Catalytic enantioselective α-tosyloxylation of ketones using iodoaryloxazoline catalysts: Insights on the stereoinduction process

Article abstract of DOI:10.1021/jo302393u

A family of iodooxazoline catalysts was developed to promote the iodine(III)-mediated α-tosyloxylation of ketone derivatives. The α-tosyloxy ketones produced are polyvalent chiral synthons. Through this study, we have unearthed a unique mode of stereoinduction from the chiral oxazoline moiety, where the stereogenic center alpha to the oxazoline oxygen atom is significant. Computational chemistry was used to rationalize the stereoinduction process. The catalysts presented promote currently among the best levels of activity and selectivity for this transformation. Evaluation of the scope of the reaction is presented.

Full text of DOI:10.1021/jo302393u

Article
pubs.acs.org/joc
Catalytic Enantioselective α‑Tosyloxylation of Ketones Using
Iodoaryloxazoline Catalysts: Insights on the Stereoinduction Process
Audrey-Anne Guilbault, Benoit Basdevant, Vincent Wanie, and Claude Y. Legault*
́ ́
Department of Chemistry, University of Sherbrooke, 2500 boul. de l’Universite, Sherbrooke, Quebec J1K 2R1, Canada
S
* Supporting Information
ABSTRACT: A family of iodooxazoline catalysts was developed to
promote the iodine(III)-mediated α-tosyloxylation of ketone derivatives.
The α-tosyloxy ketones produced are polyvalent chiral synthons. Through
this study, we have unearthed a unique mode of stereoinduction from the
chiral oxazoline moiety, where the stereogenic center alpha to the
oxazoline oxygen atom is significant. Computational chemistry was used to
rationalize the stereoinduction process. The catalysts presented promote
currently among the best levels of activity and selectivity for this
transformation. Evaluation of the scope of the reaction is presented.
Scheme 1. (a) Concept of α-Tosyloxylation of Ketones
Using HTI; (b) Concept of Catalytic Iodine(III)-Mediated
α-Tosyloxylation
INTRODUCTION
■
With the goal to provide environmentally friendly solutions to
the field of oxidation reactions, hypervalent iodine compounds
have received increasing attention in recent years.1 They are
polyvalent electrophiles and mild oxidants. In particular, efforts
toward the development of chiral variants of these reagents
have been made.2 This has led to pioneering results in
numerous useful synthetic oxidative transformations, such as
the α-tosyloxylation of ketones,3 hydroxylative phenol dear-
omatizations,4 and dearomatizing naphthol spirolactonizations.5
Our group is interested in the α-oxidation of ketones
compounds that leads to functionalized derivatives with
versatile synthetic applications.2a In particular, the α-tosylox-
ylation of ketones enables the introduction of a potent leaving
group alpha to a carbonyl. Additionally, and in contrast to α-
halo ketones, these electrophiles are not lacrymators.6
A
menthyl),3c and 53% (53% ee) with 3.11 Achieving high
enantioselectivities remains a formidable challenge with such
catalytic systems. Here, we report progress in the use of
iodoaryloxazoline derivatives as chiral catalysts to promote the
α-tosyloxylation of ketones compounds and our insights on the
process of stereoinduction.
method to access such compounds relies on the use of toxic
thallium(III) reagents.7 An iodine(III)-mediated variant has
been popularized by Koser et al.8 and uses hydroxy(tosyloxy)-
iodobenzene9 (Scheme 1a, HTIB). The process is an
environmentally more moderate alternative to the Thallium-
mediated process. Togo et al.10 demonstrated a variant that
requires only catalytic amounts of an iodoaryl catalyst and the
presence of a co-oxidant (m-CPBA) in the reaction medium
(Scheme 1b).
With these factors in mind, it is particularly interesting to
consider a catalytic enantioselective variant of the trans-
formation that can yield chiral α-tosyloxy ketones, polyvalent
chiral synthons. The latter allow for a rapid and divergent
synthesis of numerous α-chiral substituted ketones. Pioneering
work in this field has been done by Wirth et al., in terms of both
chiral stoichiometric reagents3e,f and chiral iodoaryl cata-
lysts.3b−d Currently the best enantioselectivities for the catalytic
enantioselective α-tosyloxylation of propiophenone is 78%
(27% ee) with catalysts 1, 42% (39% ee) with 2 (R* =
We envision utilizing catalysts with the general structure A
(Scheme 2), harboring a chiral oxazoline moiety ortho to the
iodine. Inspiration for this type of scaffold was drawn from the
family of PHOX (phosphinooxazoline) ligands C (Scheme 2)
Received: October 30, 2012
© XXXX American Chemical Society
A
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Scheme 2. Concept of Chiral Iodoaryloxazoline Catalysts
Table 1. Evaluation of the Chiral Iodoaryloxazoline Catalysts
a
b
entry
catalyst
yield [%]
ee [%]
used in organometallic catalysis.12 Upon oxidation, the iodane
center can be coordinated by the oxazoline (Scheme 2, B).
Birman et al. recently used similar chiral iodine(V) reagents for
the oxidation of o-alkylphenols.13 Birman’s work and ours
demonstrate that the oxazoline moiety is compatible with
hypervalent iodine species of various oxidation states.
1
4
7
2
5 (S)
4 (S)
2
5
3
6
34
2
<1 (S)
2 (S)
4
7a
8
5
2
1 (R)
13 (S)
24 (S)
6 (S)
6
10a
11a
7b
10b
11b
11c
12
9
8
7
9
RESULTS AND DISCUSSION
8
66
80
60
59
55
43
12
■
9
12 (S)
33 (S)
30 (S)
4 (R)
6 (S)
A first family of catalysts was readily prepared using standard
synthetic methods (Scheme 3).14 The corresponding carboxylic
10
11
12
13
14
Scheme 3. Synthesis of the Iodoaryloxazoline Catalysts
13
7 (S)
a
b
Isolated yields after flash chromatography. Determined ia chiral
HPLC.
did not offer any noticeable activity or selectivity (entries 1−3,
Table 1). The 1,2-phenyl scaffold was then explored, offering
broader potential for aromatic substitution. Catalysts 7a, 8, 10a,
and 11a, derived from 2-iodobenzoic acid, did not show any
noticeable activity (entries 4−6, Table 1).
Introduction of an alkyl group ortho to the iodine center in
catalysts 7b, 10b, 11b, 11c, and 12, however, led to a drastic
improvement in activity (entries 8−12, Table 1). We have
recently explained this drastic acceleration effect on iodoamide-
derived catalysts.15 Most chiral catalysts rely on a chiral Lewis
base ortho to the iodine to coordinate the electrophilic iodane
center following oxidation. For the α-tosyloxylation reaction to
proceed, the Lewis base must uncoordinate from the iodane to
free an electrophilic site for the nucleophile (i.e., enol). With
stronger Lewis bases, such as amide or oxazoline groups, the
energy required to dissociate the base can become rate-limiting
and even prevent reaction. It is then necessary to destabilize the
iodane intermediate, i.e., through introduction of a substituent
ortho to the iodine atom, so that dissociation can occur at an
acceptable rate. A naphthyl scaffold was used for catalyst 9, in
order to achieve similar destabilization without the use of an
alkyl group. This catalyst shows lower activity (entry 13, Table
1). Attempts to replace the methyl group by a second chiral
oxazoline, i.e., in catalyst 13, showed lower activity (entry 14,
Table 1). In all cases 5% to 20% of Baeyer−Villiger reaction
products from 14 and 15 were found. The quantities were
inversely proportional to the catalyst activity.
acids were initially converted to their analogue acyl chlorides,
followed by amide formation. Depending on the nature of the
resulting amide, different cyclization conditions were used.
Using these synthetic routes, catalysts 4−13 were obtained with
yields between 30% and 75% over three steps (Scheme 4).
Catalyst activities and selectivities were evaluated using a
model reaction for the α-tosyloxylation of propiophenone (14),
and the results are summarized in Table 1. Catalysts 4−6,
derived from the 1,8-naphthyl scaffold, were initially tested but
Scheme 4. Iodoaryloxazoline Catalysts Synthesized
Most catalysts offered almost no enantioselectivities, even in
the presence of bulky oxazolines (entry 12, Table 1).
Surprisingly, the best enantioselectivities were obtained from
catalysts bearing a stereogenic center alpha to the oxazoline-
oxygen (entries 9−11, Table 1). To gain insights about the
stereoinduction process, catalysts 16−18 (Scheme 5) were
synthesized, and their performance was evaluated with regards
to the model reaction (Table 1); the results are summarized in
Table 2.
Complete removal of the stereogenic center alpha to the
oxazoline-nitrogen did not result in a noticeable loss of
enantioselectivity (entry 2, Table 2). Replacement of the
B
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state), it is not the most electrophilic intermediate, due to the
strong nitrogen coordination on the iodane center. Protonation
thus furnishes necessary activation to lead to Int-B, a much
more electrophilic bis-cationic intermediate.
Scheme 5. Iodoaryloxazoline Catalysts 16−18
In intermediate Int-B, the oxazoline rotates to position its
oxygen toward the iodine atom to maximize attractive
Coulombic interactions (Figure 1b). In such an intermediate,
Table 2. Evaluation of Chiral Catalysts 16−18
a
b
entry
catalyst
yield [%]
ee [%]
1
2
3
4
11b
16
60
56
60
54
33 (S)
30 (S)
31 (S)
25 (R)
17
18
a
b
Isolated yields after flash chromatography. Determined ia chiral
HPLC.
phenyl group of catalyst 16 for a bulky aliphatic moiety (i.e., c-
hexyl) in catalyst 17 did not result in a loss in enantioselectivity
(entry 3, Table 2), indicating that the role of the phenyl group
is mainly for steric hindrance. Additionally, the sense of
stereoinduction is almost exclusively controlled by the
stereogenic center alpha to oxazoline oxygen, as the epimer
(18) of catalyst 11b led to an inversion of the sense of
induction with similar enantioselectivity. This unique mode of
stereoinduction from an oxazoline group is quite surprising. To
the best of our knowledge, this is the first example of a chiral
oxazoline in which the stereoinduction is controlled by the
stereogenic center alpha to the oxygen atom.
We studied the reaction intermediates computationally to
find a rationale for this surprising behavior.16 Due to the excess
of toluenesulfonic acid (TsOH) with respect to the catalyst, the
oxazoline is driven to its protonated state. Calculations show
that protonation of catalyst 11b is exergonic, with a ΔGrxn value
of −12.6 kcal/mol (Scheme 6a). This value is in agreement
Figure 1. Optimized structures of Int-A11b (a) and Int-B11b (b).16
the stereogenic center adjacent to the oxygen atom is near the
reactive iodine center and influences the approach of the
substrate. Additionally, the O−I interaction in Int-B is much
weaker than the N−I interaction of Int-A, which is evident
from the iodine−heteroatom distance (Figure 1). This
effectively introduces torsion strain in Int-B. The presence of
the methyl group ortho to the iodine thus favor the protonation
of Int-A. Calculations have shown that protonation of Int-A
derived from catalyst 11a is more endergonic (+14.9 kcal/mol),
in accord with this rationale, and explain the positive effect of
the methyl group on catalyst activity. To demonstrate the
viability of Int-B in the reaction conditions, we elected to
methylate catalyst 11b to its corresponding N-methyl
oxazolinium tetrafluoroborate salt. Methylation using methyl
iodide, followed by counterion exchange, yielded the desired
salt 19 in 94% yield (Scheme 7).
Scheme 6. Calculated Free Energies (kcal/mol) of
Protonation of Catalyst 11b (a) and Corresponding Iodane
Int-A11b (b)
Scheme 7. Synthesis of the N-Methylated salt of 11b
Salt 19 is stable under the α-tosyloxylation conditions with
no noticeable degradation over extended (>48 h) periods. It
was then used as a catalyst for the α-tosyloxylation of
propiophenone (Scheme 8). The enantioselectivity and sense
of chiral induction with 19 was close to what was obtained with
with the approximate expected value (−9.8 kcal/mol)
calculated from the experimental pKa(water) values of a
protonated oxazoline (4.4)17 and TsOH (−2.8).18 In its
reduced state, the catalyst is thus found almost exclusively in its
protonated form.
Scheme 8. α-Tosyloxylation of 14 Using Catalyst 19
A very different behavior is observed with the iodane
intermediates (Scheme 6b). Following oxidation, protonation
of the oxazoline in iodane intermediate Int-A is endergonic.
While Int-A is the most stable iodane intermediate (resting
C
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catalyst 11b, although a slight increase in activity and higher
yield were observed.
The effect of various substituents on the catalyst aromatic
ring was studied to enhance activity and selectivity. The results
are summarized in Table 4. Replacement of the methyl group
We elected to pursue the study with catalyst 11b, as it is a
neutral non-hygroscopic solid. We were able to enhance yield
and selectivity by first premixing catalyst, substrate, and TsOH,
followed by slow addition of m-CPBA over 1 h. With this
approach, we were able to surpass 19 in terms of yield and
selectivity. Conversely, slow addition of TsOH over a premixed
solution of the substrate, catalyst, and m-CPBA led to yields
equivalent to those with 19, although at the expense of
enantioselectivity. While no definitive catalyst degradation
products could be isolated, N-oxidation of the neutral oxazoline
nitrogen with m-CPBA is most probable. Premixing of the
catalyst and TsOH thus greatly minimized N-oxidation through
strongly favorable protonation. Using these optimized con-
ditions, the effect of solvent on yields and selectivities was
evaluated. The results are summarized in Table 3.
Table 4. Optimization of Electronic Properties of the
Catalyst for the Model Reaction
a
b
entry
R1
R2
catalyst
yield [%]
ee [%]
1
2
3
4
5
6
Me
H
ent-11b
11d
72
15
71
54
80
44 (R)
<1
CF3
OMe
Me
H
H
11e
22 (R)
28 (R)
48 (R)
45 (R)
OMe
Cl
F
11f
Me
11g
Table 3. Solvent Effect on the α-Tosyloxylation of
Propiophenone under Optimized Model Reaction
Conditions
Me
11h
80
a
b
Isolated yields after flash chromatography. Determined ia chiral
HPLC.
ortho to the iodine by a strong electron-withdrawing inductive
group (CF3), resulted in an almost inactive catalyst (entry 2,
Table 4). Accordingly, replacement of the methyl with an
electron-donating group (MeO) resulted in a catalyst with
similar activity but decreased selectivity. A 4-methoxy-6-methyl
variant was evaluated to assess whether the detrimental effect of
the methoxy group is of mostly electronic nature or whether it
interferes sterically with the approach of the nucleophile. Both
activity and selectivity decreased noticeably (entry 4, Table 4).
Consequently, electron-withdrawing inductive groups para to
the iodine were introduced (entries 5 and 6, Table 4), and a
chloro substitution was found to yield the optimal catalyst
(11g).
We explored the reaction scope with catalyst 11g and treated
a variety of ketones under the described conditions (Table 5).
Variation of the alkyl chain of propiophenone does not result in
significant differences in terms of yields or enantioselectivities
(entries 1−3, Table 5). Use of a cyclic ketone such as indanone
gave a decrease in selectivity (entry 4, Table 5). Surprisingly,
tetralone is unreactive under the reaction conditions (entry 5,
Table 5). The method tolerates well electron-withdrawing
groups on the aryl ring of propiophenone (entries 8−11, Table
5), but electron-donating groups result in a drastic decrease in
reactivity (entries 6 and 7, Table 5), with the p-methoxy
derivative being almost unreactive (entry 6, table 5).
Introduction of ortho substitution on the aryl ring of
propiophenone also has a detrimental effect on yield and
selectivity (entry 12, Table 5). Finally, aliphatic ketones were
tested and found to be unreactive under the reaction conditions
(entries 13−15, Table 5). Rate-limiting enolization could
explain the differences in terms of reactivity.
a
b
entry
solvent
yield [%]
ee [%]
36
1
MeCN
MeCN
77
<5
73
72
67
43
67
17
69
45
49
51
41
27
64
c
2
3
MeCN/DCM (2:1)
MeCN/DCM (1:1)
MeCN/DCM (1:2)
DCM
43
44
48
54
45
50
46
54
45
50
47
32
38
4
5
6
7
MeCN/PhMe (1:1)
PhMe
8
9
MeCN/CHCl3 (1:1)
CHCl3
10
11
12
13
14
15
16
MeCN/1,2-DCE (1:1)
1,2-DCE
Et2O
THF
EtOAc
H2O
<5
b
a
Isolated yields after flash chromatography. Determined ia chiral
HPLC. 4 Å molecular sieve was added to the reaction.
c
The use of less polar solvents was found to give enhanced
enantioselectivities (entries 6, 8, 10, 12, 13, 15, Table 3). The
observation was expected, as less polar solvents are known to
allow for stronger electrostatic interactions and, in this context,
for shorter O−I distances in Int-B. In most cases, this was also
accompanied by a drastic loss of yields. The best alternative
solvent was found to be dichloromethane (DCM), allowing for
enantioselectivities of up to 54% ee (entry 6, Table 3) as well as
an increased solubility of substrate and reagent. To circumvent
the loss of yield, mixtures of MeCN and DCM were tested
(entries 3−5, Table 3) and a 1:1 solution was found to be ideal
(entry 4, Table 3). Water was not tolerated as a reaction solvent
(entry 16, Table 3). Yet, no product formation was observed
upon addition of a molecular sieve to the reaction flask (entry
2, Table 3). We conclude that the water that is bound to TsOH
is necessary for the reaction to proceed.
In order to further reduce the environmental impact of the
method, we last explored the nature of the sulfonic acid used as
well as the effect of the stoichiometry of the acid and co-
oxidant. Toluenesulfonic acid can readily be replaced by
methanesulfonic acid19 with a decrease in enantioselectivity, but
with no cost on yield (Scheme 9). Reduction of the number of
equivalents of m-CPBA and TsOH is also readily possible, at
the cost of longer reaction times (Table 6). Hence, by lowering
the stoichiometry of m-CPBA and TsOH to 1.5 equiv, it is
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Table 5. Study of Reaction Scope of the α-Tosyloxylation of
Table 6. Effet of m-CPBA and TsOH Equivalents
Ketones
a
b
entry
X [equiv]
time [h]
yield [%]
ee [%]
1
2
3
4
5
6
7
3.0
3.0
3.0
3.0
1.5
1.5
1.5
48
24
12
6
79
80
69
61
74
62
48
48
45
45
46
46
43
48
24
12
41
a
b
Isolated yields after flash chromatography. Determined ia chiral
HPLC.
understanding of the reaction mechanism. Further work toward
the development of novel chiral catalysts based on this scaffold
is under way as well as deeper mechanistic studies to better
understand the process.
COMPUTATIONAL DETAILS
■
All calculations were performed with the Gaussian 09 package.20 All
structures reported were fully optimized including PCM equilibrium
solvation model for acetonitrile and BONDI cavity model,21 with the
MPW1K hybrid density functional22 in combination with the 6-
31+G(d,p) basis set for all atoms except iodine and LANL2DZdp +
LANL2DZ ECP for iodine.23 Unless otherwise stated, a fine grid
density was used for numerical integration in the calculations.
Harmonic vibrational frequencies were computed for all optimized
structures to verify that they were minima, possessing zero imaginary
frequencies. Energies reported incorporate unscaled energy corrections
based on the vibrational analyses and temperature of 298 K.
EXPERIMENT SECTION
■
General Remarks. All nonaqueous reactions involving air- or
moisture-sensitive compounds were run under an inert atmosphere
(nitrogen or argon) with rigid exclusion of moisture from reagents and
glassware using standard techniques.24 All glassware was stored in the
oven and/or was flame-dried prior to use under an inert atmosphere of
gas. Anhydrous solvents were obtained either by distillation over
sodium (THF, ether, benzene, toluene) or over calcium hydride
(CH2Cl2, Et3N, ClCH2CH2Cl). Analytical thin-layer chromatography
(TLC) was performed on precoated, glass-backed silica gel (Merck 60
F254). Visualization of the developed chromatogram was performed by
UV absorbance, aqueous cerium molybdate, ethanolic phosphomo-
lybdic acid, iodine, or aqueous potassium permanganate. Flash column
chromatography was performed using 230−400 mesh silica (EM
Science or Silicycle) of the indicated solvent system according to
standard technique.25 Melting points were obtained on a Buchi
melting point apparatus and are uncorrected. Infrared spectra were
taken on a FTIR instrument and are reported in reciprocal centimeters
(cm−1). Nuclear magnetic resonance spectra (1H, 13C, DEPT, COSY,
HMQC) were recorded either on a 300 or 400 MHz spectrometers.
Chemical shifts for 1H NMR spectra are recorded in parts per million
from tetramethylsilane with the solvent resonance as the internal
standard (chloroform, δ 7.27 ppm, acetonitrile, δ 1.94 ppm). Data are
reported as follows: chemical shift, multiplicity (s = singlet, d =
doublet, t = triplet, q = quartet, qn = quintet, sext = sextuplet, m =
multiplet, and br = broad), coupling constant in Hz, integration.
Chemical shifts for 13C NMR spectra are recorded in parts per million
from tetramethylsilane using the central peak of deuterochloroform
(77.23 ppm) as the internal standard. All spectra were obtained with
complete proton decoupling. When ambiguous, proton and carbon
assignments were established using COSY, NOESY, HMQC, and
a
b
Isolated yields after flash chromatography. Determined ia chiral
HPLC.
Scheme 9. α-Mesyloxylation of 14 Using Catalyst 11g
possible to achieve very similar yields and enantioselectivities
over 48 h reaction time (entry 5, Table 6).
CONCLUSION
■
The iodine(III)-mediated catalytic enantioselective α-tosylox-
ylation of ketone compounds remains a highly valuable yet
challenging reaction to master. With this family of iodoarylox-
azoline-based catalysts, we were able to further improve on
previously achieved enantioselectivities, while maintaining
useful activity. We further report an unprecedented mode of
stereoinduction from chiral oxazolines that provides a better
E
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DEPT experiments. High resolution mass spectra were obtgained
using either a ZAB (EI) or UPLC-Q-TOF (ESI) mass spectrometer.
Analytical high performance liquid chromatography was performed on
an HPLC system equipped with diode array UV detector. Data are
reported as follows: (column type, eluent, flow rate: retention time
(tR)).
(dd, J = 14.3, 8.0 Hz, 1H), 1.49 (s, 3H), 1.45 (s, 3H) ppm; 13C NMR
(100 MHz, CDCl3) δ 162.5, 142.1, 139.3, 135.6, 132.2, 131.9, 131.0,
129.8, 129.3, 128.7, 127.2, 126.5, 125.4, 92.3, 87.8, 76.1, 36.5, 22.6
ppm; IR (neat) 3060, 3027, 2969, 2917, 2850, 1659, 1496, 1444, 1372,
1291, 1195, 1128, 1076, 990 cm−1; HRMS EI (m/z): [M]+ calcd for
C22H20INO 441.0590, found 441.0594. [α]25D +3.72 (c 0.43, CHCl3).
(S)-4-tert-Butyl-2-(8-iodonaphthalen-1-yl)-4,5-dihydrooxa-
zole (6). To a solution of 8-iodo-1-naphthoic acid26 (1.00 g, 3.36
mmol) in 25.0 mL of SOCl2 was added 5 drops of DMF. The reaction
mixture was stirred for 2 h at 80 °C. The excess of thionyl chloride was
removed under reduced pressure using a coldfinger trap. To a solution
of (S)-tert-leucinol (500 mg, 4.24 mmol) and triethylamine (1.18 mL,
8.48 mmol) in 15.0 mL of DCM was added dropwise a solution of the
crude naphthoyl chloride (1.33 g, 4.24 mmol) in 15.0 mL of DCM at 0
°C. The reaction mixture was stirred for 18 h at room temperature.
The solution was diluted in DCM and HCl 1 N, and the layers were
separated. The aqueous layer was back-extracted twice with DCM. The
combined organic extracts were washed with water and dried over
Na2SO4. The solvent was removed under reduced pressure to provide
1.52 g (90%) of (S)-N-(2-hydroxy-2,4,4-trimethylpentan-3-yl)-8-iodo-
1-naphthamide. General cyclization procedure (d): To thionyl
chloride (23.1 mL, 317 mmol) was added a solution of this amide
(1.08 g, 2.73 mmol) in DCM (25.0 mL) at −10 °C. The reaction
mixture was stirred for 2.5 h at room temperature. The thionyl
chloride excess was removed under reduced pressure using a coldfinger
trap. The reaction mixture was diluted in DCM and NaOH 1 N, and
the layers were separated. The aqueous layer was back-extracted with
DCM. The combined organic extracts were washed with water and
dried over Na2SO4. The solvent was removed under reduced pressure,
and the crude mixture was purified by column chromatography on
silica gel with EtOAc/hexanes (20:80) to provide 638 mg (62%) of 6
as a brown solid; Tfus 88−90 °C; Rf 0.39 (EtOAc/hexanes, 20:80); 1H
NMR (300 MHz, CDCl3) δ 8.18 (d, J = 7.3 Hz, 1H), 7.82−7.70
(m,3H), 7.39 (t, J = 7.6 Hz, 1H), 7.02 (t, J = 7.7 Hz, 1H), 4.52 (dd, J =
10.1, 8.9 Hz, 1H), 4.28 (t, J = 8.5 Hz, 1H), 4.12 (dd, J = 10.1, 8.8 Hz,
1H), 1.02 (s, 9H) ppm; 13C NMR (75 MHz, CDCl3) δ 164.3, 141.7,
135.1, 132.0, 131.3, 130.9, 129.7, 129.2, 129.0, 128.0, 126.0, 125.1,
92.0, 76.6, 34.2, 26.4 ppm; IR (neat) 3060, 2959, 2902, 2869, 1726,
1662, 1477, 1346, 1257, 1184, 1138, 1003, 953, 911 cm−1; HRMS EI
(S)-2-(8-Iodonaphthalen-1-yl)-4-isopropyl-5,5-dimethyl-4,5-
dihydrooxazole (4). General amide formation procedure 1: To a
solution of 8-iodo-1-naphthoic acid26 (5.00 g, 16.8 mmol) in 125 mL
of SOCl2 was added 25 drops of DMF. The reaction mixture was
stirred for 3 h at 80 °C. The excess of thionyl chloride was removed
under reduced pressure using coldfinger trap. To a solution of (S)-3-
amino-2,4-dimethylpentan-2-ol27 (2.0 g, 15.2 mmol) and triethylamine
(6.39 mL, 45.51 mmol) in 43.0 mL of 1,4-dioxane was added dropwise
a solution of the crude naphthoyl chloride (4.79 g, 15.2 mmol) in 43.0
mL of 1,4-dioxane was at 0 °C.28 The reaction mixture was stirred 18 h
at room temperature. The solution was diluted in DCM and water,
and the layers were separated. The aqueous layer was back-extracted
with DCM. The combined organic extracts were washed with water
and dried over Na2SO4. The solvent was removed under reduced
pressure to provide 5.76 g (92%) of (S)-N-(2-hydroxy-2,4-
dimethylpentan-3-yl)-8-iodo-1-naphthamide. General cyclization pro-
cedure (a): To a solution of this amide (96 mg, 0.233 mmol) in DCM
(2.6 mL) was added MsOH (94 μL, 1.38 mmol) at 0 °C, and the
reaction mixture was stirred for 18 h at 40 °C. The solution was
diluted in DCM and NaHCO3 (aq), and the layers were separated.
The aqueous layer was back-extracted with DCM. The combined
organic extracts were washed with water and dried over Na2SO4. The
solvent was removed under reduced pressure, and the crude mixture
purified by column chromatography on silica gel with EtOAc/hexanes
(20:80) to provide 56 mg (62%) of 4 as a beige solid; Tfus 126−128
1
°C; Rf 0.35 (EtOAc/hexanes, 20:80); H NMR (300 MHz, CDCl3) δ
8.25 (dd, J = 7.4, 1.1 Hz, 1H), 7.86 (t, J = 7.6 Hz, 2H), 7.71 (dd, J =
7.1, 1.4 Hz, 1H), 7.47 (dd, J = 8.0, 7.3 Hz, 1H), 7.13 (t, J = 7.8 Hz,
1H), 3.60 (d, J = 10.4 Hz, 1H), 2.10−1.95 (m, 1H), 1.73 (s, 3H), 1.42
(s, 3H), 1.24 (d, J = 6.5 Hz, 3H), 1.04 (d, J = 6.5 Hz, 3H) ppm; 13C
NMR (75 MHz, CDCl3) δ 161.4, 141.8, 135.3, 131.5, 130.7, 129.6,
126.9, 125.1, 91.9, 87.7, 81.9, 28.4, 22.1, 21.9, 20.8 ppm; IR (neat)
3770, 3706, 3051, 2970, 2872, 2827, 1659, 1467, 1370, 1285, 1195,
1117, 1026, 990, 916 cm−1; HRMS EI (m/z): [M]+ calcd for
C18H20INO 393.0590, found 393.0574. [α]25 +0.65 (c 1.23, CHCl3).
(S)-4-Benzyl-2-(8-iodonaphthalen-1-yDl)-5,5-dimethyl-4,5-di-
hydrooxazole (5). To a solution of 8-iodo-1-naphthoic acid26 (5.00
g, 16.78 mmol) in 125 mL of thionyl chloride was added 25 drops of
DMF. The reaction mixture was stirred at 80 °C for 3 h. The excess of
thionyl chloride was removed under reduced pressure using a
coldfinger trap. To a solution of (S)-3-amino-2-methyl-4-phenyl-
butan-2-ol27 (283 mg, 1.58 mmol) and triethylamine (0.67 mL, 4.75
mmol) in 5.0 mL of 1,4-dioxane was added dropwise a solution of the
crude naphthoyl chloride (500 mg, 1.58 mmol) in 5.0 mL of 1,4-
dioxane at 0 °C.28 The reaction mixture was stirred for 18 h at room
temperature. The solution was diluted in DCM and water, and the
layers were separated. The aqueous layer was back-extracted with
DCM. The combined organic extracts were washed with water and
dried over Na2SO4. The solvent was removed under reduced pressure
to provide 607 mg (84%) of (S)-N-(3-hydroxy-3-methyl-1-phenyl-
butan-2-yl)-8-iodo-1-naphthamide. General cyclization procedure (b):
To a solution of this amide (549 mg, 1.20 mmol) in 1,2-DCE (14.2
mL) was added MsOH (490 μL, 7.17 mmol) at 0 °C. The reaction
mixture was stirred for 18 h at 85 °C. The solution was diluted in
DCM and NaHCO3 (aq), and the layers were separated. The aqueous
layer was back-extracted with DCM two times. The combined organic
extracts were washed with water and dried over Na2SO4. The solvent
was removed under reduced pressure, and the crude mixture was
purified by column chromatography on silica gel with EtOAc/hexanes
(20:80) to provide 350 mg (66%) of 5 as a yellow oil; Rf 0.25 (EtOAc/
hexanes, 20:80); 1H NMR (300 MHz, CDCl3) δ 8.26 (dd, J = 7.4, 1.1
Hz, 1H), 7.87 (ddd, J = 7.7, 6.6, 1.1 Hz, 2H), 7.75 (dd, J = 7.1, 1.4 Hz,
1H), 7.49 (dd, J = 8.0, 7.3 Hz, 1H), 7.41−7.28 (m, 5H), 7.15 (t, J = 7.7
Hz, 1H), 4.41 (t, J = 7.7 Hz, 1H), 3.37 (dd, J = 14.3, 7.4 Hz, 1H), 2.92
(m/z): [M]+ calcd for C17H18INO 379.0433, found 379.0421. [α]25
D
+83.3 (c 1.39, CHCl3).
(S)-2-(2-Iodophenyl)-4-isopropyl-5,5-dimethyl-4,5-dihy-
drooxazole (7a). General amide formation procedure 1 was
followed: 2-iodobenzoic acid (202 mg, 0.814 mmol), SOCl2 (5.0
mL, 68.5 mmol), (S)-3-amino-2,4-dimethylpentan-2-ol27 (107 mg,
0.811 mmol), triethylamine (0.34 mL, 2.43 mmol); 277 mg (95%) of
(S)-N-(2-hydroxy-2,4-dimethylpentan-3-yl)-2-iodobenzamide. General
cyclization procedure (a) was followed: To a solution of the amide was
added MsOH (0.31 mL, 4.56 mmol). The crude product was purified
by column chromatography on silica gel with EtOAc/hexanes (20:80)
to provide 160 mg (61%) of 7a as a yellow oil; Rf 0.74 (EtOAc/
hexanes, 30:70); 1H NMR (300 MHz, CDCl3) δ 7.91 (dd, J = 8.1, 0.8
Hz, 1H), 7.60 (dd, J = 7.7, 1.8 Hz, 1H), 7.35 (dt, J = 7.6, 1.1 Hz, 1H),
7.07 (dt, J = 7.7, 1.7 Hz, 1H), 3.52 (d, J = 8.2 Hz, 1H), 2.00−1.87 (m,
1H), 1.56 (s, 3H), 1.45 (s, 3H), 1.18 (d, J = 6.5 Hz, 3H), 1.05 (d, J =
6.6 Hz, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 162.1, 140.4, 134.1,
131.3, 130.6, 127.7, 94.6, 87.4, 80.8, 29.4, 29.1, 21.5, 21.2, 20.6 ppm;
IR (neat) 3068, 2969, 2867, 1658, 1641, 1584, 1467, 1426, 1376, 1331,
1246, 1081, 1037, 1016, 914 cm−1; HRMS EI (m/z): [M]+ calcd for
C14H18INO 343.0433, found 343.0444. [α]25D −39.8 (c 1.26, CHCl3).
(S)-2-(2-Iodo-3-methylphenyl)-4-isopropyl-5,5-dimethyl-4,5-
dihydrooxazole (7b). General amide formation procedure 1 was
followed: 2-iodo-3-methylbenzoic acid (204 mg, 0.778 mmol), SOCl2
(5.0 mL, 68.5 mmol), (S)-3-amino-2,4-dimethylpentan-2-ol27 (103
mg, 0.780 mmol), triethylamine (0.32 mL, 2.28 mmol); 285 mg
(100%) of (S)-N-(2-hydroxy-2,4-dimethylpentan-3-yl)-2-iodo-3-meth-
ylbenzamide. General cyclization procedure (a) was followed: To a
solution of this amide was added MsOH (0.31 mL, 4.56 mmol). The
crude product was purified by column chromatography on silica gel
with EtOAc/hexanes (20:80) to provide 131 mg (48%) of 7b as a
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beige solid; Tfus 74−78 °C; Rf 0.62 (EtOAc/hexanes, 20:80); 1H NMR
(300 MHz, CDCl3) δ 7.30−7.19 (m, 3H), 3.50 (d, J = 8.2 Hz, 1H),
2.46 (s, 3H), 1.93 (dq, J = 13.2, 6.6 Hz, 1H), 1.55 (s, 3H), 1.45 (s,
3H), 1.16 (d, J = 6.5 Hz, 2H), 1.03 (d, J = 6.6 Hz, 3H) ppm; 13C NMR
(75 MHz, CDCl3) δ 163.4, 142.8, 136.1, 130.8, 127.7(2), 101.8, 87.4,
80.9, 29.5, 29.1, 21.6, 21.3, 20.8 ppm; IR (neat) 3060, 2979, 2867,
1689, 1658, 1640, 1585, 1548, 1465, 1442, 1242, 1176, 1119, 1076,
1022, 910 cm−1; HRMS EI (m/z): [M]+ calcd for C15H20INO
357.0590, found 357.0594. [α]25 −1.13 (c 1.06, CHCl3).
(d, J = 8.4 Hz, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.61−7.50 (m, 3H), 3.60
(d, J = 8.2 Hz, 1H), 2.06−1.94 (m, 1H), 1.63 (s, 3H), 1.51 (s, 3H),
1.22 (d, J = 6.5 Hz, 3H), 1.08 (d, J = 6.6 Hz, 3H) ppm; 13C NMR (100
MHz, CDCl3) δ 163.7, 134.8, 134.5, 134.1, 133.6, 128.8, 128.3, 128.2,
127.5, 126.6, 101.8, 87.7, 81.0, 29.5, 29.1, 21.6, 21.3, 20.8 ppm; IR
(neat) 3065, 2969, 2931, 2874, 1668, 1463, 1367, 1329, 1243, 1085,
1023, 961, 927 cm−1; HRMS EI (m/z): [M]+ calcd for C18H20INO
393.0590, found 393.0593. [α]25 −12.9 (c 0.55, CHCl3).
D
(3aS,8aR)-2-(2-Iodophenyl)-8,8a-dihydro-3aH-indeno[1,2-d]-
oxazole (10a). General amide formation procedure 1 was followed:
2-iodobenzoic acid (5.00 g, 20.2 mmol), SOCl2 (100 mL, 1.37 mol),
crude benzoic acyl (806 mg, 3.03 mmol), (1S,2R)-1-amino-2,3-
dihydro-1H-inden-2-ol (454 mg, 3.03 mmol), triethylamine (1.27 mL,
9.08 mmol); 1.15 g (100%) of N-((1S,2R)-2-hydroxy-2,3-dihydro-1H-
inden-1-yl)-2-iodobenzamide. General cyclization procedure (b) was
followed: To a solution of this amide (926 mg, 2.44 mmol) was added
MsOH (0.99 mL, 14.7 mmol). The crude product was purified by
column chromatography on silica gel with EtOAc/hexanes (30:70) to
provide 267 mg (35% bsmr) of 10a as a brown oil; Rf 0.57 (EtOAc/
(S)-4-Benzyl-2-(2-iodophenDyl)-5,5-dimethyl-4,5-dihydrooxa-
zole (8). General amide formation procedure 1 was followed: 2-
iodobenzoic acid (5.00 g, 20.2 mmol), SOCl2 (100 mL, 1.37 mol),
crude benzoic acyl (913 mg, 3.43 mmol), (S)-3-amino-2-methyl-4-
phenylbutan-2-ol27 (610 mg, 3.43 mmol), triethylamine (1.44 mL,
10.3 mmol); 1.40 g (100%) of (S)-N-(3-hydroxy-3-methyl-1-phenyl-
butan-2-yl)-2-iodobenzamide. General cyclization procedure (b) was
followed: To a solution of this amide (1.32 g, 3.23 mmol) was added
MsOH (1.31 mL, 19. mmol). The crude product was purified by
column chromatography on silica gel with EtOAc/hexanes (20:80) to
provide 943 mg (75%) of 8 as a yellow oil; Rf 0.57 (EtOAc/hexanes,
1
hexanes, 30:70); H NMR (300 MHz, CDCl3) δ 7.88 (d, J = 7.8 Hz,
1
30:70); H NMR (300 MHz, CDCl3) 7.91 (d, J = 7.1 Hz, 1H), 7.58
1H), 7.56 (d, J = 7.7 Hz, 2H), 7.36−7.27 (m, 4H), 7.07 (t, J = 7.7 Hz,
1H), 5.79 (d, J = 7.9 Hz, 1H), 5.53 (ddd, J = 8.2, 5.6, 2.9 Hz, 1H),
3.57−3.41 (m, 2H) ppm; 13C NMR (75 MHz, CDCl3) δ 141.6, 140.3,
139.7, 133.5, 131.5, 130.8, 128.5, 127.7, 127.4, 125.7, 125.2, 94.6, 83.7,
77.1, 39.6 ppm; IR (CHCl3) 3060, 3031, 2960, 2922, 2835, 1951,
1721, 1659, 1640, 1625, 1578, 1477, 1463, 1425, 1348, 1291, 1229,
1171, 1090, 1018, 980, 851 cm−1; HRMS EI (m/z): [M]+ calcd for
(d, J = 7.7 Hz, 1H), 7.40−7.18 (m, 6H), 7.09 (t, J = 7.7 Hz, 1H), 4.21
(dd, J = 8.3, 6.8 Hz, 1H), 3.10 (dd, J = 14.1, 8.3 Hz, 1H), 2.85 (dd, J =
14.1, 6.7 Hz, 1H), 1.45 (d, J = 2.3 Hz, 6H) ppm; 13C NMR (75 MHz,
CDCl3) δ 162.9, 140.3, 139.2, 1341, 131.5 130.7, 129.1, 128.4, 127.8,
126.2, 94.7, 87.3, 75.7, 37.5, 28.7, 22.1 ppm; IR (CHCl3) 3084, 3065,
3027, 2969, 2926, 2864, 1946, 1659, 1635, 1583, 1492, 1468, 1434,
1367, 1329, 1291, 1248, 1166, 1080, 10032, 1009, 918 cm−1; HRMS
EI (m/z): [M]+ calcd for C18H18INO 391.0433, found 391.0437.
C16H12INO, 360.9963, found 360.9969. [α]25 −135.5 (c 1.42,
D
CHCl3).
[α]25 −71.4 (c 1.18, CHCl3).
(3aS,8aR)-2-(2-Iodo-3-methylphenyl)-8,8a-dihydro-3aH-
indeno[1,2-d]oxazole (10b). To a solution of 2-iodo-3-methyl-
benzoic acid (500 mg, 1.91 mmol) in 19.0 mL of benzene and a drop
of DMF was added SOCl2 (2.12 mL, 29.1 mmol) at 0 °C.30 After the
mixture was refluxed for 3 h, excess SOCl2 was removed under
reduced pressure using a coldfinger trap, which gave 535 mg (100%)
of the acyl chloride. To a solution of (1S,2R)-1-amino-2,3-dihydro-1H-
inden-2-ol (285 mg, 1.91 mmol) and triethylamine (0.80 mL, 5.72
mmol) in 4.8 mL of 1,4-dioxane was slowly added a solution of the
crude benzoic acyle (535 mg, 1.91 mmol) in 4.8 mL of 1,4-dioxane at
0 °C.28 The mixture was stirred for 18 h at room temperature. The
solvent was removed under reduced pressure, the reaction mixture was
diluted in DCM and water, and the layers were separated. The
aqueous layer was back-extracted three times with DCM. The
combined organic extracts were washed three times with water and
dried over Na2SO4. The solvent was removed under reduced pressure
to provide 751 mg (100%) of the crude amide. To a solution of the
amide (513 mg, 1.31 mmol) in 13.0 mL of 1,2-DCE was added MsOH
(0.53 mL, 7.83 mmol) at 0 °C. The solution was stirred for 7 h at 85
°C. The reaction mixture was diluted in DCM and NaHCO3 (aq), and
the layers were separated. The aqueous layer was back-extracted three
times with DCM. The combined organic extracts were washed three
times with water and dried over Na2SO4. The solvent was removed
under reduced pressure, and the crude mixture was purified by column
chromatography on silica gel with hexane/EtOAc (80:20 to 50:50) to
provide 286 mg (58%) of 10b as a beige solid; Tfus 104−106 °C; Rf
D
1-Iodo-2-naphthoic acid. To a solution of (1-iodonaphthalen-2-
yl)methanol29 (500 mg, 1.76 mmol) in 18.0 mL of CH3CN and 3.5
mL of water was added KMnO4 (556 mg, 3.52 mmol). The reaction
mixture was stirred for 18 h at room temperature. To the reaction
mixture was added an aqueous solution of NaHSO3, and the mixture
was stirred for 15 min. The solution was diluted in EtOAc, and the
layers were separeted. The aqueous layer was back-extracted three
times with EtOAc. The combined organic extracts were washed with
brine and dried over Na2SO4. The solvent was removed under reduced
pressure, and the crude product was diluted in benzene. The solvent
was removed under reduced pressure to provide 517 mg (98%) of the
title compound as a yellow solid; Tfus 198−202 °C; Rf 0.15 (EtOAc/
hexanes, 20:80); 1H NMR (400 MHz, CD3OD) δ 8.30 (d, J = 8.4 Hz,
1H), 7.89 (d, J = 8.3 Hz, 1H), 7.82 (d, J = 7.9 Hz, 1H), 7.65−7.50 (m,
3H) ppm; 13C NMR (100 MHz, CD3OD) δ 134.8, 134.4, 133.5,
129.0, 128.5, 128.4, 127.8, 125.0, 98.4 ppm; IR (KBr) 3041, 2686,
2362, 2005, 1965, 1925, 1682, 1456, 1402, 1269, 956, 760 cm−1;
HRMS EI (m/z): [M]+ calcd for C11H7IO2 297.9491, found 297.9493.
(S)-2-(1-Iodonaphthalen-2-yl)-4-isopropyl-5,5-dimethyl-4,5-
dihydrooxazole (9). General amide formation procedure 2: To a
solution of 1-iodo-2-naphthoic acid14 (50 mg, 0.167 mmol) and
triethylamine (26 μL, 0.185 mmol) in 1.0 mL of DCM was added a
solution of TFAA (23 μL, 0.167 mmol) in 0.7 mL of DCM at 0 °C.
The reaction mixture was stirred for 30 min at 0 °C. To this solution at
0 °C was added pyridine (14 μL, 0.167 mmol), and the reaction
mixture was stirred for 40 min. To this solution was added a solution
of triethylamine (26 μL, 0.185 mmol) and (S)-3-amino-2,4-
dimethylpentan-2-ol27 (24 mg, 0.185 mmol) in 0.5 mL of DCM at
0 °C. The reaction mixture was stirred for 18 h at room temperature.
The reaction mixture was diluted in DCM and washed with 10% citric
acid (aq). The organic layer was washed with brine and saturated
NaHCO3 (aq). The organic layer was dried over Na2SO4, and the
solvent was removed under reduced pressure to provide 36 mg (52%)
of (S)-N-(2-hydroxy-2,4-dimethylpentan-3-yl)-1-iodo-2-naphthamide.
General cyclization procedure (a) was followed: To a solution of the
amide (36 mg, 0.088 mmol) in DCM (0.8 mL) was added MsOH (34
μL, 0.528 mmol). The crude product was purified by column
chromatography on silica gel with EtOAc/hexanes (5:95 to 30:70) to
provide 24 mg (69%) of 9 as a yellow oil; Rf 0.51 (EtOAc/hexanes,
20:80); 1H NMR (400 MHz, CDCl3) δ 8.30 (d, J = 8.5 Hz, 1H), 7.82
1
0.25 (EtOAc/hexanes, 20:80); H NMR (400 MHz, CDCl3) δ 7.58−
7.53 (m, 1H), 7.30−7.20 (m, 6H), 5,78 (d, J = 7.9 Hz, 1H), 5.56−5.51
(m, 1H), 3.51−3.48 (m, 2H), 2.45 (s, 3H) ppm; 13C NMR (100 MHz,
CDCl3) δ 165.7, 142.8, 141.6, 139.8, 135.3, 131.0, 128.4, 127.7, 127.6,
127.3, 125.6, 125.1, 101.7, 83.8, 77.2, 39.5, 29.3 ppm; IR (neat) 3063,
3039, 2972, 1657, 1569, 1457, 1351, 1298, 1233, 1168, 1121, 1079,
1003, 849, 787 cm−1; HRMS EI (m/z): [M]+ calcd for C17H14INO
375.0120, found 375.0121. [α]25 −147.9 (c 1.16, CHCl3).
D
(4R,5R)-2-(2-Iodophenyl)-4-methyl-5-phenyl-4,5-dihydroox-
azole (11a).15 To a suspension of 2-iodobenzoic acid (195 mg, 0.79
mmol) in benzene (7.9 mL) was added SOCl2 (0.88 mL, 12.0 mmol)
and a drop of DMF at 0 °C. After the mixture was refluxed for 3 h, and
excess SOCl2 was removed under reduced pressure, affording the
crude acyl chloride product. A solution of the crude acyl chloride (210
mg, 0.79 mmol) in DCM (0.7 mL) was slowly added to a solution of
G
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(1S,2R)-(+)-norephedrine (119 mg, 0.79 mmol) and triethylamine
(0.11 mL, 0.79 mmol) in DCM (0.7 mL) at 0 °C. The mixture was
stirred at room temperature for 18 h. The solvent was removed under
reduced pressure, the reaction mixture was diluted in DCM and water,
and the layers were separated. The organic layer was dried over
Na2SO4, and the solvent was removed under reduced pressure to
provide 221 mg (74%) of N-((1S,2R)-1-hydroxy-1-phenylpropan-2-
yl)-2-iodobenzamide. General cyclization procedure (c): To a solution
of this amide (221 mg, 0.58 mmol) in THF (3.9 mL) was added
triphenylphosphine (189 mg, 0.72 mmol) followed by DIAD (0.14
mL, 0.72 mmol) at 0 °C. The reaction mixture was stirred at room
temperature for 18 h. The solvent was removed under reduced
pressure, and the crude mixture was purified by column chromatog-
raphy on silica gel with hexanes/EtOAc (80:20) to provide 90 mg
(43%) of 11a as a white solid; Tfus 65−67 °C, Rf 0.38 (EtOAc/
hexanes, 20:80); 1H NMR (400 MHz, CDCl3) δ 7.96 (dd, J = 8.0, 1.1
Hz, 1H), 7.71 (dd, J = 7.7, 1.7 Hz, 1H), 7.45−7.34 (m, 6H), 7.12 (dt, J
= 7.7, 1.7 Hz, 1H), 5.14 (d, J = 8.1 Hz, 1H), 4.27 (dq, J = 8.1, 6.7 Hz,
1H), 1.53 (d, J = 6.7 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ
163.1, 140.4, 139.9, 133.5, 131.6, 130.6, 128.7, 128.3, 127.8, 125.8,
94.8, 88.61, 71.1, 21.3 ppm; IR (neat) 3057, 3028, 2963, 2921, 1658,
1581, 1463, 1316, 1292, 1233, 1109, 1079, 1009, 967, 755, 725, 696
cm−1; HRMS EI (m/z): [M]+ calcd for C16H14INO 363.0120, found
363.0114. [α]D = −33.7° (c 1.32, CHCl3).
(4R,5R)-2-(2-Iodo-3-methylphenyl)-4-methyl-5-phenyl-4,5-
dihydrooxazole (11b).15 General amide formation procedure 1 was
followed: 2-iodo-3-methylbenzoic acid (1.00 g, 3.82 mmol), SOCl2
(4.2 mL, 58.2 mmol), (1S,2R)-(+)-norephedrine (578 mg, 3.82
mmol), triethylamine (0.54 mL, 3.82 mmol); 1.51 g (100%) of N-
((1S,2R)-1-hydroxy-1-phenylpropan-2-yl)-2-iodo-3-methylbenzamide.
General cyclization procedure (c) was followed: To a solution of this
amide (1.51 g, 3.82 mmol) were added triphenylphosphine (1.25 g,
4.78 mmol) and DIAD (0.94 mL, 4.78 mmol). Isolated 848 mg (59%)
of 11b as a white solid; Tfus 70−72 °C; Rf 0.68 (EtOAc/hexanes,
40:60); 1H NMR (400 MHz, CDCl3) δ 7.46−7.26 (m, 8H), 5.16 (d, J
= 8.3 Hz, 1H), 4.27 (dq, J = 8.3, 6.6 Hz, 1H), 2.51 (s, 3H), 1.55 (d, J =
6.7 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 164.4, 142.9, 139.9,
135.4, 131.1, 128.7, 128.3, 127.8, 127.6, 125.9, 101.9, 88.7, 71.1, 29.5,
21.1 ppm; IR (neat) 3057, 3028, 2968, 2921, 1666, 1446, 1316, 1127,
1079, 1009, 967, 790, 749, 698 cm−1; HRMS EI (m/z): [M]+ calcd for
C17H16INO 377.0277, found 377.0278. [α]25D −23.2 (c 1.10, CHCl3).
(4R,5R)-2-(3-Ethyl-2-iodophenyl)-4-methyl-5-phenyl-4,5-di-
hydrooxazole (11c). A solution of 3-ethylanthranilic acid (1.02 g,
6.16 mmol) and H2SO4 (2.00 mL, 38.2 mmol) in water (13.5 mL) was
heated until the acid was completely dissolved. After cooling to 10 °C,
a solution of NaNO2 (425 mg, 6.16 mmol) in water (0.95 mL) was
added. The resulting mixture was added to a solution of KI (3.07 g,
18.5 mmol) in water (14.5 mL), and the mixture was heated to 100 °C
for 20 min. After cooling to room temperature, the mixture was cooled
to −20 °C for 2 h. The resulting precipitate was collected and air-
dried, and the solid was dissolved in Na2CO3 (aq). The solution was
filtrated, reacidified with HCl conc, and cooled to −20 °C for 1 h. The
resulting precipitate was collected and dried to provide 1.26 g (74%)
of 2-iodo-3-ethylbenzoic acid. General amide formation procedure 1
was followed: 2-iodo-3-ethylbenzoic acid (205 mg, 0.743 mmol),
SOCl2 (0.83 mL, 11.3 mmol); 2-iodo-3-methylbenzoyl chloride (218
mg, 0.743 mmol), (1S,2R)-(−)-norephedrine (112 mg, 0.741 mmol),
triethylamine (0.10 mL, 0.736 mmol); 291 mg (96%) of 3-ethyl-N-
((1R,2S)-1-hydroxy-1-phenylpropan-2-yl)-2-iodobenzamide as a yel-
low oil. General cyclization procedure (c) was followed: To a solution
of this amide (291 mg, 0.711 mmol) was added triphenylphosphine
(233 mg, 0.888 mmol) followed by DIAD (0.18 mL, 0.890 mmol).
The crude mixture was purified by column chromatography on silica
gel with EtOAc/hexanes (5:95 to 50:50) to provide 116 mg (42%) of
11c as a colorless oil; Rf 0.34 (EtOAc/hexanes, 20:80); 1H NMR (400
MHz, CDCl3) δ 7.48−7.24 (m, 8H), 5.16 (d, J = 8.3 Hz, 1H), 4.27
(dq, J = 8.2, 6.6. Hz, 1H), 2.84 (q, J = 7.5 Hz, 2H), 1.55 (d, J = 6.6 Hz,
3H), 1.22 (t, J = 7.5 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ
164.6, 147.9, 139.9, 135.8, 129.9, 128.7, 128.3, 128.1, 127.7, 125.9,
101.1, 88.8, 71.1, 35.0, 21.1, 14.6 ppm; IR (neat) 3062, 3032, 2967,
2928, 2870, 1667, 1573, 1495, 1455, 1414, 1372, 1331, 1319, 1301,
1173, 1130, 1086, 1010, 976, 903, 799, 756, 726, 699 cm−1; HRMS EI
(m/z): [M]+ calcd for C18H18INO 391.0433, found 391.0441. [α]25
D
−21.2 (c 0.49, CHCl3).
(5S,6S,9R)-2-(2-Iodo-3-methylphenyl)-6-isopropyl-9-methyl-
3-oxa-1-azaspiro[4.5]dec-1-ene (12). General amide formation
procedure 1 was followed: 2-iodo-3-methylbenzoic acid (283 mg, 1.08
mmol), SOCl2 (1.20 mL, 16.5 mmol), ((1S,2S,5R)-1-amino-2-
isopropyl-5-methylcyclohexyl)methanol31 (200 mg, 1.08 mmol),
triethylamine (0.46 mL, 3.24 mmol); 438 mg (94%) of N-
((1S,2S,5R)-1-(hydroxymethyl)-2-isopropyl-5-methylcyclohexyl)-2-
iodo-3-methylbenzamide. General cyclization procedure (b) was
followed: To a solution of this amide (329 mg, 0.77 mmol) was
added MsOH (0.31 mL, 4.60 mmol). The crude product was purified
by column chromatography on silica gel with EtOAc/hexanes (20:80)
to provide 227 mg (72%) of 12 as a white solid; Tfus 72−74 °C, Rf 0.83
1
(EtOAc/hexanes, 20:80); H NMR (400 MHz, CDCl3) δ 7.27−7.21
(m, 3H), 4.37 (d, J = 8.3 Hz, 1H), 3.94 (d, J = 8.3 Hz, 1H), 2.47 (s,
3H), 2.10−1.97 (m, 2H), 1.93 (ddd, J = 13.0, 3.5, 2.3 Hz, 1H), 1.87−
1.80 (m, 1H), 1.71 (ddd, J = 25.8, 13.0, 3.5 Hz, 1H), 1.58 (dq, J =
13.3, 3.5 Hz, 1H), 1.23 (ddd, J = 12.4, 3.7, 1.0 Hz, 1H), 1.15 (dd, J =
22.1, 9.5 Hz, 1H), 1.01−088 (m, 10H) ppm; 13C NMR (100 MHz,
CDCl3) δ 163.3, 142.7, 136.4, 130.7, 127.8, 127.2, 102.0, 77.8, 75.4,
50.3, 49.7, 35.2, 29.3, 28.6, 26.3, 24.2, 22.5, 22.4, 18.6 ppm; IR (neat)
3051, 2950, 2906, 2866, 1658, 1575, 1451, 1357, 1316, 1286, 1127,
1079, 1009, 973, 932, 784, 719 cm−1; HRMS EI (m/z): [M]+ calcd for
C19H26INO 411.1059, found 411.1061. [α]25D +16.2 (c 0.97, CHCl3).
(4S,4′S)-2,2′-(2-Iodo-1,3-phenylene)bis(4-isopropyl-5,5-di-
methyl-4,5-dihydrooxazole) (13). General amide formation
procedure 2 was followed: 2-iodoisophthalic acid32 (100 mg, 0.342
mmol), TFAA (96 μL, 0.684 mmol), DMAP instead of pyridine (92
mg, 0.754 mmol), triethylamine (106 μL, 0.754 mmol), (S)-3-amino-
2,4-dimethylpentan-2-ol27 (99 mg, 0.752 mmol). Isolated 102 mg,
0.197 mmol (58%) of the amide as a beige solid. General cyclization
procedure (b) was followed: To a solution of this amide was added
MsOH (77 μL, 1.18 mmol). Isolated 73 mg (77%) of 13 a yellow oil;
Rf 0.15 (EtOAc/hexanes, 60:40); 1H NMR (400 MHz, CDCl3) δ 7.50
(d, J = 7.7 Hz, 2H), 7.35 (dd, J = 8.0, 7.2 Hz, 1H), 3.51 (d, J = 8.1 Hz,
2H), 2.00−1.88 (m, 2H), 1.55 (s, 6H), 1.45 (s, 6H), 1.15 (d, J = 6.5
Hz, 6H), 1.03 (d, J = 6.6 Hz, 6H) ppm; 13C NMR (100 MHz, CDCl3)
δ 162.8, 136.9, 131.5, 127.6, 95.7, 87.6, 80.9, 29.5, 29.1, 21.6, 21.3, 20.7
ppm; IR (neat) 2968, 2927, 2868, 1658, 1575, 1457, 1369, 1286, 1239,
1192, 1115, 1068, 1021, 938, 837, 784, 719 cm−1; HRMS EI (m/z):
[M]+ calcd for C22H31IN2O2 482.1430, found 482.1432. [α]25
−47.1 (c 0.48, CHCl3).
=
D
General Procedure for Catalyst Evaluation on Substrate 14
(Table 1). To a solution of the catalyst 11b (0.024 mmol) in 1.3 mL
of CH3CN was added p-TsOH·H2O (138 mg, 0.73 mmol) and m-
CPBA 77% (162 mg, 0.72 mmol). To this solution was added
propiophenone (34 mg, 0.25 mmol). The resulting solution was
stirred at room temperature for 48 h and then quenched with Na2S2O3
(aq). The aqueous layer was extracted with AcOEt (3×). The
combined organic layers were washed twice with NaHCO3 (aq) and
brine and dried over Na2SO4. The solvent was removed under reduced
pressure, and the crude mixture was purified by column chromatog-
raphy on silica gel with EtOAc/hexanes (5:95 to 20:80) to provide 46
mg (60%) of 15 as a white solid of the S enantiomer (33% ee), Rf 0.42,
1
(EtOAc/hexanes, 20:80); H NMR (300 MHz, CD3CN) 7.86 (d, J =
7.0 Hz, 2H), 7.74 (d, J = 8.2 Hz, 2H), 7.58 (t, J = 7.4 Hz, 1H), 7.44 (t,
J = 7.7 Hz, 2H), 7.25 (d, J = 8.1 Hz, 2H), 5.78 (q, J = 7.0 Hz, 1H),
2.39 (s, 3H), 1.58 (d, J = 7.0 Hz, 3H) ppm. The ee was determined by
HPLC on the purified product: Chiracel AS-H column, 50:50
hexanes/i-PrOH, 0.7 mL/min, rt, tR = 10.1 min (S), tR = 11.6 min
(R).3c
2-Iodo-3-methylbenzaldehyde. The title compound was
obtained following a literature procedure33 using (2-iodo-3-
methylphenyl)methanol (4.02 g, 16.2 mmol) and PCC (4.19 g, 19.5
mmol). The crude product was purified by flash chromatography with
EtOAc/hexanes (10:90) to provide 3.6 g (90%) of the title compound
1
as a white solid; Tfus 46−48 °C, Rf 0.87 (EtOAc/hexanes, 20:80); H
H
dx.doi.org/10.1021/jo302393u | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
NMR (400 MHz, CDCl3) δ 10.21 (s, 1H), 7.66 (dd, J = 7.6, 1.7 Hz,
1H), 7.47 (dd, J = 7.3, 1.1 Hz, 1H), 7.32 (t, J = 7.5 Hz, 1H), 2.52 (s,
3H) ppm; 13C NMR (100 MHz, CDCl3) δ 197.0, 143.2, 135.9, 135.3,
128.2, 127.6, 108.0, 28.5 ppm; IR (neat) 3065, 2979, 2855, 2731, 1690,
1673, 1570, 1447, 1371, 1236, 1016, 907, 779, 694 cm−1; HRMS EI
(m/z): [M]+ calcd for C8H7IO 245.9542, found 245.9547.
chromatography on silica gel with EtOAc/hexanes (15:85) to provide
11 mg (23%) of 17 as a colorless oil; Rf 0.71 (EtOAc/hexanes, 40:60);
1H NMR (400 MHz, CDCl3) δ 7.31−7.22 (m, 3H), 4.46 (ddd, J = 9.7,
8.5, 7.1 Hz, 1H), 4.07 (dd, J = 14.5, 9.8 Hz, 1H), 3.79 (dd, J = 14.5, 8.5
Hz, 1H), 2.50 (s, 3H), 1.98 (d, J = 12.9 Hz, 1H), 1.83−1.60 (m, 5H),
1.35−1.00 (m, 5H) ppm; 13C NMR (100 MHz, CDCl3) δ 165.8,
142.9, 135.9, 131.0, 127.7, 127.6, 101.8, 84.8, 58.1, 42.3, 29.6, 28.7,
28.0, 26.4, 25.8, 25.6 ppm; IR (neat) 2927, 2852, 1729, 1662, 1574,
1463, 1449, 1405, 1340, 1263, 1238, 1175, 1125, 1088, 1012, 974, 927,
888, 839 cm−1; HRMS EI (m/z): [M]+ calcd for C16H20INO
(R)-tert-Butyl (2-Cyclohexyl-2-hydroxyethyl)carbamate. The
title compound was obtained following a literature procedure34 using
2-cyclohexyloxirane35 (516 mg, 4.09 mmol), (S,S)-(salen)CoII
complex (49.5 mg, 0.08 mmol), p-nitrobenzoic acid (26.7 mg, 0.16
mmol), and tert-butylcarbamate (218 mg, 1.86 mmol). The crude
product was purified by column chromatography on silica gel with
EtOAc/hexanes (30:70) to provide 318 mg (70%) of the title
369.0590, found 369.0587. [α]25 +8.53 (c 0.95, CHCl3).
D
(4R,5S)-2-(2-Iodo-3-methylphenyl)-4-methyl-5-phenyl-4,5-
dihydrooxazole (18). To a solution of (1R,2S)-(−)-norephedrine
(122 mg, 0.807 mmol) in 4.8 mL of DCM was added 2-iodo-3-
methylbenzaldehyde14 (200 mg, 0.813 mmol). After the reaction
mixture was stirred with 1.30 g of 4 Å MS for 16h at room
temperature, NBS (144 mg, 0.809 mmol) was added. The reaction
mixture was stirred for 45 min at room temperature. The solution was
filtered on Celite and washed with NaHCO3 (aq) and brine. The
organic layer was dried over Na2SO4, and the solvent was removed
under reduced pressure. The crude product was purified by flash
chromatography with EtOAc/hexanes/Et3N (19:80:1) to provide 153
mg (50%) of 18 as a colorless oil; Rf 0.33 (EtOAc/hexanes, 30:70); 1H
NMR (400 MHz, CDCl3) δ 7.42−7.26 (m, 8H), 5.82 (d, J = 9.7 Hz,
1H), 4.67 (dq, J = 9.7, 7.0 Hz, 1H), 2.52 (s, 3H), 0.91 (d, J = 7.0 Hz,
3H) ppm; 13C NMR (100 MHz, CDCl3) δ 164.6, 142.9, 136.5, 135.5,
131.1, 128.1, 127.7, 126.1, 101.8, 84.6, 65.7, 29.5, 17.5 ppm; IR (neat)
3063, 3032, 2974, 2928, 1664, 1574, 1495, 1450, 1402, 1376, 1342,
1316, 1301, 1248, 1170, 1125, 1091, 1012, 967, 907, 788, 731, 698
cm−1; HRMS EI (m/z): [M]+ calcd for C17H16INO 377.0277, found
1
compound (>99% ee) as a dark orange oil. H NMR (300 MHz,
CDCl3) δ 4.89 (s, 1H), 3.46−3.30(m, 2H), 3.11−2.98 (m, 1H), 1.90−
1.60 (m, 6H), 1.45 (s, 9H), 1.29−0.94 (m, 5H) ppm.
(R)-tert-Butyl (2-Hydroxy-2-phenylethyl)carbamate. Title
compound was obtained following a literature procedure34 using
styrene oxide (2.1 mL, 18.2 mmol), (S, S)-(salen)CoII complexe (200
mg, 0.331 mmol), p-nitrobenzoic acid (111 mg, 0.662 mmol), and tert-
butylcarbamate (970 mg, 8.28 mmol). The crude product was purified
by flash chromatography with toluene/Et2O (30:70) to provide 541
1
mg (51%) of the title compound (>99% ee) as a colorless oil. H
NMR (300 MHz, CDCl3) δ 7.37−7.23 (m, 5H), 5.02 (bs, 1H), 4.84−
4.73 (m, 1H), 3.53−3.35 (m, 1H), 3.30−3.14 (m, 1H), 3.01 (bs, 1H),
1.44 (s, 9H) ppm.
(R)-2-(2-Iodo-3-methylphenyl)-5-phenyl-4,5-dihydrooxazole
(16). To a suspension of (R)-tert-butyl (2-hydroxy-2-phenylethyl)-
carbamate14 (472 mg, 1.99 mmol) in dichloromethane (6.0 mL) was
added TFA (4.0 mL, 51.7 mmol). The mixture was stirred at room
temperature for 6 h, and the solvent was removed under reduced
pressure to provide the corresponding amino alcohol as the TFA salt
in quantitative yield. To a solution of amino alcohol TFA salt (30 mg,
0.122 mmol) in 1.1 mL of toluene was added an excess of K2CO3, and
the mixture was stirred for 5 min. To the solution was added 180 mg
of 4 Å MS and 2-iodo-3-methylbenzaldehyde (30 mg, 0.122 mmol).
The reaction mixture was stirred for 16 h at room temperature. NBS
(22 mg, 0.122 mmol) was then added, and the reaction was stirred 5
min with K3PO4 (78 mg, 0.366 mmol). The mixture was stirred for 5 h
and filtered on Celite to remove the molecular sieve. The organic layer
was washed with saturated solution of NaHCO3 (aq) and brine. The
organic layer was dried over Na2SO4, and the solvent was removed
under reduced pressure. The crude mixture was purified by column
chromatography on silica gel with EtOAc/hexanes (5:95 to 40:60) to
provide 10 mg (23%) of 16 as a colorless oil; Rf 0.53 (EtOAc/hexanes,
30:70); 1H NMR (400 MHz, CDCl3) δ 7.47−7.25 (m, 8H), 5.70 (dd,
J = 9.9, 9.2 Hz, 1H), 4.54 (dd, J = 14.7, 10.2 Hz, 1H), 4.05 (dd, J =
14.7, 8.8 Hz, 1H), 2.52 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ
165.4, 143.1, 140.3, 135.2, 131.2, 128.7, 128.3, 127.8, 127.7, 126.1,
101.9, 81.6, 63.3, 29.6 ppm; IR (neat) 3063, 3033, 2951, 2868, 1664,
1569, 1457, 1333, 1257, 1168, 1122, 1084, 1012, 938, 784, 759, 698
cm−1; HRMS EI (m/z): [M]+ calcd for C16H14INO 363.0120, found
377.0271. [α]25 +157.9 (c 0.79, CHCl3).
D
(4R,5R)-2-(2-Iodo-3-methylphenyl)-3,4-dimethyl-5-phenyl-
4,5-dihydrooxazolium Tetrafluoroborate (19). The title com-
pound was obtained as colorless oil (94% yield) according to the
following procedure: 11b (28 mg, 0.074 mmol) was dissolved in
CH3Cl (0.5 mL). MeI (31 mg, 0.215 mmol) was added then the
reaction mixture was heated at 80 °C for 3 h. The solvent was removed
under reduced pressure, and the resulting solid was washed with
diethyl ether. The solid was dissolved in CH2Cl2 (1 mL), and AgBF4
(14 mg, 0.074 mg) was added. The reaction mixture was stirred for 5
min, and the resulting precipitate was removed by filtration. The
solvent was evaporated under reduced pressure to provide the salt 19
(94%) as a deliquescent solid; 1H NMR (400 MHz, CDCl3) δ 7.88 (d,
J = 5.6 Hz, 1H), 7.67 (d, J = 3.7 Hz, 2H), 7.62−7.43 (m, 6H), 5.93 (s,
1H), 4.85 (s, 1H), 3.32 (s, 3H), 2.54 (s, 3H), 1.76 (d, J = 6.4 Hz, 3H)
ppm; 13C NMR (101 MHz, CDCl3) δ 173.7, 143.7, 134.6, 132.1,
131.4, 130.1, 129.8, 129.2, 128.4, 127.9, 99.1, 94.1, 66.6, 33.2, 28.6,
15.0 ppm; 19F NMR (377 MHz, CDCl3) δ −152.26 ppm; IR (neat)
1664, 1433, 1389, 1290, 1212, 1059, 917, 887, 799, 764, 700 cm−1;
HRMS ESI (m/z): calcd for C18H19INO+ [M−BF4]+ 392.0506, found
392.0514; [α]25 +24.2° (c 0.9, CHCl3).
D
(4S,5S)-2-(3-(Trifluoromethyl)-2-iodophenyl)-4,5-dihydro-4-
methyl-5-phenyloxazole (11d). 2-Amino-3-trifluoromethylbenzoic
acid (1 g, 4.87 mmol) was dissolved at 0 °C into concentrated HCl (3
mL). The solution was stirred at 0 °C for 15 min, and then ice (2 g)
was added. After 10 min a solution of NaNO2 (370 mg, 5.36 mmol) in
water (2 mL) was added and stirred for 10 min. A solution of KI
(3.56g, 21.4 mmol) in water (6 mL) was then added. The reaction
mixture was stirred at room temperature for 16 h. The reaction
mixture was extracted with ethyl acetate (3 × 20 mL), and the
combined organic layers were washed with saturated Na2S2O3 (aq)
and brine. The organic layer was dried over MgSO4, and the solvent
was removed under reduced pressure to provide 1.37g (93%) of 2-
iodo-3-trifluoromethylbenzoic acid as a beige solid that was used
without further purification. To a supsension of 2-iodo-3-trifluor-
omethylbenzoic acid (720.5 mg, 2.28 mmol) in benzene (22.6 mL)
was added SOCl2 (2.49 mL, 34.2 mmol) and a drop of DMF at 0 °C.
The reaction mixture was refluxed for 3 h, and then the excess SOCl2
was removed under reduced pressure, affording the crude acyl chloride
product. A solution of the crude acyl chloride (762.6 mg, 2.28 mmol)
363.0114. [α]25 −59.6 (c 1.10, CHCl3).
D
(R)-5-Cyclohexyl-2-(2-iodo-3-methylphenyl)-4,5-dihydroox-
azole (17). To a suspension of (R)-tert-butyl (2-cyclohexyl-2-
hydroxyethyl)carbamate14 (229 mg, 0.941 mmol) in 2.8 mL of
DCM was added TFA (1.9 mL, 24.5 mmol). The mixture was stirred
at room temperature for 3 h, and the solvent was removed under
reduced pressure to provide the corresponding amino alcohol as the
TFA salt in quantitative yield.15 General amide formation procedure 1
was followed: 2-Iodo-3-methylbenzoic acid (267 mg, 1.02 mmol),
SOCl2 (1.13 mL, 15.6 mmol); the crude acyl chloride (286 mg, 1.02
mmol), amino alcohol TFA salt (262 mg, 1.02 mmol), triethylamine
(0.29 mL, 2.04 mmol). The crude product was purified by flash
chromatography with EtOAc/hexanes (30:70) to provide 112 mg
(28%) of (S)-N-(2-cyclohexyl-2-hydroxyethyl)-2-iodo-3-methylbenza-
mide as a white solid. General cyclization procedure (c) was followed:
To a solution of the amide (49 mg, 0.127 mmol) was added
triphenylphosphine (42 mg, 0.160 mmol) followed by DIAD (32 μL,
0.158 mmol). The crude mixture was purified by column
I
dx.doi.org/10.1021/jo302393u | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
in DCM (4.4 mL) was slowly added to a solution of (1R,2S)-
(−)-norephedrine (299.2 mg, 2.28 mmol) and triethylamine (0.32 mL,
2.28 mmol) in CH2Cl2 (4.4 mL) at 0 °C. The mixture was stirred at
room temperature for 18 h. The solvent was removed under reduced
pressure, and the reaction mixture was washed with a solution of citric
acid (10% in water) and with saturated Na2S2O3 and brine. The
organic layer was dried over MgSO4, and the solvent was removed
under reduced pressure to provide 1.02 g (100%) of 3-
(trifluoromethyl)-N-((1R,2R)-1-hydroxy-1-phenylpropan-2-yl)-2-iodo-
benzamide. To a solution of this amide (1.02 g, 2.28 mmol) in THF
(15 mL) was added triphenylphosphine (747.5 mg, 2.85 mmol),
followed by DIAD (0.59 mL, 2.85 mmol) at 0 °C. The reaction
mixture was stirred at room temperature for 18 h. The solvent was
removed under reduced pressure, and the crude mixture was purified
by column chromatography on silica gel with hexanes/EtOAc (80:20)
and then toluene/acetonitrile to provide 393.3 mg (40%) of 11d as a
light yellow oil. Rf = 0.49 (20% EtOAc/hexanes); 1H NMR (300 MHz,
CDCl3) δ 7.77−7.62 (m, 2H), 7.52 (t, J = 7.7 Hz, 1H), 7.47−7.30 (m,
5H), 5.20 (d, J = 8.4 Hz, 1H), 4.30 (dq, J = 8.3, 6.7 Hz, 1H), 1.56 (d, J
= 6.7 Hz, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 163.8 (s), 145.0
(s), 139.4 (s), 138.5 (s), 134.8 (s), 129.0 (d, J = 5.6 Hz), 128.9 (s),
128.6 (s), 128.1 (s), 125.9 (s), 122.7 (d, J = 274.6 Hz), 92.9 (s), 89.2
(s), 71.1 (s), 21.0 (s) ppm; IR (neat) 1669, 1418, 1298, 1195, 175,
1137, 1064, 971, 807, 699 cm−1; HRMS ESI (m/z): calcd for
reduced pressure. The crude mixture was dissolved in 7.7 mL of
MeCN/H2O (25:1), and NaH2PO4·H2O (31 mg, 0.224 mmol), 50%
H2O2 (0.13 mL, 2.24 mmol), and a solution of 80% NaClO2 (253 mg,
2.24 mmol) in 0.29 mL of water were added at 0 °C. After the reaction
mixture was stirred for 1 h at room temperature, a saturated solution of
NaHSO3 (aq) and a solution of HCl (1 N) were added. The organic
layer was extracted tree times with EtOAc. The organic layer was dried
over Na2SO4, and the solvent was removed under reduced pressure to
yield 561 mg (86%) of the crude benzoic acid as a white solid, which
was used without further purification. General amide formation
procedure 1 was followed: The crude benzoic acid (200 mg, 0.685
mmol), SOCl2 (0.76 mL, 10.4 mmol); the crude benzoic acyl chloride
(212 mg, 0.685 mmol), (1R,2S)-(−)-norephedrine (104 mg, 0.685
mmol), triethylamine (96 μL, 0.685 mmol); 263 mg (90%) of N-
((1R,2S)-1-hydroxy-1-phenylpropan-2-yl)-2-iodo-5-methoxy-3-meth-
ylbenzamide as a yellow oil. General cyclization procedure (c) was
followed: To a solution of this amide (263 mg, 0.618 mmol) was
added triphenylphosphine (205 mg, 0.782 mmol) followed by DIAD
(0.15 mL, 0.762 mmol). The crude mixture was purified by column
chromatography on silica gel first with EtOAc/hexanes (5:95 to 50:50)
then with acetone/toluene (0:100 to 10:90) to provide 133 mg (53%)
1
of 11f as a colorless oil; Rf 0.44 (EtOAc/hexanes, 40:60); H NMR
(400 MHz, CDCl3) δ 7.46−7.31 (m, 5H), 6.97 (d, J = 3.0 Hz, 1H),
6.91 (dd, J = 3.0, 0.5 Hz, 1H), 5.15 (d, J = 8.4 Hz, 1H), 4.25 (dq, J =
8.4, 6.6 Hz, 1H), 3.80 (s, 3H), 2.48 (s, 3H), 1.54 (d, J = 6.7 Hz, 3H)
ppm; 13C NMR (100 MHz, CDCl3) δ 164.3, 159.2, 144.0, 139.8,
135.9, 128.7, 128.3, 125.9, 117.8, 113.0, 90.6, 88.9, 71.1, 55.5, 29.5,
21.1 ppm; IR (neat) 3065, 3031, 2965, 2926, 2840, 1667, 1588, 1494,
1461, 1339, 1260, 1206, 1172, 1129, 1057, 1012, 964, 911, 851, 797,
757, 734, 698 cm−1; HRMS EI (m/z): [MH]+ calcd for C18H19INO2
C17H14F3INO+ [MH]+ 432.0067, found 432.0074; [α]25 = +5.8° (c
D
0.5,CHCl3).
(4S,5S)-2-(2-Iodo-3-methoxyphenyl)-4-methyl-5-phenyl-4,5-
dihydrooxazole (11e). A solution of 2-amino-3-methoxybenzoic
acid (2.00 g, 12.0 mmol) and H2SO4 (4.0 mL, 74.2 mmol) in water
(26.0 mL) was heated until the acid dissolved. After cooling to room
temperature, a solution of NaNO2 (825 mg, 12.0 mmol) in water (1.84
mL) was added at 10 °C. The resulting solution was added to a
solution of KI (5.95 g, 36.0 mmol) in water (27.0 mL), and the
mixture was heated at 140 °C over 45 min. After cooling to room
temperature, the mixture was cooled to −20 °C for 2 h. The resulting
precipitate was filtered, and the solid was dissolved in Na2CO3 (aq).
The solution was filtered, reacidified with HCl conc to pH < 2 and
cooled to −20 °C for 1 h. The resulting precipitate was collected, air-
dried for 10 min, and dried under reduced pressure 1 h to provide 2.80
g (84%) of 2-iodo-3-methoxybenzoic acid as a beige solid which was
used without further purification. General amide formation procedure
1 was followed: 2-Iodo-3-methoxybenzoic acid (1.00 g, 3.60 mmol),
SOCl2 (4.0 mL, 54.9 mmol), 2-iodo-3-methoxybenzoyl chloride (1.07
g, 3.60 mmol), (1R,2S)-(−)-norephedrine (544 mg, 3.60 mmol),
triethylamine (0.51 mL, 3.60 mmol); 228 mg (81%) of N-((1S,2R)-1-
hydroxy-1-phenylpropan-2-yl)-2-iodo-3-methoxybenzamide as a beige
solid. General cyclization procedure (c) was followed: To a solution of
this amide (1.42 g, 3.45 mmol) was added triphenylphosphine (1.13 g,
4.31 mmol) followed by DIAD (0.85 mL, 4.31 mmol). The crude
mixture was purified by column chromatography on silica gel first with
EtOAc/hexanes (10:90 to 30:70) and then with CH2Cl2 to provide
744 mg (55%) of 11e as a white solid; Tfus 44−46 °C; Rf 0.23 (EtOAc/
408.0461, found 408.0464. [α]25 +25.4 (c 0.56, CHCl3).
D
(4S,5S)-2-(5-Chloro-2-iodo-3-methylphenyl)-4-methyl-5-
phenyl-4,5-dihydrooxazole (11g). A solution of 2-amino-5-chloro-
3-methylbenzoic acid (590 mg, 2.69 mmol) and H2SO4 (0.89 mL, 16.7
mmol) in water (5.8 mL) was heated until the acid was completely
dissolved. After, cooling to 10 °C, a solution of NaNO2 (186 mg, 2.69
mmol) in water (0.41 mL) was added. The resulting solution was
added to a solution of KI (1.34 g, 8.07 mmol) in water (6.2 mL), and
the mixture was heated to 130 °C over 30 min. After cooling to room
temperature, the mixture was cooled to −20 °C for 2 h. The resulting
precipitate was collected and air-dried, and the solid was dissolved in
Na2CO3 (aq). The solution was filtered, reacidified with HCl conc,
and cooled to −20 °C for 1 h. The resulting precipitate was collected
and dried to provide 471 mg (59%) of 5-chloro-2-iodo-3-
methylbenzoic acid. General amide formation procedure 1 was
followed: The crude benzoic acid (471 mg, 1.59 mmol), SOCl2 (1.8
mL, 24.7 mmol); crude benzoic acyl chloride (501 mg, 1.59 mmol),
(1R,2S)-(−)-norephedrine (240 mg, 1.59 mmol), triethylamine (0.22
mL, 1.59 mmol); 617 mg (90%) of 5-chloro-N-((1R,2S)-1-hydroxy-1-
phenylpropan-2-yl)-2-iodo-3-methylbenzamide as a yellow oil. To a
solution of this amide (600 mg, 1.40 mmol) was added
triphenylphosphine (458 mg, 1.75 mmol) followed by DIAD (0.35
mL, 1.75 mmol). The crude mixture was purified by column
chromatography on silica gel first with EtOAc/hexanes (5:95 to
50:50), second with acetone/toluene (5:95), and then with EtOAc/
hexanes (5:95 to 15:85) to provide 249 mg (43%) of 11g as a colorless
1
hexanes, 20:80); H NMR (300 MHz, CDCl3) δ 7.46−7.30 (m, 6H),
7.23 (dd, J = 7.6, 1.2 Hz, 1H), 6.89 (dd, J = 8.2, 1.2 Hz, 1H), 5.15 (d, J
= 8.2 Hz, 1H), 4.27 (dq, J = 13.3, 6.7 Hz, 1H) 3.90 (s, 3H), 1.54 (d, J
= 6.7 Hz) ppm; 13C NMR (100 MHz, CDCl3) δ 163.7, 158.5, 139.9,
136.2, 129.3, 128.7, 128.3, 125.9, 122.8, 112.3, 88.8, 88.0, 71.1, 56.7,
21.2 ppm; IR (neat) 3067, 3030, 2965, 2925, 2854, 1667, 1585, 1565,
1494, 1465, 1422, 1373, 1324, 1264, 1179, 1134, 1093, 1041, 972, 911
cm−1; HRMS EI (m/z): calcd for C17H16INO2 [M]+ 393.0226, found
393.0232. [α]25 +23.5 (c 0.80, CHCl3).
1
oil; Rf 0.43 (EtOAc/hexanes, 20:80); H NMR (400 MHz, CDCl3) δ
7.44−7.29 (m, 7H), 5.15 (d, J = 8.4 Hz, 1H), 4.27 (dq, J = 8.4, 6.5 Hz,
1H), 2.49 (s, 3H), 1.53 (d, J = 6.6 Hz, 3H) ppm; 13C NMR (100
MHz, CDCl3) δ 163.2, 144.7, 139.6, 136.6, 134.0, 130.9, 128.8, 128.4,
127.6, 125.9, 99.3, 89.0, 71.1, 29.3, 21.1 ppm; IR (neat) 3031, 2965,
2924, 1667, 1565, 1495, 1453, 1406, 1375, 1317, 1301, 1140, 1012,
974, 955, 885, 867, 773, 755, 698 cm−1; HRMS EI (m/z): [MH]+
(4S,5S)-2-(2D-Iodo-5-methoxy-3-methylphenyl)-4-methyl-5-
phenyl-4,5-dihydrooxazole (11f). To a solution of (2-iodo-5-
methoxy-3-methylphenyl)methanol36 (622 mg, 2.24 mmol) in 7.2 mL
of acetone was added dropwise Jones reagent (0.72 mL, 1.95 mmol of
CrO3) at 0−5 °C. The reaction mixture was stirred for 20 min at 0 °C
and stirred for 18 h at room temperature. The reaction mixture was
diluted in EtOAc, and NaHSO3 (aq) was added. The solution was
poured into HCl 1 N and extracted with EtOAc tree times. The
organic layer was dried over Na2SO4 and the solvent removed under
calcd for C17H16ClINO 411.9965, found 411.9989. [α]25 +23.6 (c
D
0.75, CHCl3).
(4S,5S)-2-(5-Fluoro-2-iodo-3-methylphenyl)-4,5-dihydro-4-
methyl-5-phenyloxazole (11h). 3-Fluoro-5-methylbenzoic acid (1g,
6.49 mmol) and KNO3 (721 mg, 7.13 mmol) were dissolved in
concentrated H2SO4 (8 mL) at 0 °C. The mixture was stirred at room
temperature for 1 h. Water (15 mL) was added, and the resulting
J
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The Journal of Organic Chemistry
Article
precipitate was filtered and dried to provide 879.5 mg (68%) of 5-
fluoro-3-methyl-2-nitrobenzoic acid, which was used without further
purification. 5-Fluoro-3-methyl-2-nitrobenzoic acid (770 mg, 3.87
mmol) and SnCl2 (4.36g, 19.33 mmol) were dissolved in ethanol (7.7
mL). The mixture was heated at 70 °C for 30 min. After cooling at
room temperature, the pH was adjusted to 7−8 with saturated
NaHCO3 (aq). The mixture was extracted with EtOAc, and the
organic layer was washed with brine, filtered through Celite, and dried
over MgSO4 to provide 2-amino-5-fluoro-3-methylbenzoic acid (629.2
mg, 3.71 mmol), which was used without further purification. 2-
Amino-5-fluoro-3-methylbenzoic acid (465.5 mg, 2.75 mmol) was
dissolved at 0 °C into concentrated HCl (1.5 mL). After 15 min under
stirring, ice (1 g) was added at 0 °C. After 10 min a solution of NaNO2
(208.9 mg, 3.03 mmol) in water (1 mL) was added. After 10 min a
solution of KI (1.83g, 11.0 mmol) in water (3 mL) was added. The
mixture was stirred at room temperature for 16 h. The reaction
mixture was extracted with EtOAc, and the combined organic layers
were washed with saturated Na2S2O3 (aq) and brine. The organic layer
was dried over MgSO4, and the solvent was removed under reduced
pressure to provide 287 mg (37%) of 2-iodo-5-fluoro-3-methylbenzoic
acid as a beige solid. General amide formation procedure 1 was
followed: The crude benzoic acid (287 mg, 1.10 mmol); SOCl2 (1.2
mL, 16.5 mmol); crude benzoic acyl chloride (303.4 mg, 1.02 mmol),
(1R,2S)-(−)- norephedrine (133.8 mg, 1.02 mmol) and triethylamine
(0.144 mL, 1.02 mmol); 422 mg (100%) of 5-fluoro-N-((1R,2R)-1-
hydroxy-1-phenylpropan-2-yl)-2-iodo-3-methylbenzamide. To a sol-
ution of this amide (421.5 g, 1.02 mmol) in THF (6.8 mL) was added
triphenylphosphine (334.4 g, 1.28 mmol) followed by DIAD (0.279
mL, 1.28 mmol) at 0 °C. The reaction mixture was stirred at room
temperature for 18 h. The solvent was removed under reduced
pressure, and the crude mixture was purified by column chromatog-
raphy on silica gel with hexanes/EtOAc (80:20) then toluene/
acetonitrile to provide 192.6 mg (43%) of 11h as a light yellow oil; Rf
= 0.45 (20% EtOAc/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.47−
7.29 (m, 5H), 7.17 (dd, J = 8.4, 3.0 Hz, 1H), 7.08 (dd, J = 9.0, 2.9 Hz,
1H), 5.15 (d, J = 8.4 Hz, 1H), 4.27 (dq, J = 13.3, 6.7 Hz, 1H), 2.51 (s,
3H), 1.54 (d, J = 6.6 Hz, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ
163.4 (s), 162.1 (d, J = 248.1 Hz), 145.3 (d, J = 7.5 Hz), 139.6 (s),
136.6 (d, J = 8.4 Hz), 128.8 (s), 128.5 (s), 125.9 (s), 118.2 (d, J = 21.4
Hz), 115.1 (d, J = 23.8 Hz), 95.1 (s), 89.0 (s), 71.1 (s), 29.6 (s), 21.1
(s) ppm; IR (neat) 2963, 2924, 1667, 1587, 1456, 1337, 1175, 1119,
1016, 981, 867, 756, 698 cm−1; HRMS ESI (m/z): calcd for
C17H15FINO [MH]+ 396.0255, found 396.0261; [α]25D +15.8° (c 0.5,
CHCl3).
1-Oxo-1-phenyloctan-2-yl 4-Methylbenzenesulfonate (21).
The title compound was obtained as light brown solid (73% yield, 49%
1
ee) according to the general α-tosyloxylation procedure: H NMR
(400 MHz, CDCl3) δ 7.88−7.78 (m, 2H), 7.77−7.68 (m, 2H), 7.62−
7.52 (m, 1H), 7.44 (dd, J = 10.8, 4.8 Hz, 2H), 7.24 (t, J = 6.7 Hz, 2H),
5.58 (dd, J = 8.2, 4.9 Hz, 1H), 2.39 (s, 3H), 1.96−1.74 (m, 2H), 1.48−
1.37 (m, 1H), 1.33 (ddd, J = 12.6, 9.2, 5.0 Hz, 1H), 1.27−1.11 (m,
6H), 0.83 (t, J = 6.9 Hz, 3H) ppm; HRMS ESI (m/z): calcd for
C21H26NaO4S [MNa]+ 397.1444, found 397.1444. The ee was
determined by HPLC analysis on the purified product: Chiracel AS-
H column, 83:17 hexanes/i-PrOH, 1.0 mL/min, rt, tR = 8.9 min (S), tR
= 9.5 min (R).3c
2,3-Dihydro-1-oxo-1H-inden-2-yl 4-Methylbenzenesulfo-
nate (22). The title compound was obtained as colorless solid
(60% yield, 33% ee) according to the general α-tosyloxylation
procedure: 1H NMR (400 MHz, CDCl3) δ 7.92 (d, J = 8.3 Hz,
2H), 7.72 (d, J = 7.7 Hz, 1H), 7.64 (t, J = 7.5 Hz, 1H), 7.43 (d, J = 8.6
Hz, 1H), 7.38 (d, J = 8.3 Hz, 3H), 5.12 (dd, J = 8.0, 4.8 Hz, 1H), 3.64
(dd, J = 17.2, 8.0 Hz, 1H), 3.26 (dd, J = 17.2, 4.7 Hz, 1H), 2.46 (s,
3H) ppm; HRMS ESI (m/z): calcd for C16H14NaO4S [MNa]+
325.0505, found 325.0508. The ee was determined by HPLC analysis
on the purified product: Chiracel AS-H column, 50:50 hexanes/i-
PrOH, 0.7 mL/min, rt, t1 = 16.5 min, t2 = 20.7 min.3c
1-Oxo-1-p-tolylpropan-2-yl 4-Methylbenzenesulfonate (25).
The title compound was obtained as light brown solid (48% yield, 45%
ee) according to the general α-tosyloxylation procedure: Rf = 0.48
(20% EtOAc/hexanes); Tfus = 81 °C; 1H NMR (400 MHz, CDCl3) δ
7.84−7.66 (m, 4H), 7.34−7.18 (m, 4H), 5.82−5.69 (m, 1H), 2.40 (s,
3H), 2.39 (d, J = 5.9 Hz, 3H), 1.57 (dd, J = 6.9, 3.3 Hz, 3H) ppm; 13C
NMR (101 MHz, CDCl3) δ 194.5, 145.2, 145.1, 133.7, 131.3, 130.0,
129.7, 129.1, 128.2, 77.6, 22.0, 21.9, 19.1 ppm; IR (neat) 1705, 1364,
1177, 817, 776, 666 cm−1; HRMS ESI (m/z): calcd for C17H18NaO4S
[MNa]+ 341.0818, found 341.0810. The ee was determined by HPLC
analysis on the purified product: Chiracel AS-H column, 50:50
hexanes/i-PrOH, 0.7 mL/min, rt, tR = 10.9 min (S), tR = 12.8 min (R).
1-(4-Fluorophenyl)-1-oxopropan-2-yl 4-methylbenzenesul-
fonate (26). The title compound was obtained as light brown solid
(77% yield, 46% ee) according to the general α-tosyloxylation
procedure: Rf = 0.50 (20% EtOAc/hexanes); Tfus = 68 °C; 1H
NMR (400 MHz, CDCl3) δ 8.01−7.86 (m, 2H), 7.78−7.68 (m, 2H),
7.32−7.23 (m, 2H), 7.11 (t, J = 8.6 Hz, 2H), 5.68 (q, J = 6.9 Hz, 1H),
2.40 (s, 3H), 1.56 (d, J = 6.9 Hz, 3H) ppm; 13C NMR (101 MHz,
CDCl3) δ 192.7, 166.6, 164.1, 144.5, 132.6, 131.0, 130.9, 129.1, 127.2,
115.4, 115.2, 76.8, 21.0, 17.9 ppm; IR (neat) 1701, 1362, 1177, 818,
758, 666 cm−1; HRMS ESI (m/z): calcd for C16H15FNaO4S [MNa]+
345.0567, found 345.0555. The ee was determined by HPLC analysis
on the purified product: Chiracel AS-H column, 50:50 hexanes/i-
PrOH, 0.7 mL/min, rt, tR = 10.4 min (S), tR = 12.4 min (R).
1-(3,4-Difluorophenyl)-1-oxopropan-2-yl 4-Methylbenzene-
sulfonate (27). The title compound was obtained as white solid (66%
yield, 42% ee) according to the general α-tosyloxylation procedure: Rf
General Optimized α-Tosyloxylation Procedure (Table 6).
Compound 11g (11.1 mg, 0.027 mmol) was dissolved in acetonitrile/
CH2Cl2 (1:1) (0.6 mL). Propiophenone (36.4 mg, 0.271 mmol) and
p-TsOH hydrate (154.7 mg, 0.810 mmol) were added. A solution of
m-CPBA (184.4 mg, 77% pure, 0.803 mmol) in acetonitrile/CH2Cl2
(1:1) (0.8 mL) was added over 1 h. The reaction mixture was stirred
for 23 h. The reaction mixture was washed with a saturated solution of
Na2S2O3 (aq), and the aqueous layer was extracted with EtOAc. The
combined organic layers were washed with a saturated solution of
NaHCO3 (aq) then brine. The organic layer was dried over MgSO4,
and the solvent was evaporated under reduced atmosphere. The crude
mixture was purified by column chromatography on silica gel with
EtOAc/hexanes (5:95 to 20:80) to provide 61 mg (80%) of 15 as a
white solid of the R enantiomer (48% ee).
1
= 0.36 (20% EtOAc/hexanes); Tfus = 83 °C; H NMR (300 MHz,
CDCl3) δ 7.80−7.66 (m, 4H), 7.31−7.18 (m, 3H), 5.62 (q, J = 7.0 Hz,
1H), 2.42 (s, 2H), 1.57 (d, J = 6.9 Hz, 3H) ppm; 13C NMR (75 MHz,
CDCl3) δ 192.7 (s), 155.7 (d, J = 12.8 Hz), 152.1 (t, J = 13.3 Hz),
148.7 (d, J = 12.7 Hz), 145.4 (s), 133.1 (s), 130.6 (s), 129.8 (s), 127.9
(s), 126.1 (s), 118.0 (dd, J = 43.7, 17.7 Hz), 77.4 (s), 21.6 (s), 18.4 (s)
ppm; 19F NMR (377 MHz, CDCl3) δ = −128.2, −135.6 ppm; IR
(neat) 1704, 1363, 1177, 871, 816, 753, 666 cm−1; HRMS ESI (m/z):
calcd for C16H14F2NaO4S [MNa]+ 363.0473, found 363.0478. The ee
was determined by HPLC analysis on the purified product: Chiracel
AS-H column, 50:50 hexanes/i-PrOH, 0.7 mL/min, rt, tR = 9.7 min
(S), tR = 11.8 min (R).
1-(4-Chlorophenyl)-1-oxopropan-2-yl 4-Methylbenzenesul-
fonate (28). The title compound was obtained as colorless solid
(82% yield, 42% ee) according to the general α-tosyloxylation
procedure: Rf = 0.62 (20% EtOAc/hexanes); Tfus = 102 °C; 1H
NMR (400 MHz, CDCl3) δ 7.88−7.79 (m, 2H), 7.77−7.70 (m, 2H),
7.47−7.38 (m, 2H), 7.26 (dd, J = 6.0, 4.4 Hz, 2H), 5.67 (q, J = 6.9 Hz,
1H), 2.41 (s, 3H), 1.61−1.54 (m, 3H) ppm; 13C NMR (101 MHz,
1-Oxo-1-phenylbutan-2-yl 4-Methylbenzenesulfonate (20).
The title compound was obtained as cololess solid (70% yield, 48% ee)
1
according to the general α-tosyloxylation procedure: H NMR (400
MHz, CDCl3) δ 7.84 (dd, J = 8.2, 1.0 Hz, 2H), 7.74 (d, J = 8.3 Hz,
2H), 7.58 (t, J = 7.4 Hz, 1H), 7.44 (t, J = 7.7 Hz, 2H), 7.25 (t, J = 7.0
Hz, 2H), 5.55 (dd, J = 7.9, 5.0 Hz, 1H), 2.39 (s, 3H), 2.05−1.83 (m,
2H), 0.97 (t, J = 7.4 Hz, 3H) ppm; HRMS ESI (m/z): calcd for
C17H18NaO4S [MNa]+ 341.0818, found 341.0810. The ee was
determined by HPLC analysis on the purified product: Chiracel AS-
H column, 83:17 hexanes/i-PrOH, 1.0 mL/min, rt, tR = 12.5 min (S),
tR = 16.9 min (R).3c
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Article
CDCl3) δ 194.1, 145.4, 140.6, 133.5, 132.2, 130.5, 130.1, 129.3, 128.2,
77.7, 21.9, 18.8 ppm; IR (neat) 1702, 1364, 1176, 816, 773, 666 cm−1;
HRMS ESI (m/z): calcd for C16H15ClNaO4S [MNa]+, 361.0272,
found 361.0262; The ee was determined by HPLC analysis on the
purified product: Chiracel AS-H column, 50:50 hexanes/i-PrOH, 0.7
mL/min, rt, tR = 10.9 min (S), tR = 12.8 min (R).
1-(3-(Trifluoromethyl)phenyl)-1-oxopropan-2-yl 4-Methyl-
benzenesulfonate (29). The title compound was obtained as
colorless oil (65% yield, 44% ee) according to the general α-
tosyloxylation procedure: 1H NMR (400 MHz, CDCl3) δ 8.10 (d, J =
8.5, 2H), 7.83 (d, J = 7.8, 1H), 7.71 (d, J= 8.3 Hz 2H), 7.60 (t, J = 7.7,
1H), 7.29−7.21 (m, 2H), 5.70 (q, J = 7.0, 1H), 2.40 (s, 3H), 1.61 (d, J
= 7.0, 3H) ppm; HRMS ESI (m/z): calcd for C17H15F3NaO4S [MNa]+
395.0535, found 395.0532. The ee was determined by HPLC analysis
on the purified product: Chiracel AS-H column, 83:17 hexanes/i-
PrOH, 1.0 mL/min, rt, tR = 7.9 min (S), tR = 8.6 min (R).3c
ACKNOWLEDGMENTS
■
This work was supported by the National Science and
Engineering Research Council (NSERC) of Canada, the
Fonds Quebecois de Recherche−Nature et Technologies
́
(FQRNT), the Canada Foundation for Innovation (CFI), the
FQRNT Centre in Green Chemistry and Catalysis (CGCC),
and the Universite
were provided by the Res
performance (RQCHP). A.-A.G. is grateful to Hydro-Queb
́
de Sherbrooke. Computational resources
eau quebecois de calcul de haute
ec
́
́
́
́
and FQRNT for postgraduate scholarships.
REFERENCES
■
(1) (a) Uyanik, M.; Ishihara, K. Chem. Commun. 2009, 2086.
(b) Dohi, T.; Kita, Y. Chem. Commun. 2009, 2073. (c) Richardson, R.
D.; Wirth, T. Angew. Chem., Int. Ed. 2006, 45, 4402. (d) Wirth, T.
Angew. Chem., Int. Ed. 2005, 44, 3656 and references therein.
(e) Tohma, H.; Kita, Y. In Hypervalent Iodine Chemistry; Wirth, T., Ed.;
Springer: Berlin, 2003; p 209. (f) Zhdankin, V. V.; Stang, P. J. Chem.
Rev. 2002, 102, 2523. (g) Moriarty, R. M.; Prakash, O. Org. React
2001, 57, 327. (h) Varvoglis, A. Hypervalent Iodine in Organic Synthesis;
Academic Press: San Diego, 1997.
1-(2-(Trifluoromethyl)phenyl)-1-oxopropan-2-yl 4-Methyl-
benzenesulfonate (30). The title compound was obtained as
colorless oil (53% yield, 19% ee) according to the general α-
1
tosyloxylation procedure: Rf = 0.63 (20% EtOAc/hexanes); H NMR
(300 MHz, CDCl3) δ 7.66 (dd, J = 10.4, 6.1 Hz, 3H), 7.61−7.51 (m,
2H), 7.44 (dd, J = 5.1, 3.7 Hz, 1H), 7.25 (d, J = 8.1 Hz, 2H), 5.50 (q, J
= 6.9 Hz, 1H), 2.41 (s, 3H), 1.53 (d, J = 6.9 Hz, 3H) ppm; 13C NMR
(75 MHz, CDCl3) δ = 198.8, 145.1, 135.9, 133.2, 131.6, 130.7, 129.8,
127.7, 127.6 (q, J = 63.1 Hz), 127.5, 126.9 (q, J = 5.7 Hz), 123.1 (d, J
= 274.0 Hz), 79.2, 21.6, 17.5 ppm; IR (neat) 1724, 1369, 1177, 817,
770, 664 cm−1; HRMS ESI (m/z): calcd for C17H15F3NaO4S [MNa]+
395.0535, found 395.0528. The ee was determined by HPLC analysis
on the purified product: Chiracel AS-H column, 87:17 hexanes/i-
PrOH, 1.0 mL/min, rt, tR = 11.4 min (S), tR = 12.4 min (R).
1-Oxo-1-phenylpropan-2-yl Methanesulfonate (34). Catalyst
11g (11.1 mg, 0.027 mmol) was dissolved in acetonitrile/CH2Cl2
(1:1) (0.6 mL). Propiophenone (36.4 mg, 0.271 mmol) and
methanesulfonic acid (77.7 mg, 0.809 mmol) were added. A solution
of m-chloroperoxybenzoic acid (184.4 mg, 0.803 mmol) in
acetonitrile/CH2Cl2 (1:1) (0.8 mL) was added over 1 h. The reaction
was stirred for 23 h. The reaction mixture was washed with a saturated
solution of Na2S2O3 (aq), and the aqueous layer was extracted with
EtOAc. The combined organic layers were washed with a saturated
solution of NaHCO3 (aq) and then brine. The organic layer was dried
over MgSO4, and the solvent was evaporated under reduced
atmosphere. The product was purified by silica gel chromatography
with hexanes/EtOAc (80:20) to provide 49.2 mg (80%, 36% ee) of 34
as a colorless solid; Rf = 0.19 (20% EtOAc/hexanes); Tfus = 58 °C; 1H
NMR (300 MHz, CDCl3) δ 8.02−7.85 (m; 2H), 7.62 (t, J = 7.4 Hz,
1H), 7.50 (t, J = 7.6 Hz, 2H), 6.05 (q, J = 6.99 Hz, 1H), 3.13 (s, 3H),
1.65 (d, J = 7.0 Hz, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 195.3,
134.2, 133.6, 129.0, 128.6, 77.1, 39.4, 18.7 ppm; IR (neat) 1696, 1357,
1173, 819, 767, 662 cm−1; HRMS ESI (m/z): calcd for C10H12NaO4S
[MNa]+ 251.0349, found 251.0356; The ee was determined by HPLC
analysis on the purified product: Chiracel AS-H column, 83:17
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ASSOCIATED CONTENT
■
S
* Supporting Information
Characterization and NMR spectra for all new compounds. Full
Gaussian reference (ref 20), Cartesian coordinates, and
electronic and zero-point vibrational energies. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: claude.legault@usherbrooke.ca.
Notes
The authors declare no competing financial interest.
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