Design and asymmetric synthesis of chiral diaryliodonium salts

Article abstract of DOI:10.1016/j.tet.2010.05.004

The application of chiral hypervalent iodine reagents in asymmetric synthesis is highly desirable, as the reagents are metal-free, environmentally benign and employed under mild conditions. Three chiral diaryliodonium salts have been designed to provide chemoselectivity and asymmetric induction in asymmetric α-phenylation of carbonyl compounds. The synthetic routes to the selected targets are detailed herein, together with a structural investigation into the diastereoselectivity of the alkylation process.

Full text of DOI:10.1016/j.tet.2010.05.004

Tetrahedron 66 (2010) 5793e5800
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Tetrahedron
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Design and asymmetric synthesis of chiral diaryliodonium salts
*
Nazli Jalalian, Berit Olofsson
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, SE-106 91 Stockholm, Sweden
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 April 2010
Received in revised form 29 April 2010
Accepted 4 May 2010
Available online 10 May 2010
The application of chiral hypervalent iodine reagents in asymmetric synthesis is highly desirable, as the
reagents are metal-free, environmentally benign and employed under mild conditions. Three chiral di-
aryliodonium salts have been designed to provide chemoselectivity and asymmetric induction in
asymmetric a-phenylation of carbonyl compounds. The synthetic routes to the selected targets are de-
tailed herein, together with a structural investigation into the diastereoselectivity of the alkylation
process.
Keywords:
Ó 2010 Elsevier Ltd. All rights reserved.
Hypervalent iodine
Diaryl-l
3-iodanes
Asymmetric synthesis
Oxidation
Arylation reagents
1. Introduction
Hypervalent iodine compounds have emerged as selective and
environmentally benign reagents in many areas of organic syn-
thesis.1e3 Iodine(III) reagents with two heteroatom ligands are
employed in
a-oxidations of carbonyl compounds, oxidations of
alcohols, carbonecarbon bond formation, and many other
transformations.1e3
Diaryliodonium salts, also named diaryl-l
3-iodanes, are iodine
(III) reagents with two aryl ligands. They are efficient electrophilic
arylation reagents for a number of nucleophiles, including enolates,
phenols, and amines.4 Furthermore, they can be employed in
a wide range of cross-coupling reactions under metal-catalyzed or
metal-free conditions.4e6
Recent progress in hypervalent iodine chemistry has focused on
the development of catalytic methodology7e9 and asymmetric ap-
plications using chiral reagents.10 The first chiral hypervalent iodine
compound everreported, diphenyliodonium tartrate, waspublished
already in 1907.11 Surprisingly few chiral diaryliodonium salts have
since then appeared in the literature.12 In 1999, Ochiai and co-
workers reported the synthesis of 1,10-binaphthyl-2-yl(phenyl)
iodonium salts 1 (Scheme 1).13 The efficiency of the salts was eval-
Scheme 1. Asymmetric phenylation with chiral diaryliodonium salts.
Aggarwal and Olofsson used a different strategy to realize
enantioselective
a-arylation of carbonyl compounds with diaryl-
iodonium salts. Asymmetric induction was obtained by the use of
a chiral base, followed by treatment with an achiral diaryliodonium
salt. This methodology was applied in an efficient total synthesis of
(ꢀ)-epibatidine (Scheme 2).15 Although this arylation protocol is
highly enantioselective, it can only be applied to a limited set of
cyclic, prochiral substrates.
uated in arylations of b-keto esters, and gave a-phenylated products
in moderate yields and enantioselectivities.13 In a similar fashion,
Zhdankin and co-workers prepared chiral benziodazole structures,
where the N-functionalized amide moiety acted as internal anion.14
We have recently performed a theoretical study on the mech-
anism of a-arylation of carbonyl compounds with diaryliodonium
salts, which together with experimental results led to the conclu-
sion that asymmetric induction cannot be achieved by use of chiral
anions or chiral PTC.16 Thus, the design of chiral diaryliodonium
* Corresponding author. Tel.: þ46 8 674 7264; fax: þ46 8 154908; e-mail address:
berit@organ.su.se (B. Olofsson).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.05.004

5794
N. Jalalian, B. Olofsson / Tetrahedron 66 (2010) 5793e5800
electron-deficient, aryl group to the nucleophile (Scheme 3a). The
resulting chiral iodoarene could be recovered and reoxidized into
the chiral salt to provide good atom economy.
Scheme 2. Asymmetric synthesis of (ꢀ)-epibatidine.
salts, where one of the aryl moieties have substituents with ster-
eogenic elements, remains as one of few possibilities to obtain
enantioenriched
a-arylated carbonyl compounds using hyper-
valent iodine reagents.
The development of chiral hypervalent iodine(III) compounds
with two heteroatom ligands has been more successful.17 Catalytic
reactions involving chiral iodine(III) reagents have also resulted in
high enantioselectivities.18,19 In 2008, Kita and co-workers
employed chiral reagent 2, with a rigid 1,1-spiroindanone back-
bone, in oxidative spirolactonizations (Fig. 1).20 Very recently, Ish-
ihara’s group reported the use of C2-symmetric chiral iodane 3 in
the same reaction.21 Both reagents could be formed in situ from the
Scheme 3. a) Expected chemoselectivity in the arylation. (b) Target structures. (c)
Retrosynthetic analysis.
Three target structures (IeIII) were designed to fulfill these
demands, having one, two or three substituents (Scheme 3b).
ortho-Substituents with stereocenters were selected to deliver
asymmetric induction by close proximity to the iodine. Further-
more, the oxygen-based substituents should make the aryl moiety
electron-rich enough to give chemoselective phenyl transfer. The
steric bulk of the substituents was given careful consideration, as
too small substituents were likely to cause little induction, while
too large substituents could give rise to undesired chemoselectivity
by the ortho-effect. The long aliphatic chains were selected to im-
prove the solubility and thus allow arylation reactions in a variety
of solvents.
The number of substituents was expected to influence the re-
activity, asymmetric induction and chemoselectivity in arylation
reactions. In the synthesis of mono- and disubstituted targets I and
II, regioselectivity issues must be controlled, which limits the
number of possible synthetic routes. The diaryliodonium salts
would be derived from the corresponding substituted iodoarenes,
which could be prepared from the iodophenol and enantiomeri-
cally pure alcohol (R)-4, as shown for target I (Scheme 3c).
The synthesis of the diaryliodonium salts was envisioned using
the methodology recently developed in our laboratory (Scheme 4).
Symmetrical and unsymmetrical diaryliodonium triflates can be
obtained in high yields and short reaction times employing mCPBA
and trifluoromethanesulfonic acid (TfOH), as depicted in Scheme
4a.24,25 The protocol can be extended to the direct formation of
diaryliodonium triflates from iodine and arenes.24e26
corresponding aryl iodide with
a stoichiometric amount of
m-chloroperbenzoic acid (mCPBA).
Figure 1. Chiral iodine(III) reagents used in oxidative spirolactonization.
The synthesis of chiral diaryliodonium salts has been an on-
going project in our laboratory for some time. The similarity be-
tween Ishihara’s chiral iodane 3 and our chiral salts prompted us
to report our results in the synthesis of chiral, enantiopure di-
aryliodonium.
2. Results and discussion
2.1. Design and synthetic strategy
The design of chiral diaryliodonium salts is limited by the often
harsh conditions used in the synthetic routes. Therefore, the use of
acid- or base-labile substituents should be avoided. The absence of
catalytic arylation protocols, where the diaryliodonium salt is
formed in situ from the corresponding iodoarene, makes stability
issues of the target compounds a difficult problem. The recent
success in applications of chiral iodine(III) reagents with two het-
eroatom ligands has indeed often depended on catalytic formation
of the chiral iodine(III) species, thus avoiding stability issues in the
isolation.
When unsymmetric diaryliodonium salts are employed in
enolate and heteroatom arylations, the aryl groups can often be
differentiated. Generally, the more electron-deficient aryl moiety is
selectively transferred, although aryl moieties bearing ortho-sub-
stituents are sometimes transferred despite being more electron-
rich (the so-called ortho-effect).22,23
We envisioned the use of diaryliodonium salts where one of the
aryl groups is more electron-rich and has substituents bearing
stereocenters. This aryl moiety should behave as a chiral ligand and
promote asymmetric induction in the transfer of the other, more
Scheme 4. Some of our one-pot routes to diaryliodonium salts.

N. Jalalian, B. Olofsson / Tetrahedron 66 (2010) 5793e5800
5795
A variation of this synthesis, employing p-toluenesulfonic acid
2.3. Synthesis of target II
(TsOH), gives access to electron-rich diaryliodonium tosylates
(Scheme 4b). If necessary, the corresponding triflate salts are con-
veniently obtained via an in situ anion exchange.27
A regiospecific one-pot reaction utilizing arylboronic acids has also
been developed, giving diaryliodonium tetrafluoroborates in high
yields (Scheme 4c).28 Also this protocol allows an in situ anion ex-
change to triflate, which is beneficial when isolation or stability issues
are noticed. An alternative one-pot preparation of diaryliodonium
triflatesemployshydrogenperoxideinstead of mCPBAastheoxidant.29
The synthesis of the disubstituted target compound was in-
vestigated using racemic 2-octanol (rac-4). Difficulties were pre-
dicted due to the desired 1,2,3-substitution pattern, which
restricted the synthetic possibilities and was likely to cause prob-
lems related to steric hindrance.
Indeed, dialkylation of 2-iodoresorcinol32 with either mesylate
rac-6 or the corresponding tosylate 12 was unproductive. The starting
materials were recovered under normal reaction conditions, whereas
forcing conditions led to decomposition of the alkylating reagent.
Dialkylated iodoarene 13 was instead obtained by a Mitsunobu
reaction with rac-4 (Scheme 6a). Conversion of compound 13 to the
desired diaryliodonium target II was attempted with the TsOH
protocol (see Scheme 4b), but resulted in decomposition of 13 also
at low temperatures. Similar discouraging results were obtained
using BF3$OEt2 and phenylboronic acid.
2.2. Synthesis of target I
Alcohol (R)-4 was synthesized in 42% yield and >99% ee by
enzymatic kinetic resolution of racemic 2-octanol (Scheme 5a).30
The alcohol was mesylated to (R)-6 in 99% yield and used in al-
kylation of 2-iodophenol, to deliver the desired iodoarene 7 with-
out loss of enantiomeric excess (Scheme 5b). Unfortunately, all
attempts to synthesize the target I from 7 using the TsOH protocol
(see Scheme 4b) were unsuccessful, possibly due to sluggish oxi-
dation caused by steric hindrance from the ortho-substituent.
Scheme 5. Synthesis of the monosubstituted target I. CALB¼Candida Antarctica Lipase B.
The synthesis of target I was instead accomplished using the
boronic acid method (see Scheme 4c). Attempts to oxidize 7 at
ambient temperature in the presence of BF3$OEt2 led to de-
composition. Thus, the procedure was modified to oxidation of 7
with mCPBA at elevated temperature, followed by cooling to ꢀ78 ꢁC
and addition of phenylboronic acid and BF3$OEt2. Diaryliodonium
salt 8 could then be isolated in modest yield (Scheme 5b).
This synthesis, however, also led to another chiral diary-
liodonium salt 9, which was obtained in various amounts depending
on small changes in the Experimental procedure. The formation of
this compound can be explained by incomplete oxidation of
iodoarene 7, which leads to an undesired EAS reaction of 7 onto the
formed iodine(III) intermediate, upon addition of BF3$OEt2.
Due to the difficulties in oxidation of iodoarene 7, we turned to
the use of basic reaction conditions. Fortunately, treatment of 7
with BuLi followed by reaction with vinyliodonium triflate 1031
delivered diaryliodonium triflate 11 (Scheme 5c).
Scheme 6. Synthesis of the disubstituted target II. DIAD¼diisopropyl azodicarbox-
ylate; Pe¼pentyl.
As both the synthesis of 13 and further transformation to
a diaryliodonium salt proved problematic, we turned to alternative
approaches toward target II. Alkylation of 2-bromoresorcinol33
with tosylate 12 afforded disubstituted bromoarene 14, which

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N. Jalalian, B. Olofsson / Tetrahedron 66 (2010) 5793e5800
was smoothly converted to arylboronic acid 15 (Scheme 6b). Un-
fortunately, all attempts at converting 15 into target II also failed,
both when using the one-pot method depicted in Scheme 4c and
when applying preformed iodine(III) reagents such as (diacetoxy-
iodo)benzene or Koser’s reagent.34
therefore revised to a nucleophilic aromatic substitution on 1,3,5-
trifluorobenzene36 with alcohol (R)-4, which delivered 21 in
moderate yield (Scheme 7b). Arene 21 was subsequently converted
to target structure III with Koser’s reagent, giving tosylate salt 22 in
good yield.
Clearly, the substituents did not tolerate acidic conditions even
at low temperatures. Milder methods, such as reaction of Koser’s
reagent with the 1,3-disubstituted arene,35 were not applicable due
to the desired regiochemistry with coupling in the 2-position.
Having screened the available acidic methods for synthesis of
target II, we again turned to the use of basic conditions. Iodoarene
13 was lithiated and treated with vinyliodonium salt 10, which
indeed furnished disubstituted diaryliodonium salt 16 (Scheme 6c).
This methodology was subsequently repeated with enantiomeri-
cally pure material. Dialkylation of 2-bromoresorcinol with mesylate
(R)-6 proved to be the most efficient way to reach the required dia-
lkylated haloarene, and 17 was obtained in 89% yield (Scheme 6d).
Bromoarene 17 was subsequently treated with BuLi and vinyl-
iodonium salt 10, providing the disubstituted target compound 18.
Due to the apolar nature of arene 21, the enantiopurity of this
compound could not be determined by chiral GC or HPLC. Thus, the
nucleophilic aromatic substitution was repeated using fluo-
robenzene and alcohol (R)-4, yielding monosubstituted arene 23
(Scheme 8). As expected, the nucleophilic aromatic substitution
took place without loss of enantiomeric excess, which was verified
by chiral HPLC analysis of arene 23. By analogy, we anticipate for-
mation of compound 21 in >99% ee.
Scheme 8. Synthesis of monosubstituted arene 23 for ee determination.
2.4. Synthesis of target III
2.5. Structural investigations
As expected, synthesis of the trisubstituted salt proved to be
more straightforward, as regioselectivity issues were avoided.
Having experienced the difficulties discussed above with synthesis
of target II, we directly turned to methods avoiding acidic condi-
tions in formation of target III.
Thus, trisubstituted arene 19 was synthesized in 72% yield by
alkylation of 1,3,5-trihydroxybenzene with mesylate rac-6 (Scheme
7a). Arene 19 was treated with Koser’s reagent35 at low tempera-
ture to afford the desired trisubstituted diaryliodonium tosylate 20
in excellent yield.
The unforeseen difference in alkylation rate of 1,3,5-trihydroxy-
benzene with racemic and enantiomerically pure mesylate 6 was
intriguing, and necessitated a deeper investigation. When employ-
ing rac-6 in the synthesis of diaryliodonium salt 20, three di-
astereomeric pairs of enantiomers can be formed, as depicted in
Figure 2.
Figure 2. Possible diastereomers of diaryliodonium salt 20.
Close examination of the NMR spectra of diaryliodonium salts
20 and 22 revealed small shift differences between the two com-
pounds in both 1H NMR and 13C NMR. The analysis was complicated
by the different shifts observed for the ortho- and para-sub-
stituents. These peaks were identified by the 2:1 ratio observed in
compound 22. Figure 3 depicts a selection of the non-identical
peaks seen in 13C NMR, where the ortho- and para-substituents are
clearly differentiated. For remaining parts of the combined spectra,
see the Supplementary data. The NMR data of compounds 20 and
22 are listed in Table 1, with the ortho- and para-substituents
assigned.
This data indicate that two diastereomers of 20 are formed,
namely (R,S,R/S,R,S)-20 and (R,R,S/S,S,R)-20. Unfortunately, all at-
tempts to verify these results by X-ray crystallography failed, as 20
remained an oil under all recrystallization conditions tested.
Formation of only the two unsymmetric diastereomers of 20
would correspond to diastereoselective synthesis of only the (R,S,R/
S,R,S) diastereomer of arene 19. Indeed, the 13C NMR of this com-
pound shows only one diastereomer, which is slightly different
from (R,R,R)-21. Preferential formation of one of the two possible
diastereomers can be explained by rate differences in the third
alkylation caused by steric hindrance. This conclusion is supported
by the different reactivity observed in alkylations with racemic and
enantiopure mesylate 6.
Scheme 7. Synthesis of the trisubstituted target III.
The racemic synthesis was next to be repeated with enantio-
merically pure material. Surprisingly, the alkylation of trihydroxy-
benzene with mesylate (R)-6 proved difficult under all conditions,
providing mainly the mono- and dialkylated arene. The route was

N. Jalalian, B. Olofsson / Tetrahedron 66 (2010) 5793e5800
5797
Figure 3. Characteristic peaks in 13C-NMRs of 20 (blue) and 22 (red).
Table 1
NMR data of diaryliodonium salts in CDCl3 (ppm) with J couplings (Hz)a
Compound
1H NMR (400 MHz)
16 major
7.85 (2H, m), 7.53 (1H, tt, J¼7.4, 1.1), 7.47 (1H, td, J¼8.4, 0.9), 7.38 (2H, ddt, J¼8.2, 7.4, 1.5), 6.57 (2H, dd, J¼8.4, 1.3), 4.50
(2H, app sex, J¼6.1), 1.73 (2H, m), 1.59 (2H, m), 1.34e1.20 (16H, m), 1.28 (6H, d, J¼6.1), 0.87 (6H, t, J¼7.0).
7.85 (2H, m), 7.53 (1H, tt, J¼7.4, 1.1), 7.47 (1H, td, J¼8.4, 0.9), 7.38 (2H, ddt, J¼8.2, 7.4, 1.5), 6.57 (2H, dd, J¼8.4, 1.3), 4.50
(2H, app sex, J¼6.1), 1.73 (2H, m), 1.59 (2H, m), 1.34e1.20 (16H, m), 1.27 (6H, d, J¼6.1), 0.88 (6H, t, J¼7.0).
7.85 (2H, m), 7.53 (1H, tt, J¼7.4, 1.1), 7.47 (1H, t, J¼8.4), 7.37 (2H, ddt, J¼8.2, 7.4, 1.6), 6.57 (2H, d, J¼8.4), 4.50 (2H, app sex, J¼6.1), 1.74
(2H, m), 1.59 (2H, m), 1.36e1.20 (16H, m), 1.27 (6H, d, J¼6.1), 0.88 (6H, t, J¼7.0).
16 minorc
18
20b
7.85 (2H, m), 7.76 (2H, d, J¼8.1), 7.46 (1H, t, J¼7.4), 7.30 (2H, dd, J¼8.1, 7.4), 7.12 (2H, d, J¼7.9), 6.07 (2H, s), 4.40 (2H, app sex, J¼6.1) (o), 4.36
(1H, app sex, J¼6.1) (p), 2.34 (3H, s), 1.78e1.67 (3H, m), 1.65e1.50 (3H, m), 1.47e1.18 (24H, m), 1.33 (3H, d, J¼6.0) (p), 1.26 (6H, d, J¼6.1) (o), 1.25
(3H, d, J¼6.1) (o), 0.89 (3H, t, J¼6.9) (p); 0.89 (3H, t, J¼7.1) (o), 0.88 (3H, t, J¼7.1) (o).
22
7.85 (2H, m), 7.77 (2H, app dt, J¼8.2, 1.8), 7.45 (1H, tt, J¼7.4, 1.1), 7.30 (2H, ddt, J¼8.2, 7.4, 1.7), 7.12 (2H, m), 6.08 (2H, s), 4.40 (2H, app sex, J¼6.1)
(o), 4.37 (1H, app sex, J¼6.1) (p), 2.34 (3H, s), 1.80e1.67 (3H, m), 1.65e1.50 (3H, m), 1.49e1.19 (24H, m), 1.34 (3H, dd, J¼6.1, 0.6) (p), 1.24
(6H, dd, J¼6.1, 0.6) (o), 0.89 (3H, t, J¼6.9) (p); 0.89 (6H, t, J¼6.9) (o).
Compound
16 major
16 minorc
18
13C NMR (100 MHz)
158.33, 136.54, 134.29, 131.89, 120.62 (CF3, J¼320), 119.03, 113.99, 105.84, 95.14, 77.35, 36.10, 31.82, 29.22, 25.58, 22.70, 19.56, 14.19.
158.31, 136.54, 134.33, 131.89, 128.33, 120.62 (CF3, J¼320), 119.03, 114.04, 105.80, 95.14, 77.35, 36.10, 31.82, 29.22, 25.58, 22.70, 19.54, 14.19.
158.31, 136.51, 134.33, 131.87, 129.35, 120.62 (CF3, J¼320), 119.03, 114.14, 105.79, 95.14, 77.35, 36.10, 31.82, 29.22, 25.59, 22.71, 19.54, 14.19.
165.51, 159.38, 143.22, 139.31, 133.61, 131.33, 131.00, 128.58, 126.19, 116.14, 93.58, 85.59, 76.26 (o), 74.91 (p), 36.38 (p), 36.02
(o), 31.83 (p), 31.79 (o), 29.30 (p), 29.18 (o), 25.54, 22.67, 21.40, 19.78 (p), 19.55 (o), 14.15.
20 major
20 minorc
165.48, 159.41, 143.22, 139.31, 133.68, 131.33, 131.00, 128.58, 126.19, 116.06, 93.63, 85.59, 76.23 (o), 74.91 (p), 36.38 (p), 36.02 (o), 31.83
(p), 31.79 (o), 29.30 (p), 29.18 (o), 25.54, 22.67, 21.40, 19.80 (p), 19.51 (o), 14.15.
22
165.44, 159.31, 143.41, 139.10, 133.55, 131.27, 130.97, 128.48, 126.13, 116.18, 93.53, 85.57, 76.14 (o), 74.87 (p), 36.30 (p), 35.96 (o), 31.76
(p), 31.72 (o), 29.23 (p), 29.13 (o), 25.49 (o), 25.47 (p), 22.61 (o), 22.59 (p), 21.33, 19.74 (p), 19.47 (o), 14.09.
a
The ortho/para pairs are marked (o) and (p) and appear in a 2:1 ratio.
Peaks of major and minor diastereomers overlap.
Peaks in italics overlap with the major diastereomer.
b
c
Diaryliodonium salt 16 is also formed as two diastereomeric
Herein, we have presented our synthetic routes toward three enan-
tiopure diaryliodonium salts, targets IeIII. Monosubstituted target I
was synthesized from the corresponding iodoarene, either by a one-
pot reactionwith mCPBA and phenylboronic acid, or by lithiation and
treatment with a vinyliodonium salt. Furthermore, an unexpected
chiral salt was obtained, with stereocenters on both aryl moieties.
Due to acid-lability of the substituents under all tested condi-
tions, the synthesis of the ortho-disubstituted target II was ac-
complished by lithiation of the corresponding bromoarene and
treatment with a vinyliodonium salt.
pairs of enantiomers; (R,R/S,S)-16 and (R,S/S,R)-16. Comparison
with the NMR data of diaryliodonium salt 18 suggests that (R,S/S,R)-
16 is the major diastereomer (Table 1).
2.6. Conclusions
Compared to chiral iodine(III) reagents with two heteroatom li-
gands, chiral diaryliodonium salts are difficult to prepare and few
reports on the synthesis and applications of these compounds exist.

5798
N. Jalalian, B. Olofsson / Tetrahedron 66 (2010) 5793e5800
The trisubstituted target III was formed by reaction of the tri-
with H2O (3ꢂ20 mL), 10% aq HCl (3ꢂ20 mL), brine (3ꢂ20 mL), dried
with Na2CO3, filtered, and concentrated under reduced pressure to
give (R)-6 (1.56 g, 97%) as a colorless oil. The product was used
substituted arene with Koser’s reagent. Remarkable reactivity dif-
ferences in were noted in the racemic and enantiopure route, which
was explained by preferential formation of two of the three pos-
sible diastereomers of the diaryliodonium salt in the racemic
synthesis.
The synthesized chiral diaryliodonium salts are anticipated to
show interesting differences in reactivity, asymmetric induction
and chemoselectivity in arylation reactions. They are currently
without further purification. 1H NMR (CDCl3, 400 MHz)
d 4.39 (1H,
dqd, J¼7.1, 6.3, 5.6 Hz), 2.98 (3H, s), 1.71 (1H, m), 1.59 (1H, m),
1.44e1.22 (8H, m), 1.40 (3H, d, J¼6.3 Hz), 0.88 (3H, t, J¼6.9 Hz); 13C
NMR (100 MHz, CDCl3): d 80.6, 38.8, 36.8, 31.7, 29.0, 25.2, 22.7, 21.3,
20
14.2;
[
a
]
D
þ9.0 (c 1.04 in CH2Cl2); HRMS (ESI): calcd for
C18H40NaO6S2 ([2MþNa]þ): 439.2159, found 439.2142.
being investigated in the asymmetric
a-arylation of carbonyl
compounds, the results of which will be reported in due time.
3.2.3. (S)-1-Iodo-2-(octan-2-yloxy)benzene (7). To a suspension of
anhydrous K2CO3 (1.38 g, 10.0 mmol) in anhydrous acetonitrile
(10 mL) was added 2-iodophenol (440 mg, 2.00 mmol) and (R)-6
(630 mg, 3.00 mmol) and the reaction was refluxed for 18 h. The
solvent was evaporated under reduced pressure and H2O was
added to the crude product. The crude mixture was extracted with
CH2Cl2 (3ꢂ15 mL), washed with brine (3ꢂ15 mL), dried with
Na2CO3, filtered, and concentrated under reduced pressure. The
crude product was purified by column chromatography (pentane/
Et2O, 25:1) to give compound 7 (692 mg, 97%, >99% ee) as a color-
less oil. The enantiomeric excess was analyzed by chiral HPLC using
OB 99.9:0.1 to 98:2 gradient over 30 min iso-hexane/i-PrOH. 1H
3. Experimental section
3.1. General experimental conditions
Commercial mCPBA was dried under vacuum at room temper-
ature for 1 h, the percentage of active oxidizing agent was de-
termined by iodometric titration after drying.37 BF3$Et2O was
stored under an argon atmosphere. THF and Et2O were dried on
a VAC Solvent Purifier. Acetonitrile was distilled from CaH2. NMP
was distilled from P2O5. All other chemicals were used as received
without further purification. Kinetic resolution was performed
using Novozyme 435 (immobilized CALB). Air- and moisture sen-
sitive reactions were carried out in flame-dried, septum-capped
flasks under an atmospheric pressure of argon. All liquid reagents
were transferred via oven-dried syringes. Sealed tubes were used in
reactions that were carried out above the boiling point of the sol-
vent NMR spectra were recorded using CDCl3 or DMSO-d6 as sol-
vent. Chemical shifts are given in parts per million relative to the
NMR (500 MHz, CDCl3):
d
7.78 (1H, dd, J¼7.8, 1.6 Hz), 7.26 (1H, ddd,
J¼8.3, 7.3, 1.6 Hz), 6.80 (1H, dd, J¼8.3, 1.3 Hz), 6.67 (1H, app td,
J¼7.5, 1.3 Hz), 4.39 (1H, app sex, J¼6.1 Hz), 1.80 (1H, dddd, J¼13.6,
10.3, 6.5, 5.2 Hz), 1.62 (1H, ddt, J¼13.6, 10.5, 5.3 Hz), 1.52e1.36 (2H,
m), 1.34 (3H, d, J¼6.1 Hz), 1.32e1.26 (6H, m), 0.88 (3H, t, J¼6.9 Hz);
13C NMR (125 MHz, CDCl3):
d 157.1, 139.7, 129.4, 122.3, 113.9, 88.4,
20
75.9, 36.6, 31.9, 29.4, 25.6, 22.7, 19.9, 14.2; [
a
]
ꢀ39.3 (c 0.72 in
D
CH2Cl2); HRMS (ESI): calcd for C14H21INaO ([MþNa]þ): 355.0529,
residual peak of CDCl3 (1H NMR
d
7.26, 13C NMR
d
77.16) or DMSO-d6
found 355.0543.
(1H NMR
d
2.50) with integration, multiplicity (s¼singlet,
d¼doublet, t¼triplet, q¼quartet, sex¼sextet, m¼multiplet,
app¼apparent) and coupling constants (Hz). Chiral GC was run on
a Varian 3800 Gas Chromatograph equipped with a CP-Chiralsil-
3.2.4. (S)-(2-(Octan-2-yloxy)phenyl)(phenyl)-iodonium
tetra-
fluoroborate (8). Iodoarene 7 (50 mg, 0.15 mmol) was pre-oxidized
during 40 min with mCPBA (35.7 mg, 0.17 mmol) in CH2Cl2 (1 mL)
at 80 ꢁC. Phenylboronic acid (20.7 mg, 0.17 mmol) and BF3$OEt2
Dex-CB (25 mꢂ0.32 mmꢂ0.25
mm) column. Chiral HPLC was run on
HPLC Waters 2695 with an auto sampler, UV detection at 230 nm,
(47 mL, 0.38 mmol) were dissolved in CH2Cl2 (1 mL) and added to
Chiralcel OB (0.46 cm i.d.ꢂ25 cm).
the reaction at ꢀ78 ꢁC. The reaction was stirred at ꢀ78 ꢁC for
30 min and then brought to room temperature and applied to
a silica plug. Elution with a CH2Cl2/MeOH gradient gave 8 (12.9 mg,
3.2. Synthesis of monosubstituted target I
17%) as an oil. 1H NMR (400 MHz, DMSO-d6):
d
8.29 (1H, dd, J¼7.9,
3.2.1. (R)-2-Octanol ((R)-4). Prepared by kinetic resolution of rac-4
following a modified literature procedure.30 To a flame dried
250 mL round bottom flask was loaded racemic 2-octanol
(12.21 mL, 76.79 mmol), isopropenyl acetate (10.0 mL, 92.14 mmol),
Na2CO3 (1.59 g, 15.0 mmol), and i-Pr2O (120 mL). The flask was
purged with argon and CALB (300 mg) was added. The reaction was
monitored by GC and when >50% of the starting material was
consumed the reaction was stopped by filtering the crude reaction
mixture through a silica plug. H2O (15 mL) was added to the filtrate,
which was extracted with ether (3ꢂ10 mL). The combined organic
phases were washed with H2O (3ꢂ10 mL) and brine (3ꢂ10 mL),
dried with MgSO4, and concentrated under reduced pressure. The
crude material was purified by flash chromatography (pentane/
Et2O, 20:1) to give (R)-4 (4.20 g, 42%, >99% ee) as a clear liquid. The
enantiomeric excess was analyzed by chiral GC on the corre-
sponding acetylated compound, using a gradient from 70 to 86 ꢁC
over 9 min. Analytical data were in agreement with the literature.38
1.6 Hz), 8.02 (2H, m), 7.62 (1H, tt, J¼7.4, 1.1 Hz), 7.61 (1H, ddd, J¼8.8,
7.4, 1.6 Hz), 7.49 (2H, m), 7.29 (1H, dd, J¼8.8, 1.2 Hz), 7.06 (1H, ddd,
J¼7.9, 7.4, 1.2 Hz), 4.67 (1H, app sex, J¼6.0 Hz), 1.65 (1H, m), 1.54
(1H, m), 1.32e1.17 (8H, m), 1.15 (3H, d, J¼6.0 Hz), 0.86 (3H, t,
J¼7.0 Hz).
3.2.5. (S,S)-(2-(Octan-2-yloxy)phenyl)(3-iodo-[4-(octan-2-yloxy])
phenyl)iodonium tetrafluoroborate (9). Formed as a byproduct in
the synthesis of iodonium salt 8, isolated by flash chromatography
(CH2Cl2/MeOH 100:0/100:1) in 9% as a yellow oil. 1H NMR
(400 MHz, CDCl3):
d
8.25 (1H, d, J¼2.4 Hz), 8.03 (1H, dd, J¼9.0,
2.4 Hz), 7.76 (2H, dd, J¼8.4, 1.5 Hz), 7.56 (1H, ddd, J¼8.2, 7.4, 1.5 Hz),
7.02 (2H, m), 6.83 (1H, d, J¼9.4 Hz), 4.56 (1H,app sex, J¼6.1 Hz), 4.45
(1H, app sex, J¼6.1 Hz), 1.87e1.74 (2H, m), 1.71e1.58 (2H, m),
1.50e1.29 (16H, m), 1.36 (3H, d, J¼6.1 Hz), 1.35 (6H, d, J¼6.1 Hz),
0.89 (3H, t, J¼6.9 Hz); 0.87 (3H, t, J¼6.9 Hz); 13C NMR (100 MHz,
CDCl3):
d 160.9, 155.2, 145.8, 138.1, 135.7, 135.0, 124.1, 115.6, 114.3,
103.9, 98.2, 90.5, 76.9, 70.7, 36.3, 36.1, 31.8, 29.3, 29.3, 25.6, 25.4,
3.2.2. (R)-Octan-2-yl methanesulfonate ((R)-6). To a solution of (R)-
4 (5.0 mL, 31.79 mmol) and Et3N (1.6 mL, 11.5 mmol) in CH2Cl2
(40 mL) at ꢃꢀ5 ꢁC was added MsCl (0.65 mL, 8.5 mmol) drop-wise
while maintaining a temperature below 0 ꢁC. The reaction was
stirred at room temperature for an additional 20 min and then
quenched by addition of H2O. The water phase was extracted with
Et2O (3ꢂ20 mL) and the combined organic phases were washed
22.7, 22.7,19.6,19.5,14.2; [
a
]
20 þ52.0 (c 0.10 in CH2Cl2); HRMS (ESI):
D
calcd for C28H41I2O2 ([MꢀBF4]þ): 663.1190, found 663.1160.
3.2.6. (E)-[2-[(Trifluoromethanesulfonyl)oxy]-L-heptenyl](phenyl)-
iodonium triflate (10). To a solution of (diacetoxyiodo)benzene
(2.30 g, 7.28 mmol) in CH2Cl2 (10 mL) was added TfOH (1.30 mL,
14.56 mmol) at 0 ꢁC. The mixture was allowed to reach rt and

N. Jalalian, B. Olofsson / Tetrahedron 66 (2010) 5793e5800
5799
stirred for 2 h. Then 1-heptyne (0.68 mL, 5.20 mmol) was added
drop-wise at 0 ꢁC, and the reaction was stirred at rt for another 2 h.
The solvent was evaporated under reduced pressure to yield dark
solids. Ether was added to cause precipitation and the resulting
solid was filtered, washed with ether, and dried in vacuo to give 10
(2.55 mg, 56%) as a white solid. Mp 126e128 ꢁC; 1H NMR (500 MHz,
m), 1.36e1.25 (12H, m), 1.34 (6H, dd, J¼6.1, 0.6 Hz), 0.88 (6H, t,
J¼6.9 Hz); 13C NMR (100 MHz, CDCl3):
d 158.7, 129.3, 106.4, 82.3,
75.9, 36.6, 31.9, 29.4, 25.6, 22.7, 20.0, 14.2; HRMS (ESI): calcd for
C44H74I2O4 ([2MþNa]þ): 943.3569, found 943.3585.
3.3.3. 2-Bromo-1,3-bis(octan-2-yloxy)benzene (14). To a suspension
of anhydrous K2CO3 (2.70 g, 19.6 mmol) in anhydrous MeCN
(15 mL) was added 2-bromobenzene-1,3-diol33 (1.00 g, 5.30 mmol)
and tosylate 12 (3.30 g, 11.6 mmol) and the reaction was refluxed
for 18 h. The solvent was concentrated under reduced pressure and
H2O was added to the crude product. The crude mixture was
extracted with CH2Cl2 (3ꢂ15 mL), washed with brine (3ꢂ15 mL),
dried with Na2CO3, filtered, and concentrated under reduced
pressure. The crude product was purified by column chromatog-
raphy (pentane/Et2O, 25:1) to give compound 14 (527 mg, 24%) as
CDCl3):
d
7.97 (2H, dd, J¼8.4, 1.0 Hz), 7.64 (1H, tt, J¼7.5, 1.0 Hz), 7.49
(2H, dd, J¼8.4, 7.5 Hz), 7.11 (1H, s), 2.79 (2H, t, J¼7.7 Hz), 1.53 (2H,
m) 1.28 (4H, m), 0.86 (3H, t, J¼6.9 Hz); 13C NMR (100 MHz, CDCl3):
d
162.7, 134.9, 132.7, 132.4, 120.0 (CF3, q, J¼319 Hz), 118.4 (CF3, q,
J¼320 Hz), 114.0, 92.8, 34.9, 31.0, 25.8, 22.3, 13.8; HRMS (ESI): calcd
for C14H17F3IO3S ([MꢀOTf]þ): 448.9890, found 448.9888.
3.2.7. (S)-(2-(Octan-2-yloxy)phenyl)(phenyl) iodonium triflate (11).
Iodoarene 7 (100 mg, 0.31 mmol) was dissolved in anhydrous Et2O
(1.25 mL) and cooled to ꢀ78 ꢁC before addition of n-BuLi (1.6 M,
a yellow oil. 1H NMR (500 MHz, CDCl3):
d
7.13 (1H, t, J¼8.3 Hz), 6.52
194
mL, 0.31 mmol). The mixture was stirred for 1 h at rt, cooled
(2H, d, J¼8.3 Hz), 4.37 (2H, app sex, J¼6.1 Hz), 1.80 (2H, dddd,
J¼13.5, 10.3, 6.5, 5.2 Hz), 1.61 (2H, ddt, J¼13.5, 10.5, 5.3 Hz),
1.51e1.37 (4H, m), 1.33 (6H, d, J¼6.1 Hz), 1.32e1.26 (12H, m), 0.88
again to ꢀ78 ꢁC and vinyliodonium salt 10 (169 mg, 0.26 mmol)
was added from a solid addition tube. The mixture was stirred for
2 h 40 min at ꢀ78 ꢁC and was then allowed to reach rt over 2 h. The
crude mixture was evaporated under reduced pressure and purified
by column chromatography (CH2Cl2/MeOH 100:0/100:1) to give
11 (55 mg, 38%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3):
(6H, t, J¼6.9 Hz); 13C NMR (125 MHz, CDCl3):
d 156.5, 127.8, 107.5,
105.0, 76.0, 36.6, 31.9, 29.4, 25.6, 22.7, 20.0, 14.2; HRMS (ESI): calcd
for C22H37BrNaO2 ([MþNa]þ): 435.1869, found 435.1884.
d
7.93 (2H, dd, J¼8.5, 1.1 Hz), 7.75 (1H, dd, J¼8.0, 1.5 Hz), 7.61 (1H, tt,
3.3.4. (2,6-Bis(octan-2-yloxy)phenyl)boronic acid (15). Anhydrous
THF (4 mL) was added to a round bottom flask containing 14
(200 mg, 0.48 mmol) under argon. The solution was cooled to
ꢀ78 ꢁC and n-BuLi (0.6 M, 0.90 mL, 0.54 mmol) was added drop-
wise. The reaction was brought to rt and stirred for 1 h followed by
J¼7.5, 1.3 Hz), 7.56 (1H, ddd, J¼8.5, 7.4, 1.5 Hz), 7.45 (2H, m), 7.01
(2H, m), 4.52 (1H, app sex, J¼6.1 Hz), 1.72 (1H, m), 1.56 (1H, m),
1.34e1.24 (8H, m), 1.25 (3H, d, J¼6.1 Hz), 0.87 (3H, t, J¼6.9 Hz); 13C
NMR (125 MHz, CDCl3):
d 155.3, 136.2, 135.4, 135.1, 132.6, 132.3,
123.9, 120.4 (CF3, q, J¼320 Hz), 114.3, 112.1, 103.7, 77.1, 36.0, 31.8,
addition of B(OiPr)3 (391
m
L, 1.70 mmol) at ꢀ78 ꢁC. After another
20
29.2, 25.5, 22.7, 19.4, 14.1; [
a
]
ꢀ10.3 (c 0.32 in CH2Cl2); HRMS
16 h, the reaction was quenched by addition of 1 M HCl (aq) (10 mL)
and the mixture was refluxed for 18 h. The organic phase was
separated and H2O phase was extracted with ether (3ꢂ10 mL). The
combined organic phases were washed with brine (1ꢂ50 mL),
dried with MgSO4, and concentrated under reduced pressure to
afford 15 (195 mg, >99%) as a slightly yellow oil, which was used
D
(ESI): calcd for C20H26IO ([MꢀOTf]þ): 409.1023, found 409.1042.
3.3. Synthesis of disubstituted target II
3.3.1. Octan-2-yl toluenesulfonate (12). To a solution of racemic 2-
octanol (5.00 mL, 31.8 mmol) and DMAP (200 mg, 0.05 mmol) in
pyridine (20 mL) at ꢀ5 ꢁC was added TsCl (6.00 g, 31.5 mmol)
portion-wise so that the temperature was kept below 0 ꢁC. This
temperature was kept for 1 h, and then the reaction was left to stir
at rt for 24 h. The precipitate was filtered off and the filtrate was
pored into ice-diluted HCl (40 mL, 4 M) and stirred for 20 min. The
organic phase was separated and the water phase was extracted
with Et2O (3ꢂ40 mL). The combined organic phases were washed
H2O (3ꢂ20 mL), 10% aq HCl (3ꢂ20 mL), brine (3ꢂ20 mL), and dried
(MgSO4), and concentrated in vacuo to give 12 (6.24 g, 94%) as
a colorless oil, that was used without further purification. 1H NMR
without further purification. 1H NMR (400 MHz, CDCl3):
d 7.51 (2H,
s), 7.31 (1H, t, J¼8.4 Hz), 6.56 (2H, d, J¼8.4 Hz), 4.51 (2H, app sex,
J¼6.1 Hz), 1.87e1.78 (2H, m) 1.71e1.61 (2H, m), 1.51e1.40 (4H, m),
1.37 (6H, d, J¼6.1 Hz), 1.36e1.25 (12H, m), 0.80 (6H, t, J¼6.9 Hz); 13C
NMR (100 MHz, CDCl3):
d 164.5, 132.8, 106.4, 75.7, 36.7, 31.9, 29.4,
25.7, 22.8, 20.0, 14.3; HRMS (ESI): calcd for C22H39BNaO4
([MþNa]þ): 401.2834, found 401.2856.
3.3.5. 2,6-Bis(octan-2-yloxy)phenyl(phenyl)iodonium triflate (16).
Prepared from iodoarene 13 and vinyliodonium salt 10 as described
for 11. The crude product was purified by column chromatography
(CH2Cl2/MeOH 100:0/100:1) to give 16 (60 mg, 44%) as a light
brown oil. Two diastereomers of 16 were observed in NMR; (R,S/S,
R) as major and (R,R/S,S) as minor, see Table 1; HRMS (ESI): calcd for
C28H42IO2 ([MꢀOTf]þ): 537.2224, found 537.2230.
(400 MHz, CDCl3):
d
7.78 (2H, dt, J¼8.3, 1.7 Hz), 7.32 (2H, m), 4.59
(1H, dqd, J¼7.1, 6.3, 5.5 Hz), 2.43 (3H, s), 1.64e1.54 (1H, m),
1.50e1.40 (1H, m), 1.25 (3H, d, J¼6.3 Hz), 1.25e1.10 (8H, m), 0.85
(3H, t, J¼7.1 Hz); 13C NMR (100 MHz, CDCl3):
d 144.5, 134.7, 129.8,
127.8, 80.8, 36.6, 31.7, 28.9, 24.9, 22.6, 21.7, 21.0, 14.1; HRMS (ESI):
calcd for C30H48NaO6S2 ([2MþNa]þ): 591.2785, found 591.2804.
3.3.6. (S,S)-(2-Bromo-1,3-bis(octan-2-yloxy)-benzene
(17)). Pre-
pared from 2-bromobenzene-1,3-diol and (R)-6 as described for 7,
3.3.2. 2-Iodo-1,3-bis(octan-2-yloxy)benzene (13). To a solution of
obtained in 89% yield as a pale yellow oil. 1H NMR (400 MHz,
PPh3 (233 mg, 0.89 mmol), 2-iodobenzene-1,3- diol32 (100 mg,
CDCl3):
d
7.13 (1H, t, J¼8.3 Hz), 6.51 (2H, d, J¼8.3 Hz), 4.37 (2H, app
0.42 mmol), 2-octanol (141
0.89 mmol) in anhydrous THF (2 mL) at 0 ꢁC was added DIAD
(175 L, 0.89 mmol). The reaction was left to stir at room temper-
ature during 2 h and quenched with 5% HCl. The reaction was
extracted with ether (3ꢂ5 mL), dried with MgSO4, filtrated, and the
solvent was evaporated at reduced pressure. The crude material
was purified by column chromatography (pentane/EtOAc 250:1) to
afford compound 13 (64 mg, 33%) as a colorless oil. 1H NMR
(500 MHz, CDCl3):
4.38 (2H, app sex, J¼6.1 Hz), 1.80 (2H, dddd, J¼13.5, 10.4, 6.5,
5.2 Hz), 1.62 (2H, ddt, J¼13.5, 10.8, 5.5 Hz), 1.49 (2H, m), 1.40 (2H,
mL, 0.89 mmol), and Et3N (124
mL,
sex, J¼6.1 Hz),1.80 (2H, dddd, J¼13.5, 10.1, 6.5, 5.2 Hz),1.61 (2H, ddt,
J¼13.5, 10.1, 5.5 Hz), 1.51e1.37 (4H, m), 1.36e1.24 (12H, m), 1.33 (6H,
d, J¼6.1 Hz), 0.88 (6H, t, J¼6.9 Hz); 13C NMR (100 MHz, CDCl3):
m
d 156.4,127.7,107.5,104.9, 76.0, 36.6, 31.9, 29.4, 25.6, 22.7, 20.0,14.2;
[a
]
20 ꢀ54.1 (c 0.29 in CH2Cl2); HRMS (ESI): calcd for C22H37BrNaO2
D
([MþNa]þ): 435.1869, found 435.1870.
3.3.7. (S,S)-(2,6-Bis(octan-2-yloxy)phenyl)(phenyl)iodonium triflate
(18). Prepared from bromoarene 17 and vinyliodonium salt 10 as
described for 11. The crude product was purified by column chro-
matography (CH2Cl2/MeOH 100:0/100:1) to give 18 (50.0 mg,
d
7.16 (1H, t, J¼8.2 Hz), 6.42 (2H, d, J¼8.2 Hz),

5800
N. Jalalian, B. Olofsson / Tetrahedron 66 (2010) 5793e5800
36%) as a light orange oil. NMR data: see Table 1; [
a]
20 ꢀ39.2 (c 0.12
J¼7.3, 1.0 Hz), 6.90 (2H, m), 4.35 (1H, app sex, J¼6.1 Hz), 1.74 (1H,
m), 1.57 (1H, m), 1.50e1.36 (2H, m), 1.35e1.25 (6H, m), 1.30 (3H, d,
D
in CH2Cl2); HRMS (ESI): calcd for C28H42IO2 ([MꢀOTf]þ): 537.2224,
found 537.2220.
J¼6.1 Hz), 0.87 (3H, t, J¼6.9 Hz); 13C NMR (125 MHz, CDCl3):
d 158.4,
20
129.6, 120.5, 116.0, 74.0, 36.7, 32.0, 29.5, 25.7, 22.8, 19.9, 14.2; [a]
D
3.4. Synthesis of trisubstituted target III
þ19.1 (c 0.47 in CH2Cl2); HRMS (ESI): calcd for C28H45O2
([2MþH]þ): 413.3414, found 413.3310.
3.4.1. 1,3,5-Tris(octan-2-yloxy)benzene (19). To
a suspension of
K2CO3 (0.96 g, 6.97 mmol) in MeCN (3 mL) was added 1,3,5-trihy-
droxybenzene (0.18 g, 1.40 mmol) and (rac)-6 (1.45 g, 6.97 mmol)
and the reactionwas refluxed for 18 h. H2O (10 mL) was added to the
reaction mixture and extracted with Et2O (3ꢂ20 mL). The combined
organic phases were washed with brine (1ꢂ20 mL), dried with
MgSO4, filtered, and concentrated under reduced pressure. The
crude product was purified by flash chromatography (pentane/
EtOAc 100:0/100:1) to give 19 (0.46 g, 72%) as an orange oil. 1H
Acknowledgements
This work was financially supported by the Swedish Research
Council, the Royal Swedish Academy of Sciences and K & A Wal-
lenberg Foundation.
Supplementary data
1H and 13C NMRs of all reported compounds are available.
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2010.05.004. These data include
MOL files and InChIKeys of the most important compounds
described in this article.
NMR (500 MHz, CDCl3)
d
6.04 (3H, s), 4.30 (3H, app sex, J¼6.1 Hz),
1.73 (3H, m), 1.54 (3H, m),1.48e1.24 (24H, m), 1.29 (9H, d, J¼6.1 Hz),
0.89 (9H, t, J¼6.9 Hz); 13C NMR (125 MHz, CDCl3):
d 160.23, 96.21,
73.92, 36.71, 31.96, 29.43, 25.71, 22.75, 19.98, 14.20; HRMS (ESI):
calcd for C30H54NaO3 ([MþNa]þ): 485.3965, found 485.5998.
3.4.2. 2,4,6-Tris(octan-2-yloxy)phenyl(phenyl)iodonium
tosylate
References and notes
(20). Arene rac-14 (150 mg, 0.32 mmol) was dissolved in CH2Cl2
(1 mL) and the reaction mixture was cooled to ꢀ10 ꢁC. PhI(OH)OTs
(127 mg, 0.32 mmol) was added in one portion and the reaction
was stirred at room temperature for 21 h. The reaction mixture was
applied to a silica column and purified by flash chromatography
(CH2Cl2/MeOH 100:0/10:1) to give 20 (256 mg, 96%) as a dark
orange oil. Two diastereomers of 20 were observed in NMR; (R,S,R/
S,R,S) and (R,R,S/S,S,R). Furthermore, different NMR signals were
observed in a 2:1 ratio for the o- and p-substituents, see Table 1;
HRMS (ESI): calcd for C36H58IO3 ([MꢀOTs]þ): 665.3425, found
665.3435.
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sion of NaH (83 mg, 1.98 mmol) in anhydrous NMP (2 mL) was
added (R)-4 (0.24 mL, 1.51 mmol) drop-wise at 0 ꢁC and the re-
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17. See Hirt, U. H.; Schuster, M. F. H.; French, A. N.; Wiest, O. G.; Wirth, T. Eur. J. Org.
Chem. 2001, 1569e1579 and references cited therein.
18. Quideau, S.; Lyvinec, G.; Marguerit, M.; Bathany, K.; Ozanne-Beaudenon, A.;
Buffeteau, T.; Cavagnat, D.; Chénedé, A. Angew. Chem., Int. Ed. 2009, 48,
4605e4609.
19. 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, 5315e5328.
action was left to stir for 15 min. 1,3,5-Trifluorobenzene (39 mL,
0.38 mmol) was added to the mixture and the reaction was refluxed
at 100 ꢁC during 17 h. The reaction was quenched by addition of
satd NH4Cl, after cooling to room temperature. The organic phase
was separated and the water phase was extracted with Et2O
(3ꢂ10 mL). The combined organic phases were washed with H2O
(1ꢂ20 mL) and brine (1ꢂ20 mL), dried with MgSO4, and concen-
trated under reduced pressure. The crude material was purified by
flash chromatography (pentane/Et2O, 500:1/200:1) to give 21
20. Dohi, T.; Maruyama, A.; Takenaga, N.; Senami, K.; Minamitsuji, Y.; Fujioka, H.;
Caemmerer, S. B.; Kita, Y. Angew. Chem., Int. Ed. 2008, 47, 3787e3790.
21. Uyanik, M.; Yasui, T.; Ishihara, K. Angew. Chem., Int. Ed. 2010, 49, 2175e2177.
22. Oh, C. H.; Kim, J. S.; Jung, H. H. J. Org. Chem. 1999, 64, 1338e1340.
23. Lancer, K. M.; Wiegand, G. H. J. Org. Chem. 1976, 41, 3360e3364.
24. Bielawski, M.; Zhu, M.; Olofsson, B. Adv. Synth. Catal. 2007, 349, 2610e2618.
25. Bielawski, M.; Olofsson, B. Chem. Commun. 2007, 2521e2523.
26. Bielawski, M.; Olofsson, B. Org. Synth. 2009, 86, 308e314.
27. Zhu, M.; Jalalian, N.; Olofsson, B. Synlett 2008, 592e596.
28. Bielawski, M.; Aili, D.; Olofsson, B. J. Org. Chem. 2008, 73, 4602e4607.
29. Merritt, E. A.; Malmgren, J.; Klinke, F. J.; Olofsson, B. Synlett 2009, 2277e2280.
(89 mg, 51%) as a dark orange oil. 1H NMR (400 MHz, CDCl3)
d 6.03
(3H, s), 4.29 (3H, app sex, J¼6.1 Hz), 1.72 (3H, m), 1.54 (3H, m),
1.47e1.25 (24H, m), 1.28 (9H, d, J¼6.1 Hz), 0.89 (9H, t, J¼6.9 Hz); 13C
NMR (100 MHz, CDCl3):
d 160.20, 96.11, 73.90, 36.69, 31.95, 29.43,
20
25.71, 22.75, 19.99, 14.22; [
a
]
þ25.6 (c 1.87 in CH2Cl2); HRMS
D
(ESI): calcd for C30H54NaO3 ([MþNa]þ): 485.3965, found 485.5997.
3.4.4. (R,R,R)-(2,4,6-Tris(octan-2-yloxy)phenyl)(phenyl)iodonium to-
sylate (22). Prepared from (R,R,R)-14 as described for rac-15,
obtained in 82% yield as a dark orange oil. Different NMR signals
€
30. Martin-Matute, B.; Edin, M.; Bogar, K.; Kaynak, F. B.; Backvall, J.-E. J. Am. Chem.
Soc. 2005, 127, 8817e8825.
31. Kitamura, T.; Kotani, M.; Fujiwara, Y. Tetrahedron Lett. 1996, 37, 3721e3722.
32. Tsujiyama, S.-i.; Suzuki, K. Org. Synth. 2007, 84, 272e284.
33. Lüning, U.; Abbass, M.; Fahrenkrug, F. Eur. J. Org. Chem. 2002, 2002, 3294e3303.
34. Carroll, M. A.; Pike, V. W.; Widdowson, D. A. Tetrahedron Lett. 2000, 41,
5393e5396.
were observed in a 2:1 ratio for the o- and p-substituents, see Table
20
1. [
a
]
þ37.6 (c 0.78 in CH2Cl2); HRMS (ESI): calcd for C36H58IO3
([MꢀDOTs]þ): 665.3425, found 665.3446.
35. Dohi, T.; Ito, M.; Morimoto, K.; Minamitsuji, Y.; Takenaga, N.; Kita, Y. Chem.
Commun. 2007, 4152e4154.
3.4.5. (R)-(Octan-2-yloxy)benzene (23). Prepared from fluo-
robenzene and (R)-4 as described for arene 21. The reaction was
stopped after 18 h, before complete conversion had been obtained,
to give arene 23 (89 mg, 51%) as a pale yellow oil. 1H NMR
36. Kim, A.; Powers, J. D.; Toczko, J. F. J. Org. Chem. 2006, 71, 2170e2172.
37. Vogel, A. I.; Furniss, B. S.; Hannaford, A. J.; Rogers, V.; Smith, P. W. G.; Tatchell,
A. R. Vogel’s Textbook of Practical Organic Chemistry; Prentice Hall: USA, 1978; p
1280.
38. Berkessel, A.; Sebastian-Ibarz, M. L.; Müller, T. N. Angew. Chem., Int. Ed. 2006, 45,
6567e6570.
(500 MHz, CDCl3):
d
7.27 (2H, ddt, J¼8.7, 7.3, 1.3 Hz), 6.92 (1H, tt,