New chiral iodooxazoline catalysts for the I(III)-mediated α-tosyloxylation of ketones: Refining the stereoinduction model

Article abstract of DOI:10.1016/j.tetasy.2013.08.002

A new family of iodooxazoline catalysts, derived from widely available chiral ketones (menthone and camphor), was developed to promote the iodine(III)-mediated α-tosyloxylation of ketone derivatives. The reaction conditions to achieve the direct formation

Full text of DOI:10.1016/j.tetasy.2013.08.002

Tetrahedron: Asymmetry xxx (2013) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
New chiral iodooxazoline catalysts for the I(III)-mediated
a-tosyloxylation of ketones: refining the stereoinduction model
⇑
Marie-Ève Thérien, Audrey-Anne Guilbault, Claude Y. Legault
University of Sherbrooke, Department of Chemistry, 2500 boul. de l’Université, Sherbrooke (Québec) J1K 2R1, Canada
a r t i c l e i n f o
a b s t r a c t
Article history:
A new family of iodooxazoline catalysts, derived from widely available chiral ketones (menthone and
Received 20 June 2013
Accepted 6 August 2013
Available online xxxx
camphor), was developed to promote the iodine(III)-mediated
a-tosyloxylation of ketone derivatives.
The reaction conditions to achieve the direct formation of the oxazoline moieties from the corresponding
aminoalcohols and an aldehyde were explored and optimized. These catalysts were tested for the
a-tosyloxylation of propiophenone and led to new information on the stereoinduction process. The
results demonstrate that modulation of the steric hindrance around the iodane center is critical to obtain
good activity. Additionally, from the selectivities observed, a preliminary predictive model is proposed.
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
TsO
I
OH
O
O
HTIB
Research to develop hypervalent iodine-mediated synthetic
methodologies has shown a steady increase in recent years.1 This
is due in most part to the capacity of these reagents to replace tran-
sition metals in synthetically useful oxidative transformations.2 In
fact, hypervalent iodine reagents are considered the oxidation
reagents of choice for numerous synthetic transformations. As a
result, there have been numerous efforts put toward the develop-
ment of stereoselective methods involving these reagents, either
stoichiometrically or in a catalytic fashion.3 Chiral iodoarene com-
pounds, used either as reagents or catalysts, have found their way
into such methodologies. Examples of successful enantioselective
transformations have been reported for hydroxylative phenol
dearomatization, using catalysts 1 and 2,4 and dearomatizing naph-
thol spirolactonization, using reagent 35 and catalyst 4 (Fig. 1).6
(a)
(b)
R'
R'
OTs
R
R
HTIB
O
m-CPBA
+
R'
TsO
I
OH
*
R
TsOH
Ar*
I(III)
OTs
I(I)
I
O
m-CBA
R'
Ar*
R
Scheme 1. (a) General
of catalytic iodine(III)-mediated
a
-tosyloxylation of ketones using HTIB. (b) Simplified cycle
a
-tosyloxylation.
CO2H
O
O
A = C(O)NHAr
OAc
AcO
I
popularized by Koser et al. using hydroxy(tosyloxy)iodobenzene
HTIB,7 enables easy access to very useful synthons, the alpha-
tosyloxy ketones. In one simple step, these non-lacrymogenic8
electrophiles can be obtained in good yield. Moreover, it was
recently demonstrated by Togo et al. that this reaction could be
rendered catalytic in the hypervalent iodine reagent.9
I
A
A
OH
I
I
*
I
O
O
OMe
2
1
4
3
Figure 1. Representative iodoarene compounds used in hypervalent iodine med-
Despite more than 15 years of research on this particular
reaction,10–12 the enantioselectivities obtained with either
chiral reagents or catalysts have never exceeded 58% ee. Currently
the best enantioselectivities for the catalytic enantioselective
iated enantioselective reactions.
One synthetic transformation that has been particularly chal-
lenging to achieve in a stereoselective manner is the a-tosyloxyla-
tion of ketone compounds. This reaction (Scheme 1), initially
a-tosyloxylation of propiophenone is 27% ee (78% yield) with
catalyst 5,10b 39% ee (42% yield) with 6 (R⁄ = menthyl),10b and
53% ee (53% yield) with 7 (Fig. 2).11 We recently reported on a
new family of catalysts based on the iodoaryloxazoline scaffold
⇑
Corresponding author. Tel.: +1 819 821 7006; fax: +1 819 821 8017.
E-mail address: claude.legault@usherbrooke.ca (C.Y. Legault).
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.08.002
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2
M.-È. Thérien et al. / Tetrahedron: Asymmetry xxx (2013) xxx–xxx
and were able to obtain, with catalyst 8b, up to 54% ee (48% ee and
quantity of BF3ꢀOEt2, followed by reduction using LiAlH4, aminoal-
cohols 9–12 were rapidly obtained (Fig. 3). For aminoalcohol 9b,
the necessary corresponding ketone was obtained using a litera-
ture procedure.16 This aminoalcohol was made in order to directly
80% yield under optimized conditions) for the
a-tosyloxylation of
propiophenone,13 placing it among the best catalysts for this
transformation.
evaluate the effect of the increased steric hindrance on the
oxylation reaction.
a-tosyl-
*RO
O
N
I
I
OMe
I
I
Ph
Et
O
OH
NH2
NH2
NH2
R
OH
OH
8a
, R = H
6
7
5
OH
11
8b
, R = Cl
NH2
R
10
12
9a
9b
, R = H
Figure 2. The best catalysts reported for the enantioselective
a-tosyloxylation of
, R = Ph
ketone compounds.
Figure 3. Aminoalcohols obtained following Dimitrov et al. procedures.
We have found through an investigation of the stereoinduction
process that it was the stereogenic center alpha to the oxygen atom
that was responsible for the stereoselectivities. To the best of our
knowledge, this is the first case of this type of unusual stereoinduc-
tion from a chiral oxazoline moiety. This also brings an important
challenge. While access to chiral oxazolines bearing chirality alpha
to the nitrogen atom is well known and mostly relies on chiral
alpha-amino acids as starting materials,14 access to oxazolines
bearing a stereogenic center alpha to the oxygen atom is more
challenging and rare (Scheme 2). Herein we report the synthesis
of new iodoaryloxazoline catalysts bearing a sterically hindered
stereogenic center alpha to the oxazoline oxygen. Their potential
Additionally, the aminoalcohol 13 was obtained using an alter-
native procedure described in the literature and illustrated in
Scheme 4.17
a
b
c
O
NOH
NH2
OH
O
O
O
13
Scheme 4. Synthesis of aminoalcohol 13. Reagents and conditions: (a) Se2O, Ac2O,
reflux, 14 h, 80%; (b) H2NOHꢀHCl, pyridine, EtOH, 20 min, rt, 29%; (c) LiAlH4, Et2O,
1.5 h, rt, 80%.
to promote the enantioselective
be discussed (Scheme 1).
a-tosyloxylation of ketones will
O
Different synthetic approaches were evaluated for the synthesis
of iodooxazolines. While oxazoline synthesis from aminoalcohols
with no stereogenic center alpha to the oxygen usually rely on
the simple activation (e.g., SOCl2, MsOH) of the alcohol of the cor-
responding amide (Scheme 5a), it was envisioned that the steric
hindrance of aminoalcohols and possible epimerization of the cor-
responding amide could lead to problems in such methods. In or-
der to avoid the need to activate the alcohol and to simplify the
synthesis, we elected to carry out a direct oxidative condensation
of the aminoalcohols on an aldehyde substrate (Scheme 5b). This
method, developed by Glorius et al., is reported to work well for
a variety of aminoalcohols.18
R'
amino acids
*
N
R
R
O
*
R'
N
available chiral pool?
Scheme 2. Challenge of accessing chiral oxazolines bearing a stereogenic center
alpha to the oxygen atom.
2. Results and discussion
With the challenge to access novel chiral oxazolines in mind, we
envisioned exploiting the inherent chirality of widely available chi-
ral ketones. The general synthetic approach is described in
Scheme 3. The formation of a cyanohydrin followed by its reduc-
tion would lead rapidly to the corresponding aminoalcohol. We
elected to use menthone and camphor as starting ketones because
of their low cost and wide availability.
HO
SOCl2
O
O
O
or
1) Activation
R
MsOH
(a)
Ar
OH
Ar
N
H
R
N
Ar
2)
H2N
OH
R
H2N
OH
R'
R
R
R'
R'
O
O
O
[O]
R
R''
(b)
OH
OH
O
Ar
H
N
N
Ar
Ar
O
H
NH2
N
R
R'
R
R'
R
N
R'
Scheme 5. Different approaches to access the chiral oxazolines.
O
In order to evaluate the feasibility of this synthetic route, the
Scheme 3. General synthetic strategy to access oxazolines bearing a sterically
hindered stereogenic center alpha to the oxygen.
iodoaryl aldehyde 14 was synthesized from commercially available
2-iodo-3-methylbenzoic acid using the procedure illustrated in
Scheme 6. The necessity for a methyl group ortho to the iodine
atom is to achieve high catalytic activity, as was demonstrated
by our group previously.19
Following the procedures reported by Dimitrov et al.,15 involv-
ing the formation of a cyanohydrin using TMSCN with a catalytic
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M.-È. Thérien et al. / Tetrahedron: Asymmetry xxx (2013) xxx–xxx
3
I
O
I
OH
I
O
of the new catalysts afforded a level of enantioselectivity compara-
ble to 8a, derived from norephedrine. Additionally, comparison of
catalysts 15a and 15b (entries 2 vs 3) showed a drastic decrease
in catalytic activity. Presumably, replacing the i-Pr group of 15a
by a bulkier dimethylphenyl group prevents efficient access to
the iodane reactive center.
a
b
OH
14
Scheme 6. Synthesis of aldehyde 14. Reagents and conditions: (a) NaBH4, I2, THF, rt,
From these results and recent advances from our group and
Zhang et al.,11 a predictive stereoinduction model can be proposed.
First of all, computational evidence points to a dissociative path-
way, in which the enol form of the ketone substrate reacts with
a highly electrophilic iodonium intermediate.13 Enol will approach
trans to the OH group, the most electronegative group on the iod-
onium. The reactive intermediate can adopt two conformations.
For example, in the case of Zhang’s catalyst 7, two rotamers 17a
and 17b are possible (Scheme 8). The approach of enol will be fa-
vored on 17a due to the minimized steric interactions with the cat-
alyst perpendicular phenyl group.
85%; (b) PCC, CH2Cl2, 16 h, rt, 90%.
Initial tests to generate the desired oxazolines from the litera-
ture conditions resulted in low yields. We hypothesized that the
steric hindrance of both reactants resulted in a slow reaction,
which prompted us to modify the reported conditions. Optimiza-
tion of the reaction time and solvent led to the conditions de-
scribed in Scheme 7. Using these optimized conditions, catalysts
15a–f could be obtained in modest to fair yields.
R
I
O
I
N
i) Na2SO4
R'
MeCN, 2 h, r.t.
H2N
OH
R'
OH
O
R
ii) NBS, 1.5 h
r.t.
Ar
R
14
9-13
15a-f
OH
I
I
OH
OH
I
I
N
N
R
17a
17b
Ar
O
O
Scheme 8. Simplified representation of the rational for the facial selectivity of
Zhang’s catalyst 7.
R
15a, R = H, 50%
15c, 34%
15b
, R = Ph, 44%
In the case of catalysts 8a and 15f, similar discrimination is pos-
sible due to the rotational restriction of the protonated oxazoline
moieties, favoring orientation of the oxazoline-oxygen toward
the iodonium center.13 From the low selectivities observed for cat-
alysts 15a–15e, introduction of a bulky stereogenic center alpha to
the oxazoline-oxygen seems highly detrimental to the facial selec-
tivity on the iodonium center. Conversely, facial selectivity on the
iodonium species from catalysts 8a and 15f, bearing secondary chi-
ral centers alpha to the oxygen-oxazoline correlates with the abso-
lute stereochemistry of the final product. A simple predictive
model, based on the facial selectivity on the iodonium intermedi-
ates int-7, int-8a, and int-15f, is represented in Scheme 9. The
low enantioselectivities could therefore be due to a lack of facial
discrimination on the enol substrate.
N
I
O
I
N
I
O
O
N
15d, 18%
15e, 46%
15f, 28%
Scheme 7. Synthesis of the iodoaryloxazoline catalysts.
With catalysts 15a–f in hand, we evaluated them in the model
-tosyloxylation reaction of propiophenone. The optimized condi-
a
tions used for iodooxazoline catalysts were previously found by
our group.13 The results are summarized in Table 1.
Table 1
TsO-
OH
TsO-
NH
Evaluation of the activity and selectivity of the new iodoaryloxazoline catalysts
OH
I
O
O
NH
Catalyst (10 mol %)
TsOH (3 equiv)
(R)-product
(S)-product
O
O
Me
TsO-
Me
int-15f
Me
int-8a
I
Ph
Ph
TsO-
m-CPBA (3 equiv)
slow addition over 1 h
MeCN/DCM(1:1), r.t., 24 h
OTs
16
Entry
Catalyst
Yielda (%)
eeb (%)
1
2
3
4
5
6
7
8a
72
64
19
79
14
26
71
44 (R)
17 (S)
8 (S)
8 (S)
3 (S)
I
15a
15b
15c
15d
15e
15f
TsO-
int-7
OH
Scheme 9. Simple model to correlate the facial selectivity on the iodonium
intermediate with the final product configuration.
3 (S)
34 (R)
a
Isolated yield.
Determined by chiral HPLC.
b
3. Conclusion
For the sake of comparison, our best iodooxazoline catalyst pre-
We have developed a new family of iodooxazoline catalysts
based on sterically hindered aminoalcohols derived from chiral ke-
tones. From the results obtained, it now seems clear that there is a
viously developed,13 8a was also tested. Despite the presence of a
bulky stereogenic center alpha to the oxazoline-oxygen atom, none
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4
M.-È. Thérien et al. / Tetrahedron: Asymmetry xxx (2013) xxx–xxx
limit in terms of the bulkiness of the chiral group that can be pres-
ent next to the iodine center on these catalysts. Additionally, we
can conclude that quaternary stereogenic centers alpha to the
oxazoline oxygen atom might prevent efficient facial discrimina-
tion on the iodonium intermediate. In contrast, secondary stereo-
genic centers are predisposed to result in better facial selectivity
on the iodonium intermediate. With the additional information ob-
tained from our group and others, we are currently working on a
computational model to better explain the stereoselectivities
observed, as well as propose solutions to finally achieve high
selectivites in what remains a great challenge of hypervalent io-
dine chemistry. Work on other families of chiral catalysts will be
reported in due course.
the solution was stirred for 1.5 h. The solvents were removed un-
der reduced pressure. The mixture was diluted in CH2Cl2 and
washed twice with a saturated aqueous NaHCO3 solution then
once with brine. The organic layer was dried over Na2SO4 and
the solvent was removed under reduced pressure. The crude prod-
uct was purified by flash chromatography with hexanes:EtOAc
(85:15) to provide 178 mg (50%) of (5R,6R,9R)-2-(2-iodo-3-methyl-
phenyl)-6-isopropyl-9-methyl-1-oxa-3-azaspiro[4.5]dec-2-ene as
a yellow oil; Rf 0.31 (hexanes:EtOAc, 85:15); 1H NMR (400 MHz,
CDCl3) d 7.23–7.28 (m, 3H), 4.04 (d, J = 14.8 Hz, 1H), 3.71 (d,
J = 14.8 Hz, 1H), 2.48 (s, 3H), 1.69–2.23 (m, 4H), 1.39–1.63 (m,
3H), 1.17–1.29 (m, 1H), 0.89–1.10 (m, 10H) ppm; 13C NMR
(100 MHz, CDCl3) d 165.3, 142.9, 135.9, 130.9, 127.7, 127.4,
101.7, 90.6, 59.9, 49.5, 47.7, 34.5, 29.9, 29.6, 26.3, 25.0, 24.4,
22.1, 19.3 ppm; IR (neat) 3042, 2951, 2920, 2869, 1659, 1571,
1455, 1342, 1174, 1128, 1088, 1012, 972, 920, 789, 771,
722 cmꢁ1; HRMS EI (m/z): [MH]+ calcd for C19H27INO, 412.1132;
4. Experimental
4.1. General remarks
found 412.1135. ½a D25
¼ ꢁ18:5 (c 0.97, CHCl3).
ꢂ
Compounds 9–12,15 13,17 and 1413 were all prepared according
to reported procedures. All non-aqueous reactions involving air or
moisture sensitive compounds were run under an inert atmo-
sphere (nitrogen or argon) with rigid exclusion of moisture from
reagents and glassware using standard techniques. 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),
over calcium hydride (CH2Cl2, Et3N, and ClCH2CH2Cl). Analytical
thin-layer chromatography (TLC) was performed on precoated,
glass-backed silica gel (Merck 60 F254). Visualization of the devel-
oped chromatogram was performed by UV absorbance, aqueous
cerium molybdate, ethanolic phosphomolybdic 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 the standard tech-
nique. 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
(cmꢁ1). Nuclear magnetic resonance spectra (1H, 13C, DEPT, COSY,
and HMQC) were recorded either on a 300 MHz or 400 MHz spec-
trometers. Chemical shifts for 1H NMR spectra are recorded in parts
per million from tetramethylsilane with the solvent resonance as
the internal standard (chloroform, d 7.27 ppm, acetonitrile, d
1.94 ppm). Data are reported as follows: chemical shift, multiplic-
ity (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 DEPT experiments. High resolution mass
spectra were performed using UPLC-Q-TOF (ESI) mass spectrome-
ters. Analytical High Performance Liquid Chromatography was per-
formed on an HPLC system equipped with diode array UV detector.
Data are reported as follows: (column type, eluent, flow rate:
retention time (tr)).
4.2.2. (5R,6S,9R)-2-(2-Iodo-3-methylphenyl)-9-methyl-6-(2-
phenylpropan-2-yl)-1-oxa-3-azaspiro[4.5]dec-2-ene 15b
The general procedure was followed: (1R,2S,5R)-1-(amino-
methyl)-5-methyl-2-(2-phenylpropan-2-yl)cyclohexanol (111 mg,
0.42 mmol),
2.1 mL
CH3CN,
2-iodo-3-methylbenzaldehyde
(104 mg, 0.42 mmol), NBS (138 mg, 0.777 mmol). The crude prod-
uct was purified by flash chromatography with hexanes:EtOAc
(85:15) to provide 90 mg (44%) of (5R,6S,9R)-2-(2-iodo-3-methyl-
phenyl)-9-methyl-6-(2-phenylpropan-2-yl)-1-oxa-3-azaspiro[4.5]
dec-2-ene as a yellow oil; Rf 0.33 (hexanes:EtOAc, 85:15); 1H NMR
(400 MHz, CDCl3) d 7.35–7.20 (m, 7H), 7.09 (t, J = 6.8 Hz, 1H), 4.13
(d, J = 15.1 Hz, 1H), 3.74 (d, J = 14.9 Hz,1H), 2.51 (s, 3H), 2.19 (d,
J = 12.6 Hz, 1H), 2.06 (d, J = 11.5 Hz,1H), 1.64–1.37 (m, 10H),
1.14–0.82 (m, 4H) ppm; 13C NMR (100 MHz, CDCl3) d 164.6,
150.8, 143.0, 135.2, 131.0, 127.8 (2), 127.6, 125.9, 125.4, 101.9,
91.2, 60.0, 53.8, 50.1, 41.5, 34.9, 30.1, 29.9, 29.7, 26.4, 25.6,
21.8 ppm; IR (neat) 3059, 2952, 2924, 2869, 2219, 1657, 1575,
1498, 1456, 1370, 1345, 1292, 1262, 1178, 1134, 1089, 1013,
972, 911, 840, 790, 776, 727, 701 cmꢁ1; HRMS EI (m/z): [MH]+
calcd for C25H31INO, 488.1445; found 488.1447. ½a D25
¼ ꢁ18:2 (c
ꢂ
0.91, CHCl3).
4.2.3. (5S,6S,9R)-2-(2-Iodo-3-methylphenyl)-6-isopropyl-9-methyl-
1-oxa-3-azaspiro[4.5]dec-2-ene 15c
The general procedure was followed: (1S,2S,5R)-1-(amino-
methyl)-2-isopropyl-5-methylcyclohexanol (144 mg, 0.777 mmol),
4.9 mL
CH3CN,
2-iodo-3-methylbenzaldehyde
(191 mg,
0.777 mmol), NBS (138 mg, 0.777 mmol). The crude product was
purified by flash chromatography with hexanes:EtOAc (85:15) to
provide 108 mg (34%) of (5S,6S,9R)-2-(2-iodo-3-methylphenyl)-6-
isopropyl-9-methyl-1-oxa-3-azaspiro[4.5]dec-2-ene as a yellow
oil; Rf 0.31 (hexanes:EtOAc, 85:15); 1H NMR (400 MHz, CDCl3) d
7.23–7.26 (m, 3H), 4.04 (d, J = 14.8 Hz, 1H), 3.72 (d, J = 14.8 Hz,
1H), 2.49 (s, 3H), 1.94–2.23 (m, 2H), 1.95–2.03 (m, 1H), 1.70–1.81
(m, 2H), 1.39–1.59 (m, 3H), 1.01–1.11 (m, 1H), 1.96–1.97 (m,
6H), 0,92 (d, J = 6.9 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) d
165.3, 142.9, 135.9, 130.8, 127.7, 127.4, 101.7, 90.6, 64.8, 59.8,
49.4, 47.6, 34.4, 29.8, 26.3, 24.9, 24.4, 22.1, 19.3 ppm; IR (neat)
3045, 2951, 2923, 2869, 1661, 1571, 1454, 1345, 1265, 1177,
1128, 1085, 1009, 969, 923, 789, 771, 722 cmꢁ1; HRMS EI (m/z):
[MNa]+ calcd for C19H26INONa, 434.0951; found 434.0950.
4.2. Preparation of the iodoaryloxazoline catalysts
4.2.1. (5R,6R,9R)-2-(2-Iodo-3-methylphenyl)-6-isopropyl-9-methyl-
1-oxa-3-azaspiro[4.5]dec-2-ene 15a
½
a 2D5
ꢂ
¼ ꢁ12:7 (c 1.32, CHCl3).
General procedure: To a solution of (1R,2S,5R)-1-(aminomethyl)-
2-isopropyl-5-methylcyclohexanol (161 mg, 0.869 mmol) in
4.35 mL of CH3CN was added 2-iodo-3-methylbenzaldehyde
(214 mg, 0.869 mmol). After the mixture was stirred for 2 h at
room temperature, NBS (155 mg, 0.869 mmol) was added and
4.2.4. (1R,2S,4R)-20-(2-Iodo-3-methylphenyl)-1,7,7-trimethyl-
40H-spiro[bicyclo[2.2.1]heptane-2,50-oxazole] 15d
The general procedure was followed: (1S,2S,4R)-2-(aminomethyl)-
1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol (43 mg, 0.235 mmol),
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M.-È. Thérien et al. / Tetrahedron: Asymmetry xxx (2013) xxx–xxx
5
1.18 mL CH3CN, 2-iodo-3-methylbenzaldehyde (58 mg, 0.235
mmol), NBS (42 mg, 0.235 mmol). The crude product was purified
by flash chromatography with hexanes:EtOAc (80:20) to provide
17 mg (18%) of (1R,2S,4R)-20-(2-iodo-3-methylphenyl)-1,7,7-tri-
methyl-40H-spiro[bicyclo[2.2.1] heptane-2,50-oxazole] as a color-
less oil; Rf 0.30 (hexanes:EtOAc, 80:20); 1H NMR (300 MHz, CDCl3)
d 7.23–7.32 (m, 3H), 4.29 (d, J = 15.0 Hz, 1H), 3.65 (d, J = 15.1 Hz,
1H), 2,50 (s, 3H), 2.19–2.28 (m, 1H), 1.91–2.07 (m, 2H), 1.72–1.83
(m, 2H), 1.24–1.45 (m, 2H), 0.96 (s, 3H), 0.88 (d, J = 9.0 Hz, 6H)
ppm; 13C NMR (100 MHz, CDCl3) d 164.9, 142.9, 136.2, 130.9,
127.8, 127.7, 101.7, 95.0, 67.0, 52.4, 48.5, 47.5, 45.6, 29.9, 29.7,
29.6, 27.5, 20.3, 20.0, 11.3 ppm; IR (neat) 3045, 2951, 2872, 2358,
1662, 1571, 1455, 1388, 1345, 1272, 1177, 1131, 1091, 1012, 969,
893, 777, 719 cmꢁ1; HRMS EI (m/z): [MH]+ calcd for C19H25INO,
of m-CPBA (162 mg, 77% pure, 0.72 mmol) in acetonitrile:CH2Cl2
(1:1) (0.8 mL) was added over 1 h. The reaction was stirred for
24 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 crude mixture was purified by column chroma-
tography on silica gel with EtOAc:hexanes (5:95 to 20:80) to
provide 56 mg (73%) of 16 as a white solid of the (R)-enantiomer
(44% ee).13 The ee were determined by HPLC on the purified prod-
uct: Chiracel AS-H column, 50:50 hexanes:i-PrOH, 0.7 mL/min, rt,
tS = 10.1 min (S), tR = 11.6 min (R).
410.0975; found 410.0982. ½a D25
ꢂ
¼ ꢁ11:8 (c 0.54, CHCl3).
Acknowledgments
4.2.5. (1R,2R)-20-(2-Iodo-3-methylphenyl)-1,7,7-trimethyl-40H-
spiro[bicyclo[2.2.1]heptane-2,50-oxazole] 15e
This work was supported by the National Science and Engineer-
ing Research Council (NSERC) of Canada, the Fonds Québecois de
Recherche—Nature et Technologies (FQRNT), the Canada Founda-
tion for Innovation (CFI), the FQRNT Centre in Green Chemistry
and Catalysis (CGCC), and the Université de Sherbrooke. Computa-
tional resources were provided by the Réseau québécois de calcul
de haute performance (RQCHP). A.-A.G. is grateful to Hydro-
Québec and FQRNT for postgraduate scholarships.
The general procedure was followed: (1S,2R,4R)-2-(amino-
methyl)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol (20 mg, 0.109
mmol), 0.55 mL CH3CN, 2-iodo-3-methylbenzaldehyde (27 mg,
0.109 mmol), NBS (20 mg, 0.109 mmol). The crude product was
purified by flash chromatography with hexanes:EtOAc (80:20) to
provide 16 mg (36%) of (1R,2R)-20-(2-iodo-3-methylphenyl)-1,7,7-
trimethyl-40H-spiro[bicyclo[2.2.1]heptane-2,50-oxazole] as a color-
less oil; Rf 0.32 (hexanes:EtOAc, 80:20); 1H NMR (300 MHz, CDCl3)
d 7.23–7.28 (m, 3H), 4.16 (d, J = 14.8 Hz, 1H), 3.85 (d, J = 14.7 Hz,
1H), 2.56 (ddt, J = 13.9, 3.6, 0.8 Hz, 1H), 2.50 (s, 3H), 1.25–1.84
(m, 5H), 1.08–1.17 (m, 4H), 0.90 (d, J = 2.7 Hz, 6H) ppm; 13C NMR
(100 MHz, CDCl3) d 165.4, 142.8, 136.0, 130.9, 127.8, 127.7,
101.7, 95.7, 63.9, 52.1, 49.3, 48.2, 45.7, 30.2, 29.6, 27.1, 20.6,
20.3, 10.3 ppm; IR (neat) 2951, 2872, 1662, 1571, 1452, 1391,
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;
HRMS EI (m/z): [MNa]+ calcd for C19H24INONa, 432.0795; found
432.0795. ½a 2D5
¼ ꢁ31:9 (c 1.15, CHCl3).
ꢂ
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3a,4,5,6,7,7a-hexahydro-4,7-methanobenzo[d]oxazole 15f
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trimethylbicyclo[2.2.1]heptan-2-ol (215 mg, 1.27 mmol), 6.35 mL
of CH3CN, 2-iodo-3-methylbenzaldehyde (312 mg, 1.27 mmol),
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chromatography with hexanes:EtOAc (85:15) to provide 128 mg
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(26%)
of
(3aS,4R,7S,7aR)-2-(2-iodo-3-methylphenyl)-8,8-di-
methyl-3a,4,5,6,7,7a-hexahydro-4,7-methanobenzo[d]oxazole as a
colorless oil; Rf 0.27 (hexanes:EtOAc, 85:15); 1H NMR (400 MHz,
CDCl3) d 7.17–7.23 (m, 3H), 4.41 (d, J = 8.7 Hz, 1H), 4.20 (d,
J = 8.7 Hz, 1H), 2.43 (s, 3H), 2.13 (d, J = 4.5 Hz, 1H), 1.67–1.75 (m,
2H), 1.44–1.52 (m, 2H), 1.18 (s, 3H), 1.01 (d, J = 2.4 Hz, 3H), 0.83
(s, 3H) ppm; 13C NMR (100 MHz, CDCl3) d 165.9, 143.1, 135.4,
131.2, 127.7, 127.4, 101.9, 91.9, 48.7, 48.6, 47.1, 32.1, 29.8, 29.7,
26.1, 23.4, 19.3, 11.4 ppm; IR (neat) 3045, 2954, 2885, 1653,
1574, 1459, 1391, 1357, 1327, 1121, 1084, 991, 970, 786,
725 cmꢁ1; HRMS EI (m/z): [MH]+ calcd for C18H23INO, 396.0819;
found 396.0830. ½a D25
¼ þ14:6 (c 1.01, CHCl3) (see Figs. 1–3).
ꢂ
4.2.7. General a-tosyloxylation procedure for the evaluation of
catalysts (Table 1)
Catalyst 8a (9.1 mg, 0.025 mmol) was dissolved in acetoni-
trile:CH2Cl2 (1:1) (0.6 mL). Propiophenone (134.0 mg, 0.25 mmol)
and p-TsOH hydrate (138 mg, 0.73 mmol) was added. A solution
Please cite this article in press as: Thérien, M.-È;. et al. Tetrahedron: Asymmetry (2013), http://dx.doi.org/10.1016/j.tetasy.2013.08.002