Cl2/TFE (10:1), TsOH•H2O (1.5 eq.) were added. The reaction mixture
was stirred for 4 h at 0 ºC then 16 h at room temperature. Quenched with a (1:1) mixture of
saturated aqueous NaHCO3 and saturated aqueous Na2S2O3 (0.5 mL). Then water (4 mL) was
added, and the aqueous phase was extracted with CH2Cl2 (3 × 5 mL). The combined organic layers
were filtered through a TELOS phase separator and concentrated under vacuum to give the crude
product. The product 1,2ꢀdiphenylꢀ1ꢀpentanone 8 was isolated by TLC (hexane/ethyl acetate 9:1).
General procedure for the stochiometric oxidative rearrangement of aryl alkene
derivative using chiral hypervalent iodine reagents:14
To a solution of alkene (0.09 mmol), iodine(III) reagent (0.11 mmol, 1.2 eq) and methanol (0.26
mmol, 3 eq) in CH2Cl2:TFE (10:1 v/v) (1.5 mL) at –78 ºC, was added TsOH•H2O (21 mg, 0.11
o
mmol, 1.2 eq). The reaction was stirred for 4 h at –78 C, then 16 h at room temperature, then
quenched with a 1:1 mixture of aqueous sat. NaHCO3 and sat. Na2S2O3 (0.5 mL). Water (4 mL) was
added and the aqueous phase was extracted with CH2Cl2 (3 × 5 mL). The combined organic layers
were filtered through a TELOS phase separator and concentrated under vacuum to give the crude
product. The product 1,2ꢀdiphenylꢀ1ꢀpentanone 8 was isolated by TLC (hexane/ethyl acetate 9:1).
(2R)ꢀ1,2ꢀDiphenylꢀ1ꢀpentanone 814
1,1ꢀDiphenylpentene (20 mg, 0.09 mmol), iodine(III) reagent 1 (65.4 mg, 0.11 mmol), TsOH•H2O
(20 mg, 0.11 mmol) and methanol (11 ꢁL, 0.27 mmol) were reacted according to the general
procedure to give the product as a colorless (10 mg, 50%).
1H NMR (400 MHz, CDCl3): δ = 7.92 (d, J = 7.6 Hz, 2H), 7.44 (t, J = 7.4 Hz, 1H), 7.35 (t, J = 7.7
Hz, 2H), 7.29 – 7.20 (m, 4H), 7.18ꢀ7.12 (m, 1H), 4.52 (t, J = 7.3 Hz, 1H), 2.17ꢀ2.06 (m, 1H), 1.84 –
1.71 (m, 1H), 1.36 – 1.14 (m, 2H), 0.88 (t, J = 7.3 Hz, 3H) ppm.
(2ꢀFluoroꢀ1ꢀmethoxypentaneꢀ1,1ꢀdiyl)dibenzene 11a
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Colorless oil (48 mg, 30%)
;
IR (neat) υ/cmꢀ1: 3024, 2958, 1076; H NMR (400 MHz, CDCl3): δ =
7.50 – 6.99 (m, 10H), 5.39 – 5.17 (m, 1H), 3.12 (s, 3H), 1.54 – 1.40 (m, 2H), 1.40 – 1.22 (m, 2H),
0.80 (t, J = 7.0 Hz, 3H) ppm; 13C {1H} NMR (126 MHz, CDCl3): δ = 141.2, 128.6, 127.9, 127.2 (d,
J = 10.0 Hz), 95.8 (d, J = 182.0 Hz), 83.7 (d, J = 19.3 Hz), 52.7 (d, J = 12.2 Hz), 31.4, 19.1, 13.9
ppm; 19F NMR (471 MHz, CDCl3): δ = –186.99 ppm; HRMS (ESIꢀTOF) m/z: [MꢀMeOH+H]+
calculated for C17H18F = 241.1393; found: 241.1393.
2ꢀFluoroꢀ1,1ꢀdiphenylpentanꢀ1ꢀol 11b
Colourless solid (15 mg, 10%); m.p.: 109 – 111 ºC; IR (solid) υ/cmꢀ1: 3556, 33028, 2958; 1H NMR
(500 MHz, CDCl3): δ = 7.47 (d, J = 7.5 Hz, 2H), 7.35 – 7.10 (m, 8H), 5.31 (dd, J = 47.4, 10.2 Hz,
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1H), 2.52 (s, 1H), 1.82 – 1.50 (m, 1H), 1.59 – 1.37 (m, 1H), 1.37 – 0.96 (m, 2H), 0.80 (t, J = 7.1 Hz,
3H) ppm; 13C {1H} NMR (126 MHz, CDCl3): δ = 144.8, 128.3, 127.2 (d, J = 20.6 Hz), 126.8,
125.9, 96.1 (d, J = 177.8 Hz), 79.1 (d, J = 21.0 Hz), 30.9 (d, J = 21.2 Hz), 18.9, 13.8 ppm; 19F NMR
(471 MHz, CDCl3): δ = –189.48 ppm; HRMS (ESIꢀTOF) m/z: [MꢀH2O+H]+ calculated for C17H18F
= 241.1393; found: 241.1390.
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Acknowledgements
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We thank the Chemistry Department, Umm AlꢀQura University, Makkah, Saudi Arabia, for the
financial support and scholarship to JQ and a private sponsor for the fellowship to ME. We thank
the EPSRC National Mass Spectrometry Facility, Swansea, for mass spectrometric data.
Supporting Information
Catalyst Screening
Oxidant Screening
1H and 13C NMR spectral data of all compounds
(1) Hypervalent Iodine Chemistry (Ed.: Wirth, T.), Top. Curr. Chem. Springer, Berlin, 2016, Vol.
373.
(2) Zhdankin, V. V. Hypervalent Iodine Chemistry: Preparation, Structure and Synthetic
Application of Polyvalent Iodine Compounds; John Wiley & Sons, New York, 2014.
(3) Yoshimura, A.; Zhdankin, V. V. Chem. Rev. 2016, 116, 3328–3435.
(4) Richardson, R. D.; Wirth, T. Angew. Chem. 2006, 118, 4510–4512; Angew. Chem. Int.
Ed. 2006, 45, 4402–4404.
(5) Singh, F. V.; Wirth, T. Chem. Asian J. 2014, 9, 950–971.
(6) For reviews, see: (a) Kumar, R.; Wirth, T. Top. Curr. Chem. 2015, 373, 243–261; (b)
Berthiol, F. Synthesis 2015, 47, 587–603; (c) Parra, A.; Reboredo, S. Chem. Eur. J. 2013, 19,
17244–17260; (d) Liang, H.; Ciufolini, M. Angew. Chem. 2011, 123, 12051–12053; Angew.
Chem. Int. Ed. 2011, 50, 11849–11851.
(7) Fujita, M.; Okuno, S.; Lee, H. J.; Sugimura, T.; Okuyama, T. Tetrahedron Lett. 2007, 48,
8691–8694.
(8) Uyanik, M.; Yasui, T.; Ishihara, K. Angew. Chem. 2010, 122, 2221–2223; Angew. Chem. Int.
Ed. 2010, 49, 2175–2177.
(9) Farid, U.; Wirth, T. Angew. Chem. 2012, 124, 3518–3522; Angew. Chem. Int. Ed. 2012, 51,
3462–3465.
(10) Farid, U.; Malmedy, F.; Claveau, R.; Albers, L.; Wirth, T. Angew. Chem. 2013, 125, 7156–
7160; Angew. Chem. Int. Ed. 2013, 52, 7018–7022.
(11) Schäfer, S.; Wirth, T. Angew. Chem. 2010, 122, 2846–2850; Angew. Chem. Int. Ed. 2010,
49, 2786–2789.
(12) Whalley, W. B. J. Chem. Soc. 1949, 3016.
(13) (a) Lou, S.; Fu, G. C. J. Am. Chem. Soc. 2010, 132, 1264–1266; (b) Marelli, E.; Renault, Y.;
Sharma, S. V.; Nolan, S. P.; Goss, R. J. M. Chem. Eur. J. 2017, 23, 3832–3836.
(14) Brown, M.; Kumar, R.; Rehbein, J.; Wirth, T. Chem. Eur. J. 2016, 22, 4030–4035.
(15) Haubenreisser, S.; Wöste, T. H.; Martínez, C.; Ishihara, K.; Muñiz, K. Angew. Chem. 2016,
128, 422–426; Angew. Chem. Int. Ed. 2016, 55, 413–417.
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