New hypervalent iodine reagents for electrophilic trifluoromethylation and their precursors: Synthesis, structure, and reactivity

Article abstract of DOI:10.1016/j.tet.2010.04.125

Several new five- and a six-membered heterocyclic monochloroiodanes, including two cationic species, were synthesized. Three of which were used for the preparation of corresponding trifluoromethylation reagents. These compounds were characterized by X-ray crystallography for a comparative structural study. A reactivity study on the trifluoromethylation of para-toluenesulfonic acid has been conducted in order to compare initial rates. Compounds having a longer I-O bond display a higher reactivity.

Full text of DOI:10.1016/j.tet.2010.04.125

Tetrahedron 66 (2010) 5753e5761
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
New hypervalent iodine reagents for electrophilic trifluoromethylation and
their precursors: synthesis, structure, and reactivity
ꢀ
Katrin Niedermann, Jan M. Welch, Raffael Koller, Ján Cvengros, Nico Santschi, Philip Battaglia,
*
Antonio Togni
Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology, ETH Zurich, 8093 Zürich, Switzerland
a r t i c l e i n f o
a b s t r a c t
Article history:
Several new five- and a six-membered heterocyclic monochloroiodanes, including two cationic species,
were synthesized. Three of which were used for the preparation of corresponding trifluoromethylation
reagents. These compounds were characterized by X-ray crystallography for a comparative structural
study. A reactivity study on the trifluoromethylation of para-toluenesulfonic acid has been conducted in
order to compare initial rates. Compounds having a longer IeO bond display a higher reactivity.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 31 March 2010
Received in revised form 28 April 2010
Accepted 29 April 2010
Available online 6 May 2010
Keywords:
Trifluoromethylation
Hypervalent iodine
X-ray analysis
Reactivity study
Monochloroiodane
1. Introduction
During our attempts to prepare hypervalent I-trifluoromethyl
compounds we found that acyclic starting materials such as
The first report of an organic hypervalent iodine compound by
Willgerodt, (dichloro-
3-iodo)benzene,1 inspired the synthesis of
(difluoroiodo)toluene could not be transformed to the desired
product, probably because the corresponding trifluoromethyl
compounds are not stable, as indicated by the formation of CF3I.
This finding is consistent with the fact that cyclic iodanes have
a considerably higher stability than their acyclic analogues.9 This
stabilization is usually explained by the bridging of an apical and an
equatorial position by a five-membered ring and by better overlap
of the lone pair electrons on the iodine atom with the aromatic
system of the benzene ring.10 There are several classes of hetero-
cyclic iodane compounds known, the majority of which are de-
rivatives of a five-membered ring benziodoxole 2c. In Figure 1 some
examples of heterocyclic five- or six-membered rings are repre-
sented by benziodazoles 5a/b, benziodathiazoles 6, benziodox-
athioles 7, cyclic phosphonates/phosphinate 8, and a phosphate 9.11
Monochloroiodanes such as 2a and 2b are useful intermediates
for the synthesis of the electrophilic trifluoromethylation reagents
1aec. To the best of our knowledge the X-ray crystal structures of
only four monochloroiodanes (2b,122c,12e145a,14,15 and 5b16) have
been published so far. The synthesis of 2a was published in 1979 by
Martin.17 However, no X-ray analysis was reported. Since we were
interested in modifying our already existing trifluoromethylation
reagents 1aec to enhance their reactivity and selectivity, we pre-
pared and characterized a variety of new monochlorides, including
six-membered heterocycles and cationic derivatives, as precursors
for new trifluoromethylating reagents. Although it is possible to
l
a plethora of new hypervalent iodine compounds. These com-
pounds find widespread applications in organic synthesis such as in
CeC, C-heteroatom, and heteroatomeheteroatom bond formation,
oxidation, fragmentation, and rearrangement reactions.2 In 2006,
we published the syntheses of the new hypervalent iodine com-
pounds 1aec3 (Scheme 1) reagents for electrophilic tri-
fluoromethylation, showing remarkable reactivity toward several
nucleophiles such as thiols,4 activated methylene compounds,4
aromatic compounds,5 sulfonic acids,6 alcohols,7 and phosphines.8
These compounds are synthesized in three steps: Oxidation of
the appropriate 2-substituted iodobenzene to the cyclic iodine
compounds 2aec, ligand exchange to the corresponding acetoxy
compounds 3aec and in the last step an umpolung reaction using
the nucleophilic Ruppert/Prakash reagent with a catalytic amount
of fluoride to form the electrophilic trifluoromethylation reagents
1aec. Upon electrophilic trifluoromethylation of various substrates
the reagents are converted to the respective starting materials
4aec, which may be isolated and reused as recyclable CF3-carriers.
* Corresponding author. Tel.: þ41 44 632 2236; fax: þ41 44 632 1310; e-mail
address: atogni@ethz.ch (A. Togni).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.04.125

5754
K. Niedermann et al. / Tetrahedron 66 (2010) 5753e5761
Scheme 1. Synthetic cycle of trifluoromethylation reagents 1aeb.
synthesis of alcohols 10 and 11. However, under the same condi-
tions alcohol 12 did not form and could only be obtained in the
absence of CeCl3 in low yield. Alcohol 13 was prepared according to
a slightly modified procedure described by Yamataka,18 and 14 was
synthesized in a similar manner. Alcohols 10e14 were oxidized to
the corresponding monochloroiodanes 16e20 under standard
t
conditions using BuOCl as oxidant in CH2Cl2. Alcohol 15 was syn-
thesized in two steps from the known ester 21, which was obtained
by a five-step procedure as described by Tanida and Irie.21 The
conversion of ester 21 to alcohol 22 by twofold Grignard addition
was achieved in good yield using a slight excess of methyl Grignard
at reflux temperature. In the next step, alcohol 22 was iodinated by
directed ortho-lithation with sBuLi/TMEDA in n-hexane at reflux
temperature followed by the addition of 1,2-diiodoethane. Com-
pound 15 was oxidized under similar conditions as described above
to the six-membered cyclic monochloroidane 23 (Scheme 3).
Figure 1. Examples of heterocyclic iodanes less common than benziodoxoles.
convert several neutral monochloroiodanes to the corresponding
CF3-compounds, including a six-membered heterocyclic derivative,
following the synthetic procedure shown in Scheme 1, the
attempted synthesis of corresponding cationic species was
unsuccessful.
2. Synthesis
2.1. Synthesis of monochloroiodanes
Starting from alcohols 10e14 and 15 the corresponding neutral
chlorides were prepared upon oxidation using tBuOCl (Scheme 2).
Recently, we reported a concise synthesis of 2-iodobenzyl al-
cohols via the addition of 2-iodophenyl Grignard reagents to ke-
tones in the presence of CeCl3.20 This method was applied to the
Scheme 3. Synthesis of six-membered cyclic iodane 23.
Scheme 4 shows the synthesis of oxazolidine 24 and 2-(2-
iodophenyl)pyridine (25). Oxazolidine 24 was synthesized in two
steps from 2-iodobenzoic acid chloride (26) in 41% overall yield. In
the first step acid chloride 26 was reacted with 2-amino-2-methyl-
propanol in a mixture of 1,4-dioxane and aq NaHCO3 to form amide
27, which was cyclized to form oxazolidine 24. The pyridine de-
rivative 25 was synthesized in 2 steps starting from 2-phenyl-
pyridine (28) in 58% yield. Intermediate 29 was prepared by
a slightly modified procedure published by Sanford et al.22 Com-
pound 25 was accessed by halide exchange.
Scheme 4. Synthesis of oxazoline 24 and 2-(iodophenyl)pyridine (25).
Scheme 2. Synthesis of neutral five-membered heterocyclic monochloroiodanes. (a)
synthesized without the addition of CeCl3; (b) synthesized according to a reported
procedure;18 (c) 14 was not isolated in pure form but directly converted to 20 in 44%
yield over two steps; (d) synthesized according to a reported procedure.19
Precursors 24 and 25 were protonated using HBF4 prior to oxi-
dation with tBuOCl to yield the cationic 1-chloro- 3-iodanes 30 and
l
31 in good yields (Scheme 5).

K. Niedermann et al. / Tetrahedron 66 (2010) 5753e5761
5755
3. Solid-state structural analyses
3.1. The chloriodanes
Crystals suitable for X-ray measurements of compound 2a
were obtained by slow evaporation of a dichloromethane solution.
Compounds 16e18, 20, and 23 were crystallized from CH2Cl2 by
diffusion of pentane or Et2O into a saturated solution. Under these
conditions, 19 crystallizes in the space group P-1 incorporating
a solvent molecule; using EtOAc instead of CH2Cl2 leads to crys-
tallization in P21/c. Table 2 summarizes the important bond
lengths, bond, and torsion angles for all oxygen-bonded mono-
chloroiodanes (2aec, 16e20, and 23). The crystal structures of all
monochloroiodanes clearly show a distorted T-shaped geometry
around iodine, typical for members of the hypervalent iodine(III)
class. In all five-membered heterocycles the CleIeO angles are
significantly smaller than 180ꢀ due to the repulsion of the two
lone pairs at iodine as predicted by the VSEPR model. The OeIeC
(1)eC(6) torsion angle of ꢁ17.17(15)ꢀ in compound 20 indicates
that the five-membered heterocyclic unit displays an envelope-
type conformation with the oxygen atom lying outside the plane
defined by the phenyl ring. As summarized in Table 1 and illus-
trated in Figure 2, this angle flattens in the series
20e19e17e2ae16e18e2b/c, such that compound 2c shows al-
most perfect coplanarity with the adjacent phenyl ring (torsion
angle 1.8ꢀ).
Scheme 5. Synthesis of cationic 1-chloro-l
3-iodane 30 and 31.
2.2. Synthesis of hypervalent trifluoromethyl compounds
As shown in Scheme 1, the trifluoromethylated compounds
1aec were obtained from the corresponding iodanes 2aec by
a procedure involving two consecutive ‘ligand exchange’ processes.
The acetoxy derivatives 3aec are formed as intermediates and react
with TMSCF3 as the nucleophilic CF3-source in the presence of
a catalytic amount of a fluoride to the trifluoromethylating reagents
1aec. The new CF3-iodanes 32, 33, and 34 were thus prepared from
the corresponding monochloroiodanes 16, 19, and 23 following this
procedure. The yield of the crucial final step is highly dependent on
the structure of the intermediate acetoxy derivative. Thus, com-
pound 34, the only six-membered iodacycle, could only be obtained
in 14% yield (Table 1).
The CleI bond lengths lie between 2.438(2) and 2.5751(13) Ǻ
and increase in the series 2b/ce16e18e2a/19e17e20, while the
IeO bond length (2.110(5) to 2.0169(14) Ǻ) decreases. These find-
ings can mainly be ascribed to electronic effects derived from the
substituents. The fine ordering is probably due to packing effects
and remote intermolecular contacts in the solid state. In contrast to
the IeCl and IeO-bond lengths the IeC(1) bond lengths remain
constant except for compound 18, which may be explained by steric
effects. The six-membered heterocyclic compound 23 shows an
even longer IeC(1) bond-length and has a half-chair-type confor-
mation with the two methyl groups in axial and equatorial position
(similar to the corresponding trifluoromethyl compound 34 shown
in Fig. 5, vide infra). An almost perfect T-shape geometry is ob-
served around the iodine atom, as indicated by the CleIeO angle of
178.87(4)ꢀ. The oxygen atom deviates from the plane defined by the
adjacent aryl ring to a similar extent as in compound 16, (OeIeC
(1)eC(6) torsion angles of 13.60(14)ꢀ and ꢁ12.4(3)ꢀ, respectively).
Table 1
Summary of synthetic results for new trifluoromethyl derivatives 32e34a
Entry
1
Product Nr.
Acetate source
AgOAc
Yield [%]
37
2
KOAc
KOAc
81
14
3
a
All syntheses were carried out without isolating the acetate intermediate in
CH3CN with an excess of TMSCF3 and TBAT as catalytic fluoride source.
Table 2
Bond lengths, bond angles, and torsion angles of monochloroiodanes 2aec, 16e20, and 2
2a
2b12
2c12
16
17a
18
19b
20
23
Bond lengths [Ǻ]
CleI
2.5491(8)
2.042(2)
2.102(3)
2.438(2)
2.110(5)
2.105(7)
2.461(1)
2.5135(9)
2.049(2)
2.108(3)
2.5751(13)
2.5741(13)
2.016(3)
2.005(3)
2.104(5)
2.113(5)
2.5201(7)
2.0511(18)
2.117(2)
2.5406(7)
2.0437(2)
2.107(2)
2.5805(6)
2.0169(14)
2.108(2)
2.5703(6)
2.0220(15)
2.1259(19)
OeI
2.091(3)
2.100(4)
C(1)eI
Bond angles [ꢀ]
OeIeCl
171.06(7)
80.57(10)
91.45(8)
172.0(1)
78.9(2)
93.2(2)
171.96(8)
79.5(1)
170.17(7)
80.67(10)
90.77(9)
170.10(9)
170.94(10)
79.68(15)
79.05(16)
90.68(13)
92.23(14)
170.51(5)
80.20(9)
90.43(7)
169.86(5)
79.89(9)
91.15(7)
171.61(5)
80.5(7)
178.87(4)
88.86(7)
92.02(5)
OeIeC(1)
C(1)eIeCl
92.6(1)
91.27(6)
Torsion angles [ꢀ]
OeIeC(1)eC(6)
10.8(2)
6.0(3)
ꢁ6.4(6)
ꢁ4.7(5)
1.8(3)
3.3(3)
10.0(2)
2.9(3)
ꢁ12.4(3)
18.0(3)
8.36(18)
3.9(2)
15.82(17)
13.1(2)
17.17(15)
15.18(18)
13.60(14)
12.74(15)
CleIeC(1)eC(2)
ꢁ11.4(4)
12.4(4)
a
Asymmetric unit contains two independent molecules.
Values given for P21/n modification.
b

5756
K. Niedermann et al. / Tetrahedron 66 (2010) 5753e5761
be30e31 (2.563 to 2.4406(4) Ǻ) and are comparable to the short
CleIebond of 2b/c (2.438(2) and 2.461(1) Ǻ, respectively). In the
same series the NeI bond lengths increase from 5a (2.06 Ǻ), over 5b
(2.113 Ǻ), to 30 (2.190(3) Ǻ) and 31 (2.2273(12) Ǻ) (Table 3).
Table 3
Bond lengths, bond angles, and torsion angles of nitrogen-containing iodanes
5a/b and 30/31
5aa
5bb
30
31
Bond lengths [Ǻ]
CleI
NeI
C(1)eI
2.56c
2.06c
2.19c
2.563c
2.4612(9)
2.190(3)
2.112(3)
2.4406(4)
2.2273(12)
2.1054(14)
2.113c
2.101c
Bond angles [ꢀ]
NeIeCl
C(1)eIeN
C(1)eIeCl
171c
80c
170.6c
169.15(7)
77.56(11)
91.65(9)
171.12(3)
77.36(5)
94.21(4)
79.0c
91.6c
90c
Torsion angles [ꢀ]
NeIeC(1)eC(6)
CleIeC(1)eC(2)
1.17c
1.96c
ꢁ1.1(2)
ꢁ1.8(3)
ꢁ1.01(10)
ꢁ4.27(12)
Figure 2. Structural overlap of compounds 2aec and 16e20 generated with the pro-
gram MERCURY. (a) one of two independent molecules in the asymmetric unit; (b)
structure given for the P21/n modification.
a
Values taken from Ref. 15.
Values taken from Ref. 16.
Standard deviations not available.
b
c
X-ray-quality single crystals of the cationic compounds 30 and 31
were obtained by diffusion of Et2O and CH2Cl2, respectively, into
saturated acetonitrile solutions. The crystal structures of these highly
hygroscopic materials are shown in Figure 3. Not surprisingly, the
cationic species 30 and 31 show IeF contacts to the BFꢁ4 counter ions
ranging between 3.028(3) and 3.173(1) Ǻ. In compounds 30 and 31
the nitrogen atom is almost perfectly coplanar with the adjacent aryl
ring (torsion angles of ꢁ1.1(2) and 1.01(10)ꢀ, respectively), similarly
to compound 2b/c. The CleIebonds decrease in the series 5a/
3.2. Trifluoromethylating reagents
Single crystals for X-ray analysis for the new trifluoromethylated
compound 32 were obtained by sublimation, while compounds 33
and 34 were crystallized by cooling a saturated pentane solution.
Selected bond lengths, bond angles, and torsion angles are given in
Table 4 and ORTEP representations of the structures are shown in
Figure 4.
Table 4
Bond lengths, bond angles, and torsion angles of trifluoromethylating reagents
1aa
1ba
32
33
34
Bond lengths [Ǻ]
F3CeI
OeI
2.267(2)
2.1176(14) 2.2014(15) 2.121(2) 2.1380(10) 2.0979(14)
2.1211(19) 2.115(2) 2.123(3) 2.1153(12) 2.1314(18)
2.229(2)
2.262(4) 2.2580(14) 2.304(2)
C(1)eI
Bond angles [ꢀ]
OeIeCF3
169.77(8) 169.41(7) 169.69(13) 170.17(5) 177.90(6)
C(1)eIeO
C(1)eIeCF3
78.72(6)
91.10(8)
77.07(7)
92.37(8)
78.15(11) 78.44(4)
91.56(15) 91.75(5)
87.23(6)
91.06(7)
Torsion angles [ꢀ]
OeIeC(1)eC(6)
F3CeIeC(1)eC(2)
11.5(1) ꢁ12.11(15) ꢁ15.4(2) ꢁ10.84(8)
13.2(2)
14.94(14)
ꢁ11.7(2) ꢁ14.7(3) ꢁ14.45(11) 16.15(14)
a
Values taken from Ref. 3.
Figure 3. ORTEP drawing of compounds 30 (left) and 31 (right). Thermal ellipsoids are
drawn at the 50% probability level, hydrogen atoms are omitted for clarity.
Figure 4. ORTEP drawing of compound 32e34 (left to right). Thermal ellipsoids drawn at the 50% probability level, hydrogen atoms are omitted for clarity reasons.

K. Niedermann et al. / Tetrahedron 66 (2010) 5753e5761
5757
The same trends observed for the chloro compounds can be
detected for the alcohol-derived trifluoromethyl compounds
1a/b and 32e34 though in a less pronounced manner, as shown
in Figure 5.
Unfortunately, no strongly convincing correlations between
X-ray structural parameters and reactivity toward toluenesulfonic
acid monohydrate were found. However, two vague, expected
trends in observed bond lengths and reactivity behavior do appear
to be present. Very generally, it seems that reagents with shorter
CF3eI bond distances and longer IeO distances tend to be slightly
more reactive toward toluenesulfonic acid. This is in keeping with
the previous observation that protonation of the reagent at oxygen
(weakening of the IeO bond) is critical for the trifluoromethylation
under acidic conditions.6
Part of the difficulty in assessing and comparing the structural
and rate data seems to stem from packing effects, especially the
strong intermolecular interactions between the alkoxide groups
and iodine (III) centers of neighboring molecules in the crystal. It
should also be noted that the initial rate runs were not repeated and
therefore also incur a degree of unreliability. However, in this case,
our experience strongly indicates that with sufficient care such
experiments yield reproducible rate data within the standard de-
viations of the curve fitting routines.23
Figure 5. Correlation of bond lengths in chloro- and trifluoromethyliodanes.
5. Conclusion
Similar to the monochloroiodanes, a short IeO bond leads to an
elongated F3CeI bond. The IeO bonds in the CF3-compounds are
longer than in the corresponding chloro derivatives. The majority of
the trifluoromethyl derivatives pack in a similar manner as their
monochloro precursors and therefore show similar intermolecular
contacts. If analogous packing is not observed, as in the case of
compound 33, bond length comparisons should be taken with care.
However, our results show that the CF3 derivatives of correspond-
ing monochloroiodanes with long CleI bonds are likely to have long
F3CeI bonds as well.
In conclusion, we synthesized and characterized several new
five- and a six-membered heterocyclic monochloroiodanes, in-
cluding two cationic species. The synthesis and the crystal struc-
tures of three new trifluoromethylating reagents are shown. These
structures were compared with the X-ray structures of the mono-
chloroiodanes and were tested in a reactivity study on the tri-
fluoromethylation of para-toluenesulfonic acid. Although the data
presented here should be taken as a qualitative guide and not as
a rigorous quantitative study, it seems that the enhancement of
reagent activity toward sulfonic acids is observed in structures
containing a weakened IeO bond. Assessment of reagent perfor-
mance relative to substrates other than those containing acidic
hydroxyl groups remains a task for the future.
4. Reactivity study
With the wealth of structural information available for 1-chloro-
and 1-trifluoromethyl-1,2-benziodoxoles, studies were undertaken
to correlate the structural features of the trifluoromethyl com-
pounds to their relative reactivities toward a standard substrate.
The primary goal of such studies is to identify structural features,
which are potentially advantageous with regard to CF3-group
transfer that might be exploited to develop improved reagents. To
this end, the initial rates of reaction (v0) of compounds 1aec and
32e34 were measured for mixtures of 0.1 M trifluoromethylating
agent and 0.1 M toluenesulfonic acid monohydrate in a 5:1 mixture
of CDCl3/tert-butanol at 298 K. As previously reported,6 this re-
action occurs smoothly at room temperature and displays a clean
second order kinetics. The results of these studies are summarized
in Table 5 and the experimental details of the investigations are
included in the Experimental section.
6. Experimental
6.1. General
All commercially available chemicals were of reagent grade
and were used without further purification. Alcohol 13,18 mono-
chloroiodanes 2a,17 19,19 and ester 2221 were prepared according
to known procedures. Et2O, THF, and pentane were dried over Na/
benzophenone, CH2Cl2, and CH3CN were dried over CaH2. All re-
actions were carried out using standard Schlenk techniques under
an argon atmosphere. Flash column chromatography was carried
out on silica gel 60 (230e400 mesh) from Fluka. TLC-plates were
purchased from Merck (silica gel 60 F254). NMR spectra were
recorded on Bruker AC-200, DPX-250, DPX-300, DPX-400, DPX-
500. Chemical shifts are given relative to tetramethylsilane for 1H
and 13C NMR spectra. For 19F NMR spectra, CFCl3 was used as an
external standard. The following abbreviations have been used to
describe the signals: s for singlet; d for doublet; t for triplet; q for
quadruplet; m for multiplet; u for unresolved and br for broad
signals. High resolution mass-spectra were measured by the MS-
Service des Laboratoriums für Organische Chemie, ETH Zürich. Ele-
mental analyses were carried out by the Mikroelementanalytisches
Laboratorium der ETH Zürich. Intensity data of single crystals glued
to a glass capillary were collected at the given temperature
(usually 100 K) on Bruker SMART APEIX platforms with CCD de-
tector and graphite monochromated Mo Ka-radiation
Table 5
Initial rate constants of the trifluoromethylation of toluenesulfonic acid mono-
hydrate with reagents 1aec and 32e34
Entry
Reagent
n0[mol/L s]
1
2
3
4
5
6
1c
33
34
1a
32
1b
2.3ꢂ10ꢁ5
5.3ꢂ10ꢁ6
9.4ꢂ10ꢁ7
5.7ꢂ10ꢁ7
3.4ꢂ10ꢁ7
1.2ꢂ10ꢁ7
(
l
¼0.71073 Å). The program SMART served for data collection;
integration was performed with the software SAINT.24 The struc-
ture was solved by direct methods or Patterson methods, re-
spectively, using the program SHELXS-97.25 The refinement and
Reaction conditions: 0.1 M trifluormethylating agent, 0.1 M toluenesulfonic acid
monohydrate, solvent: 5:1 CDCl3/tBuOH, 298 K.

5758
K. Niedermann et al. / Tetrahedron 66 (2010) 5753e5761
all further calculations were carried out using SHELXL-97.26 All
non-hydrogen atoms were refined anisotropically using weighted
full-matrix least-squares on F2. The hydrogen atoms were in-
cluded in calculated positions and treated as riding atoms using
SHELXL default parameters. In the end absorption correction was
applied (SADABS)27 and weights were optimized in the final re-
finement cycles. The absolute configuration of chiral compounds
was determined on the basis of the Flack parameter.28,29 CCDC
771236e771247 and 771565 contain the supplementary crystal-
lographic data for compounds 2a, 34, 31, 16, 32, 17, 30, 23, 18, 19
(in P-1), 33, 20, and 19 (in P21/c). These data can be obtained free
of charge from the Cambridge Crystallographic Data Center via
http://www.ccdc.cam.ac.uk/dada_request/cif.
(2 mL) at ꢁ17 ꢀC. The mixture was stirred at this temperature for
20 h. Then it was allowed to warm up to ꢁ12 ꢀC, additonal TMSCF3
(0.13 mL) was added and the stirring was continued for 24 h at
ambient temperature. Pentane (20 mL) was added and the solution
was filtered through cotton and concentrated. The crude product
was purified by flash-chromatography (Alox, hexane/EtOAc¼50:1)
to give 32 as a white solid (0.48 g, 37%). X-ray quality crystals were
obtained by sublimation under high vacuum (0.015 mbar, 60 ꢀC);
dH(300 MHz, CDCl3) 7.52e7.56 (2H, m, Harom), 7.40e7.45 (2H, m,
Harom), 1.90e1.94 (2H, m, CH), 1.63e1.78 (7H, m, CH), 1.25e1.29 (1H,
m, CH); dC (75 MHz, CDCl3) 149.5, 130.5, 129.5, 127.9 (q, J 2.7 Hz),
127.3, 111.3 (q, J 3 Hz, CI), 110.9 (q, J 397.0 Hz, CF3), 78.1 (COH), 38.5,
25.7, 22.4; dF (188 MHz, CDCl3) ꢁ40.3; HRMS (EI): Mþ, found
370.0044, C13H14F3IO requires 370.0041.
6.1.1. 1-(2-Iodophenyl)cyclohexanol (10). Anhydrous CeCl3 (713 mg,
2.89 mmol, 1.5 equiv) was suspended in dry THF (8 mL) and stirred
for 12 h at room temperature. In a second Schlenk flask 1,2-diio-
dobenzene (955 mg, 2.89 mmol,1.5 equiv) was dissolved in dry THF
(10 mL) under argon. After cooling to ꢁ30 ꢀC isopropylmagnesium
chloride (1.45 mL, 2.0 M solution in THF, 2.89 mmol, 1.5 equiv) was
added dropwise and the resulting orange colored mixture was
warmed to ꢁ20 ꢀC over a period of 20 min. The reaction was
monitored by GC/MS. Both flasks were cooled to ꢁ78 ꢀC and the
freshly prepared Grignard reagent was added slowly to the CeCl3
suspension by means of a syringe. The mixture was warmed to
room temperature to ensure the complete formation of organo-
cerium species by transmetallation. After cooling again to ꢁ78 ꢀC
cyclohexanone (0.2 mL,1.92 mmol) was added and the mixture was
allowed to warm up to rt overnight. After dilution with Et2O
(20 mL) the reaction mixture was hydrolyzed in an ice bath with
satd aq NH4Cl solution (20 mL), the layers were separated and the
aqueous phase was extracted twice with Et2O (20 mL). The com-
bined organic layers were dried over anhydrous Na2SO4 and
evaporated to dryness in vacuo. After purification of the crude
product by flash chromatography (hexane/EtOAc 50:1 then 5:1) 10
(384 mg, 66%) was isolated as a white powder; dH(300 MHz, CDCl3)
7.99 (1H, t, J 7.9 Hz, Harom), 7.62 (1H, t, J 7.9 Hz, Harom), 7.35 (1H, t, J
7.8 Hz, Harom), 6.92 (1H, t, J 7.4 Hz, Harom), 2.32 (1H, s, OH),
2.02e2.21 (4H, m, CH), 1.69e1.91 (5H, m, CH), 1.28e1.42 (1H, m,
CH); dC (75 MHz, CDCl3): 148.4, 143.0, 128.6, 128.2, 127.0, 93.5 (CI),
74.0 (COH), 36.0, 25.3, 22.0; HRMS (EI): Mþ, found 302.0162,
C12H15IO requires 302.0168.
6.1.4. 9-(2-Iodophenyl)bicyclo[3.3.1]nonan-9-ol (11). Starting from
bicyclo[3.3.1]nonan-9-one (183 mg, 1.3 mmol), 11 was synthesized
in analogy to compound 10. Column chromatography (hexane/
EtOAc 50:1 then 10:1) gave a white powder (363 mg, 82%);
dH(300 MHz, CDCl3) 8.03 (1H, t, J 7.7 Hz, Harom), 7.62 (1H, t, J 7.5 Hz,
Harom), 7.35 (1H, t, J 7.5 Hz, Harom), 6.91 (1H, t, J 6.9 Hz, Harom), 3.03
(2H, s, CH), 2.40e2.51 (3H, m, CH), 1.57e2.03 (10H, m, CH), 1.41 (1H,
m, CH); dC (75 MHz, CDCl3) 145.4,143.9,129.4,128.6,127.6, 93.6 (CI),
76.1 (COH), 34.8, 29.9, 27.6, 20.8, 19.9; HRMS (EI): Mþ, found
342.0477, C15H19IO requires 342.0481.
6.1.5. 1-Chlorospiro[1l3,2-benziodaoxole-3.90-bicyclo[3.3.1]nonane]
(17). Starting from ortho-iodobenzyl alcohol 11 (356 mg,
1.04 mmol) 17 was synthesized in analogy to 16 to yield a yellow
solid (360 mg, 92%). Single crystals for X-ray analysis were obtained
by diffusion of pentane into
a saturated CH2Cl2 solution;
dH(300 MHz, CDCl3) 8.16 (1H, d, J 6.0 Hz, Harom), 7.81 (1H, d, J 6.0 Hz,
Harom), 7.51 (2H, m, Harom), 1.52e2.35 (14H, m, 14H, CH); dC
(75 MHz, CDCl3) 147.7, 129.7, 129.5, 129.0, 128.9, 118.9 (CI), 88.6
(COH), 36.5, 28.8, 28.7, 20.1, 20.0; HRMS (EI): Mþ, found 376.0086,
C15H18ClIO requires 376.0091.
6.1.6. 2-(2-Iodophenyl)-1-methoxy-2-propanol
(12). 1,2-Diiodo-
benzene (0.2 mL, 1.5 mmol) was dissolved in THF (5 mL) and cooled
to ꢁ30 ꢀC. After the addition of iPrMgCl (1 mL, 2 M in THF, 2 mmol,
1.3 equiv) the solution was allowed to warm to ꢁ20 ꢀC within
15 min and stirred at this temperature for 20 min. At ꢁ78 ꢀC
methoxyacetone (0.14 mL, 1.5 mmol, 1 equiv) in THF (2 mL) was
added and the suspension was stirred at ꢁ78 ꢀC during 4 h and in
addition 3 h at rt. The resulting yellow solution was diluted with
Et2O (10 mL) and ice cooled NH4Cl was added. The aqueous phase
was extracted with Et2O (3ꢂ10 mL) and the combined organic
phases were washed with H2O (20 mL) and brine (20 mL), dried
over MgSO4, filtered, and the solvent removed under reduced
pressure. After purification by flash chromatography (cyclohexane/
EtOAc 6:1) compound 12 (0.105 g, 24%) was isolated as a colorless
oil; Rf (cyclohexane/EtOAc 6:1) 0.24; dH (300 MHz, CDCl3)7.98 (1H,
d, J 7.8 Hz, Harom), 7.77 (1H, dd, J 7.8 Hz, 1.2, Harom),7.37 (1H, t, J
8.1 Hz, Harom), 6.92(1H, dt, J 8.1, 1.2 Hz, Harom), 3.95 (2H, dd, J 165,
9.5 Hz, CH2), 3.39 (3H, s, OCH3), 3.29 (1H, s, OH), 1.71 (3H, s, CH3); dC
(63 MHz; CDCl3) 162.3, 146.2, 142.7, 128.8, 128.11, 128.06, 93.0, 77.5,
74.6, 59.3, 24.7; m/z (EI) 265 (MþꢁCH3O, 8), 246 (MþꢁC2H5O, 100);
231 (MþꢁC3H8O, 44), 203 (MþꢁC4H9O2, 11%); HRMS (EI): Mþ,
found 291.9953, C10H13IO2 requires 291.9955.
6.1.2. 1-Chlorospiro[1l3,2-benziodaoxole-3.10-cyclohexane] (16). A
round bottomed flask was charged with alcohol 10 (380 mg,
1.26 mmol) and CH2Cl2 (4 mL) and cooled to 0 ꢀC. To the slightly
yellow reaction mixture tBuOCl (148
mL, 1.27 mmol, 1.01 equiv) was
added and the mixture was warmed to rt over night. The solution
was concentrated and the crude product was recrystallized from
CH2Cl2 to give compounds 16 as a yellow solid (403 mg, 95%). Single
crystals for X-ray analysis were obtained by diffusion of pentane
into a saturated CH2Cl2 solution; dH(300 MHz, CDCl3) 8.04 (1H, d, J
7.5 Hz, Harom), 7.50e7.59 (2H, m, Harom), 7.18 (1H, d, J 6.9 Hz, Harom),
1.90e1.94 (2H, m, CH), 1.58e1.82 (7H, m, CH), 1.22e1.36 (1H, m,
CH); dC (75 MHz, CDCl3) 149, 130.8, 130.5, 128.5, 126.1, 115.2 (CI),
86.4 (COH), 37.2, 25.4, 22.1; HRMS (EI): Mþ, found 335.9771,
C12H14ClIO requires 335.9778.
6.1.3. 1-(Trifluoromethyl)spiro[1l3,2-benziodaoxole-3.10-cyclohex-
ane] (32). Chlorobenziodaoxole 16 (1.2 g, 3.5 mmol) was dissolved
in CH3CN (25 mL) under argon and AgOAc (0.44 g, 3.7 mmol,
1.05 equiv) was added. The resulting suspension was stirred for 3 h,
filtered, and concentrated to yield the corresponding acetate, which
was used without further purification. It was dissolved in CH3CN
(30 mL) and TMSCF3 (0.8 mL, 5.3 mmol, 1.5 equiv) was added, fol-
6.1.7. 1-Chloro-3-methoxymethyl-3-methyl-1H,3H-l
3-dihydro-1,2-
benziodoxole (18). Starting from ortho-iodobenzyl alcohol 12
(105 mg, 0.34 mmol) 18 was synthesized in analogy to 16 to yield
a yellow solid (63.4 mg, 58%); [Found: C, 36.61; H, 3.62; O, 9.81; Cl,
10.83; I, 38.73. C10H12O2ClI requires C, 36.78; H, 3.70; O, 9.80; Cl,
10.86; I, 38.86%];dH (300 MHz, CDCl3) 8.03(1H, d, J9.0 Hz, Harom), 7.57
lowed by a solution of TBAT (3.8 mg, 7 mmol, 0.2 mol %) in CH3CN

K. Niedermann et al. / Tetrahedron 66 (2010) 5753e5761
5759
(2H, t, J 9.3 Hz, Harom), 7.22 (1H, d, J 7.5, Harom), 3.55 (2H, dd, J 25.7,
11.4 Hz, CH2), 3.35 (3H, s, OCH3),1.55 (3H, s, CH3); dC (63 MHz, CDCl3)
146.4, 130.8, 130.7, 128.3, 127.1, 115.2, 86.1, 79.7, 59.8, 25.2; m/z (EI),
246 (MþꢁC2H5OCl, 48), 231 (MþꢁC3H8OCl, 82), 203 (MþꢁC4H8O2Cl,
(CH3)2), 0.93 (3H, d, J 6.7 Hz, CH(CH3)2), 0.84 (3H, d, J 6.8 Hz, CH
(CH3)2); dC (75 MHz, CDCl3) 147.11, 143.19, 130.50, 130.38, 128.53,
128.27, 128.07, 127.19, 125.64, 116.19, 92.44, 38.84, 17.49, 16.64.
ꢃ
20%);HRMS(EI):Mþ ꢁC2H5O,280.9225;C8H7ClIOrequires 280.9230.
6.1.10. 2-(3,4-Dihydro-2H-1,4-methynonaphthalen-1-yl)-propan-2-
ol (22). In a two-neck round bottom flask (50 mL) with reflux con-
denser CH3MgI (3.8 mL, 3 M in Et2O,11 mmol, 2.2 equiv) was diluted
with Et2O (20 mL). At 0 ꢀC ethyl ester 21 (1.133 g, 5.2 mmol) dis-
solved in Et2O (6 mL) was slowly added. The mixture was refluxed
during 2 h, then cooled to 0 ꢀC and satd aq NH4Cl was slowly added.
The mixture was extracted with Et2O (3ꢂ15 mL), the organic phase
dried over K2CO3, filtered, and the solvent was removed under re-
ducedpressure. Afterpurification byflashchromatography(hexane/
EtOAc 5:1) compound 22 (0.982 g, 93%) was isolated as a colorless
oil; [Found: C, 82.94; H, 8.98; O, 8.15. C14H18O requires C, 83.12; H,
8.97; O, 7.91%]; Rf (hexane/EtOA 5:1) 0.4; dH (300 MHz, CDCl3)
7.50e7.47 (1H, m, Harom), 7.24e7.10 (3H, m, Harom), 3.36 (1H, br s, CH),
2.31e2.01 (2H, m, CHHeqCHHeq), 1.74 (1H, dq, J8.6, 2.1 Hz, CHHendo),
1.71 (1H, s, OH), 1.62 (1H, dd, J 6.9, 1.5 Hz, CHexoH), 1.54 (3H, s, CH3),
1.52 (3H, s, CH3), 1.39e1.17 (2H, m, CHaxHCHaxH); dC (62.9 MHz,
CDCl3) 149.4, 146.8, 125.5, 125.3, 121.6, 120.8, 72.3, 62.8, 49.5, 42.9,
29.4, 27.7, 27.6, 27.5; m/z (EI) 202.14 (Mþ, 42.7%),116.1 (100%); HRMS
(EI): Mþ, found 202.1355, C14H18O requires 202.1353.
6.1.8. 1-Trifluoromethyl-3-methyl-3-phenyl-1H,3H-l
3-dihydro-1,2-
benziodoxole (33). A 100 mL Schlenk flask was charged with KOAc
(1.43 g, 14.5 mmol, 1.65 equiv), which was dried under vacuum
using a heat gun. In counter-flow, chloride 19 (3.16 g, 8.81 mmol,
1.0 equiv) was added. CH3CN (25 mL) was added via syringe to give
a yellow suspension. After stirring for 1 h at rt the now white
suspension was filtered into a 100 mL Schlenk flask under argon. To
the colorless solution further CH3CN (20 mL) was added. After
cooling to ꢁ19 ꢀC, TMSCF3 (2.1 mL, 14 mmol, 1.6 equiv) was added,
followed by TBAT (5.4 mg, 0.088 mmol, 1 mol %) in CH3CN (2 mL).
The reaction mixture was stirred for 24 h at ꢁ16 ꢀC, then warmed to
ꢁ12 ꢀC, at which temperature further TMSCF3 (0.33 mL, 2.2 mmol,
0.25 equiv) was added. The reaction mixture was warmed to rt and
the solvent was removed under vacuum. Dry pentane (40 mL) was
added to the remaining brown solid, and the resulting mixture was
filtered through a pad of dry Alox in a Young-filter. The clean, col-
orless solution was partially evaporated until a white solid pre-
cipitated. The suspension was cooled to ꢁ40 ꢀC and the solvent was
decanted. The white crystalline residue was dried under vacuum to
yield 33 (2.80 g, 81%) as a white solid.
Enantiomerically pure 33 did not crystallize upon concentration
and cooling, therefore the solution was concentrated under vacuo to
give a colorless oil having identical spectroscopical properties as the
racemate; [Found: C, 46.00; H, 3.10; F, 14.49. C10H12O2ClI requires C,
45.94; H, 3.08; F, 14.53%]; dH (300 MHz, CDCl3) 7.63e7.52 (2H, m,
Harom), 7.49e7.39 (4H, m, Harom), 7.36e7.21 (3H, m, Harom), 1.86 (3H,
s, CH3); dF (282 MHz, CDCl3) ꢁ39.74 (d, J 1.4 Hz, CF3); dC (75 MHz,
CDCl3) 147.95, 147.51, 130.49, 130.08 (q, J 0.6 Hz), 129.36, 128.33,
128.11 (q, J 2.8 Hz), 127.10, 126.13, 112.08 (q, J 2.9 Hz), 110.65 (q, J
395.7 Hz, CF3), 80.19, 30.83. m/z (MALDI) 393.0 (MHþ, 100%); HRMS
(MALDI): MHþ, found 392.9958, C15H12F3IO requires 392.9957.
6.1.11. 2-(8-Iodo-3,4-dihydro-2H-1,4-methanonaphthalene-1-yl)-
propan-2-ol (15). In a two-neck round bottom flask with a reflux
condenser, alcohol 22 (1.36 g, 6.7 mmol) was dissolved in n-hexane
(27 mL) and TMEDA (2.2 mL, 14.6 mmol, 2.2 equiv) was added. The
solution was cooled to ꢁ78 ꢀC and sBuLi (11.4 mL, 1.3 M in hexane,
14.8 mmol, 2.2 equiv) was slowly added. The reaction mixture was
heated to reflux for 20 h, afterward it was cooled to ꢁ78 ꢀC and 1,2-
diiodoethane (0.811 g, 2.9 mmol, 1.3 equiv) in THF (3 mL) was
slowly added. The mixture was allowed to warm slowly to rt over
night (16 h). Afterward satd aq Na2S2O3 was added and the mixture
was extracted with Et2O. The organic phase was washed with brine,
dried over Na2SO4, filtered, and the solvent was removed under
vacuum. The residue was purified by flash chromatography (hex-
ane/EtOAc 10:1) to give compound 15 (1.18 g, 54%) as a colorless oil;
[Found: C, 51.43; H, 5.26; O, 4.90; I, 38.78. C14H17OI requires C,
51.24; H, 5.22; O, 4.88; I 38.67%]; Rf (hexane/EtOAc 10:1) 0.27; dH
(300 MHz, CDCl3)7.70 (1H, dd, J 7.9, 1.1 Hz, Harom), 7.17 (1H, dd, J
7.0,1.0 Hz, Harom), 6.77 (1H, dd, J 7.9,7.1 Hz, Harom), 3.38 (1H, br s,
1OH), 3.32e3.30 (1H, s, CH), 2.16e1.98 (2H, m, CHHeqCHHeq), 1.71
(3H, s, CH3), 1.67e1.58 (2H, m, CH2), 1.38 (3H, s, CH3), 1.34e1.21 (2H,
m, CHaxHCHaxH); dC (62.9 MHz, CDCl3) 154.0, 150.6, 139.2, 127.5,
120.8, 89.3, 71.7,66.5, 50.7, 43.1, 29.7, 29.5, 28.6, 26.8; m/z (EI) 328.0
(Mþ, 37.9%), 270.0 (100%); HRMS (EI): Mþ, found 328.0317, C14H17IO
requires 328.0319.
6.1.9. 1-Chloro-3-isopropyl-3-phenyl-1H,3H-l
3-dihydro-1,2-benzio-
doxole (20). A round bottom flask was charged with Mg turnings
(675 mg, 27.8 mmol,1.5 equiv) and Et2O (10 mL). To this suspension
was added 2-iodopropane (1.95 mL, 19.4 mmol, 1.05 equiv) at a rate
to keep the suspension at reflux. After complete addition of 2-
iodopropane the suspension was cooled to rt. In a second round
bottom flask 2-iodobenzophenone (5.70 g, 18.5 mmol, 1.0 equiv)
was dissolved in Et2O (20 mL) and cooled to 0 ꢀC. To this solution
the Grignard reagent was added dropwise to give a dark orange
suspension which was further stirred at 0 ꢀC. After 2 h the sus-
pension was warmed up to rt and quenched with satd NH4Cl. The
phases were separated and the aqueous phase was extracted with
Et2O. The combined organic phases were dried over MgSO4 and
concentrated to give a yellow oil (5.08 g). Purification proved to be
cumbersome. Therefore, the crude reaction mixture was used for
the next step without further purification. A round bottom flask
was charged with the crude reaction mixture (500 mg, 1.42 mmol,
6.1.12. 1-Chloro-3,3-dimethyl-3a,6-methano-3a,4,5,6,-tetrahydro-
1H,3H-l
3-ioda-2-oxa-phenalene (23). Starting from ortho-iodo-
benzyl alcohol 15 (1.12 g, 3.4 mmol) 23 was synthesized in analogy
to 16 to yield colorless crystals (1.09 g, 88%). Single crystals for X-
ray analysis were obtained by diffusion of pentane into a saturated
CH2Cl2 solution; [Found: C, 46.44; H, 4.54; Cl,10.07; I, 34.77; O, 4.51.
C14H16ClIO requires C, 46.37; H, 4.45; Cl, 9.78; I, 34.99; Cl, 9.78; I,
34.99; O, 4.41%]; dH (250 MHz, CD2Cl2) 8.25e8.18 (1H, m, Harom),
7.37e7.30 (2H, m, Harom), 3.41 (1H, u, CH), 2.14e2.01 (2H, m,
CHHeqCHHeq), 1.61 (2H, s, CH2), 1.55 (3H, s, CH3), 1.44 (3H, s, CH3),
1.26 (2H, d, J 7.5 Hz, CHaxHCHaxH); dC (63 MHz, CD2Cl2) 153.59,
144.73, 129.48, 125.28, 122.55, 106.66, 75.19, 57.20, 49.22, 42.12,
28.78, 28.50, 26.48, 24.02. m/z(EI) 347.0 (MþꢁCH3, 25%); HRMS (EI):
MþꢁCH3, found 346.9695. C14H16ClIO requires 346.9695.
1.0 equiv) and CH2Cl2 (10 mL) and the solution was cooled to 0 ꢀC.
t
To the slight yellow reaction mixture BuOCl (161
mL, 1.42 mmol,
1.0 equiv) was added, following by warming to rt over night. The
solution was concentrated and redissolved in a minimum amount
of CH2Cl2 and layered with Et2O to give bright yellow crystals. The
procedure was repeated two times and the combined crystals were
recrystallized from CH2Cl2 and Et2O to give bright yellow crystals
(246 mg, 44% over two steps). [Found: C, 49.73; H, 4.22; O, 4.27; Cl,
9.25. C16H16OClI requires C, 49.70; H, 4.17; O, 4.14; Cl, 9.17%]; dH
(300 MHz, CDCl3) 8.01 (1H, dd, J 1.3, 8.0 Hz, Harom), 7.64e7.40 (5H,
m, Harom), 7.39e7.21 (3H, m, Harom), 2.70 (1H, hept, J 6.7 Hz, CH
6.1.13. 1-Trifluoromethyl-3,3-dimethyl-3a,6-methano-3a,4,5,6-tetra-
hydro-1H,3H-l
3-ioda-2-oxa-phenalene (34). Dry KOAc (0.337 g,

5760
K. Niedermann et al. / Tetrahedron 66 (2010) 5753e5761
3.4 mmol, 1.7 equiv) and 23 (0.733 g, 2.0 mmol) were suspended in
CH3CN (5 mL). After 4 h the suspension was filtered, washed with
CH3CN (2ꢂ2.5 mL) and the filtrate was cooled to ꢁ40 ꢀC. TMSCF3
(0.45 mL, 3.0 mmol, 1.5 equiv) followed by TBAT (0.2 mL, 0.03 M in
CH3CN, 0.3 mol%) was added and the mixture was stirred over
night (16 h). The mixture was allowed to warm to 0 ꢀC (5 ꢀC/1 h),
130.5, 127.8, 94.8, 79.4, 68.2, 28.3 (2C); m/z (EI) 301.0 (Mþ, 98), 286
(MþꢁCH3, 100%); HRMS (EI) Mþ 300.9959 found C11H12INO re-
quires 300.9961.
6.1.16. 7-Chloro-5,5-dimethyl-7l l
3-ioda-3-oxa-6 5-azatricyclo
[6.4.0.02,6]dodeca-1(8),2(6),9,11-tetraen-6-yliumtetrafluoroborate
(30). Oxazolidine 24 (485 mg, 1.61 mmol) was dissolved in Et2O
(6 mL). After the addition of HBF4$Et2O (0.7 mL, 51e57% in Et2O,
2.41 mmol, 1.5 equiv) a white precipitate was formed, which was
filtered off after 90 min, washed with Et2O and dissolved in
CH2Cl2 (14 mL). In the dark, tBuOCl (0.33 mL, 3.22 mmol,
2.0 equiv) was added dropwise. A white precipitate was formed
immediately. After the suspension was stirred for additional 5 h,
all volatile compounds were removed under reduced pressure.
The white solid was washed with Et2O and dried under HV to
yield compound 30 (542 mg, 80%) as a white solid; X-ray quality,
highly hygroscopic single crystals were obtained as plates by
diffusion of a saturated acetonitrile solution into CH2Cl2; [Found:
C, 31.11; H, 2.84; Cl, 3.28; C11H12BClF4INO requires C, 31.21; H,
2.86; Cl, 8.37; I, 29.97%]; dH (250 MHz, CD3CN) 8.48 (1H, d, J 8.8,
Harom), 8.20 (2H, m, Harom), 8.03 (1H, t, J 7.5 Hz, Harom), 4.94 (2H, s,
CH2), 1.58 (6H, s, 2ꢂCH3); dC (62.9 MHz, CD3CN) 171.2, 138.1, 132.6,
131.3, 129.4, 123.2, 122.0, 86.0, 69.0, 26.6; dF (188.3 MHz, CD3CN)
after 2 h and 4 h TMSCF3 (67 mL, 0.45 mmol, 0.22 equiv) was added,
when the temperature reached 0 ꢀC TMSCF3 (0.15 mL, 1 mmol,
0.5 equiv) was added and the mixture was allowed to warm to rt
where it was stirred for 3 h. The solvent was removed under re-
duced pressure and, after purification by flash chromatography
(pentane/Et2O 2:1), 34 (114 mg, 14%) was isolated as a microcrys-
talline solid; [Found: C, 45.47; H, 4.09; F, 14.34; I, 32.29. C15H16OF3I
requires C, 45.47; H, 4.07; F, 14.39; I, 32.03%]; Rf (pentane/Et2O 2:1)
0.25; dH (500 MHz, CDCl3) 7.48 (1H, d, J 8.5 Hz, Harom), 7.29 (1H, d, J
7.0 Hz, Harom), 7.17 (1H, dd, J 8.5, 7.0 Hz, Harom), 3.36 (1H, u, CH),
2.05 (2H, m, CHHeqCHHeq), 1.67 (1H, dq, J 9.0, 2.0 Hz, CH2,endo), 1.54
(1H, dd, J 9.0, 1.3 Hz, CH2,exo), 1.49 (3H, s, CH3), 1.38 (3H, s, CH3),
1.37e1.21 (2H, m, CHaxHCHaxH); dC (75.5 MHz, CDCl3) 154.8, 149.9,
129.1, 125.3, 122.6, 116.6 (q, J 403 Hz, CF3), 110.9 (q, 3JC,F 3.2 Hz, CI),
72.4, 58.9, 49.0, 42.6, 29.3, 28.7, 26.6 (2C); dF (188 MHz, CDCl3)
1
ꢁ44.2 (s, JC,F 403 Hz, CF3); m/z (EI) 381.0 (MþꢁCH3, 43%), 43.0
(100%) HRMS (EI): MþꢁCH3 found 380.9962, C14H18O requires
ꢃ
380.9958.
-151.3; m/z (MALDI) 335.7 (Mþ , 8.2%), 302.0 (MHþꢁCl, 100%);
ꢃ
HRMS (MALDI): Mþ
335.9647.
, found 335.9644, C11H12ClINO requires
6.1.14. N-(1-Hydroxy-2-methyl-2-propyl)-2-iodobenzenecarbamide
(27). In
a two-neck round bottom flask 2-amino-2-methyl-
propanol (0.76 mL, 7.9 mmol, 1.1 equiv) was added to 1,4-dioxane
(180 mL) and aq NaHCO3-solution (0.5 M, 220 mL). Using an
dropping funnel iodobenzoic acid chloride (26) (2.01 g, 7.5 mmol)
dissolved in 1,4-dioxane (20 mL) was added during 5 min to the
white suspension. In addition, the reaction was stirred at rt for 3 h.
The mixture was extracted with EtOAc, and the combined org.
phases were washed with HCl-solution (4 M, 100 mL), NaOH-so-
lution (10 M, 100 mL) and brine (100 mL), dried over MgSO4 and,
after removal of the solvent, the product (1.430 g, 60%) was iso-
lated as a white microcrystalline solid; [Found: C, 41.6; H, 4.5; N,
4.4; O, 10.0; I, 39.7. C11H14NO2I requires C, 41.4; H, 4.4; N, 4.4; O,
10.0; I, 39.8%]; dH (250 MHz, CDCl3) 7.88 (1H, d, J 7.8 Hz, Harom),
7.41 (1H, dd, J 4.3, 0.3 Hz, Harom), 7.29e7.09 (1H, m, Harom), 5.84
(1H, br s, NH), 4.32 (1H, t, J 9.0 Hz, OH), 3.75 (2H, d, J 6.3 Hz, CH2),
1.45 (6H, s, 2ꢂCH3); dC (75.5 MHz, CDCl3) 170.1, 142.4, 139.8, 131.2,
128.3, 128.2, 92.3, 70.3, 57.2, 24.6; m/z (EI) 287.99 (MþꢁCH3O,
100); HRMS (EI): MþꢁCH3O, found 287.9880, C10H11NOI requires
287.9885.
6.1.17. 2-(2-Bromophenyl)pyridine
(29). Pd(OAc)2
(72 mg,
0.32 mmol, 0.18 equiv), NBS (334.4 mg, 1.88 mmol, 1.1 equiv), and
2-phenylpyridine (28) (0.25 mL, 1.75 mmol) were dissolved in
acetonitrile (10 mL). The solution was warmed to 100 ꢀC and the
flask was sealed with a Teflon cap. The mixture was refluxed for
48 h, then concentrated under reduced pressure. Chromatographic
purification (EtOAc/hexane 1:20) yielded compound 28 as a color-
less oil (295 mg, 72%); Rf (EtOAc/hexane 1:2) 0.45; dH (CDCl3,
300 MHz) 8.73(1H, d, J4.4 Hz), 7.77 (1H, td, J 7.7, 1.6 Hz), 7.69 (1H,
dd, J 8.0, 0.76 Hz), 7.61 (1H, d, J 7.9 Hz), 7.55 (1H, dd, J 7.6, 1.6 Hz),
7.41 (1H, td, J 7.5, 0.9 Hz), 7.34e7.23 (2H, m).
6.1.18. 2-(2-Iodophenyl)pyridine (25). 2-(2-Bromophenyl)pyridine
(29) (295 mg, 1.26 mmol) was dissolved in 10 mL THF, then cooled
to ꢁ78 ꢀC and nBuLi (0.88 mL, 1.6 M in hexane 1.41 mmol, 1.1 equiv)
was added. The lithiation was completed after 1 h and thereafter
quenched with I2-solution (5.4 mL, 1 M in THF, 5.4 mmol,
4.3 equiv). The reaction mixture was allowed to warm up to rt and
was stirred for additional 12 h. An aqueous workup with satd NH4Cl
solution was then performed. Chromatographic purification
(EtOAc/hexane 1:3) yielded 22 (284.8 mg,1.01 mmol, 80%) as a yel-
low oil; dH (CDCl3, 300 MHz) 8.71(1H, d, J 4.3 Hz), 7.99 (1H, d, J
7.9 Hz), 7.83 (1H, td, J 7.7, 1.7 Hz), 7.52(1H, d, J 7.8 Hz,), 7.46 (2H, m),
7.35(1H, ddd, J 7.5, 5.0, 1.1 Hz), 7.12(1H, ddd, J 8.0, 5.1, 4.0 Hz); dC
(CD3CN, 75 MHz): 160.2, 148.5, 144.6, 139.6, 137.4, 130.3, 128.4,
124.8, 123.3, 117.3, 96.4.
6.1.15. 2-(2-Iodophenyl)-4,4-dimethyl-4,5-dihydro-1,3-oxazole
(24). Amide 27 (10.20 g, 32.0 mmol) and DMAP (587 mg, 4.8 mmol,
0.15 equiv) were dissolved in CH2Cl2 (200 mL) and Et3N (20 mL
154 mmol, 4.8 equiv) was added. The white suspension was cooled
to 0 ꢀC and TsCl (7.41 g, 38.8 mmol, 1.2 equiv) was added. After
complete addition the suspension was allowed to warm to rt and
was stirred during 16 h. H2O (100 mL) was then added and the
resulting mixture was heated to reflux during 1 h. The mixture was
extracted with CH2Cl2, the combined organic phases were washed
with H2O and brine and dried over MgSO4, filtered, and the solvent
was removed under reduced pressure. The yellow suspension was
taken up in EtOAc and filtered over SiO2. After the solvent was re-
moved under reduced pressure, the residue was suspended in
pentane, filtered and oxazoline 24 (6.534 g, 68%) was obtained as
a colorless oil after the solvent was removed under reduced pres-
sure; [Found: C, 44.16; H, 4.01; I, 41.87, N, 4.75; O, 5.33. C11H12INO
requires C, 43.88; H, 4.02; I, 42.14; N, 4.65; O, 5.31%]; dH (300 MHz;
CDCl3) 7.92 (1H, d, J 7.8, Harom); 7.59 (1H, dd, J 7.8 and 1.5, Harom);
7.38 (1H, t, J 7.5, Harom); 7.12 (1H, dt, J 7.5 and 1.5, Harom); 4.16 (2H, s,
CH2), 1.44 (6H, s, CH3); dC (63 MHz; CDCl3) 162.8, 140.1, 134.0, 131.5,
6.1.19. 8-Chloro-8l l
3-ioda-7 5-azatricyclo-[7.4.0.02,7]trideca-1
(9),2,4,6,10,12-hexaen-7-ylium tetrafluoroborate (31). 2-(2-Iodo-
phenyl)pyridine (25) (205 mg, 0.73 mmol) was dissolved in Et2O
(2.5 mL). After dropwise addition of HBF4$Et2O (0.31 mL, 51e57%
in Et2O, 1.07 mmol, 1.5 equiv) a pale brown precipitate formed.
The solvent was decanted after 90 min by syringe and the residual
solid was washed once with Et2O (2.5 mL), then dried under HV.
CH2Cl2 (6.0 mL) was added yielding a clear solution. Dropwise
t
addition of BuOCl (0.16 mL, 0.15 mmol, 2.0 equiv) in the dark at rt
yielded a white precipitate. The suspension was stirred for addi-
tional 12 h, then all volatiles were removed under HV. The re-
sidual solid was washed with CH2Cl2 and dried under HV to yield

K. Niedermann et al. / Tetrahedron 66 (2010) 5753e5761
5761
compound 31 (257 mg, 0.64 mmol, 87%) as a pale yellow solid; X-
ray quality, highly hygroscopic single crystals (platelets) were
obtained by diffusion of CH2Cl2 into a saturated solution of the
product in CH3CN; [Found: C, 32.68; H, 2.11; N, 3.44. C11H8NBF4ClI
requires C, 32.76; H, 2.00; N, 3.47%] dH (CD3CN, 300 MHz) 9.04
(1H, d, J 5.9 Hz), 8.64e8.53 (3H, m), 8.40 (1H, d, J 7.9 Hz),
8.06e8.02 (2H, m), 7.90 (1H, td, J 6.6, 1.3 Hz); dC (CD3CN, 75 MHz)
150.4, 144.3, 143.3, 135.6, 132.6, 132.3, 129.6, 129.1, 127.5, 123.7,
115.0; dF (CD3CN, 188 MHz): ꢁ150.8; m/z (EI):315.9 (Mþ, 9.6),
312.0 (100%); HRMS (EI): Mþ, 315.9383 found 202.1351, C11H8ClIN
requires 315.9484.
were fit to [c]¼n0tþb for a linear increase to a maximum of 10%
conversion in order to extract initial rate values (n0).
Acknowledgements
This work was supported by ETH Zurich and the Swiss National
Science Foundation. R.K. thanks SSCI (Stipendienfonds der
Schweizerischen Chemischen Industrie) and ETH for financial
support. We thank Dr. P. Butti for measuring the crystal structures
of compound 19 (in P-1), 20, 23, and 32 and Dr. F. Camponovo for
the structure solution of compound 33, and R. Aardoom for helpful
discussion and advice.
6.2. General procedure for rate studies
Supplementary data
All reactions were monitored by 19F NMR spectroscopy using
a Bruker AVANCE DPX 400 MHz NMR spectrometer operating at
376 MHz. Experimental temperatures (298 K) were maintained
using a Bruker BVT3000 temperature control unit calibrated with
a digital thermometer fit to a 5 mm NMR tube. Initially, the tem-
perature in the spectrometer was equilibrated on a ‘standard’
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2010.04.125. These data in-
clude MOL files and InChIKeys of the most important compounds
described in this article.
References and notes
sample containing reagent 1a (600 m
L, 0.1 M in CDCl3/tBuOH 5:1)
and the internal standard (PhCF3, 0.05 M) and the shim was opti-
mized. A second tube charged with correct amount of the tri-
1. Willgerodt, C. J. Prakt. Chem. 1886, 33, 145.
2. Wirth, T. Angew. Chem. 2005, 117, 3722; Wirth, T. Angew. Chem., Int. Ed. 2005, 44,
3656.
fluoromethylating agent (300
containing 0.05 M PhCF3) and the appropriate amount of para-
toluenesulfonic acid monohydrate (300
L, 0.2 M in CDCl3/tBuOH
m
L, 0.2 M in CDCl3/tBuOH 5:1
3. Eisenberger, P.; Gischig, S.; Togni, A. Chem.dEur. J. 2006, 12, 2579.
4. Kieltsch, I.; Eisenberger, P.; Togni, A. Angew. Chem. 2007, 119, 768; Kieltsch, I.;
Eisenberger, P.; Togni, A. Angew. Chem., Int. Ed. 2007, 46, 754.
5. Stanek, K.; Koller, R.; Togni, A. J. Org. Chem. 2008, 73, 7678.
6. Koller, R.; Huchet, H.; Battaglia, P.; Welch, J. M.; Togni, A. Chem. Commun. 2009,
5993.
7. Koller, R.; Stanek, K.; Stolz, D.; Aardoom, R.; Niedermann, K.; Togni, A. Angew.
Chem., Int. Ed. 2009, 48, 4332.
8. Eisenberger, P.; Kieltsch, I.; Armanino, N.; Togni, A. Chem. Commun. 2008, 1575.
m
5:1 containing 0.05 M PhCF3) was added. The tube was shaken
vigorously for 10e15 s after which it was exchanged with the
standard in the spectrometer and the acquisition program was
started.
9. Martin, J. C.; Perozzi, E. F. Sience 1976, 191, 154.
10. Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2002, 102, 2523.
11. Stang, P. J.; Zhdankin, V. V. Chem. Rev. 1996, 96, 1123.
12. Takahashi, M.; Nanba, H.; Kitazawa, T.; Takeda, M.; Ito, Y. J. Coord. Chem. 1996,
27, 371.
13. Koser, G. F.; McConville, D. B.; Rabah, G. A.; Youngs, W. J. J. Chem. Cryst. 1995, 25,
857; Clemente, D. A.; Marzotto, A. J. Chem. Cryst. 2003, 33, 933.
14. Prout, K.; Stevens, N. M.; Coda, A.; Tazzoli, V.; Shaw, R. A.; Demir, T. Z. Natur-
forsch., B: Chem. Sci. 1976, 31, 687.
15. Douglas, G. N.; Gougoutas, J. Z. J. Org. Chem. 1975, 40, 2129.
16. Balthazor, T. M.; Godar, D. E.; Stults, B. R. J. Org. Chem. 1979, 44, 1447.
17. Amey, R. L.; Martin, J. C. J. Org. Chem. 1979, 44, 1779.
18. Yamataka, H.; Yamaguchi, K.; Takatsuka, T.; Hanafusa, T. Bull. Chem. Soc. Jpn.
1992, 65, 1157.
6.2.1. Acquisition program. A pseudo 2D NMR experiment designed
for kinetic measurements was utilized to monitor the reaction
progress for all rate experiments. The time interval between in-
dividual acquisitions (d1), number of acquisitions averaged (one
data point was obtained as the average of two individual acquisi-
tions) and total number of data points could be varied to effect the
frequency of acquisition, signal to noise ratio and experiment du-
ration, respectively.
6.2.2. Data processing. For each data point, integrals corresponding
to the 19F NMR resonances of the trifluoromethyl group of the tri-
fluoromethylating reagent, the trifluoromethyl group of the newly
formed trifluoromethyl para-toluenesulfonate and PhCF3 internal
standard were extracted using Bruker’s XWinNMR 3.5 software
package. The resulting data were exported as tables of integral
values for each signal over all data points measured. The 19F NMR
integration data were then imported into SigmaPlot10 and the data
point numbers transformed into time values by multiplying by the
correct acquisition duration and number of acquisitions averaged
per data point. The time vs 19F NMR integration data thus generated
19. Rabah, G. A.; Koser, G. F. Tetrahedron Lett. 1996, 37, 6453.
ꢀ
20. Cvengros, J.; Stolz, D.; Togni, A. Synthesis 2009, 16, 2818.
21. Irie, T.; Tanida, H. J. Org. Chem. 1978, 43, 3274.
22. Dick, A. R.; Hull, K. L.; Sanford, M. S. JACS 2004, 126, 2300.
23. Welch, J.M.; Koller, R.; Togni, A., in preparation.
24. SAINTþ, Software for CCD Diffractometers, v. 6.01; Bruker AXS,: Madison, WI,
2001; and SAINT, v. 6.02.
25. Sheldrick, G. Acta Cryst. Sect. A 1990, 46, 467.
26. Scheldrick, G. M. SHELXL-97 Program for Crystal Structure Refinement; Uni-
€
€
€
versitat Gottingen: Gottingen, Germany, 1999.
27. Blessing, R. Acta Cryst. Sect. A 1995, 51, 33.
28. Flack, H. Acta Cryst. Sect. A 1983, 39, 876.
29. Bernardinelli, G.; Flack, H. D. Acta Cryst. Sect. A 1985, 41, 500.