Stereoselective and Regioselective Pinacol-Type Rearrangement of a Fused Bicyclic Oxetanol Scaffold

Article abstract of DOI:10.1002/ejoc.201701214

The Paternò-Büchi reaction between benzaldehyde and trimethylsilyloxycyclopentene gave access to an unprecedented silyl ether derivative of 6-oxabicyclo[3.2.0]heptan-1-ol. The bicyclic structure underwent selective reductive ring opening and acid-catalyzed pinacol-type rearrangement reactions with complete regioselectivity, accompanied by moderate to excellent mechanism-dependent diastereoselectivity.

Full text of DOI:10.1002/ejoc.201701214

A Journal of
Accepted Article
Title: Stereoselective and regioselective pinacol-type rearrangement of
a fused bicyclic oxetanol scaffold
Authors: Nicola Melis, Alberto Luridiana, Régis Guillot, Francesco
Secci, Angelo Frongia, Thomas Boddaert, and David J. Aitken
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201701214
Link to VoR: http://dx.doi.org/10.1002/ejoc.201701214
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10.1002/ejoc.201701214
European Journal of Organic Chemistry
FULL PAPER
Stereoselective and regioselective pinacol-type rearrangement of
a fused bicyclic oxetanol scaffold
Nicola Melis,[a,b] Alberto Luridiana,[a,b] Régis Guillot,[c] Francesco Secci,[b] Angelo Frongia,[b] Thomas
Boddaert*[a] and David J. Aitken*[a]
Abstract: The Paternò-Büchi reaction between benzaldehyde and
trimethylsilyloxycyclopentene gave access to unprecedented silyl
ether derivatives of 6-oxabicyclo[3.2.0]heptan-1-ol. These bicyclic
structures underwent selective reductive ring opening as well as
acid-catalysed
pinacol-type
rearrangement
with
complete
regioselectivity, accompanied by moderate or excellent mechanism-
dependent diastereoselectivity.
Scheme 1. Brønsted or Lewis acid initiated rearrangement.
Introduction
Paternò-Büchi reaction between benzaldehyde
1 and the
The oxetane ring is a notable structural feature in natural
products[1] and is present in a large panel of synthetic molecules
used in drug discovery[2] and in peptidomimetic design.[3] The
ring strain facilitates ring-opening or expansion reactions,[4]
making oxetanes attractive intermediates in multi-step synthesis.
Among the approaches available for their preparation,[5] the
Paternò-Büchi reaction is arguably one of the most efficient.
Many studies have been made of this [2+2] photocycloaddition
reaction between a carbonyl compound and an alkene, and
cyclopentane silyl enol ether 2 (Table 1). This latter compound
has not previously been engaged in a Paternò-Büchi reaction, to
the best of our knowledge. The bicyclic product 3 has a 6-
oxabicyclo[3.2.0]heptane core, which has previously been
targeted by different synthetic approaches.[13] In addition to
being an analogue of the valued bicyclo[3.2.0]heptane
skeleton,[14] it might be expected to undergo interesting
rearrangements arising from the presence of both the protected
tertiary alcohol and the strained oxetane ring. However, with the
numerous synthetic applications have been described.[6]
A
exception of
a few analogues of more complex natural
series of studies has been carried out by Bach and co-workers[7]
on the Paternò-Büchi reaction between aromatic aldehydes and
silyl enol ethers.[8] An attractive feature of this corpus of work is
that the product oxetanyl silyl ethers can be usefully engaged in
further transformations such as nucleophilic displacements,[7c,9]
reductive ring cleavage,[7d,10] and acid-mediated ring opening
reactions.[8d,11] In these latter cases pinacol-type rearrangements
are observed, giving mixtures of two isomeric ketones a and b,
in which the product ratio depends on the oxetane ring
substituents and on the nature of the acid catalyst (Scheme 1).
products,[15] examples of 6-oxabicyclo[3.2.0]heptanes bearing an
oxygen function at the 1-position are virtually unknown.[16,17]
Results and Discussion
We first investigated the photochemical reaction (Hg vapor lamp,
Pyrex® reaction vessel) between benzaldehyde 1 and two
equivalents of silyl enol ether 2 in different solvents (Table 1). In
low polarity media (benzene, trifluorotoluene, cyclohexane,
toluene; entries 1-4) the reaction was inefficient and the
expected diastereoisomeric product mixture 3a/3b was isolated
in only 27-33% yields. Large amounts of side-products 4,
evidently resulting from condensation of meso- and DL-1,2-
diphenyl-1,2-ethanediol (the benzaldehyde photoreduction
products[18]) with silyl enol ether 2, were observed. In contrast,
the use of acetonitrile as the solvent led to much better results,
with only minimal formation of compounds 4, leading to the
requisite bicyclic oxetanes 3a and 3b, which were separated by
chromatography and isolated in 42% combined yield (entry 5). In
all cases, complete regioselectivity and cis ring-junction
geometry were observed, while the 3a/3b ratio was only slightly
in favour to the exo-compound 3a.
Inspired by these observations and pursuing our own
interest in the synthesis and study of highly functionalized four-
membered ring compounds,[12] we undertook the study of the
[a]
N. Melis, A. Luridiana, T. Boddaert, D. J. Aitken
CP3A Organic Synthesis Group, ICMMO, CNRS UMR 8182
Université Paris Sud, Université Paris Saclay
15 rue Georges Clemenceau, 91405 Orsay Cedex, France
E-mail: thomas.boddaert@u-psud.fr
david.aitken@u-psud.fr
http://www.icmmo.u-psud.fr/Labos/CP3A/index.php
N. Melis, A. Luridiana, F. Secci, A. Frongia
Dipartimento di Scienze Chimiche e Geologiche
Università degli studi di Cagliari, Complesso Universitario di
Monserrato
[b]
[c]
This selectivity profile is in agreement with mechanistic
arguments regarding the Paternò-Büchi reaction with electron-
rich α,α-disubstituted alkene partners.[7h,19] With a view to
preparing other 1-hydroxy-6-oxabicyclo[3.2.0]heptane derivati-
ves, we investigated the photochemical reactivity of compound 3
with three other carbonyl compounds (p-anisaldehyde, acetone,
benzophenone) but only complex reaction mixtures were
obtained and no bicyclic products were forthcoming.
S.S. 554, Bivio per Sestu, I-09042, Monserrato, Cagliari, Italy
R. Guillot
Services Communs, ICMMO, CNRS UMR 8182
Université Paris Sud, Université Paris Saclay
15 rue Georges Clemenceau, 91405 Orsay Cedex, France
Copies of 1H and 13C NMR spectra for all new compounds and
crystallographic data are presented in the Supporting Information.
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10.1002/ejoc.201701214
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Table 1. Influence of the solvent on the Paternò-Büchi reaction of 1 with 2.
conditions, which would be expected to lead to a cyclopentane-
1,2-diol. Indeed, when compounds 3a, 3b and 5a were
subjected
to
palladium-catalysed
hydrogenolysis,
the
diastereochemically pure trans-1,2-diol 6 was obtained in each
case (Scheme 3). With 3a and 3b the reaction took longer but,
as anticipated,[10c,d] the silyl protecting group was removed under
these conditions. The solvent of choice was ethyl acetate, which
invariably provided diol
6 in near-quantitative yield. This
compound has only been synthesised once before, in two steps
from 1-benzylcyclopentene in an undisclosed yield.[20] A single
crystal of 6 was submitted to X-ray diffraction analysis which
confirmed its molecular structure.
ratio
ratio
entry
solvent
3a
3b[c]
yield[d]
3/4[a]
3a/3b[b]
1
2
3
4
5
C6H6
C6H5CF3
C6H12
36:64
43:57
36:64
33:67
>95:5
56:44
55:45
57:43
62:38
65:35
27%
22%
16%
20%
34%
6%
5%
33%
27%
27%
33%
42%
11%
13%
8%
C6H5CH3
CH3CN
Scheme 3. Syntheses of compound 6 and its crystal structure.
[a] meso- and DL-1,2-Diphenylglycol adducts 4 were formed in a 60/40 ratio
in all cases. [b] Ratio determined from the crude 1H NMR spectra. [c] The
low isolated yield of 3b can be explained by its relatively low stability during
the chromatographic separation. [d] Combined yield of isolated
diastereoisomers 3a and 3b.
We then turned our attention to the reactivity of the protected
and unprotected 6-oxabicyclo[3.2.0]heptan-1-ols in acidic media.
When compounds 3a and 3b were treated with a large excess of
trifluoroacetic acid (TFA) in dichloromethane at 0 °C, 2-
phenylcyclohex-2-enone 7 was obtained in yields of 64% and
78%, respectively (Scheme 4). Likewise, treatment of compound
5a in the same conditions provided compound 7 in 63% yield.
We hypothesised that this chemical transformation could arise
from a pinacol-type rearrangement to give a 3-hydroxy-2-
phenylcyclohexanone, akin to that observed by Bach for
monocyclic systems (Scheme 1) with the distinctive feature of
being completely regioselective (for the b-isomer), followed by
facile dehydration. X-ray diffraction of a single crystal of 7
confirmed its molecular structure.
With the bicyclic adducts 3a and 3b in hand, we examined
their chemical reactivity and first performed the selective
removal of the silyl protecting group. This was achieved
efficiently using tetra-n-butylammonium fluoride (TBAF) in THF
at 0 °C, to provide the corresponding tertiary alcohols 5a and 5b
in 77% and 83% yields, respectively (Scheme 2). Single crystals
suitable for X-ray diffraction analysis were obtained for each of
them, confirming their molecular structures and their relative
stereochemical configurations.
Scheme 4. TFA-mediated formation of compound 7 and its crystal structure.
We therefore focused our attention on the reactivity of the 6-
oxabicyclo[3.2.0]heptan-1-ol derivatives in the presence of a
Lewis acid (Table 2). Treatment of the silyl-protected exo-
derivative 3a with a slight excess of AlCl3 for 45 min at –78 °C in
dichloromethane furnished 3-hydroxy-2-phenylcyclohexanone as
a single regioisomer and with very high diastereoselectivity in
favour to the trans-isomer (8/9a ratio 97:3); compound 8 was
isolated in 70% yield (entry 1). When the same reaction was
performed on the unprotected exo-derivative 5a, the
Scheme 2. Preparation of compounds 5a and 5b and their crystal structures.
We investigated the reactivity of the protected and
unprotected 6-oxabicyclo[3.2.0]heptan-1-ols under reducing
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10.1002/ejoc.201701214
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diastereoselectivity was slightly lower (8/9a ratio 89:11);
compound 8 was isolated in 62% yield in addition to the cis-
isomer 9a (10% yield) and the dehydration product 7 (10% yield)
(entry 2). Since the amount of cyclohexenone 7 observed in
crude reaction mixtures was negligible (less than 5%), its
appearance was attributed to the facile dehydration of 8 and 9a
during their chromatographic separation on silica gel.
in Scheme 5. On the basis of literature precedents for Lewis acid
assisted epoxide rearrangement[21] and our own observations on
the ring expansion of oxaspiropentanes to cyclobutanones,[22]
we suggest that the rearrangement might be the result of a
double SN2 type inversion via an epoxide intermediate.
Coordination of a Lewis acid to one of the lone pairs of the ring
oxygen atom (intermediates I) would induce oxetane ring fission
and concomitant epoxide formation (intermediates II). This spiro-
epoxide would evolve via a pinacol-type migration to give
intermediates 8’ and 9’ which furnish 8 and 9 upon work-up.
This concerted and completely stereoselective sequence (3a or
5a  8; 3b or 5b  9) would be in competition with an
Table 2. AlCl3-mediated rearrangements of compounds 3 and 5.
alternative pathway implicating
a
benzylic carbocation
intermediate (intermediates III), which would be significant if
oxetane ring fission were faster than epoxide formation. In such
a
case, the carbocation would equilibrate between two
conformations (endo-III and exo-III) leading to a mixture of
products 8 and 9.
entry
1
R
TMS
H
sub.
3a
ratio 8/9[a]
97:3
yield[b]
On the above premise, the decisive factor in the competition
between the concerted and the carbocation pathways is the
Lewis acid coordination mode. Bidentate coordination of the
Lewis acid to both the exocyclic and endocyclic oxygen atoms
should promote oxetane cleavage but not epoxide formation,
thus facilitating carbocation formation. This is only feasible when
the Lewis acid coordination is on the exo face of the 6-
oxabicyclo[3.2.0]heptan-1-ol skeleton. In contrast, Lewis acid
coordination on the endo face of the bicyclic core structure
would be entirely conducive to the concerted rearrangement
pathway (Scheme 5). For compound 3a (R1 = Ph; R2 = H; R =
TMS) the exo-phenyl substituent and the bulky silyl ether
essentially favour endo face coordination and the concerted
mechanism dominates. For compound 5a (R1 = Ph; R2 = H; R =
H) the steric hindrance of the exo face is reduced and bidentate
mode exo face coordination is not totally excluded, leading to a
slight depletion of stereoselectivity for 5a (dr 89:11) with respect
to 3a (dr 97:3). For compounds 3b (R1 = H; R2 = Ph; R = TMS)
and 5b (R1 = H; R2 = Ph; R = H) the steric hindrance of the endo
face by the phenyl substituent clearly favours exo face (and
therefore bidentate) coordination of the Lewis acid. In these
cases the carbocation pathway competes significantly with the
concerted route, resulting in lower stereoselectivity.
70% (8)
2
5a
89:11
62% (8); 10% (9a); 10% (7)
38% (8); 13% (9a); 13% (9b)
22% (8); 47% (9a); 10% (7)
3[c]
4
TMS
H
3b
33:67[d]
32:68
5b
[a] Ratio determined from the crude 1H NMR spectra. [b] Isolated products
after chromatography. [c] Reaction time 90 min. [d] Compound 9 was
determined from the crude as a 45:55 mixture of 9a and 9b.
When the endo-derivatives 3b and 5b were treated with
AlCl3 in dichloromethane, complete regioselectivity was again
observed but the diasteroselectivity was remarkably inverted.
Protected
endo-derivative
3b
furnished
3-hydroxy-2-
phenylcyclohexanone preferentially as the cis-isomer (8/9 ratio
33:67). The cis-isomer was obtained as a mixture of unprotected
and silylated forms (9a/9b ratio 45:55). After chromatographic
separation, compounds 8, 9a and 9b were obtained in 38%,
13% and 13% yield, respectively (entry 3). When the
unprotected endo-derivative 5b was treated with AlCl3 for 45 min
at –78 °C in dichloromethane the cis-isomer was again formed
preferentially (8/9a ratio 32:68) and provided after
chromatography compounds 8 and 9a, in 22% and 47% yield,
respectively, as well as the dehydration product 7 (10% yield)
(entry 4). The trans-configuration of compound 8 was confirmed
by X-ray diffraction analysis of a single crystal (Figure 1).
Conclusions
We have established a gram scale preparation of bicyclic
oxetane scaffolds via
a
Paternò-Büchi reaction. These
compounds allow expedient access to the corresponding trans-
cyclopentane-1,2-diol or cyclohex-2-enone derivatives. While
acid mediated pinacol-type rearrangement of monocyclic
oxetanyl silyl ethers was already known to proceed via two
regioisomeric processes (Scheme 1), the bicyclic scaffolds
studied
here
underwent
completely
regioselective
rearrangements, accompanied by an excellent stereoselectivity
when the phenyl substituent at the 7-position was located on the
exo face. Collectively, these observations confirm and extend
the theoretical interest and the synthetic value of functionalized
oxetanyl silyl ethers obtained via Paternò-Büchi reactions.
Figure 1. Crystal structure of compound 8.
To explain the stereoselectivity profile of the above-noted
transformations of 3 and 5, we postulate the mechanism shown
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10.1002/ejoc.201701214
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Scheme 5. Left: Proposed mechanism for the AlCl3-mediated rearrangement, Right: endo and exo modes of Lewis acid coordination.
tetrahydrofuran (1 M, 1.5 equiv.). The reaction was stirred under argon
for 4 h at 0 °C and then quenched with water. The resulting mixture was
diluted with EtOAc and the two phases were separated. The organic
phase was washed with water (2 times) and the resulting aqueous phase
was extracted with EtOAc (3 times). The combined organic phases were
then dried with Na2SO4 and concentrated under reduced pressure to give
the crude mixture, which was purified by flash chromatography to afford
the requisite alcohol 5a or 5b.
Experimental Section
General Experimental: All reagents and solvents were of commercial
grade and were used without further purification, with the exception of
acetonitrile which was distilled from P2O5, dichloromethane which was
dried over activated alumina, tetrahydrofuran which was distilled from
sodium/benzophenone, NaI which was dried under high vacuum at 90 °C
for 12 h and triethylamine which was distilled over potassium hydroxide.
Flash chromatography was performed on columns of silica gel (35–70
μm). Analytical thin-layer chromatography was carried out on commercial
0.25 mm silica gel plates which were visualized by UV fluorescence at
254 nm then revealed using a p-anisaldehyde solution, phosphomolybdic
acid solution (10% in EtOH) or a ninhydrin solution (0.3% in n-BuOH).
Retention factors (Rf) are given for such TLC analyses. Melting points
were obtained in open capillary tubes and are uncorrected. Fourier-
transform Infrared (IR) spectra were recorded for neat samples using an
ATR diamond accessory; maximum absorbances (ν) are given in cm-1.
Nuclear magnetic resonance (NMR) data were acquired on
spectrometers operating at 360/250 MHz for 1H, and at 100/90/63 MHz
for 13C. Chemical shifts () are reported in ppm with respect to
tetramethylsilane ( = 0 ppm). Splitting patterns for 1H NMR and 13C
NMR signals are designated as: s (singlet), d (doublet), t (triplet), q
(quartet), quint (quintuplet), broad singlet (br. s) or m (multiplet). Coupling
constants (J) are reported in Hz. High-resolution mass spectrometry
(HRMS) data were recorded using on a spectrometer equipped with an
electrospray ionization source either in positive or negative mode as
appropriate, with a tandem Q-TOF analyzer. Details on X-ray diffraction
analysis data are given in the Supporting Information.
General procedure C for hydrogenolysis: To a solution of protected or
deprotected cycloadduct 3a, 3b or 5a (1 equiv.) in EtOAc was added the
Pd/C 10% or Pd(OH)2. The reaction mixture was stirred under H2
atmosphere for 26 h and then filtered through a pad of Celite® and rinsed
with EtOAc. The solvent was removed under reduced pressure to give
the crude mixture, which was purified by flash chromatography to afford
the diol 6.
General procedure D for TFA-mediated rearrangement: To a solution
of protected or deprotected cycloadduct 3a, 3b or 5a (1 equiv.) in
dichloromethane was added TFA (130 equiv.) at 0 °C. After being stirred
for 26 h at 0 °C, the reaction was concentrated under reduced pressure
to give the crude mixture, which was purified by flash chromatography to
afford the cyclohexanone 7.
General procedure E for AlCl3-mediated rearrangement: To a solution
of protected or deprotected cycloadduct 3a, 3b, 5a or 5b (1 equiv.) in
dichloromethane was added AlCl3 (1.5 or 3 equiv.) at –78 °C. After the
appropriate time (see Table 2) at –78 °C, the reaction was quenched with
water and extracted with dichloromethane (3 times). The combined
organic phases were washed with a saturated aqueous solution of
NaHCO3 then brine, dried over Na2SO4 and concentrated under reduced
pressure to give the crude mixture, which was purified by flash
chromatography to afford the protected and/or deprotected alcohols 8
and 9.
General procedure A for the Paternò-Büchi Reaction: A 60 mM
solution of benzaldehyde 1 (1 equiv.) and silyl enol ether 2 (2 equiv.) in
the appropriate solvent (degassed with an argon stream for 30 min) was
placed in a cylindrical immersion photochemical reactor. The solution
was irradiated for 6 h with a 400 W medium-pressure Hg lamp fitted with
a Pyrex® filter and a water-cooling jacket and the reaction mixture was
concentrated under reduced pressure to give the crude mixture, which
was purified by flash chromatography to afford the requisite
photoadducts 3a and 3b.
(cyclopent-1-en-1-yloxy)trimethylsilane 2: Based on the literature
procedure:[23] To a dispersion of anhydrous NaI (64 mmol, 9.55 g, 1.25
equiv.) in acetonitrile (80 mL) were added cyclopentanone (51 mmol,
4.28 g, 4.50 mL, 1 equiv.) followed by Et3N (64 mmol, 6.45 g, 8.88 mL,
1.25 equiv.). TMSCl (58 mmol, 6.31 g, 7.42 mL, 1.14 equiv.) was then
added dropwise and the solution was stirred at room temperature for 1 h.
General procedure B for silylated group removal: To a solution of 3a
or 3b (1 equiv.) in tetrahydrofuran was added a solution of TBAF in
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10.1002/ejoc.201701214
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Pentane was added and the mixture was stirred vigorously for 10
minutes. The two layers were then separated and the acetonitrile phase
was extracted with pentane. The combined pentane phases were
washed with water and brine, dried over Na2SO4 and concentrated under
reduced pressure to give the crude product 2 (used without further
purification) as a colorless oil (6.48 g, 81%). Rf (PE): 0.79; IR ν: 2959,
(11 mL), flash chromatography (PE/Et2O 80:20 → 50: 50) gave the
products 5b as colourless crystal (173 mg, 83%). Rf (50:50 PE/Et2O):
0.30; IR ν: 3719, 3372, 2952, 1499, 1297, 1109; MP: 81-83 °C; H NMR
(360 MHz, CDCl3) δ: 7.42-7.22 (m, 5H), 5.80 (s, 1H), 5.06 (d, J = 2.9 Hz,
1H), 3.07-1.86 (br.m, 1H), 1.98 (dd, J = 13.1, 5.7 Hz, 1H), 1.86-1.59 (m,
4H), 1.42-1.31 (m, 1H). 13C NMR (90 MHz, CDCl3) δ: 137.9 (C), 128.3
(2CH), 127.4 (CH), 124.5 (2CH), 91.8 (CH), 90.3 (CH), 85.0 (C), 34.0
(CH2), 32.5 (CH2), 24.4 (CH2); HRMS (ESI-): Calcd. for C12H13O2 (M - H+),
m/z 189.0921, found 189.0911; X-ray: CCDC 1550690.
1
1
2901, 2852, 1642, 1344, 1250, 1184, 921, 894, 837, 752; H NMR (250
MHz, CDCl3) δ: 4.64-4.57 (m, 1H), 2.31-2.19 (m, 4H), 1.91-1.77 (m, 2H),
0.20 (s, J = 1.9 Hz, 9H); 13C NMR (63 MHz, CDCl3) δ: 155.2 (C), 102.2
(CH), 33.7 (CH2), 28.9 (CH2), 21.5 (CH2), 0.1 (3CH3); HRMS (ESI+/ESI-):
unstable.
trans-1-benzylcyclopentane-1,2-diol 6: From 3a: According to the
general procedure C using 3a (0.38 mmol, 100 mg, 1 equiv.) and Pd/C
(50 mg) in EtOAc (11 ml), flash chromatography (PE/Et2O 90:10) gave
the diol 6 as a colourless crystal (72 mg, 99%). From 3b: According to
the general procedure C using 3b (0.23 mmol, 60 mg, 1 equiv.) and Pd/C
(30 mg) in EtOAc (6 ml), flash chromatography (PE/Et2O 90:10) gave the
diol 6 as a white solid (43 mg, 97%). From 5a: According to the general
procedure C using 5a (0.33 mmol, 63 mg, 1 equiv.) and Pd/C (30 mg) in
EtOAc (7 ml), flash chromatography (PE/Et2O 90:10) gave the diol 6 as a
white solid (63 mg, 99%). Rf (50:50 PE/Et2O): 0.2; MP: 71-73 °C; IR ν:
3377, 3329, 2922, 2849, 1732, 1490, 1395, 1295, 1079, 979, 702; 1H
NMR (250 MHz, CDCl3) δ: 7.55-7.12 (m, 5H), 3.84-3.76 (br. m, 1H), 3.06
(A of AB quartet, J = 13.5 Hz, 1H), 2.84 (B of AB quartet, J = 13.5 Hz,
1H), 2.29-2.09 (m, 1H), 1.95-1.70 (m, 4H), 1.67-1.42 (m, 3H); 13C NMR
(63 MHz, CDCl3) δ: 137.9 (C), 130.5 (2CH), 128.6 (2CH), 126.7 (CH),
83.6 (C), 79.0 (CH), 40.9 (CH2), 35.6 (CH2), 32.9 (CH2), 20.2 (CH2);
HRMS (ESI+): Calcd. for C12H16O2Na (M + Na+), m/z 215.1043, found
215.1040; X-ray: CCDC 1550691.
exo-trimethyl((7-phenyl-6-oxabicyclo[3.2.0]heptan-1-yl)oxy)silane 3a
and
endo-trimethyl((7-phenyl-6-oxabicyclo[3.2.0]heptan-1-yl)oxy)-
silane 3b: According to the general procedure A using benzaldehyde 1
(12 mmol, 1.22 mL, 1 equiv.) and silyl enol ether 2 (24 mmol, 3.74 g, 2
equiv.) in acetonitrile (200 mL), flash chromatography (PE/Et2O 98:2 →
94:6) gave the products 3a as a pale yellow oil (1.06 g, 34%) and 3b as a
pale yellow oil (261 mg, 8%). 3a: Rf (90:10 PE/Et2O): 0.7; IR ν: 2956,
2879, 1335, 1252, 1236, 1201, 968, 927, 898, 837, 748, 696 ; 1H NMR
(360 MHz, CDCl3) δ: 7.50-7.19 (m, 5H), 5.30 (s, 1H), 5.12 (d, J = 3.5 Hz,
1H), 2.35-2.13 (m, 2H), 2.12-1.97 (m, 2H), 1.78-1.62 (m, 2H), -0.18 (s,
9H); 13C NMR (90 MHz, CDCl3) δ: 139.5 (C), 127.87 (2CH), 127.85
(2CH), 127.8 (CH), 92.6 (CH), 92.0 (CH), 84.8 (C), 39.1 (CH2), 33.1
(CH2), 24.2 (CH2), 1.5 (3CH3); HRMS (ESI+): Calcd. for C15H22NaO2Si (M
+ Na+), m/z 285.1281, found 285.1280. 3b: Rf (90:10 PE/Et2O): 0.90; IR
ν: 2954, 2878, 1252, 1200, 1142, 1131, 992, 967, 902, 836, 738, 700; 1H
NMR (360 MHz, CDCl3) δ: 7.50-7.19 (m, 5H), 5.80 (s, 1H), 5.16 (d, J =
2.7 Hz, 1H), 2.02-1.94 (m, 1H), 1.83-1.59 (m, 4H), 1.48-1.37 (m, 1H),
0.24 (s, 9H); 13C NMR (63 MHz, CDCl3) δ: 138.5 (C), 128.1 (2CH), 127.1
(CH), 124.7 (2CH), 90.6 (CH), 90.5 (CH), 86.1 (C), 34.8 (CH2), 32.4
(CH2), 24.0 (CH2), 2.0 (3CH3); HRMS (ESI+): Calcd. for C15H22NaO2Si (M
+ Na+), m/z 285.1281, found 285.1270.
4,5-dihydro-[1,1'-biphenyl]-2(3H)-one 7: From 3a: According to the
general procedure D using 3a (0.31 mmol, 81 mg, 1 equiv.) and TFA
(40.2 mmol, 4.58 g, 3.07 mL, 130 equiv.) in dichloromethane (4 ml) at
0
°C, flash chromatography (PE/Et2O 90:10
→
50:50) gave
cyclohexenone 7 as a colourless crystal (42 mg, 78%). From 3b:
According to the general procedure D using 3b (0.27 mmol, 70 mg, 1
equiv.) and TFA (34.7 mmol, 4.0 g, 2.7 mL, 130 equiv.) in
dichloromethane (4 ml) at 0 °C, flash chromatography (PE/Et2O 90:10 →
50:50) gave cyclohexenone 7 as a white solid (29 mg, 64%). From 5a:
According to the general procedure D using 5a (0.26 mmol, 50 mg, 1
equiv.) and TFA (34.2 mmol, 3.9 g, 2.6 mL, 130 equiv.) in
dichloromethane (4 ml) at 0 °C, flash chromatography (PE/Et2O 90:10 →
50:50) gave cyclohexenone 7 as a white solid (28 mg, 63%). Rf (50:50
PE/Et2O): 0.6; MP: 91-93 °C; IR ν: 3718, 3372, 2932, 3856, 2839, 1669,
1366, 1264, 1250, 1184, 988, 837; 1H NMR (360 MHz, CDCl3) δ: 7.39-
7.23 (m, 5H), 7.06 (t, J = 4.2 Hz, 1H), 2.65-2.59 (m, 2H), 2.58-2.53 (m,
2H), 2.18-2.05 (m, 2H); 13C NMR (100 MHz, CDCl3) δ: 198.1 (C), 148.1
(CH), 140.5 (C), 136.7 (C), 128.7 (2CH), 128.1 (2CH), 127.7 (CH), 39.2
(CH2), 26.7 (CH2), 23.0 (CH2); HRMS (ESI+): Calcd. for C12H13O (M + H+),
m/z 173.0961, found 173.0956; Spectral data were identical to those
described in the literature;[25] X-ray: CCDC 1550692.
cis-2,3-diphenyl-1,4-dioxaspiro[4.4]nonane 4a: Rf (90:10 PE/Et2O):
0.95; H NMR (250 MHz, CDCl3) δ: 7.13-6.97 (m, 10H), 5.40 (br. s, 2H),
1
2.41-2.32 (m, 2H), 2.07-1.99 (m, 2H), 1.89-1.79 (m, 4H); 13C NMR (63
MHz, CDCl3) δ: 137.7 (2C), 127.6 (4CH), 127.3 (2CH), 127.0 (4CH),
119.2 (C), 81.6 (2CH), 36.7 (CH2), 36.4 (CH2), 24.4 (CH2), 23.4 (CH2).
Spectral data were identical to those described in the literature.[24]
trans-2,3-diphenyl-1,4-dioxaspiro[4.4]nonane 4b: Rf (90:10 PE/Et2O):
0.93; 1H NMR (360 MHz, CDCl3) δ: 7.37-7.30 (m, 6H), 7.28-7.23 (m, 4H),
4.73 (s, 2H), 2.20-2.07 (m, 4H), 1.91-1.74 (m, 4H); 13C NMR (90 MHz,
CDCl3) δ: 137.1 (2C), 128.5 (4CH), 128.3 (2CH), 126.8 (4CH), 119.7 (C),
85.6 (2CH), 37.8 (2CH2), 23.7 (2CH2); HRMS (ESI+): Calcd. for
C19H20O2Na (M + Na+), m/z 303.1361, found 303.1345. Spectral data
were identical to those described in the literature.[24]
exo-7-phenyl-6-oxabicyclo[3.2.0]heptan-1-ol 5a: According to the
general procedure B using the cycloadduct 3a (0.38 mmol, 100 mg, 1
equiv.) and a solution of TBAF (0.57 mL, 1.2 equiv.) in tetrahydrofuran (4
mL), flash chromatography (PE/Et2O 80:20) gave the products 5a as
colourless crystal (55 mg, 77%). Rf (80:20 PE/Et2O): 0.21; IR ν: 3399,
2958, 1453, 1329, 1231, 1125, 1101, 1073, 957, 922, 750, 696; MP: 67-
70 °C; 1H NMR (360 MHz, CDCl3) δ: 7.51-7.32 (m, 5H), 5.45 (s, 1H), 4.98
(d, J = 3.4 Hz, 1H), 2.33-2.17 (m, 1H), 2.14-1.99 (m, 3H), 1.78-1.67 (m,
3H). 13C NMR (75 MHz, CDCl3) δ: 137.7 (C), 129.0 (2CH), 128.5 (CH),
126.3 (2CH), 93.7 (CH), 90.8 (CH), 82.8 (C), 37.1 (CH2), 33.3 (CH2), 23.7
(CH2); HRMS (ESI-): Calcd. for C12H13O2 (M - H+), m/z 189.0921, found
189.0925; X-ray: CCDC 1550689.
trans-3-hydroxy-2-phenylcyclohexanone 8, cis-3-hydroxy-2-phenyl-
cyclohexanone 9a and cis-2-phenyl-3-(trimethylsilyloxy)cyclo-
hexanone 9b: From 3a: According to the general procedure E using 3a
(0.27 mmol, 70 mg, 1 equiv.) and AlCl3 (0.40 mmol, 53 mg, 1.5 equiv.) in
dichloromethane (7 ml) at -78 °C, flash chromatography (PE/Et2O 80:20
→ 40:60) gave trans-cyclohexanol 8 as a colourless crystal (36 mg, 70%).
From 5a: According to the general procedure E using 5a (0.22 mmol, 42
mg,
1 equiv.) and AlCl3 (0.33 mmol, 43 mg, 1.5 equiv.) in
dichloromethane (5 ml) at -78 °C, flash chromatography (PE/Et2O 80:20
→ 40:60) gave cis-cyclohexanol 9a as a colourless oil (4 mg, 10%),
trans-cyclohexanol 8 as a white solid (26 mg, 62%) and cyclohexenone 7
as a white solid (4 mg, 10%). From 3b: According to the general
procedure E using 3b (0.25 mmol, 68 mg, 1 equiv.) and AlCl3 (0.37 mmol,
50 mg, 1.5 equiv.) in dichloromethane (7 ml) at -78 °C, flash
endo-7-phenyl-6-oxabicyclo[3.2.0]heptan-1-ol 5b: According to the
general procedure B using the cycloadduct 3b (1.09 mmol, 284.2 mg, 1
equiv.) and a solution of TBAF (1.64 mL, 1.5 equiv.) in tetrahydrofuran
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10.1002/ejoc.201701214
European Journal of Organic Chemistry
FULL PAPER
chromatography (PE/Et2O 80:20 → 40:60) gave cis-cyclohexanol 9a as a
colourless oil (6 mg, 13%), trans-cyclohexanol 8 as a white solid (19 mg,
38%) and protected cis-cyclohexanol 9b as a pale yellow oil (8 mg, 13%).
From 5b: According to the general procedure E using 5b (0.3 mmol, 57
[7]
a) F. Vogt, K. Jꢀdicke, J. Schrꢀder, T. Bach, Synthesis 2009, 4268-
4273; b) T. Bach, K. Jödicke, K. Kather, R. Fröhlich, J. Am. Chem. Soc.
1997, 119, 2437-2445; c) T. Bach, F. Eilers, K. Kather, Liebigs Ann.
1997, 1529-1536; d) T. Bach, K. Jödicke, B. Wibbeling, Tetrahedron
1996, 52, 10861-10878; e) T. Bach, Liebigs Ann. 1995, 855-865; f) T.
Bach, K. Jödicke, K. Kather, J. Hecht, J. Angew. Chem. Int. Ed. 1995,
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K. Jꢀdicke, T. Bach, Chem. Ber. 1993, 126, 2457-2466 and references
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mg,
1 equiv.) and AlCl3 (0.45 mmol, 60 mg, 1.5 equiv.) in
dichloromethane (6 ml) at -78 °C, flash chromatography (PE/Et2O 80:20
→ 40:60) gave cis-cyclohexanol 9a as a colourless oil (27 mg, 47%),
trans-cyclohexanol 8 as a white solid (13 mg, 22%) and cyclohexenone 7
as a white solid (6 mg, 10%). 8: Rf (50:50 PE/Et2O): 0.05; MP: 93-94 °C;
IR ν: 3463, 3052, 3030, 2944, 2862, 1698, 1400, 1321, 1022, 750, 735;
1H NMR (250 MHz, CDCl3) δ: 7.43-7.27 (m, 3H), 7.20-7.11 (m, 2H), 4.01
(dt, J = 10.4, 4.2 Hz, 1H), 3.56 (d, J = 10.4 Hz, 1H), 2.61-2.40 (m, 2H),
2.40-2.29 (m, 1H), 2.19-2.05 (m, 1H), 1.97-1.79 (m, 1H), 1.79-1.59 (m,
2H); 13C NMR (90 MHz, CDCl3) δ: 207.3 (C), 134.8 (C), 129.9 (2CH),
129.0 (2CH), 128.0 (CH), 75.0 (CH), 67.2 (CH), 41.1 (CH2), 33.1 (CH2),
20.9 (CH2); HRMS (ESI+): Calcd. for C12H14O2Na (M + Na+), m/z
213.0886, found 213.0888; X-ray: CCDC 1550693. 9a: Rf (50:50
[8]
[9]
For related work by other groups, see: a) H. J. Park, U. C. Yoon, H.-Y.
Lee, D. W. Cho, P. S. Mariano, J. Org. Chem. 2012, 77, 10304-10313;
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1
PE/Et2O): 0.2; IR ν: 3437, 3030, 2944, 2870, 1706, 1598, 1122, 698; H
NMR (360 MHz, CDCl3) δ: 7.40-7.25 (m, 5H), 4.32 (d, J = 2.8 Hz, 1H),
3.74 (d, J = 2.8 Hz, 1H), 2.60-2.50 (m, 1H), 2.49-2.37 (m, 2H), 2.37-1.87
(m, 4H); 13C NMR (90 MHz, CDCl3) δ: 208.2 (C), 136.2 (C), 130.0 (2CH),
128.6 (2CH), 127.5 (CH), 74.5 (CH), 62.1 (CH), 41.9 (CH2), 32.1 (CH2),
21.0 (CH2); HRMS (ESI+): Calcd. for C12H14O2Na (M + Na+), m/z
213.0886, found 213.0891. Spectral data were identical to those
described in the literature.[26] 9b: Rf (50:50 PE/Et2O): 0.65; 1H NMR (250
MHz, CDCl3) δ: 7.35-7.26 (m, 5h), 4.37-4.31 (m, 1H), 3.75 (d, J = 2.7 Hz,
1H), 2.65-2.52 (m, 2H), 2.47-2.30 (m, 2H), 2.05-1.91 (m, 2H), -0.13 (s,
9H); 13C NMR and IR: The low stability of this compound and the small
isolated amount of it did not allow for a 13C NMR experiment nor IR
analysis; HRMS (ESI+): Calcd. for C15H22O2SiNa (M + Na+), m/z
285.1281, found 285.1283.
[10] a) T. Bach, K. Kather, J. Org. Chem. 1996, 61, 3900-3901; b) T. Bach,
C. Lange, Tetrahedron Lett. 1996, 37, 4363-4364; c) T. Bach, Liebigs
Ann. 1995, 1045-1053; d) T. Bach, Tetrahedron Lett. 1994, 35, 1855-
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Keywords: Lewis acids • Oxetanol • Paternò-Büchi reaction •
Photochemistry • Rearrangement
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FULL PAPER
Oxetanol rearrangement
Nicola Melis, Alberto Luridiana, Régis
Guillot, Francesco Secci, Angelo
Frongia, Thomas Boddaert* and David J.
Aitken*
Page No. – Page No.
The 6-oxabicyclo[3.2.0]heptan-1-ol derivatives, obtained by an efficient
photochemical Paternò-Büchi reaction, were enrolled to a regio- and
stereoselective Lewis acid-catalysed pinacol-type rearrangement
Stereoselective and regioselective
pinacol-type rearrangement of a
fused bicyclic oxetanol scaffold
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