Synthesis of new enantiomerically pure organoiodine catalysts and their application in the α-functionalization of ketones

Article abstract of DOI:10.1055/s-0029-1218640

The synthesis of enantiomerically pure iodoarenes and their application to the α-oxysulfonylation of propiophenone, and the lactonization of 5-oxo-5-phenylpentanoic acid using MCPBA as stoichiometric oxidant are reported to give useful synthetic intermedi

Full text of DOI:10.1055/s-0029-1218640

PAPER
1023
Synthesis of New Enantiomerically Pure Organoiodine Catalysts and Their
Application in the a-Functionalization of Ketones
Functionalization
of
Ketones
C
atalyze
a
d by Hyper
r
valent Iodine
CF
ompounds arooq,a,b Sascha Schäfer,a Azhar-ul-Haq Ali Shah,a,c Diana Maria Freudendahl,a Thomas Wirth*a
a
Cardiff University, School of Chemistry, Main Building, Park Place, Cardiff CF10 3AT, UK
Fax +44(29)20876968; E-mail: wirth@cf.ac.uk
b
c
COMSATS Institute of Information Technology, Abbottabad, Pakistan
Kohat University of Science and Technology, Kohat, Pakistan
Received 29 September 2009; revised 25 November 2009
Abstract: The synthesis of enantiomerically pure iodoarenes and
their application to the a-oxysulfonylation of propiophenone, and
the lactonization of 5-oxo-5-phenylpentanoic acid using MCPBA
as stoichiometric oxidant are reported to give useful synthetic inter-
mediates in good yields and moderate enantioselectivities.
O
–OTs
I+
O
O
HO
Et
2
Ph
Ph
Key words: hypervalent iodine reagents, organocatalysis, oxida-
tion, stereoselective synthesis
p-TsOH•H2O, CH2Cl2
–30 °C, 4 h
OTs
1
3
Scheme 1 Enantioselective a-oxytosylation of propiophenone
Hypervalent iodine compounds have found broad applica-
tion in organic chemistry and are frequently used in syn-
thesis.1 The investigation of their efficiency as oxidants
and electrophilic reagents besides the development of new
reactions of such species is of current interest. They are of
high synthetic potential by virtue of the fact that they are
nonmetallic oxidation and oxygenation reagents, thus cir-
cumventing the problem of toxicity associated with many
of the transition metals commonly used for carrying out
such reactions. The past three decades have revealed the
use of hypervalent iodine compounds as very versatile and
mild oxidation and oxygenation reagents replacing toxic
and heavy metal-containing reagents, thus providing more
environmental friendly reaction conditions. They can also
be employed as electrophilic reagents, for example, for
functionalizations of alkenes and subsequent halolacton-
izations,2 dioxytosylations,3 or a-oxytosylations4 and a-
oxysulfonylation.5 Mostly hypervalent iodine compounds
bearing two heteroatom ligands on iodine(III) as well as
their polymer-supported derivatives are used, but the
drawback of these reaction is that l3-iodanes must be used
in stoichiometric amounts and that the preparation of this
reagent requires an additional oxidative transformation
step from the parent iodoarene.
Although hypervalent iodine compounds have been
known for more than a century, only recently the catalytic
use of iodine compounds in synthesis has been devel-
oped.1i,7 First investigations in iodocatalysis were under-
taken by Fujita and co-workers with anodic gem-
difluorination of thiodiketals mediated by aryl iodides.8
Ochiai and co-workers9 as well as Kita and co-workers10
used MCPBA as a potent stoichiometric oxidant in reac-
tions using iodoarenes as catalysts. We recently reported
the first catalytic use of enantiomerically pure iodoarenes
in asymmetric reactions,11 which opened the possibility to
employ a wide range of enantiomerically pure iodoarenes
with various structural features as catalysts.12 Different
other organocatalysts have been investigated as well for
the functionalization of carbonyl compounds in the a-po-
sition.13
Here we report the synthesis of different chiral iodoarenes
and their use as catalysts for the synthesis of enantiomer-
ically enriched a-oxytosylated and a-oxysulfonylated
phenones.
Starting from 2-iodobenzoic acid, 3-iodobenzoic acid,
and 2-iodophenylacetic acid, the catalysts 4–17 were pre-
pared in good to excellent yields (59–97%) by esterifica-
tion with enantiomerically pure alcohols (Table 1). The
employed alcohols were derived from dimethyl and dieth-
yl tartrate, enantiopure 1-phenylethanol and 2-bromoben-
zyl alcohol, an indane derivative, and hydroquinidine. The
reaction was carried out by activation with 1,3-dicyclo-
hexylcarbodiimide (DCCI) and 4-(dimethylamino)pyri-
dine (DMAP).14
Due to the high interest in enantioselective reactions, em-
ployment of enantiomerically pure hypervalent iodine
compounds has been investigated recently, for example,
the a-oxytosylation of ketones such as 1.6 In this way,
synthetically valuable tosylates such as 3 can be obtained
in up to 40% ee by using stoichiometric amounts of hyper-
valent iodine reagent 2 (Scheme 1).
The synthesis of compounds 4 and 5 proceeded in excel-
lent yields (86% and 97%, respectively, Table 1, entries 1
and 2). In contrast, compound 6 was isolated in slightly
lower yield (66%, Table 1, entry 3). The reason for that
could be found in the fact that 2-iodophenylacetic acid ex-
SYNTHESIS 2010, No. 6, pp 1023–1029
Advanced online publication: 08.01.2010
DOI: 10.1055/s-0029-1218640; Art ID: T18909SS
x
x
.
x
x
.2
0
1
0
© Georg Thieme Verlag Stuttgart · New York

1024
U. Farooq et al.
PAPER
Table 1 Enantiomerically Pure Iodoarenes 4–17 Prepared
(continued)
hibits less steric repulsion compared to 2-iodobenzoic ac-
id. This trend is also observed for compounds 7 and 8
(59% and 62% yield, Table 1, entries 4 and 5). The reac-
tion of (S)-(–)-1-phenylethanol with 2-iodophenylacetic
acid and 2-iodobenzoic acid gave the desired compounds
in high yields (91% and 92%, Table 1, entries 9 and 10).
Similar high yields were observed in the synthesis of com-
pounds 11, 12, and 13 (Table 1, entries 8–10). The addi-
tional bromine atom does not show any steric hindrances,
which could have led to lower yields. Compound 14 was
synthesized from racemic trans-2-bromo-2,3-dihydro-
1H-inden-1-ol in nearly quantitative yield (Table 1, entry
11). The two enantiomers could be separated quantitative-
ly by preparative HPLC (Chiralcel OD-H). The hydroqui-
nidine derived products 15, 16, and 17 were obtained in
good (67% for 15, Table 1, entry 12) to excellent yields
(88% for 16 and 90% for 17, Table 1, entries 13 and 14).
The same arguments for the slightly lower yield of com-
pound 6, 7, and 8 can be invoked for compound 15. Over-
all the desired compounds were synthesized in high yields
and high purity (Table 1).
R*-OH
DCCI
DMAP
CO2H
CO2R*
0,1
0,1
CH2Cl2
I
I
Entry Ar*I
Yield (%)a
92
O
Ph
7
8
10
11
O
O
O
I
O
92
94
I
Br
O
9
10
11
12
13
14
Br
I
O
Table 1 Enantiomerically Pure Iodoarenes 4–17 Prepared
93
O
Br
I
R*-OH
DCCI
DMAP
CO2H
CO2R*
0,1
0,1
O
CH2Cl2
I
I
97b
O
Entry Ar*I
Yield (%)a
86
I
Br
OH
O
O
Et
N
1
2
3
4
5
6
CO2Et
H
O
O
CO2Et
OH
I
I
O
12
13
14
15
16
17
67
88
90
97
66
MeO
CO2Me
O
O
CO2Me
I
N
O
O
Et
N
OH
H
CO2Et
I
I
CO2Et
O
MeO
O
O
O
I
N
O
4
7
59
I
Et
N
O
H
CO2Et
CO2Et
O
I
MeO
O
O
O
I
5
6
8
9
62
91
I
N
O
O
a Isolated yield.
b Isolated yield of the racemate.
CO2Me
CO2Me
Ph
O
I
Synthesis 2010, No. 6, 1023–1029 © Thieme Stuttgart · New York

PAPER
Functionalization of Ketones Catalyzed by Hypervalent Iodine Compounds
1025
Initial studies towards iodoarene catalysis were per- zylic position on the selectivity of the reaction detected.
formed using the reaction of propiophenone (1) in aceto- The bromophenyl-substituted precatalysts 11–13
nitrile with 10 mol% iodoarene, 1.5 equivalents of (Table 2, entries 8–10) showed good to excellent conver-
commercial 70–77% wet MCPBA as the stoichiometric sions and isolated yields. The best ee value (26%, Table 2,
oxidant, and p-toluenesulfonic acid monohydrate (p- entry 8) was discovered for catalyst 11. The best result for
TsOH·H2O) as the source of sulfonate nucleophile. The this reaction was 40% ee6c so far, which indicates that this
reaction using stoichiometric hypervalent iodine com- catalyst is a promising candidate for other asymmetric re-
pounds can usually be performed at low temperatures actions. The bromine atom may serve as a coordinating
(–30 °C) to maximize enantioselectivity,6c but at this tem- group so that the stereogenic center in benzylic position at
perature the reaction employing catalytic amounts of io- the bromophenyl moiety can influence the selectivity of
doarenes and MCPBA as oxidant proceed very slowly, the reaction. The comparison with the results for precata-
consistent with our earlier findings and the results of lyst 10 underlines this stabilizing effect of the bromine at-
Togo.15 This suggests that the formation of the hyperval- om. A drastic loss of enantioselectivity was observed if
ent iodine species is the rate-determining step in the cata- the iodine atom is moved from the 2- to the 3-position at
lytic cycle. Therefore, the reactions were conducted at the phenyl moiety (12, Table 2, entry 9). The coordinative
room temperature for three to four days.
stabilization of the transient l3-iodane species is lost. Also
for catalyst 13 this observation was found as the ester moi-
ety was shifted by one CH2 group. Although the conver-
sion and the yield achieved with the indane derivative 14
(Table 2, entry 11) showed no significant selectivity. For
the alkaloid-based catalysts 15–17 (Table 2, entries 12
and 14) a minor enantioselectivity was found favoring the
R-enantiomer for 15 and the S-enantiomer for 16 and 17.
The structures of the tartaric acid derived catalysts 4–8 all
have various oxygen atoms with the potential to coordi-
nate to the iodine in a transient l3-iodane. But this coordi-
nation is either not efficient or does not lead to substantial
selectivities in the a-oxytosylation of propiophenone as
shown in Table 2.
Compounds 9 and 10 showed a low conversion of the sub-
strate as well as a low yield (Table 2, entries 6 and 7).
There was no influence of the stereogenic centre in ben-
Based on the results obtained in this first reaction, further
studies towards the reactivity and selectivity of the cata-
lysts 4–17 were carried out on the lactonization reaction
of 5-oxo-5-phenylpentanoic acid (18) to 5-(phenylcarbo-
nyl)dihydrofuran-2(3H)-one (19) as shown in Table 3.16
The reaction conditions were similar to the previous ones
apart from the fact that 20 mol% p-TsOH·H2O was used.
Also for this reaction no inert atmosphere or anhydrous
solvents were necessary.
Table 2 Enantiomerically Pure Iodoarenes as Catalysts in the
a-Oxytosylation of Propiophenone (1)
Ar*I (10 mol%)
p-TsOH•H2O (1.5 equiv)
O
O
*
Ph
Ph
MCPBA (1.5 equiv)
MeCN, r.t., 3–4 d
OTs
1
3
For the lactonization reaction leading to product 19 little
enantioselectivity was found. The isolated yields varied
from 19% (Table 3, entry 3) to 67% (Table 3, entries 8
and 10). For catalyst 16 no reaction was observed at all.
The absence of enantioselectivity in the lactonization re-
action indicates that during the reaction probably no tosy-
lated intermediate is formed, which then could undergo an
SN2-type reaction to form the lactone 19. The reaction
seems to proceed via a substrate-iodoarene complex type
intermediate.6c The necessity of the addition of p-
TsOH·H2O would merely be due to the fact that a ligand
exchange at the hypervalent iodine species is needed to
form an active catalyst. On the other hand, a racemization
at the newly formed stereogenic center in a-position to the
carbonyl moiety during the reaction could be possible as
well. It was shown that p-TsOH·H2O can be replaced by
methanesulfonic acid leading to the cyclized compound
19 (39% yield, 2% ee), however, without the addition of a
sulfonic acid, no reaction was observed. This result is con-
sistent with the findings of Ishihara and co-workers.16
They also found that no reaction is observed whatsoever
if no MCPBA is added.
Entry Ar*I
Conversion (%)a ee (%) (config.)b Yield (%)c
1
2
4
5
71
60
80
62
60
50
50
80
65
95
90
65
74
72
3 (S)
4 (S)
5 (S)
9 (R)
7 (R)
4 (R)
0
68
48
64
40
58
45
35
70
60
93
90
50
61
65
3
6
4
7
5
8
6
9
7
10
11
12
13
14
15
16
17
8
26 (S)
1 (S)
8 (S)
1 (R)
15 (R)
6 (S)
7 (S)
9
10
11
12
13
14
The replacement of MCPBA as the stoichiometric oxidant
by cerium ammonium nitrate (with PhI as a catalyst) or
H2O2·urea (with 13 as a catalyst), both in acetonitrile, was
not successful in the cyclization reaction. The oxidative
a Determined by 1H NMR analysis of the crude reaction product.
b Determined by HPLC.
c Isolated yield.
Synthesis 2010, No. 6, 1023–1029 © Thieme Stuttgart · New York

1026
U. Farooq et al.
PAPER
In conclusion, we have shown that new enantiomerically
pure iodine containing tartaric esters, indane derivatives,
and alkaloids can be easily synthesized in good to excel-
lent yields. These compounds can be used as catalysts in
the a-oxytosylation of propiophenone to give high yields
and minor selectivities in the reaction products. They can
also be employed in the cyclization of 5-oxo-5-phenyl-
pentanoic acid to provide 5-(phenylcarbonyl)dihydrofu-
ran-2(3H)-one in moderate yields. Both catalytic
reactions can be performed without inert atmosphere and
without the need for anhydrous solvents.
Table 3 Enantiomerically Pure Iodoarenes as Catalysts in the Lac-
tonization of 5-Oxo-5-phenylpentanoic acid (18)
Ar*I (10 mol%)
O
p-TsOH•H2O (20 mol%)
O
Ph
O
CO2H
Ph
MCPBA (1.2 equiv)
MeCN, r.t., 3–4 d
O
18
19
Entry
1
Ar*I
ee (%)a
Yield (%)b
4
5
3
2
0
3
0
2
3
2
2
2
0
1
–
0
46
51
19
28
55
51
51
67
55
67
58
36
–
2
3
6
1H NMR spectra were recorded at 250 or 500 MHz and 13C NMR
spectra were measured at 62.5, 100, or 126 MHz, using CDCl3 as a
solvent and internal reference (d = 7.26/77.0) for all spectra; cou-
pling constants J are given in Hz. All reagents were purchased from
commercial suppliers and used without further purification. IR mea-
surements were taken using a Perkin-Elmer 1600 FTIR spectrome-
ter or a Bruker Alpha-E FTIR spectrometer as a liquid film or KBr
pellet. Low-resolution mass spectrometry was carried out using a
Varian Saturn 2 GC-MS spectrometer. Flash chromatography was
carried out using Fisher silica gel (35–70 mesh). All solvents used
were dried and purified by standard methods. Reactions requiring
the exclusion of air were carried out under an atmosphere of argon
or N2 in oven dried glassware. HPLC analysis was carried out on
Chiralcel OD-H and OB-H columns (hexane, i-PrOH). Optical ro-
tations were measured on an Optical Activity Ltd. AA 1000 Pola-
rimeter.
4
7
5
8
6
9
7
10
11
12
13
ent-14
15
16
17
8
9
10
11
12
13
14
Enatiomerically Pure Iodoarene Esters 4–17; General
Procedure14
64
A solution of 2-iodobenzoic acid, 3-iodobenzoic acid, or 2-iodophe-
nylacetic acid (10.0 mmol), DCCI (11.0 mmol, 2.27 g), the appro-
priate alcohol (11.0 mmol), and DMAP (1.0 mmol, 0.12 g) in
CH2Cl2 (50 mL) was stirred at r.t. until the esterification was com-
plete. The N,N-dicyclohexylurea was filtered off and the filtrate
washed with H2O (3 × 60 mL), 5% AcOH solution (3 × 60 mL) and
again with H2O (3 × 60 mL), dried (MgSO4), filtered, and the sol-
vent evaporated in vacuo to yield the crude product, which was pu-
rified by flash chromatography (silica gel; hexane–EtOAc, 8:2)
(Table 1).
a Determined by HPLC.
b Isolated yield.
potential of CAN is not high enough as after three days at
50 °C no reaction was detected. In the case of H2O2·urea
an unselective reaction was observed.
Besides acetonitrile other solvents such as dichloro-
methane, nitromethane, and tetrahydrofuran were used as
well in the lactonization reaction, but none of them
showed to be superior to acetonitrile regarding yields and
selectivities of the reaction. The speed of the reaction is
increased when stirred overnight at 50 °C in acetonitrile
(Table 4, entry 4).
4
Synthesis according to the general procedure; 2-iodophenylacetic
acid (400 mg, 1.53 mmol) and diethyl L-(+)-tartrate (345 mg, 1.67
mmol) yielded 86% (601 mg, 1.34 mmol) of 4; [a]D25 +9.62
(c 0.104, CHCl3).
IR (KBr): 3487, 2981, 1747, 1483, 1438, 1371, 1262, 1210, 1148,
1067, 1014, 860, 736 cm–1.
1H NMR (250 MHz, CDCl3): d = 1.16 (t, J = 7.2 Hz, 3 H, CH3),
1.25 (t, J = 7.2 Hz, 3 H, CH3), 3.84 (s, 2 H, CH2), 4.03–4.25 (m, 4
H, 2 × CH2), 4.67 (s, 1 H, CH), 5.40 (d, J = 2.1 Hz, 1 H, CH), 6.91
(m, 1 Harom), 7.19–7.26 (m, 2 Harom), 7.75(d, J = 8 Hz, 1 Harom).
Table 4 Iodoarene 13 in the Lactonization of 5-Oxo-5-phenylpen-
tanoic Acid (18) in Different Solvents
Entry
Temp
r.t.
Time
3 d
Solvent
MeNO2
THF
ee (%)a Yield (%)c
1
2
3
4
3
–
1
2
55
13C NMR (62.5 MHz, CDCl3): d = 14.1 (2 C), 45.7, 62.2, 62.7, 70.4,
73.4, 100.8, 128.5, 129.1, 130.7, 136.9, 139.6, 166.4, 169.2, 170.5.
b
r.t.
8 d
–
+
HRMS: m/z calcd for C16H19IO7·NH4 : 468.0514; found: 468.0513.
r.t.
3 d
CH2Cl2
MeCN
63
64
50 °C
14 h
5
Synthesis according to the general procedure; 2-iodophenylacetic
acid (400 mg, 1.53 mmol) and dimethyl L-(+)-tartrate (350 mg, 1.97
mmol) yielded 97% (630 mg, 1.49 mmol) of 5; [a]D25 +7.73 (c 0.44,
CHCl3).
a Determined by HPLC.
b Unselective reaction, starting material still present.
c Isolated yield.
Synthesis 2010, No. 6, 1023–1029 © Thieme Stuttgart · New York

PAPER
Functionalization of Ketones Catalyzed by Hypervalent Iodine Compounds
1027
IR (KBr): 3850, 2925, 1747, 1622, 1435, 1212, 1146, 1068, 1014,
736 cm–1.
IR (KBr): 3061, 2978, 1733, 1586, 1494, 1466, 1436, 1411, 766,
734 cm–1.
1H NMR (250 MHz, CDCl3): d = 3.66 (s, 3 H, CH3), 3.74 (s, 3 H,
CH3), 3.84 (s, 2 H, CH2), 4.68 (d, J = 1.9 Hz, 1 H, CH), 5.41 (d,
J = 2.1 Hz, 1 H, CH), 6.91 (m, 1 Harom), 7.24 (m, 2 Harom), 7.75 (d,
J = 8.1 Hz, 1 Harom).
1H NMR (500 MHz, CDCl3): d = 1.46 (d, J = 6.6 Hz, 3 H, CH3),
3.71 (d, J = 2.6 Hz, 2 H, CH), 5.80 (q, J = 6.6 Hz, 1 H, CH), 6.85
(dd, J = 7.5, 1.7 Hz, 1 Harom), 7.13–7.27 (m, 7 Harom), 7.75 (dd,
J = 7.9, 1.1 Hz, 1 Harom).
13C NMR (62.5 MHz, CDCl3): d = 45.1, 53.0, 53.3, 70.5, 73.3,
100.8, 128.6, 129.2, 130.8, 136.9, 139.6, 166.9, 169.3, 170.8.
13C NMR (126 MHz, CDCl3): d = 21.2, 45.5, 72.0, 100.0, 125.1,
126.8, 127.3, 127.4, 127.8, 129.6, 136.8, 138.4, 140.4, 168.7.
+
+
HRMS: m/z calcd for C14H15IO7·NH4 : 440.0201; found: 440.0200.
HRMS: m/z calcd for C16H15IO2·NH4 : 384.0455; found: 384.0487.
6
10
Synthesis according to the general procedure; 2-iodobenzoic acid
(300 mg, 1.21 mmol) and diethyl L-(+)-tartrate (274 mg, 1.33
mmol) yielded 66% (350 mg, 0.80 mmol) of 6; [a]D25 +15.23
(c 0.486, CHCl3).
Synthesis according to the general procedure; 2-iodobenzoic acid
(500 mg, 2.01 mmol) and (S)-(–)-1-phenylethanol (270 mg, 2.2
mmol) yielded 92% (650 mg, 1.85 mmol) of 10; [a]D25 +35.75
(c 0.990, CHCl3).
IR (KBr): 3488, 2981, 1739, 1582, 1526, 1465, 1428, 1370, 12454,
1132, 1098, 1059, 1015, 911, 742, 687 cm–1.
IR (KBr): 3062, 3032, 2980, 2930, 1724, 1583, 1561, 1494, 1454,
1428, 1329, 1284, 1248, 1133, 1098, 1060, 1028, 1014 cm–1.
1H NMR (250 MHz, CDCl3): d = 1.19 (t, J = 7.2 Hz, 3 H, CH3),
1.24 (t, J = 7.2 Hz, 3 H, CH3), 4.15–4.28 (m, 4 H, 2 × CH2), 4.74 (d,
J = 2.1 Hz, 1 H, CH), 5.64 (d, J = 2.1 Hz, 1 H, CH), 7.10 (dt,
J = 7.9, 1.7 Hz, 1 Harom), 7.34 (t, J = 7.9 Hz, 1 Harom), 7.82 (dd,
J = 7.7, 1.1 Hz, 1 Harom), 7.93 (d, J = 7.9 Hz, 1 Harom).
13C NMR (62.5 MHz, CDCl3): d = 14.12, 14.18, 62.3, 62.8, 70.6,
73.8, 94.3, 128.1, 131.7, 133.3, 133.4, 141.5, 164.9, 166.4, 170.7.
1H NMR (500 MHz, CDCl3): d = 1.76 (d, J = 6.6 Hz, 3 H, CH3),
6.22 (q, J = 6.5 Hz, 1 H, CH), 7.15 (t, J = 7.7 Hz, 1 Harom), 7.30–
7.50 (m, 4 Harom), 7.5–7.58 (m, 2 Harom), 7.86 (d, J = 7.7 Hz, 1
Harom), 8.01 (d, J = 7.9 Hz, 1 Harom).
13C NMR (126 MHz, CDCl3): d = 22.4, 74.1, 94.2, 126.4, 128.0,
128.2, 128.7, 131.0, 132.6, 135.4, 141.3, 141.4, 165.8.
+
HRMS: m/z calcd for C15H13IO2·NH4 : 370.0298; found: 370.0301.
+
HRMS: m/z calcd for C15H17IO7·NH4 : 454.0357; found: 454.0356.
11
7
Synthesis according to the general procedure; 2-iodobenzoic acid
(350 mg, 1.41 mmol) and (S)-1-(2-bromophenyl)ethanol (312 mg,
1.55 mmol) yielded 92% (560 mg, 1.30 mmol) of 11; [a]D25 +27.35
(c 1.126, CHCl3).
Synthesis according to the general procedure; 2-iodobenzoic acid
(878 mg, 3.54 mmol) and diethyl L-(+)-tartrate (365 mg, 1.77
mmol) yielded 59% (700 mg, 1.05 mmol) of 7; [a]D25 –20.51
(c 0.390, CHCl3).
IR (KBr): 3061, 2981, 2930, 1726, 1583, 1561, 1472, 1430, 1287,
1248, 1125, 1097, 1069, 1014, 740 cm–1.
IR (KBr): 1740, 1582, 1464, 1370, 1235, 1127, 1093, 1014, 739,
638 cm–1.
1H NMR (250 MHz, CDCl3): d = 1.19 (t, J = 7.1 Hz, 6 H, 2 × CH3),
4.16–4.25 (m, 4 H, CH2), 5.99 (s, 2 H, CH), 7.12 (dt, J = 7.7, 1.7 Hz,
2 Harom), 7.35 (t, J = 7.6 Hz, 2 Harom), 7.99 (dd, J = 7.8, 1.7 Hz, 2
Harom), 7.95 (dd, J = 7.9, 0.7 Hz, 2 Harom).
1H NMR (500 MHz, CDCl3): d = 1.54 (d, J = 6.5 Hz, 3 H, CH3),
6.32 (q, J = 6.5 Hz, 1 H, CH), 7.01 (dd, J = 7.3, 1.7 Hz, 2 Harom),
7.21 (t, J = 7.6 Hz, 1 Harom), 7.27 (t, J = 7.6 Hz, 1 Harom), 7.43 (dd,
J = 8.0, 1.0 Hz, 1 Harom), 7.46 (dd, J = 7.8, 1.4 Hz, 1 Harom), 7.73 (dd,
J = 7.8, 1.7 Hz, 1 Harom), 7.85 (d, J = 7.9 Hz, 1 Harom).
13C NMR (62.5 MHz, CDCl3): d = 14.2, 62.6, 71.7, 94.6, 128.1,
131.9, 133.1, 133.4, 141.7, 164.7, 165.6.
13C NMR (126 MHz, CDCl3): d = 21.3, 73.2, 94.2, 122.0, 127.1,
127.9, 128.0, 129.4, 131.1, 132.8, 133.0, 135.2, 140.8, 141.2, 165.4.
+
+
HRMS: m/z calcd for C22H20I2O8·NH4 : 683.9586; found: 683.9584.
HRMS: m/z calcd for C15H1279BrIO2·NH4 : 447.9404; found:
447.9394.
8
Synthesis according to the general procedure; 2-iodobenzoic acid
(878 mg, 3.54 mmol) and dimethyl L-(+)-tartrate (315 mg, 1.77
mmol) yielded 62% (700 mg, 1.09 mmol) of 8; [a]D25 –26.34
(c 1.488, CHCl3).
12
Synthesis according to the general procedure; 3-iodobenzoic acid
(350 mg, 1.41 mmol) and (S)-1-(2-bromophenyl)ethanol (312 mg,
1.55 mmol) yielded 94% (570 mg, 1.32 mmol) of 12; [a]D25 +97.59
(c 1.080, CHCl3).
IR (KBr): 2953, 1743, 1582, 1562, 1464, 1434, 1286, 1237, 1128,
1095, 1015, 740 cm–1.
1H NMR (500 MHz, CDCl3): d = 3.75 (s, 3 H, CH3), 5.99 (s, 1 H,
CH), 7.11 (dd, J = 7.5, 1.1 Hz, 1 Harom), 7.34 (t, J = 7.6 Hz, 1 Harom),
7.87 (dd, J = 7.9, 1.3 Hz, 1 Harom), 7.94 (d, J = 7.9 Hz, 1 Harom).
13C NMR (126 MHz, CDCl3): d = 53.4, 71.6, 94.6, 128.1, 131.8,
133.0, 133.5, 141.7, 164.7, 166.1.
IR (KBr): 3012, 2982, 1721, 1565, 1472, 1439, 1277, 1254, 1116,
1070 cm–1.
1H NMR (250 MHz, CDCl3): d = 1.54 (d, J = 6.5 Hz, 3 H, CH3),
6.28 (q, J = 6.5 Hz, 1 H, CH), 6.98–7.08 (m, 2 Harom), 7.20 (dt,
J = 7.5, 1.0 Hz, 1 Harom), 7.41 (dt, J = 8.1, 1.1 Hz, 2 Harom), 7.74 (d,
J = 7.9 Hz, 1 Harom), 7.93 (d, J = 7.8 Hz, 1 Harom), 8.30 (t, J = 1.6 Hz,
1 Harom).
13C NMR (62.5 MHz, CDCl3): d = 21.3, 72.7, 94.0, 122.0, 126.8,
128.0, 128.9, 129.4, 130.2, 132.2, 133.0, 138.5, 141.0, 141.9, 164.0.
+
HRMS: m/z calcd for C20H16I2O8·NH4 : 655.9273; found: 655.9269.
9
+
Synthesis according to the general procedure; 2-iodophenylacetic
acid (350 mg, 1.34 mmol) and (S)-(–)-1-phenylethanol (179 mg,
1.46 mmol) yielded 91% (446 mg, 1.22 mmol) of 9; [a]D25 +56.59
(c 0.880, CHCl3).
HRMS: m/z calcd for C15H1279BrIO2·NH4 : 447.9405; found:
447.0496.
Synthesis 2010, No. 6, 1023–1029 © Thieme Stuttgart · New York

1028
13
U. Farooq et al.
PAPER
yielded 88% (590 mg, 1.06 mmol) of 16; [a]D25 –27.28 (c 0.755,
Synthesis according to the general procedure; 2-iodophenylacetic
acid (400 mg, 1.53 mmol) and (S)-1-(2-bromophenyl)ethanol (350
mg, 1.74 mmol) yielded 93% (630 mg, 1.42 mmol) of 13;
[a]D25 –21.31 (c 2.046, CHCl3).
CHCl3).
IR (KBr): 3059, 2958, 2875, 1734, 1620, 1591, 1557, 1508, 1361,
1244, 1114, 1027 cm–1.
1H NMR (250 MHz, CDCl3): d = 1.02 (t, J = 7.0 Hz, 3 H, CH3),
1.46–1.55 (m, 1 H), 1.65–1.73 (m, 6 H), 1.99 (s, 1 H), 2.30–2.45 (m,
1 H), 3.02–3.62 (m, 6 H), 4.03 (s, 3 H, OCH3), 7.15 (t, J = 7.7 Hz,
1 H, CH), 7.24–7.46 (m, 2 Harom), 7.66 (d, J = 2.3 Hz, 1 H), 7.78 (d,
J = 7.9 Hz, 1 H), 8.00–8.10 (m, 2 H), 8.51 (s, 1 Harom), 8.72 (d,
J = 4.1 Hz, 1 Harom).
13C NMR (62.5 MHz, CDCl3): d = 11.8, 20.9, 25.1, 25.3, 26.0, 36.1,
49.1, 49.8, 56.2, 58.1, 72.6, 94.0, 100.9, 117.5, 122.9, 129.1, 129.7,
130.5, 131.3, 131.8, 138.2, 139.8, 141.8, 144.6, 147.0, 158.9, 163.1.
IR (KBr): 3066, 2982, 1746, 1587, 1563, 1471, 1435, 1411, 1333,
1208, 1161, 1148, 1133, 1074, 1046 cm–1.
1H NMR (500 MHz, CDCl3): d = 1.61 (d, J = 6.6 Hz, 3 H, CH3),
3.92 (s, 2 H, CH2), 6.30 (q, J = 6.5 Hz, 1 H, CH), 7.00 (m, 1 Harom),
7.16 (dd, J = 7.8, 1.7 Hz, 1 Harom), 7.31–7.35 (m, 3 Harom), 7.42 (dd,
J = 7.8, 1.6 Hz, 1 Harom), 7.56 (dd, J = 8.0, 1.1 Hz, 1 Harom), 7.90 (t,
J = 7.6 Hz, 1 Harom).
13C NMR (126 MHz, CDCl3): d = 21.4, 46.5, 72.3, 101.2, 121.9,
127.0, 127.7, 128.5, 128.9, 129.2, 130.8, 133.1, 137.8, 139.3, 141.1,
169.3.
HRMS: m/z calcd for C27H29IN2O3 + H+: 557.1296; found:
557.1287.
HRMS: m/z calcd for C16H1479BrIO2·NH4 : 461.9560; found:
461.9552.
+
17
Synthesis according to the general procedure; 2-iodophenylacetic
acid (300 mg, 1.14 mmol) and hydroquinidine (410 mg, 1.25 mmol)
yielded 90% (590 mg, 1.03 mmol) of 17; [a]D25 +72.71 (c 0.828,
CHCl3).
14
Synthesis according to the general procedure; 2-iodobenzoic acid
(400 mg, 1.61 mmol) and trans-2-bromo-2,3-dihydro-1H-inden-1-
ol (377 mg, 1.77 mmol) yielded 97% (690 mg, 1.56 mmol) of 14.
The enantiomers were separated by HPLC on Chiralcel OD-H
(10 °C, hexane–i-PrOH; 99:1);
[a]D25 –102.91 (c 0.740, CHCl3) for compound 14; [a]D25 +113.78
(c 0.715, CHCl3) for compound ent-14. The absolute configurations
of 14 (R,R) and ent-14 (S,S) have been assigned in comparison with
optical rotations of similar compounds.17
IR (KBr): 2932, 2870, 1740, 1620, 1590, 1508, 1472, 1432, 1336,
1227, 1155, 1084, 1027 cm–1.
1H NMR (500 MHz, CDCl3): d = 0.82 (d, J = 7.0 Hz, 3 H, CH3),
1.30–1.49 (m, 6 H), 1.60–1.71 (m, 2 H), 2.55–2.78 (m, 2 H), 2.81
(m, 2 H, CH2), 3.16 (q, J = 8.0 Hz, 1 H), 3.79 (s, 2 H, CH2), 3.83 (s,
3 H, OCH3), 6.47 (d, J = 7.0 Hz, 1 H), 6.88 (dd, J = 7.6, 1.5 Hz, 1
Harom), 7.09–7.31 (m, 5 Harom), 7.75 (d, J = 7.9 Hz, 1 Harom), 7.91 (d,
J = 9.2 Hz, 1 Harom), 8.61 (d, J = 4.5 Hz, 1 Harom).
13C NMR (126 MHz, CDCl3): d = 12.1, 23.6, 25.5, 26.0, 27.1, 37.3,
46.5, 49.9, 50.9, 55.6, 59.3, 74.3, 101.0, 101.5, 118.9, 121.9, 127.1,
128.5, 129.1, 130.7, 131.7, 137.2, 139.6, 143.7, 144.7, 147.4, 157.9,
169.6.
IR (KBr): 2945, 1731, 1580, 1458, 1428, 1346, 1240, 1130, 1090,
1046 cm–1.
1H NMR (250 MHz, CDCl3): d = 3.18 (dd, J = 17.1, 3.9 Hz, 1 H,
CHH), 3.66 (dd, J = 17.1, 6.5 Hz, 1 H, CHH), 4.57 (m, 1 H, CH),
6.45 (d, J = 3.1 Hz, 1 H, CH), 6.96 (dd, J = 7.7, 1.7 Hz, 1 Harom),
7.09–7.24 (m, 4 Harom), 7.42 (d, J = 8.1 Hz, 1 Harom), 7.61 (dd,
J = 7.7, 1.6 Hz, 1 Harom), 7.79 (dd, J = 7.9, 1.0 Hz, 1 Harom).
HRMS: m/z calcd for C28H31IN2O3 + H+: 571.1452; found:
571.1443.
13C NMR (62.5 MHz, CDCl3): d = 41.8, 49.9, 85.2, 94.4, 125.1,
126.4, 127.8, 128.1, 130.0, 131.3, 133.0, 134.7, 138.0, 141.4, 141.6,
165.9.
MS (EI): m/z (%) = 462.2 (48, M+), 460. 2 (48, M+), 334 (10), 237
(45), 214 (100), 212 (88), 132 (43), 116 (38), 105 (29), 52 (67).
a-Oxytosylation of Ketones; (1R)-1-Methyl-2-oxo-2-phenyleth-
yl 4-Methylbenzenesulfonate; Typical Procedure
Propiophenone (1; 0.33 mmol, 45 mg), an organoiodine catalyst (10
mol%), MCPBA (0.5 mmol, 86 mg), and p-TsOH·H2O (0.5 mmol,
95 mg) were dissolved in MeCN (3 mL) and stirred at r.t. for 3–4
days. After completion of the reaction, the mixture was poured into
sat. aq Na2CO3 (15 mL). The layers were separated and the aqueous
layer was extracted with CH2Cl2 (2 × 10 mL). The combined organ-
ic phases were dried (Na2SO4), filtered, and concentrated under re-
duced pressure. The crude product was purified by flash
chromatography (silica gel; hexane–EtOAc, 7:3). NMR spectro-
scopic data were similar to the data reported in the literature.16
15
Synthesis according to the general procedure; 2-iodobenzoic acid
(300 mg, 1.21 mmol) and hydroquinidine (433 mg, 1.33 mmol)
yielded 67% (450 mg, 0.81 mmol) of 15; [a]D25 +29.14 (c 0.350,
CHCl3).
IR (KBr): 2932, 1733, 1619, 1508, 1462, 1430, 1241, 1132, 1096,
1015 cm–1.
1H NMR (500 MHz, CDCl3): d = 0.81 (t, J = 7.2 Hz, 3 H, CH3),
1.39–1.62 (m, 6 H), 1.78 (s, 1 H), 2.08 (m, 1 H), 2.75–3.09 (m, 5 H),
3.40 (d, J = 7.5 Hz, 1 H, CH), 3.89 (s, 3 H, OCH3), 7.10–7.48 (m, 3
HPLC [Chiracel OB-H column, hexane–i-PrOH (40:60), 0.5 mL/
min, 40 °C]: tR = 18.1 min (R), 21.6 min (S).18
1H NMR (250 MHz, CDCl3): d = 1.60 (d, J = 6.9 Hz, 3 H, CH3),
2.41 (s, 3 H, CH3), 5.87 (q, J = 6.9 Hz, 1 H), 7.22–7.31 (m, 2 Harom),
7.40–7.50 (m, 2 Harom), 6.54–7.64 (m, 1 Harom), 7.71–7.79 (m, 2
Harom), 7.49 (m, 1 Harom), 7.55 (m, 1 Harom), 7.85 (m, 1 Harom), 7.89–
8.02 (m, 2 Harom), 8.69 (d, J = 4.5 Hz, 1 Harom).
Harom), 7.84–7.92 (m, 2 Harom).
13C NMR (126 MHz, CDCl3): d = 11.8, 22.6, 25.3, 26.1, 26.2, 36.7,
49.5, 50.3, 56.1, 59.0, 74.0, 94.1, 101.3, 118.5, 122.5, 126.8, 128.0,
130.6, 131.8, 133.0, 134.7, 139.8, 141.6, 144.8, 147.2, 158.4, 165.2.
HRMS: m/z calcd for C27H29IN2O3 + H+: 557.1296; found:
557.1287.
Lactonization of 5-Oxo-5-phenylpentanoic Acid; 5-(Phenylcar-
bonyl)dihydrofuran-2(3H)-one (19); Typical Procedure
5-Oxo-5-phenylpentanoic acid (18; 0.25 mmol, 48 mg), the I2 con-
taining catalyst (10 mol%), p-TsOH·H2O (0.05 mmol, 9 mg), and
MCPBA (0.3 mmol, 51.3 mg) were dissolved in MeCN (3 mL). The
mixture was stirred for 3–4 days. The crude reaction mixture was
then concentrated under reduced pressure, dissolved in CH2Cl2 (10
mL), and the CH2Cl2 layer was washed with sat. aq NaHCO3 (2 × 15
16
Synthesis according to the general procedure; 3-iodobenzoic acid
(300 mg, 1.21 mmol) and hydroquinidine (433 mg, 1.33 mmol)
Synthesis 2010, No. 6, 1023–1029 © Thieme Stuttgart · New York

PAPER
Functionalization of Ketones Catalyzed by Hypervalent Iodine Compounds
1029
mL). The aqueous phase was re-extracted with CH2Cl2 (2 × 15 mL).
The combined organic phases were dried (Na2SO4), filtered, con-
centrated under reduced pressure and subjected to column chroma-
tography [silica gel; petroleum ether–EtOAc, 2:1] to give 19. NMR
spectroscopic data were similar to the data reported in the litera-
ture.16
1H NMR (500 MHz, CDCl3): d = 2.42–2.67 (m, 4 H, 2 × CH2),
5.78–5.82 (m, 1 H, CH), 7.52 (dd, J = 8.4 Hz, 7.5 Hz, 2 Harom),
7.62–7.67 (m, 1 Harom), 7.99 (dd, J = 8.4 Hz, 1.3 Hz, 2 Harom).
(5) (a) Altermann, S. M.; Richardson, R. D.; Page, T. K.;
Schmidt, R. K.; Holland, E.; Mohammed, U.; Paradine, S.
M.; French, A. N.; Richter, C.; Bahar, A. M.; Witulski, B.;
Wirth, T. Eur. J. Org. Chem. 2008, 5315. (b) Shah, A. A.;
Khan, Z. A.; Choudhary, N.; Lohölter, C.; Schäfer, S.;
Marie, G. P. L.; Farooq, U.; Witulski, B.; Wirth, T. Org. Lett.
2009, 11, 3578.
(6) (a) Wirth, T.; Hirt, U. Tetrahedron: Asymmetry 1997, 8, 23.
(b) Hirt, U. H.; Springler, B.; Wirth, T. J. Org. Chem. 1998,
63, 7674. (c) Hirt, U. H.; Schuster, M. F. H.; French, A. N.;
Wiest, O. G.; Wirth, T. Eur. J. Org. Chem. 2001, 1569.
(7) Richardson, R. D.; Wirth, T. Angew. Chem. Int. Ed. 2006,
45, 4402; Angew. Chem. 2006, 118, 4510.
13C NMR (126 MHz, CDCl3): d = 24.9, 26.8, 78.2, 128.8 (2 C),
129.0 (2 C), 134.3, 134.3, 176.1, 194.3.
(8) Fuchigami, T.; Fujita, T. J. Org. Chem. 1994, 59, 7190.
(9) (a) Ochiai, M.; Takeuchi, Y.; Katayama, K.; Sueda, T.;
Miyamoto, K. J. Am. Chem. Soc. 2005, 127, 12244.
(b) Ochiai, M.; Miyamoto, K. Eur. J. Org. Chem. 2008,
4229.
(10) (a) Dohi, T.; Maruyama, A.; Yoshimura, M.; Morimoto, K.;
Tohma, H.; Kita, Y. Angew. Chem. Int. Ed. 2005, 44, 6193;
Angew. Chem. 2005, 117, 6349. (b) Dohi, T.; Kita, Y.
Chem. Commun. 2009, 2073.
Acknowledgment
We thank the Deutsche Forschungsgemeinschaft, Germany (S.S.),
the Higher Education Commission (HEC), Pakistan (U.F., A.A.S.),
Cardiff University (D.M.F.), and The Royal Society (S.S.) for fi-
nancial support.
References
(11) Richardson, R. D.; Page, T. K.; Altermann, S. M.; Paradine,
S. M.; French, A. N.; Wirth, T. Synlett 2007, 538.
(12) Dohi, T.; Maruyama, A.; Takenaga, N.; Senami, K.;
Minamitsuji, Y.; Fujioka, H.; Caemmerer, S. B.; Kita, Y.
Angew. Chem. Int. Ed. 2008, 47, 3787; Angew. Chem. 2008,
120, 3847.
(13) (a) Reisinger, C. M.; Wang, X.; List, B. Angew. Chem. Int.
Ed. 2008, 47, 8112; Angew. Chem. 2008, 120, 8232.
(b) Marigo, M.; Jørgensen, K. A. Chem. Commun. 2006,
2001. (c) Momiyama, N.; Torii, H.; Saito, S.; Yamamoto, H.
Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5374.
(d) Longbottom, D. A.; Franckevicius, V.; Kumarn, S.;
Oelke, A. J.; Wascholowski, V.; Ley, S. V. Aldrichimica
Acta 2008, 41, 3.
(1) Reviews: (a) Varvoglis, A. The Organic Chemistry of
Polycoordinated Iodine; VCH: Weinheim, 1992.
(b) Varvoglis, A. Hypervalent Iodine in Organic Synthesis;
Academic Press: London, 1997. (c) Finet, J. Ligand
Coupling Reactions with Heteroatomic Compounds;
Pergamon: Oxford, 1998. (d) Zhdankin, V. V.; Stang, P. J.
Tetrahedron 1998, 55, 10927. (e) Wirth, T.; Hirt, U. H.
Synthesis 1999, 1271. (f) Ochiai, M. In Chemistry of
Hypervalent Compounds; Akiba, K., Ed.; VCH: New York,
1999, 359. (g) Zhdankin, V. V.; Stang, P. J. Chem. Rev.
2002, 102, 2523. (h) Wirth, T. Hypervalent Iodine
Chemistry; Springer: Berlin, 2003. (i) Tohma, H.; Kita, Y.
Adv. Synth. Catal. 2004, 346, 111. (j) Wirth, T. Angew.
Chem. Int. Ed. 2005, 44, 3656; Angew. Chem. 2005, 117:
3722. (k) Zhdankin, V. V. In Science of Synthesis, Vol. 31a;
Ramsden, C., Ed.; Thieme: Stuttgart, 2007, Chap. 31.4.1,
161. (l) Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2008, 108,
5299.
(14) Hassner, A.; Alexanian, V. Tetrahedron Lett. 1978, 46,
4475.
(15) Yamamoto, Y.; Togo, H. Synlett 2006, 798.
(16) Uyanik, M.; Yasui, T.; Ishihara, K. Bioorg. Med. Chem. Lett.
2009, 19, 3848.
(2) Braddock, D. C.; Cansell, G.; Hermitage, S. A. Chem.
Commun. 2006, 2483.
(3) Rebrovic, L.; Koser, G. F. J. Org. Chem. 1984, 49, 2462.
(4) Koser, G. F.; Relenyi, A. G.; Kalos, A. N.; Rebrovic, L.;
Wettach, R. H. J. Org. Chem. 1982, 47, 2487.
(17) Boyd, D. R.; Sharma, N. D.; Smith, A. E. J. Chem. Soc.,
Perkin Trans. 1 1982, 2767.
(18) The absolute configuration was determined by independent
synthesis of 3 from (S)-(–)-lactic acid: Imfeld, M.; Suchy,
M.; Vogt, P.; Kucác, P.; Schlageter, M.; Widmer, E. Helv.
Chim. Acta 1982, 65, 1233.
Synthesis 2010, No. 6, 1023–1029 © Thieme Stuttgart · New York