Molecules 29 05474 v2

Article
Article
An Unexpected Formation of Spiro Isoxazoline-Dihydrofurane
An Unexpected Formation of Spiro Isoxazoline-Dihydrofurane
Compounds from
Compounds from Substituted
Substituted Ketofurfuryl
Ketofurfuryl Alcohols
Alcohols
Claire Cuyamendous, Mathieu Yves Laurent and Christine Saluzzo *
Claire Cuyamendous, Mathieu Yves Laurent and Christine Saluzzo *
MSO, Institut des Molécules et Matériaux du Mans (IMMM), UMR CNRS 6283, Le Mans Université,
MSO, Institut
Avenue des Molécules
O. Messiaen, et Matériaux
72085 Le du Mans
Mans, CEDEX (IMMM),
9, France; UMR CNRS 6283, Le Mans(C.C.);
[email protected] Université, Avenue O.
Messiaen, 72085 Le Mans, CEDEX 9, France;
[email protected] (M.Y.L.) [email protected] (C.C.);
[email protected] (M.Y.L.)
* Correspondence: [email protected]
* Correspondence: [email protected]
Abstract: Oximation of substituted ketofurfuryl alcohols in the presence of hydroxylamine hydro-

Abstract: Oximation of substituted ketofurfuryl alcohols in the presence of hydroxylamine hy-
chloride and pyridine in ethanol as solvent led to a new class of spiro derivatives presenting a 7-
drochloride and pyridine in ethanol as solvent led to a new class of spiro derivatives presenting
methylene-1,6-dioxa-2-azaspiro [4.4] nona-2,8-diene skeleton along with, in some cases, the predict-
a 7-methylene-1,6-dioxa-2-azaspiro [4.4] nona-2,8-diene skeleton along with, in some cases, the
able oxime. The structures of such spiro compounds were determined by 2D NMR spectroscopy.
predictable oxime. The structures of such spiro compounds were determined by 2D NMR spec-
The suggested formation of this skeleton involves an in situ oximation/dehydration/SN’ cascade re-
troscopy. The suggested formation of this skeleton involves an in situ oximation/dehydration/SN ’
action.
cascade reaction.
Keywords: spiro compound; dihydroxazole; isoxazoline; furfural; oxime; cascade reaction;

Keywords: spiro compound; dihydroxazole; isoxazoline; furfural; oxime; cascade reaction; rearrangement;
rearrangement, bis-heterocycle.
bis-heterocycle
Citation: Cuyamendous, C.; Laurent,

1. Introduction
1. Introduction
M.Y.; Saluzzo, C. An Unexpected
Formation of Bis-Heterocyclic Spiro Oxime, aa versatile
Oxime, versatile functional
functionalgroup
groupininorganic
organicchemistry,
chemistry,permits
permits the
theintroduction
introduction of
Compounds from Substituted Keto- a nitrogen
of a nitrogenatom into
atom a chemical
into a chemicalstructure [1,2].
structure Derived
[1,2]. from
Derived carbonyl
from groups,
carbonyl oximes
groups, can
oximes
furfuryl Alcohols. Molecules 1481, 29, be transformed into amines [3,4], hydroxylamines [4,5], nitriles [6], nitrile oxides
can be transformed into amines [3,4], hydroxylamines [4,5], nitriles [6], nitrile oxides [7], [7], am-
x. https://doi.org/10.3390/xxxxx ides [8],[8],
amides enamides [9], [9],
enamides imines [9] and
imines nitrones
[9] and [10],[10],
nitrones but itbut
canitalso
can be involved
also in thein
be involved prep-
the
Academic Editor: László Somsák
aration of aza-heterocycles [1,2,11–18] (Scheme
preparation of aza-heterocycles [1,2,11–18] (Scheme 1). 1).
Received:Cuyamendous,
Citation: 7 October 2024C.; Laurent,
M.Y.; Saluzzo, C. An Unexpected e.g. O isoxazoline
Revised: 15 November 2024
Formation
O cyclization N
Accepted: of
16 Spiro Isoxazoline-
November 2024
Dihydrofurane Compounds
Published: 20 November 2024 from
R1 NH NOH e.g. O
rearrangement isoxazolidine
Substituted Ketofurfuryl Alcohols. cycloaddition N
R2
Molecules 2024, 29, 5474. https:// R1 R2 H
doi.org/10.3390/molecules29225474 amide oxidation
Copyright: © 2024 by the authors. reduction N-heterocycles
R1 = H dehydration
Academic
SubmittedEditor: László Somsák
for possible open access
R1 = H
publication under the terms and
Received: 7 October 2024 O
conditions of the Creative Commons N NHOH NH2
Revised: 15 November 2024 N or
Attribution (CC BY) license
Accepted: 16 November 2024
(https://creativecommons.org/license R2 R1 R2 R1 R2
Published: 20 November 2024
s/by/4.0/). R2
nitrile oxide nitrile hydroxylamine amine
Scheme 1.
Scheme 1. Overview
Overview of
of oximes
oximes transformations.
transformations.
Copyright: © 2024 by the authors.
Licensee MDPI, Basel, Switzerland. Among
Among nitrogen-containing
nitrogen-containing heterocycles,
heterocycles, 4,5–dihydroisoxazoles
4,5–dihydroisoxazoles derivatives (five-
This article is an open access article membered
membered ring bearing
bearing N-O bond) have attracted increasing attention due to their bio-
distributed under the terms and logical
logical activities
activities [19].
[19]. Some of them are natural products such as acivicin,
acivicin, produced
produced by
by
conditions of the Creative Commons Streptomyces sviceus [20], and subereamolline
Streptomyces sviceus [20], and subereamolline A and aerothionin, isolated from marine
and aerothionin, isolated from marine
Attribution (CC BY) license (https:// sponges
sponges [21]
[21] (Figure
(Figure 1).
1). The
The latter
latter two
two present
present an
an interesting
interesting spiroisoxazoline
spiroisoxazoline backbone
backbone
creativecommons.org/licenses/by/ for which Nishiyama developed a new electrochemical synthesis involving anodic oxida-
4.0/). tion [22].
Molecules 2024, 29, x. https://doi.org/10.3390/xxxxx www.mdpi.com/journal/molecules

Molecules 2024, 29, 5474. https://doi.org/10.3390/molecules29225474 https://www.mdpi.com/journal/molecules
tion [22].
Molecules 2024, 29, x FOR PEER REVIEW 2 of 16
O
O Br Br
Br Br
Molecules 2024, 29, 5474 for which
for which Nishiyama
Nishiyama developed
developed aa new
new electrochemical
electrochemical synthesis
synthesis involving
involving anodic
anodic oxida-
oxida-
2 of 16
N O O HO
tion [22]. O
tion [22]. HO
Cl OH O N H
H H N
NH2 N O O
N O Br
O
O O
Br BrO
Br Br N
Br OBr H
Br Br N O
N O O HOO
H HO N O
N O O O
Acivicin HO Subereamolline A O Aerothionin
Cl OH HO OO N H HO Br
Cl H OH N HN
H NH2 N H N O
NH2 natural N HN O
Figure 1. Some dihydroisoxazole
N derivatives.
O O Br
O O N Br
O NH
O N H O
NH O N O O
The most common synthetic methods H O N O
for isoxazolines typically involve 1,3-dipolar
Acivicin Subereamolline A Aerothionin HO Br
Acivicin Subereamolline A Aerothionin HO
cycloaddition of nitrile oxide [23–27], nitronate [28,29] or oxime [30] with Br alkenes, includ-
ingFigure 1. Some
Some natural
functionalized
Figure 1. naturalones.
dihydroisoxazole
On the other
dihydroisoxazole derivatives.
hand, the synthesis of spiroisoxazolines is more
derivatives.
Figure 1. Some natural dihydroisoxazole derivatives.
challenging. Moreover, to the best of our knowledge, isoxazolines are scarcely engaged in
Themost
The
The mostcommon
most commonsynthetic
common syntheticmethods
methodsfor forisoxazolines
isoxazolinestypically
typicallyinvolve
involve1,3-dipolar
1,3-dipolar
a spiro linked ring withsynthetic
a THF unit methods
[31–34]. for isoxazolines
In typically
1978, Tarmakovskii involve 1,3-dipolar
et al. [31] synthesize for
cycloaddition
cycloaddition
cycloaddition of of
of nitrile
nitrile oxide
nitrileoxide [23–27],
oxide[23–27],
[23–27], nitronate
nitronate
nitronate [28,29]
[28,29]
[28,29] or
orusingoxime
oxime
or oxime [30][30] with
with
[30] with alkenes,
alkenes,
alkenes, includ-
including
includ-
the first time
ing functionalized
functionalized a spiroisoxazoline
ones. On with
thehand,
otherthe a THF
hand, unit
the synthesis
synthesis a thermal rearrangement
of spiroisoxazolines
spiroisoxazolines moreof a ni-
is more
functionalized
ing ones. ones.
On the On other
the other synthesis
hand, the of spiroisoxazolines
of is more challeng-
is
trocyclic
challenging. nitronate
Moreover, in dimethylformamide
toofthe best of our
our knowledge,(DMF) isoxazolines
knowledge, (Scheme 2, are Equation
scarcely (1) (eq.1)).inTwenty
engaged
ing. Moreover,
challenging. to the best
Moreover, to theourbestknowledge,
of isoxazolines are scarcely
isoxazolines engagedengaged
are scarcely in a spiro in
years later, Smietana et al. [32] have reported a spiro ketalization of an α-hydroxyiminoes-
aa spiro
spiroring
linked linked
linked withring
ring with aunit
a THF
with a THF
THF unit [31–34].
[31–34].
unit [31–34].
In 1978, In 1978,
In 1978, Tarmakovskii
Tarmakovskii
Tarmakovskii et
et al. et al.synthesize
[31]
al. [31] synthesize
[31] synthesize
for thefor
for
terthe(Scheme
first
the first time
time
first time 2, Equation (2)
aa spiroisoxazoline
spiroisoxazoline
a spiroisoxazoline with(eq.with
awith
THF2)).aaunit
The
THF
THF
last
unitamethodolody
using
unit using
thermal
using aa thermal
thermal reported ofby
rearrangement
rearrangement
rearrangement
Das ofet al. [33] is
aa ni-
a nitrocyclic
of ni-
based
nitronate on
trocyclic the bromination
nitronate in
in dimethylformamide
trocyclic nitronate with
dimethylformamide
in dimethylformamide pyridinium
(DMF) (Scheme (DMF) tribromide
(DMF)2,(Scheme(Scheme
Equation2,(1) of
2, aromatic
Equation isoxazoles
(1)
(eq.1)). Twenty
Equation (eq.1)).
years
(1) (eq.1)). later, contain
that
Twenty
Twenty
years
aSmietana
pendant
years later,
later, Smietana
etalcohol
al.
Smietana etal.
al.[32]
(Scheme
[32] have et [32]2,have
reported have reported
Equation
a spiro (3)aa(eq.
spiro3)).
ketalization
reported spiro ketalization
of ofan
an α-hydroxyiminoes-
an α-hydroxyiminoester
ketalization of α-hydroxyiminoes-
(Scheme 2,
ter (Scheme
ter (Scheme
Equation 2, Equation
(2) 2, Equation
(eq. 2)). The(2)
(2) (eq.
last
(eq. 2)). The
The last
methodolody
2)). last reported
methodolody
by Das
methodolody reported by Das
et al. [33]
reported by Das et al.
is based
et al.on[33]
the
[33] is
is
based on
bromination
based O
the bromination
with with
pyridinium pyridinium
tribromide tribromide
of aromatic of aromatic
isoxazoles isoxazoles
that contain
-Oon the bromination with pyridinium tribromide of aromatic isoxazoles that contain that
a contain
pendant
N+ alcohol (Scheme 2, Equation (3) (eq. 3)). O N
aa pendant
pendant
alcohol (Scheme
alcohol2, (Scheme
Equation2,(3) (eq. 3)). (3) (eq. 3)).
Equation DMF
R R eq. 1
-O NO
O N+ 70-80 °C O
-O OO
N+ 8h O N
DMF O N
R=
R COOMe, CN, Ph
DMF 55-60%
R eq. 1
eq. 1
R R
O N O 70-80 °C O
O N O 70-80 °C
8h
O
8h O N
R = COOMe,
R CN, Ph O 55-60% OEt
R = COOMe, CN, Ph NH2OH.HCl 55-60%
TBSO OEt EtOH, rt eq. 2

O ON
R
R O
O
O
OH NH22OH.HCl
to 3 h
R
O N OEtO
NH2OH.HCl OEt
TBSO OEt EtOH, rt eq. 2
EtOH, rt O 72-80% eq. 2
R = Me, H
TBSO OEt 2 to 3 h O O
O OH 2 to 3 h R O
O OH R
ArRR == Me,
Me, H N Br3 72-80%
O N
H 72-80%
H
Ar KN Br,3 CH Cl O N Ar eq. 3
ArN OH NH2CO
Br33 2 2 O O
N
O H 0 °C to rt
Br
K CO , CH Cl Ar eq. 3
N OH Ar
K22CO33, CH22Cl22
O eq. 3
N O OH O Br 62-78%
0 °C to rt
O 0 °C to rt
Br
62-78%
Scheme 2. Syntheses of spiroisoxazolines presenting a THF unit.
62-78%
Scheme2.
Scheme
Scheme 2.Syntheses
2. Synthesesof
Syntheses ofspiroisoxazolines
of spiroisoxazolinespresenting
spiroisoxazolines presentingaaaTHF
presenting THFunit.
THF unit.
unit.
We report herein the formation of a new class of spiro compounds presenting an
We
Wereport
isoxazoline
We report herein
unit
report hereinthe
along
herein the formation
thewith
formation of
ofaaanew
newclass
a dihydrofurane
formation of new class of
ofspiro
moiety
class of spiro compounds
compounds
including
spiro presenting
presentingan
a methylene
compounds presenting an
group as
an
isoxazoline
isoxazoline
shown unit
unit
in Figure
isoxazoline along with
along
2.
unit along a
with dihydrofurane
a moiety
dihydrofurane including
moiety a methylene
including a group
methylene as
with a dihydrofurane moiety including a methylene group as shown
group as
in Figurein2.Figure 2.
shown
shown in Figure 2.
RR
R 1
11
N O O
O
O O
N
N O
R
R22
R 2
Figure 2. Structure of the new class of spiroisoxazoline.
Molecules
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Molecules 2024, 29, 5474 3 of 16
Figure
Figure2.
2. Structure
Structure of
of the
the new
new class of spiroisoxazoline.
class of spiroisoxazoline.
2.
2.2.Results
Resultsand
Results andDiscussion
and Discussion
Discussion
As
As indicated in
As indicated
indicated in Scheme
in Scheme 3,3, in
in our
our retrosynthetic analysis,
retrosynthetic analysis,
retrosynthetic ketoalcohol
analysis,ketoalcohol III
ketoalcoholIII would
IIIwould
wouldbe be
beaaa
key
key intermediate
intermediate
key intermediate to to
to form
form the
the corresponding
corresponding oxime
oxime IIand/or
and/or the
the spiroderivative
spiroderivative
corresponding oxime I and/or the spiroderivative II. This II.
II. This
This
ketoalcohol
ketoalcoholIII
ketoalcohol IIIcould
III couldbebegenerated
could generated byby
thethe
functionalization
the in C-5
functionalization
functionalization position
inC-5
in C-5 of aof
position
position 2-substituted
ofaa2-substi-
2-substi-
furfurylalcohol
tuted IV
tuted furfurylalcohol easily obtained from
furfurylalcohol IV easily obtained from furfuraldehyde, a biomass
from furfuraldehyde, derivative.
furfuraldehyde,aabiomass
biomassderivative.
derivative.
NOH
NOH
R
R11
RR22 O
O
II OR
OR O
R11 R
R11 RR11 HH
R R2 O O
O OO
O O
O
NN O III OH
OH IV
IV OPG
OPG OO
RR22
IIII
Scheme3.
Scheme
Scheme 3.Retrosynthetic
3. Retrosyntheticanalysis
Retrosynthetic analysis of
analysis of oxime/isoxazoline
oxime/isoxazoline formation.
of oxime/isoxazoline formation.
formation.
2.1.
2.1.Preparation
2.1. Preparationof
Preparation ofKetoalcohol
of Ketoalcohol Key
Ketoalcohol Key Intermediates
Key Intermediates
Intermediates
AA series of
series tert-butyldimethylsilyl
of ketofurfuryl
tert-butyldimethylsilyl
A series of tert-butyldimethylsilyl alcohols
ketofurfuryl
ketofurfuryl 4a–e presenting
alcohols
alcohols 4a–e alkyl, alkenyl
4a–e presenting
presenting alkyl,
alkyl,
or aromatic groups were prepared from furfuraldehyde according to the four
alkenyl or aromatic groups were prepared from furfuraldehyde according to thefour
alkenyl or aromatic groups were prepared from furfuraldehyde according steps
to reaction
the four
sequence
steps depicted
steps reaction
reaction in Scheme
sequence
sequence 4. in
depicted
depicted in Scheme
Scheme 4.4.
1)
1)n-BuLi,
n-BuLi,THF
THF OH
OH
RR11MgX
MgX TBSCl, imidazole
R1 TBSCl, imidazole
–78
–78°C
°C 00°C °C R1
O HH O R1 DMAP, DCM O
R1
R1 R R2 O R1
O THF O O 2) R22 R2 O
THF DMAP, DCM
O 0 °C rt OH 0 °C rt OTBS 2) OTBS
O 0 °C rt OH 0 °C rt OTBS O OTBS
1a–e 2a–e O 3a–f
1a–e 2a–e 3a–f
OH O Yields
OH DMP, DCM O Yields
R1 DMP, DCM R1 R1 R2 1 2 3 4
R O R1 R O R1 R1 R2 1 2 3 4
R22 O 0 °C R22 O a Et Me 54% 72% 91% 90%
OTBS 0 °C OTBS ba Et
iPr Me
Me 54%
79% 72%
84% 56% 91% 90%
88%
OTBS OTBS Me 79% 84% 44%56% 88%
3a–f
3a–f
4a–f
4a–f cb iPr
iBu Me 71% 94% 73%
Me 71% 94% 60%44% 73%
dc iBu
3-butenyl Me 91% 92% 73%
Me 91% 92% 66%60% 73%
ed 3-butenyl Me
Ph 60% 86% 89%
Me OPh 60% 86% 50%66% 89%
fe Ph
Ph CH 2 30%
f Ph CH2OPh 50% 30%
Scheme4.4.Synthesis
Scheme Synthesisof
ofprotected
protected ketofurfuryl
ketofurfuryl alcohols 4.
Scheme 4. Synthesis of protected ketofurfuryl alcohols 4.
The
Thefirst
firststep
step involved
involved the the nucleophilic
nucleophilic addition addition of of a Grignard
Grignard reagent
reagent to to furfural
furfural
giving
The first step involved the nucleophilic addition of a Grignard reagent to furfural
givingthetheexpected
expected alcohols
alcohols 1a–e 1a–e inin 54
54 to to 91%
91% yields. After protection
yields. After protectionof ofthe
thealcohol
alcoholas as
giving the expected
tert-butyldimethylsilyloxy alcohols 1a–e in 54 to 91% yields. After protection of the alcohol as
tert-butyldimethylsilyloxy ether (OTBS), (OTBS), the the C-5C-5 functionalization
functionalizationof of the
the THF
THF ring ring was
was
tert-butyldimethylsilyloxy
performed ether (OTBS), the C-5 functionalizationmethyl of theoxirane
THF ring was
performedby bylithiation
lithiationreaction.
reaction. The The resulting anions reacted with methyl oxirane or orwith
with
performed
methylglycidyl by
methylglycidylether
lithiation reaction.
etherproviding
providing the
The resulting
the corresponding
anions
corresponding 2,5-disubtituted
reacted with
2,5-disubtituted furans
methyl oxirane
furans 3a–f
3a–fin or
ingood with
goodto to
methylglycidyl
excellent yieldsether
excellentyields (44–91%).providing
(44–91%). As already the corresponding
reported in the 2,5-disubtituted
the literature, the
literature, furans
the yield 3a–f in good
yielddepends
depends onthe
on theto
excellent
nature yields
natureofofboth
bothfuran (44–91%).
furanand As
andepoxide already
epoxide derivatives reported in the
derivatives involved in this literature, the
this reaction yield
reaction [35,36]. depends
[35,36].Subsequent on
Subsequent the
nature
oxidationof both
of the furan
free and
alcohol epoxide
function derivatives
of compounds involved3a–f in
oxidation of the free alcohol function of compounds 3a–f was carried out with Dess–Mar- this
was reaction
carried out [35,36].
with Subsequent
Dess–Martin
oxidation
periodinane of reagent
tin periodinane the reagent
free (DMP)
alcohol
(DMP)tofunction
form ofcompounds
compounds
compounds
to form 3a–f
4a–f4a–fin 30inwas
to carried
3090%
to out with Dess–Mar-
yields.
90% yields.
tin periodinane
Deprotection
Deprotectionof reagent (DMP) to form
oftert-butyldimethylsilyl
tert-butyldimethylsilyl (OTBS)compounds
(OTBS) ethers4a–f in
ethers 4a–f30 to 90% yields.
was first
4a–f was first performedwith
performed with
Deprotection
tetrabutylammonium
tetrabutylammonium fluorideof tert-butyldimethylsilyl
fluoride (TBAF) (Scheme (Scheme 5).(OTBS) ethers 4a–f
5). Unfortunately,
Unfortunately,yieldswas first performed
yieldsvaried
varied with
consider-
consider-
tetrabutylammonium
ably
ablyfrom
fromdegradation
degradationtoto87%fluoride
87%(Table(TBAF)
(Table1)1)and(Scheme
anddid didnot 5). Unfortunately,
notseem yields
seemtotobebecorrelated
correlatedwith varied
withthe consider-
thenature
nature of
ably
Rof Rfrom
1 and
1 and degradation
R2 substituents.
R2 substituents. to
The 87%use(Table
The of
use 1)
Et3of
NEt ·and
3HF did
3N·3HF not
(Scheme seem
(Scheme to5)be correlated
5) significantly with
improved
significantly the
improvedthe nature
yields
the
of
of R1 and
products
yields R5b,
2 substituents.
of products 5d 5b,and5d 5fand The 5f use
(entries 3,of
(entries Et
6 and 3,3N·3HF
6 9,
and 9,(Scheme
Table 1). These
Table 5) significantly
1). Thesedifferences
differences inimproved
yield
in yield can the
canbe
yields of
explained products
by the 5b,
presence5d and
of 5f (entries
moisture in 3,
the6 and
TBAF 9, Table
reagent,
be explained by the presence of moisture in the TBAF reagent, which decreases its reac- 1). These
which differences
decreases in
its yield can
reactivity
be explained
compared
tivity to Et
compared by3N the Etpresence
to·3HF [37]. [37].
3N·3HF of moisture in the TBAF reagent, which decreases its reac-
tivity compared to Et3N·3HF [37].
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OO OO
RR11 deprotection
deprotection RR11
RR22 OO RR22 OO
OTBS
4a–f OTBS OH
4a–f 5a–f OH
5a–f
Scheme5.5.Deprotection
Scheme Deprotectionof
oftert-butyldimethylsilyl.
tert-butyldimethylsilyl.
Table1.1.1.Tert-butyldimethylsilyl
Table
Table ether
Tert-butyldimethylsilyl
Tert-butyldimethylsilyl deprotection.
ether
ether deprotection.
deprotection.
Substrate
Substrate 444
Substrate
Entry
Entry
Entry Conditions* ** Product
Conditions
Conditions Product
Product 555 Yield
Yield %
Yield%
%
R1RR11 R22
R2R
111 4a
4a
4a Et
Et Et Me
Me
Me A
AA 5a
5a
5a 40
40
40
22 AA 14
14
2 4b
4b iPr
iPr Me
Me A 5b
5b 14
333 4b iPr Me 5b
BBB 64
64
64
444 4c
4c
4c iBu
iBu
iBu Me
Me
Me AAA 5c
5c
5c
61
61
61
55 AA Degradation
Degradation
5 4d
4d 3-Butenyl
3-Butenyl
3-Butenyl
Me
Me A 5d
5d Degradation
666 4d Me
BB
B 5d 59
59
59
77 4e
4e Ph
Ph Me
Me AA 5e
5e 87
87
7 4e Ph Me A 5e 87
88 AA 16
16
8 4f
4f Ph
Ph CH OPh
CH22OPh A 5f
5f 16
999 4f Ph CH2 OPh
B
BB 5f 86
86
86
**Condition
ConditionA:A:1.5
1.5eq.
eq.TBAF,
TBAF,THF,
THF,rt, rt,22h;
h;Condition
ConditionB: B:1.5
1.5eq.
eq.Et
Et33N·3HF,
N·3HF,CH
CH33CN,
CN,rt,
rt,16
16h.
h.
* Condition A: 1.5 eq. TBAF, THF, rt, 2 h; Condition B: 1.5 eq. Et N·3HF, CH CN, rt, 16 h.
3 3
2.2.Oximation
2.2.
2.2. Oximationof
Oximation ofofKetoalcohol
Ketoalcohol555
Ketoalcohol
Theoximation
The
The oximationof
oximation ofketones
of ketones5a–f
ketones 5a–fwas
5a–f wasthen
was thenperformed
then performedin
performed inethanol
in ethanolaccording
ethanol accordingto
according tothe
to theHan
the Han
Han
procedure
procedure [38].
[38]. However,
However, in
in these
these conditions
conditions (i.e.,
(i.e., hydroxylamine
hydroxylamine hydrochloride
hydrochloride
procedure [38]. However, in these conditions (i.e., hydroxylamine hydrochloride in the in
in the
the
presence
presence of
of pyridine),
pyridine), ketone
ketone 5a–f
5a–f led,
led, in
in some
some cases,
cases, to
to spiroisoxazoline
spiroisoxazoline derivatives
derivatives
presence of pyridine), ketone 5a–f led, in some cases, to spiroisoxazoline derivatives 6a–f 6a–f
6a–f
alongwith
along
along withor
with orwithout
or withoutthe
without theexpected
the expectedoxime
expected oxime7a–f
oxime 7a–fbeing
7a–f beingprotected
being protectedas
protected asethyl
as ethylether,
ethyl ether,the
ether, thestarting
the starting
starting
material
material having
having been
been completely
completely consumed
consumed (Scheme
(Scheme
material having been completely consumed (Scheme 6 and Table 2). 66 and
and Table
Table 2).
2).
O
O O
NN O NOH
NOH
RR11 NH OH.HCl(4
NH22OH.HCl (4equiv.)
equiv.) RR11
RR22 RR22 ++
O
O O
O RR22 O
O
OH
OH Pyr.(4equiv.),
Pyr.(4 equiv.), EtOH
EtOH OEt
5a–f
5a–f 6a–f
6a–f 7a–f OEt
7a–f
RR11
Scheme6.
Scheme
Scheme 6.6.Oximation
Oximationof
Oximation ofketones
of ketones5a–f.
ketones 5a–f.
5a–f.
Table2.
Table
Table 2.2.Oximation
Oximationof
Oximation ofketone
of ketone5.
ketone 5.5.
Substrate
Substrate 555
Substrate
Entry
Product66(Yield
Product (Yield%)
%) Product
Product77(Yield
(Yield%)
%)
Entry
Entry RR11 RR22 Product 6 (Yield %) Product 7 (Yield %)
R1 R2
11 5a
5a Et
Et Me
Me 6a(4)
6a (4) 7a(34)
7a (34)
1 5a Et Me 6a (4) 7a (34)
22 5b
5b iPr
iPr Me
Me 6b (1)
6b (1) 7b (12)
7b (12)
2 5b iPr Me 6b (1) 7b (12)
33 5c
5c iBu
iBu Me
Me 6c(14)
6c (14) 7c(14)
7c (14)
443 5c
5d
5d iBu
3-Butenyl
3-Butenyl Me
Me
Me 6c
6d (14)
(16)
6d (16) 7c
7d (14)
(32)
7d (32)
554 5d
5e
5e 3-Butenyl
Ph
Ph Me
Me
Me 6e
6e (16)
6d(61)
(61) 7e(32)
7d
7e (0)
(0)
665 5f
5f
5e Ph
PhPh CH OPh
CH22OPh
Me 6f (72)
6f (72)
6e (61) 7f (0)
7f (0)
7e (0)
6 5f Ph CH2 OPh 6f (72) 7f (0)
When the
When the substituent
substituent RR11 isis an
an alkyl
alkyl group,
group, the
the obtained
obtained yield
yield was
was very
very low
low and
and aa
mixture of
mixture of expected
expected oxime
oxime (12–34%)
(12–34%) and and spiroisoxazoline
spiroisoxazoline derivatives
derivatives (1–16%)
(1–16%) was
was ob-
ob-
When the substituent R1 is an alkyl group, the obtained yield was very low and a
served(entries
served (entries1–4,
1–4, Table
Table2).
2). When
Whenthe thesubstituent
substituentRR11isis aa phenyl
phenyl group,
group, only
only the
the spiroi-
spiroi-
mixture of expected oxime (12–34%) and spiroisoxazoline derivatives (1–16%) was observed
soxazolinederivatives
soxazoline derivatives6e 6eand
and6f 6fwere
wereisolated
isolatedin
ingood
goodyield
yield(entries
(entries55and
and6,6,Table
Table2).
2).This
This
(entries 1–4, Table 2). When the substituent R1 is a phenyl group, only the spiroisoxazoline
couldbe
could bedue
dueto tothe
themesomeric
mesomericstabilization
stabilizationeffect
effectof
ofthe
thephenyl
phenylgroup
groupononthe
theconjugated
conjugated
derivatives 6e and 6f were isolated in good yield (entries 5 and 6, Table 2). This could be due
exocyclicalkene.
exocyclic alkene.
to the mesomeric stabilization effect of the phenyl group on the conjugated exocyclic alkene.
Compared with the starting ketones 5e–f, compounds 6e–f were characterized from
Molecules 2024, 29, 5474 5 of 16
HRMS
Molecules 2024, 29, xspectra byREVIEW
FOR PEER a lack
of 3 units, compatible with the formation of the bicyclic structure 5
(Scheme 6). Moreover, an AB system correlated to both R2 and vinylic proton (HMBC
spectra S61 and S67) confirmed the cyclic isoxazoline backbone (Figure 3). Quaternary
Compared with the starting ketones 5e–f, compounds 6e–f were characterized from
carbon of the spiro junction was observed at 119.9/120.2 ppm, suggesting a ketal carbon.
HRMS spectra by a lackCompared with
of 3 units, the starting
compatible ketones
with 5e–f, compounds
the formation 6e–f were
of the bicyclic characterized
structure
The NOESY experiment (S62) for compound 6e was in accordance with Z stereo-
HRMS spectra
(Scheme 6). Moreover, an ABby a lack correlated
system of 3 units, compatible
to both R2 with
and the formation
vinylic protonof(HMBC
the bicyclic stru
chemistry of the exocyclic double bond as it showed an interaction between the two vi-
spectra S61 and(Scheme 6). Moreover,
S67) confirmed an AB
the cyclic system correlated
isoxazoline backboneto(Figure
both R23).and vinylic proton (HM
Quaternary
nylic hydrogens (Figure 3). We
spectra S61 assumed
and the same stereochemistry for compound 6f ac-
carbon of the spiro junction was S67) confirmed
observed the cyclicppm,
at 119.9/120.2 isoxazoline backbone
suggesting a ketal(Figure
carbon.3). Quater
cording to the similarity between
carbon of the both
spiro spectra.
junction was observed at 119.9/120.2 ppm, suggesting a ketal carb
The NOESY experiment (S62) for compound 6e was in accordance with Z st
AB system AB system
chemistry of the exocyclic double bond as it showed an interaction between the tw
nylic hydrogens (Figure 3). We assumed the same stereochemistry for compound 6
O O cording
H to the similarity between O Ospectra.H
both
N N
NOESY O
H AB system H AB system
H HH H HH
HMBC HMBC HMBC HMBC
O O H O O H
6e N 6f N
NOESY O for structure
Figure 3. NOESY
Figure (S62 for
3. NOESY (S626e)
forand
6e) HMBC (S61H(S61
and HMBC for 6e,
forS67
6e, for
S676f)
forexperiments
6f) experiments H determina-
determi-
for structure
nationtion
of compounds 6e and 6f. H H H H HH
of compounds 6e and 6f.
HMBC HMBC HMBC HMBC
Based The
onNOESY experiment
these results, 6e for compound
(S62)
we proposed the following 6e was in accordance
mechanism with6fZthe
to explain stereochem-
for-
istry of the exocyclic double
mation of these spiroheterocycles
Figure 3. NOESY bond
6 and as it
(S62 oximes showed
for 6e) and an
7 (Scheme
HMBC (S61interaction
7). for
First
6e,of between
S67all,
forthe the
6f) free two
hydrox-
experiments vinylic
for structure det
hydrogens (Figure
ylamine formed in situ 3). We
theof
nation assumed
expected
compounds the
oxime same The hydroxyl group of the furfuryl alcohol to
X. 6f.
6e and stereochemistry for compound 6f according
thewas
moiety similarity between both
then protonated leadingspectra.
to intermediate I1. Dehydration led to the carbocation
Based
I2 which can on these
evolved results,
Based
in two we Route
on
routes. proposed
these A: athe
results, following
we proposed
nucleophilic mechanism to
the following
substitution explain
with the lead-
mechanism
ethanol formation
to explain the
ofoxime
ing to these spiroheterocycles
7; routemation
B: an of 6 and
SNthese
1′ oximesthe
involving 7 (Scheme
spiroheterocycles oxygen 7). First
6 and
atom of of
oximes theall, the free
7 oxime
(Scheme hydroxylamine
7). First in
resulting of all,
a the free hyd
formed in situ
dearomatization ofthe
the expected
ylamine oxime
furan formed
ring by inX. The
situ
migrationthehydroxyl
expected group
oxime
of the double of theThe
X.
bond, furfuryl
and thenalcohol
hydroxyl groupmoiety
formation was
ofofthe furfuryl alc
then protonated moiety
leading was
to then protonated
intermediate I . leading
Dehydrationto intermediate
led to the
the bicyclic compound 6 with no control of the stereochemistry of the chiral spiro center.
1 I1. Dehydration
carbocation I 2 led
which to the carboc
can
I2 whichRoute
evolved in two routes. can evolved in two routes.
A: a nucleophilic Route A: awith
substitution nucleophilic substitution
ethanol leading with ethanol
to oxime
O 1′ involving
7; route B: an SNing to oxime the 7; route
oxygen B: an
atom SN1′ofinvolving
the oximethe oxygeninatom
resulting of the oxime resulting
a dearomatization
R1 of the furan ring dearomatization
by migration of the thefuran
double ringbond,
by migration
and then of formation
the double of bond,
the and then formati
bicyclic
R2 O
5 OH the bicyclic compound 6 with no control of
compound 6 with no control of the stereochemistry of the chiral spiro center. the stereochemistry of the chiral spiro ce
HCl.NH2OH (4 equiv.) NOH
O
Pyr (4 equiv.) R1
R1 EtOH R2
EtOH R2 O O
A 7
Δ, 1 h 5 OH OEt
-H
NOH NOHHCl.NH2OH (4 equiv.) NOH
H NOH
R1 - H2O
R2 Pyr (4 equiv.)
R1 R1 R1
O R2 O EtOH H2O R2 O EtOH R2 O
N O
X OH I1Δ, 1OH I2 A 7
h 2 B OEt
R2 -H
NOH NOH - H NOH O
H - H2O 6
R1 R1 R1 R1
R2 O R2 O H2O R2 O N O
X OH I1 OH2 I2
R2 B
Scheme 7. Suggested mechanism for the formation of spiranic isoxazole 6 and oxime 7. O
-H
6
3. Materials and Methods R1
3.1. General Scheme

Scheme 7. Suggested 7. Suggested
mechanism mechanism
for the formationfor
of the formation
spiranic of spiranic
isoxazole 6 and isoxazole
oxime 7. 6 and oxime 7.
Reagents were purchased from commercial suppliers and used without additional
3. Materials and Methods
purification. Furfuryl3.alcohols
Materials 1aand Methods
[39,40], 1b [39,41], 1c [39,42], 1d [43–45] and 1e [39,46]
3.1. General 3.1. General
were synthesized according to the literature procedures, with Grignard reagents pre-
Reagents were purchased
pared. Dichloromethane, Reagents from
diethyl ether
were andcommercial
THF were
purchased fromsuppliers
dried and
over
commercial used without
activated
suppliersalumina additional
and usedcol-without addit
purification.
umn in DRY STATION Furfuryl alcohols 1a
Glass Technology
purification. [39,40], 1b [39,41], 1c [39,42],
(Geneva,1aSwitzerland)
Furfuryl alcohols 1d
GTS 100
[39,40], 1b [39,41], [43–45] and [39,46]and 1e [3
1d1e[43–45]
glassware.
1c [39,42], All
were synthesized
reactions were conductedaccording to the
in oven-dried
were synthesized literature procedures,
glassware,
according under
to the with Grignard
inert procedures,
literature reagents
atmosphere with prepared.
and Grignard
were reagents
Dichloromethane,
monitored by TLC. Columndiethyl
pared. ether and THFwas
Dichloromethane,
chromatography were
diethyl dried over
ether and
performed activated
THF
using 60were alumina
dried
µm silica overcolumn
gel. in alumina
activated
Thin-
DRY STATION Glass
umn in Technology
DRY STATION (Geneva, Switzerland)
Glass TechnologyGTS 100 glassware.
(Geneva, Switzerland)AllGTS
reactions
100 glassware
were conductedreactions
in oven-dried glassware, under inert atmosphere and were monitored
were conducted in oven-dried glassware, under inert atmosphere and
by TLC. Column chromatography
monitored was performed
by TLC. Column using 60
chromatography wasµm silica gel.
performed usingThin-layer
60 µm silica gel. T
chromatography was performed with G/UV254 plates and revealed under UV light, then
Molecules 2024, 29, 5474 6 of 16
it was performed with phosphomolybdic acid or vanillin stains. All melting points were
recorded on a ThermoFisher IA9300 apparatus and were uncorrected. The NMR spectra
were acquired on a Bruker AVANCE 400 spectrometer operating at 400 and 100 MHz for
1 H and 13 C nuclei, respectively, and were recorded in CDCl . Chemical shifts and coupling
3
constants were presented in parts per million relative to Me4 Si and Hertz, respectively.
Abbreviations are as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br s,
broad signal. Proton and carbon assignments were established using COSY, HSQC, HMBC
and DEPT experiments. Infrared spectra were recorded on an FT spectrophotometer from
neat compounds using an ATR (Attenuated Total Reflexion) module. The wavenumbers
of maximum absorption peaks of IR spectroscopy are presented in cm−1 . High-resolution
mass spectra were performed on a micrOTOF QIII Bruker mass spectrometer; the method
used for HRMS was mentioned for each spectrum.
3.2. Synthesis and Characterization

3.2.1. General Protocol for Alcohol Protection
To a solution of alcohol 1 (1 equivalent) in DCM (2 mL/mmol of alcohol), TBSCl
(1.55 equivalent), imidazole (1.5 equivalent) and DMAP (0.01 eq.) were added at 0 ◦ C. The
reaction mixture was stirred overnight. Saturated aqueous solution of NH4 Cl (2 mL/mmol
of alcohol) was added and extracted with diethyl ether (3 × 1.5 mL/mmol of alcohol). The
organic phases were dried over MgSO4 , filtrated and concentrated under reduced pressure.
The crude product was purified by column chromatography to afford protected product 2.
tert-Butyl-(1-furan-2-yl-propoxy)-dimethyl-silane (2a).
The crude product obtained from the alcohol 1a (10.43 g, 82.7 mmol), TBSCl (18.87 g,
125 mmol, 1.51 equivalent), imidazole (8.25 g, 121 mmol, 1.46 equivalent) and DMAP
(99 mg, 0.81 mmol, 0.01 equivalent) was purified by column chromatography on silica gel
(cyclohexane/EtOAc 90/10) to give a colorless oil (14.40 g, 59.9 mmol, 72% yield). Rf 0.70
(cyclohexane/EtOAc 8/2); IR (neat) ν 2959, 2933, 2858, 1465, 1257, 1231, 1156, 1108, 1082,
1063, 1007, 840 cm−1 ; 1 H NMR (400 MHz, CDCl3 ) δ 7.31 (1H, dd, J = 1.8, 0.9 Hz), 6.28 (1H,
dd, J = 3.2, 1.8 Hz), 6.14 (1H, d, J = 3.2 Hz), 4.59 (1H, d, J = 6.5 Hz), 1.74–1.85 (2H, m), 0.87
(3H, t, J = 7.4 Hz), 0.86 (9H, s), 0.04 (3H, s), −0.07 (3H, s); 13 C NMR (100 MHz, CDCl3 ) δ
157.6 (Cq ), 141.3 (CH), 110.1 (CH), 105.8 (CH), 70.1 (CH), 30.2 (CH2 ), 26.0 (3CH3 ), 18.5 (Cq ),
10.0 (CH3 ), −4.7 (CH3 ), −4.9 (CH3 ); HRMS (ESI+ ) m/z calcd for C13 H24 NaO2 Si [M+Na]+ :
263.1438, found 263.1435.
tert-Butyl-(1-furan-2-yl-2-methyl-propoxy)-dimethyl-silane (2b).
The crude product obtained from the alcohol 1b (7.59 g, 54.1 mmol), TBSCl (12.73 g,
84.5 mmol, 1.56 equivalent), imidazole (5.57 g, 81.8 mmol, 1.5 equivalent) and DMAP
(cyclohexane/EtOAc 9/1); IR (neat) ν 2959, 1473, 1067, 1011, 840, 780, 732 cm−1 ; 1 H NMR
(400 MHz, CDCl3 ) δ 7.33 (1H, dd, J = 1.8, 0.8 Hz), 6.29 (1H, dd, J = 3.2, 1.8 Hz), 6.14 (1H, d,
J = 3.2 Hz), 4.33 (1H, d, J = 6.9 Hz), 2.02 (1H, octuplet, J = 6.7 Hz), 0.95 (3H, d, J = 6.7 Hz),
0.88 (9H, s), 0.80 (3H, d, J = 6.8 Hz), 0.03 (3H, s), −0.14 (3H, s); 13 C NMR (100 MHz, CDCl3 ) δ
156.9 (Cq ), 140.9 (CH), 109.8 (CH), 106.4 (CH), 74.2 (CH), 34.4 (CH), 25.8 (3CH3 ), 18.7 (CH3 ),
18.4 (CH3 ), 18.2 (Cq ), −5.0 (CH3 ), −5.2 (CH3 ); HRMS (ESI+ ) m/z calcd for C14 H26 NaO2 Si
[M+Na]+ : 277.1600, found 277.1594.
tert-Butyl-(1-furan-2-yl-3-methyl-butoxy)-dimethyl-silane (2c).
The crude product obtained from the alcohol 1c (8.89 g, 57.7 mmol), TBSCl (13.56 g,
(71 mg, 0.58 mmol, 0.01 equivalent) was purified by column chromatography on silica
gel (cyclohexane/EtOAc 95/5) to give a colorless oil (14.53 g, 54.1 mmol, 94% yield). Rf
0.71 (cyclohexane/EtOAc 9/1); IR (neat) ν 2959, 2933, 2858, 1473, 1257, 1086, 1007, 840,
780 cm−1 ; 1 H NMR (400 MHz, CDCl3 ) δ 7.32 (1H, dd, J = 1.9, 0.8 Hz), 6.28 (1H, dd, J = 3.2,
1.9 Hz), 6.13 (1H, d, J = 3.2 Hz), 4.71 (1H, dd, J = 8.2, 5.8 Hz), 1.74–1.82 (1H, m), 1.69 (1H,
sept., J = 6.7 Hz), 1.52–1.60 (1H, m), 0.87 (3H, d, J = 6.0 Hz), 0.86 (3H, d, J = 6.0 Hz), 0.85 (9H,
Molecules 2024, 29, 5474 7 of 16
s), 0.03 (3H, s), −0.12 (3H, s); 13 C NMR (100 MHz, CDCl3 ) δ 157.8 (Cq ), 141.4 (CH), 110.2
(CH), 105.8 (CH), 66.9 (CH), 46.2 (CH2 ), 26.0 (3CH3 ), 24.5 (CH), 23.3 (CH3 ), 22.3 (CH3 ),
18.4 (Cq ), −4.6 (CH3 ), −4.9 (CH3 ); HRMS (ESI+ ) m/z calcd for C15 H28 NaO2 Si [M+Na]+ :
291.1751, found 291.1753.
tert-Butyl-(1-furan-2-yl-pent-4-enyloxy)-dimethyl-silane (2d) [44,45].
The crude product obtained from the alcohol 1d (14.11 g, 92.7 mmol), TBSCl (21.80 g,
(cyclohexane/EtOAc 9/1); IR (neat) ν 2933, 2858, 1644, 1477, 1351, 1257, 1098, 1011, 918, 840,
780 cm−1 ; 1 H NMR (400 MHz, CDCl3 ) δ 7.32 (1H, dd, J = 1.8, 0.8 Hz), 6.28 (1H, dd, J = 3.2,
1.8 Hz), 6.15 (1H, ddd, J = 3.2, 0.8, 0.8 Hz), 5.79 (1H, ddt, J = 17.1, 10.2, 6.6 Hz), 5.02 (1H,
ddt, J = 17.1, 1.7, 1.7 Hz), 4.98 (1H, ddt, J = 10.2, 1.7, 1.3 Hz), 4.68 (1H, dd, J = 7.2, 5.6 Hz),
2.00-2.14 (2H, m), 1.78–1.97 (2H, m), 0.87 (9H, s), 0.04 (3H, s), −0.09 (3H, s); 13 C NMR
(100 MHz, CDCl3 ) δ 157.4 (Cq ), 141.4 (CH), 138.5 (CH), 114.9 (CH2 ), 110.2 (CH), 105.9 (CH),
68.1 (CH), 36.4 (CH2 ), 29.8 (CH2 ), 26.0 (3CH3 ), 18.4 (Cq ), −4.7 (CH3 ), −4.9 (CH3 ); HRMS
(ESI+ ) m/z calcd for C15 H26 NaO2 Si [M+Na]+ : 289.1594, found 289.1590.
tert-Butyl-(furan-2-yl-phenyl-methoxy)-dimethyl-silane (2e) [47].
The crude product obtained from the alcohol 1e (22.91 g, 132 mmol), TBSCl (30.9 g,
205 mmol, 1.55 equivalent), imidazole (13.51 g, 198 mmol, 1.5 equivalent) and DMAP
(162 mg, 0.11 mmol, 0.01 equivalent) was purified by column chromatography on silica
gel (cyclohexane/EtOAc 95/5) to give a colorless oil (35.03 g, 121 mmol, 92% yield). Rf
0.32 (cyclohexane/EtOAc 6/4); IR (neat) ν 2933, 1477, 1067, 1011 cm−1 ; 1 H NMR (400 MHz,
CDCl3 ) δ 7.40-7.44 (2H, m), 7.30-7.37 (3H, m), 7.27-7.30 (1H, m), 6,29 (1H, dd, J = 3.0, 1.7 Hz),
6.07 (1H, dd, J = 3.1, 0.7 Hz), 5.80 (1H, s), 0.93 (9H, s), 0.07 (3H, s), 0.04 (3H, s); 13 C NMR
(100 MHz, CDCl3 ) δ 157.0 (Cq ), 142.1 (Cq ), 142.0 (CH), 128.1 (2CH), 127.4 (CH), 126.3 (2CH),
110.0 (CH), 106.7 (CH), 70.6 (CH), 25.8 (3CH3 ), 18.3 (Cq ), −5.0 (2CH3 ); HRMS (ESI+ ) m/z
calcd for C17 H24 NaO2 Si [M+Na]+ : 311.1443, found 311.1438; m/z calcd for C17 H24 KO2 Si
[M+K]+ : 327.1183, found 327.1177.
3.2.2. General Protocol for Epoxide Opening

At −78 ◦ C, nBuLi solution (2 M in hexane,1 equivalent) was added dropwise to a
solution of silylated alcohol 2 (1 equivalent) in THF (1.4 mL/mmol of silylated alcohol).
The reaction mixture was slightly warmed to room temperature during 2h 30min, and
epoxide (2 eq.) was added dropwise during 10 to 15 min. The reaction was stirred at room
temperature overnight. Saturated aqueous solution of NH4 Cl (1.4 mL/mmol of silylated
alcohol) was added and extracted with diethyl ether (3 × 1 mL/mmol of silylated alcohol).
The organic phases were dried over MgSO4 , filtrated and concentrated under reduced
pressure. The crude product 3 was purified by column chromatography.
1-[5-[1-(tert-Butyl-dimethyl-silanyloxy)-propyl]-furan-2-yl]-propan-2-ol (3a).
The crude product obtained from the silylated alcohol 2a (8.8 g, 36.6 mmol), n-BuLi
(20.4 mL, 1.8 M 36.7 mmol, 1 equivalent) and methyl oxirane (5.1 mL, 73.3 mmol, 2 equiva-
lent) was purified by column chromatography on silica gel (cyclohexane/EtOAc 90/10)
to give a colorless oil (9.99 g, 33.5 mmol, 91% yield) as an inseparable 1:1 mixture of di-
astereoisomers. Rf 0.39 (cyclohexane/EtOAc 8/2); IR (neat) ν 3350, 2962, 2933, 2858, 1465,
1257, 1063, 1011, 840, 776 cm−1 ; 1 H NMR (400 MHz, CDCl3 ) δ 6.06 (1H, d, J = 3.1 Hz), 6.01
(1H, d, J = 3.1 Hz), 4.54 (1H, t, J = 6.5 Hz), 4.00-4.08 (1H, m), 2.78 (1H, ddd, J = 14.9, 4.6,
1.8 Hz), 2.70 (1H, dd, J = 14.9, 7.6 Hz), 1.72–1.82 (3H, m), 1.23 (3H, d, J = 6.2 Hz), 0.89 (3H,
d, J = 7.4 Hz), 0.87 (9H, s), 0.05 (3H, s), −0.051 and −0.055 (3H, 2s); 13 C NMR (100 MHz,
CDCl3 ) δ 156.53, 156.52, 151.42, 151.39 (2Cq ), 107.47, 107.46 (CH), 106.36, 106.35 (CH), 69.87,
69.86 (CH), 66.8, 66.7 (CH), 38.0 (CH2 ), 29.85, 29.84 (CH2 ), 25.8 (3CH3 ), 22.6 (CH3 ), 18.2 (Cq ),
321.1859, found 321.1852.
1-[5-[1-(tert-Butyl-dimethyl-silanyloxy)-2-methyl-propyl]-furan-2-yl]-propan-2-ol (3b).
Molecules 2024, 29, 5474 8 of 16
The crude product obtained from the silylated alcohol 2b (3,04 g, 11.9 mmol), n-BuLi
(9.0 mL, 17.9 mmol, 1.5 equivalent) and methyl oxirane (1.67 mL, 23.9 mmol, 2 equivalent)
was purified by column chromatography on silica gel (cyclohexane/EtOAc 98/2) to give a
yellow oil (2.08 g, 6.66 mmol, 56% yield) as an inseparable 1:1 mixture of diastereoisomers.
Rf 0.40 (cyclohexane/EtOAc 8/2); IR (neat) ν 3383, 2933, 2858, 1562, 1473, 1387, 1257, 1063,
940, 840, 776 cm−1 ; 1 H NMR (400 MHz, CDCl3 ) δ 6.05 (1H, d, J = 3.0 Hz), 6.01 (1H, m),
4.26 and 4.25 (1H, 2d, J = 6.9 Hz), 4.00-4.11 (1H, m), 2.78 (1H, dt, J = 14.9, 4.7 Hz), 2.70 (1H,
ddd, J = 14.8, 7.5, 5.0 Hz), 1.99 (1H, octuplet, J = 6.7 Hz), 1.77 and 1.75 (1H, 2d, J = 4.0 Hz),
1.22 (3H, d, J = 6.3 Hz), 0.95 and 0.94 (3H, 2d, J = 6.7 Hz), 0.86 (9H, s), 0.79 and 0.78 (3H,
2d, J = 6.7 Hz), 0.02 (3H, s), −0.136 and −0.138 (3H, 2s); 13 C NMR (100 MHz, CDCl3 ) δ
156.02, 156.00, 151.24, 151.19 (2Cq ), 107.41, 107.35 (CH), 107.18, 107.13 (CH), 74.19, 74.15
(CH), 66.9, 66.7 (CH), 37.96, 37.95 (CH2 ), 34.3 (CH), 25.8 (3CH3 ), 22.5 (CH3 ), 18.7, 18.5, 18.4,
18.2 (CH3 +Cq ), −4.9 (CH3 ), −5.2 (CH3 ); HRMS (ESI+ ) m/z calcd for C17 H33 O3 Si [M+H]+ :
313.2193, found 313.2198; calcd for C17 H32 NaO3 Si [M+Na]+ : 335.2015, found 335.2013; m/z
calcd for C17 H32 KO3 Si [M+K]+ : 351.1748, found 351.1752.
1-[5-[1-(tert-Butyl-dimethyl-silanyloxy)-3-methyl-butyl]-furan-2-yl]-propan-2-ol (3c).
The crude product obtained from the silylated alcohol 2c (8.5 g, 31.7 mmol), n-BuLi
(17.6 mL, 1.8 M, 31.7 mmol, 1 equivalent) and methyl oxirane (4.4 mL, 63.3 mmol, 2 equiv-
alent) was purified by column chromatography on silica gel (cyclohexane/EtOAc 95/5)
to give a colorless oil (4.56 g, 14.0 mmol, 44% yield) as an inseparable 1:1 mixture of di-
astereoisomers. Rf 0.31 (cyclohexane/EtOAc 8/2); IR (neat) ν 3330, 2959, 2933, 2858, 1562,
1469, 1365, 1257, 1082, 1011, 840, 780 cm−1 ; 1 H NMR (400 MHz, CDCl3 ) δ 6.06 (1H, d,
J = 3.0 Hz), 6.01 (1H, d, J = 3.0 Hz), 4.67 (1H, dd, J = 8.0, 5.7 Hz), 4.00–4.08 (1H, m), 2.78 (1H,
ddd, J = 15.0, 4.3, 3.5 Hz), 2.70 (1H, ddd, J = 15.0, 7.6, 2.5 Hz), 1.71–1.84 (2H, m), 1.62–1.67
(1H, m), 1.45–1.54 (1H, m), 1.23 (3H, d, J = 6.2 Hz), 0.90 (3H, d, J = 6.6 Hz), 0.88 (3H, d,
J = 6.6 Hz), 0.85 (9H, s), 0.04 (3H, s), −0.103 and −0.106 (3H, 2s); 13 C NMR (100 MHz,
CDCl3 ) δ 156.71, 156.68 (Cq ), 151.50, 151.45 (Cq ), 107.51, 107.46 (CH), 106.38, 106.37 (CH),
66.79, 66.65 (2CH), 45.8 (CH2 ), 38.0 (CH2 ), 25.8 (3CH3 ), 24.3 (CH), 23.1, 22.6, 22.0 (3CH3 ),
349.2169, found 349.2170.
1-[5-[1-(tert-Butyl-dimethyl-silanyloxy)-pent-4-enyl]-furan-2-yl]-propan-2-ol (3d).
The crude product obtained from the silylated alcohol 2d (8.53 g, 32.0 mmol), n-
BuLi (17.8 mL, 1.8 M, 31.9 mmol, 1 equivalent) and methyl oxirane (4.5 mL, 63.9 mmol,
2 equivalent) was purified by column chromatography on silica gel (cyclohexane/EtOAc
90/10) to give a yellow oil (6.27 g, 19.3 mmol, 60% yield) as an inseparable 1:1 mixture
of diastereoisomers. Rf 0.29 (cyclohexane/EtOAc 8/2); IR (neat) ν 3352, 2955, 2933, 2858,
1644, 1562, 1465, 1365, 1257, 1089, 1011, 840, 780 cm−1 ; 1 H NMR (400 MHz, CDCl3 ) δ 6.07
(1H, d, J = 3.0 Hz), 6.02 (1H, d, J = 3.0 Hz), 5.80 (1H, ddt, J = 17.3, 10.3, 6.3 Hz), 5.01 (1H, dq,
J = 17.3, 1.7 Hz), 4.95 (1H, dm, J = 10.4 Hz), 4.63 (1H, dd, J = 7.2, 5.6 Hz), 4.00–4.09 (1H, m),
2.78 (1H, ddd, J = 15.0, 4.8, 2.9 Hz), 2.71 (1H, ddd, J = 15.0, 7.6, 2.3 Hz), 1.97–2.18 (2H, m),
1.70–1.97 (3H, m), 1.23 (3H, d, J = 6.2 Hz), 0.87 (9H, s), 0.04 (3H, s), −0.078 and −0.083 (3H,
2s); 13 C NMR (100 MHz, CDCl3 ) δ 156.29, 156.28 (Cq ), 151.57, 151.53 (Cq ), 138.2 (CH), 114.7
(CH2 ), 107.52, 107.48 (CH), 106.53, 106.51 (CH), 67.8 (CH), 66.8, 66.7 (CH), 38.0 (CH2 ), 36.0
(CH2 ), 29.7 (CH2 ), 25.8 (3CH3 ), 22.6 (CH3 ), 18.2 (Cq ), −4.8 (CH3 ), −5.0 (CH3 ); HRMS (ESI+ )
m/z calcd for C18 H32 NaO3 Si [M+Na]+ : 347.2013, found 347.2006.
1-[5-[(tert-Butyl-dimethyl-silanyloxy)-phenyl-methyl]-furan-2-yl]-propan-2-ol (3e).
The crude product obtained from the silylated alcohol 2e (5.0 g, 17.3 mmol), n-BuLi
(8.66 mL, 17.33 mmol, 1 equivalent) and methyl oxirane (2.43 mL, 34.66 mmol, 2 equivalent)
was purified by column chromatography on silica gel (cyclohexane/EtOAc 95/5) to give a
colorless oil (3.94 g, 11.4 mmol, 66% yield) as an inseparable 1:1 mixture of diastereoisomers.
840 cm−1 ; 1 H NMR (400 MHz, CDCl3 ) δ 7.35–7.42 (2H, m), 7.30–7.35 (2H, m), 7.20–7.29 (1H,
m), 5.99 (1H, d, J = 3.1 Hz), 5.91 (1H, d, J = 3.1 Hz), 5.74 (1H, s), 3.95–4.08 (1H, m), 2.75 (1H,
dd, J = 14.9, 4.6 Hz), 2.68 (1H, dd, J = 14.9, 7.5 Hz), 1.77 (1H, bs), 1.20 (3H, dd, J = 6.1, 0.6 Hz),
Molecules 2024, 29, 5474 9 of 16
0.91 (9H, s), 0.05 and 0.034 (3H, 2s), 0.029 and 0.00 (3H, 2s); 13 C NMR (100 MHz, CDCl3 ) δ
156.2, 156.1 (Cq ), 152.3 (Cq ), 141.9 (Cq ), 128.1 (2CH), 127.4 (CH), 126.3 (2CH), 107.7, 107.59
(CH), 107.56 (CH), 70.53, 70.48 (CH), 66.7 (CH), 37.9 (CH2 ), 25.8 (3CH3 ), 22.6 (CH3 ), 18.3
(Cq ), −5.0 (2CH3 ); HRMS (ESI+ ) m/z calcd for C20 H30 NaO3 Si [M+Na]+ : 369.1862, found
369.1856; m/z calcd for C20 H30 KO3 Si [M+K]+ : 385.1601, found 385.1596.
1-[5-[(tert-Butyl-dimethyl-silanyloxy)-phenyl-methyl]-furan-2-yl]-3-phenoxy-propan-
2-ol (3f).
The crude product obtained from the silylated alcohol 2f (2.0 g, 6.93 mmol), n-BuLi
(6.1 mL, 1.14 M, 6.94 mmol, 1 equivalent) and 2-phenoxymethyl-oxirane (1.9 mL, 13.88
mmol, 2 equivalent) was purified by column chromatography on silica gel (cyclohex-
ane/EtOAc 90/10) to give a colorless oil (1.52 g, 3.47 mmol, 50% yield). Rf 0.35 (cyclohex-
ane/EtOAc 8/2); IR (neat) ν 2955, 2929, 2858, 1603, 1499, 1249, 1086, 840, 754 cm−1 ; 1 H
NMR (400 MHz, CDCl3 ) δ 7.38-7.41 (2H, m), 7.23–7.35 (4H, m), 6.82-6.99 (4H, m), 6.03 (1H,
d, J = 3.1 Hz), 5.94 (1H, d, J = 3.1 Hz), 5.73 (1H, s), 4.19-4.25 (1H, m), 3.93 (1H, ddd, J = 9.4,
3.6, 3.6 Hz), 3.86 (1H, ddd, J = 9.4, 6.5, 3.8 Hz), 2.93 (2H, d, J = 6.4 Hz), 2.38 (1H, bs), 0.90 (9H,
s), 0.04 (3H, s), 0.02 (3H, s); 13 C NMR (100 MHz, CDCl3 ) δ 158.5 (Cq ), 156.2 (Cq ), 151.2 (Cq ),
141.9 (Cq ), 129.5 (2CH), 128.1 (2CH), 127.4 (CH), 126.3 (2CH), 121.1 (CH), 114.6 (2CH), 107.9
(CH), 107.7 (CH), 70.9 (CH2 ), 70.5 (CH), 69.0 (CH), 32.4 (CH2 ), 25.8 (3CH3 ), 18.3 (Cq ), −5.0
(2CH3 ); HRMS (ESI+ ) m/z calcd for C26 H34 NaO4 Si [M+Na]+ : 461.2119, found 461.2110.
3.2.3. General Protocol for Alcohol Oxidation to Ketone

A solution of alcohol 3 (1 eq.) in DCM (2 mL/mmol of alcohol) was degassed by
bubbling a flush of argon. This solution was cooled to 0 ◦ C and DMP (1.2 equivalent)
was added. The reaction mixture was stirred at 0 ◦ C during 1h and 2h 30min at room
temperature. The reaction was quenched by adding a saturated solution of Na2 S2 O3
(2 mL/mmol of alcohol) and a saturated aqueous solution of NaHCO3 (1 mL/mmol of
alcohol). The reaction mixture was then extracted with DCM (3 × 1 mL/mmol of alcohol).
The organic phase was dried over MgSO4 , filtrated and concentrated under reduced
pressure. The crude product was purified by column chromatography to afford ketone 4.
1-[5-[1-(tert-Butyl-dimethyl-silanyloxy)-propyl]-furan-2-yl]-propan-2-one (4a).
The crude product obtained from the alcohol 3a (0.371 g, 1.24 mmol) and DMP (0.764 g,
1.80 mmol, 1.45 equivalent) was purified by column chromatography on silica gel (cy-
clohexane/EtOAc 90/10) to give a colorless oil (0.332 g, 1.12 mmol, 90% yield). Rf 0.48
1019, 911, 840, 780 cm−1 ; 1 H NMR (400 MHz, CDCl3 ) δ 6.11 (2H, s), 4.55 (1H, dd, J = 6.5,
6.5 Hz), 3.66 (2H, s), 2.14 (3H, s), 1.73–1.80 (2H, m), 0.86 (3H, t, J = 7.3 Hz), 0.85 (9H, s),
0.03 (3H, s), −0.06 (3H, s); 13 C NMR (100 MHz, CDCl3 ) δ 204.4 (Cq ), 157.2 (Cq ), 146.9 (Cq ),
108.7 (CH), 106.7 (CH), 69.8 (CH), 43.4 (CH2 ), 29.9 (CH2 ), 29.0 (CH3 ), 25.8 (3CH3 ), 18.2 (Cq ),
319.1700, found 319.1700.
1-[5-[1-(tert-Butyl-dimethyl-silanyloxy)-2-methyl-propyl]-furan-2-yl]-propan-2-one (4b).
The crude product obtained from the alcohol 3b (1.16 g, 3.71 mmol) and DMP (2.36 g,
clohexane/EtOAc 85/15) to give a yellow oil (1.02 g, 3.28 mmol, 88% yield). Rf 0.55
1365, 1257, 1071, 1026, 1011 cm−1 ; 1 H NMR (400 MHz, CDCl3 ) δ 6.11 (1H, d, J = 3.2 Hz),
6.09 (1H, d, J = 3.2 Hz), 4.27 (1H, d, J = 6.9 Hz), 3.66 (2H, s), 2.14 (3H, s), 2.00 (1H, octuplet,
J = 6.7 Hz), 0.94 (3H, d, J = 6.7 Hz), 0.87 (9H, s), 0.79 (3H, d, J = 6.7 Hz), 0.03 (3H, s), −0.12
(3H, s); 13 C NMR (100 MHz, CDCl3 ) δ 204.4 (Cq ), 156.7 (Cq ), 146.8 (Cq ), 108.6 (CH), 107.5
(CH), 74.1 (CH), 43.5 (CH2 ), 34.3 (CH), 28.9 (CH3 ), 25.8 (3CH3 ), 18.7 (CH3 ), 18.3 (CH3 ),
333.1856, found 333.1862.
1-[5-[1-(tert-Butyl-dimethyl-silanyloxy)-3-methyl-butyl]-furan-2-yl]-propan-2-one (4c).
Molecules 2024, 29, 5474 10 of 16
The crude product obtained from the alcohol 3c (1.89 g, 5.79 mmol) and DMP (3.69 g,
clohexane/EtOAc 90/10) to give a yellow oil (1.38 g, 4.25 mmol, 73% yield). Rf 0.63
1007, 840, 780 cm−1 ; 1 H NMR (400 MHz, CDCl3 ) δ 6.11 (2H, s), 4.68 (1H, dd, J = 8.1, 5.9 Hz),
3.67 (2H, s), 2.15 (3H, s), 1.48–1.79 (3H, m), 0.90 (3H, d, J = 6.1 Hz), 0.89 (3H, d, J = 6.1 Hz),
0.85 (9H, s), 0.05 (3H, s), −0.09 (3H, s); 13 C NMR (100 MHz, CDCl3 ) δ 204.3 (Cq ), 157.4
(Cq ), 147.0 (Cq ), 108.7 (CH), 106.7 (CH), 66.7 (CH), 46.0 (CH2 ), 43.4 (CH2 ), 29.0 (CH3 ), 25.8
(3CH3 ), 24.3 (CH), 23.1 (CH3 ), 22.1 (CH3 ), 18.2 (Cq ), −4.7 (CH3 ), −5.1 (CH3 ); HRMS (ESI+ )
m/z calcd for C18 H32 NaO3 Si [M+Na]+ : 347.2013, found 347.2014.
1-[5-[1-(tert-Butyl-dimethyl-silanyloxy)-pent-4-enyl]-furan-2-yl]-propan-2-one (4d).
The crude product obtained from the alcohol 3d (1.58 g, 4.87 mmol) and DMP (3.09 g,
7.29 mmol, 1.5 equivalent) was purified by column chromatography on silica gel (cyclo-
hexane/EtOAc 95/5) to give a yellow oil (1.15 g, 3.57 mmol, 73% yield). Rf 0.53 (cyclo-
hexane/EtOAc 8/2); IR (neat) ν 3078, 2955, 2933, 2858, 1722, 1477, 1361, 1257, 1093, 1011,
914, 840, 780 cm−1 ; 1 H NMR (400 MHz, CDCl3 ) δ 6.11 (2H, s), 5.80 (1H, ddt, J = 17.1, 10.3,
6.7 Hz), 5.01 (1H, dm, J = 17.1 Hz), 4.95 (1H, dm, J = 10.3 Hz), 4.64 (1H, dd, J = 7.3, 5.6 Hz),
3.67 (2H, s), 2.15 (3H, s), 1.97–2.13 (2H, m), 1.71–1.95 (2H, m), 0.87 (9H, s), 0.05 (3H, s), −0.07
(CH2 ), 108.7 (CH), 106.9 (CH), 67.8 (CH), 43.4 (CH2 ), 36.1 (CH2 ), 29.6 (CH2 ), 29.0 (CH3 ),
25.8 (3CH3 ), 18.2 (Cq ), −4.8 (CH3 ), −5.0 (CH3 ); HRMS (ESI+ ) m/z calcd for C18 H30 NaO3 Si
[M+Na]+ : 345.1856, found 345.1861.
1-[5-[(tert-Butyl-dimethyl-silanyloxy)-phenyl-methyl]-furan-2-yl]-propan-2-one (4e).
The crude product obtained from the alcohol 3e (3.9 g, 11.3 mmol) and DMP (5.73 g,
13.5 mmol, 1.2 equivalent) was purified by column chromatography on silica gel (cyclo-
hexane/EtOAc 90/10) to give a colorless oil (3.46 g, 10.0 mmol, 89% yield). Rf 0.50 (cy-
clohexane/EtOAc 7/3); IR (neat) ν 2955, 2933, 2858, 1715, 1603, 1257, 1182, 840, 780 cm−1 ;
1 H NMR (400 MHz, CDCl ) δ 7.25–7.41 (5H, m), 6.09 (1H, d, J = 3.2 Hz), 5.99 (1H, d,
3
J = 3.2 Hz), 5.74 (1H, s), 3.63 (2H, s), 2.10 (3H, s), 0.91 (9H, s), 0.05 (3H, s), 0.04 (3H, s); 13 C
NMR (100 MHz, CDCl3 ) δ 204.3 (Cq ), 156.8 (Cq ), 147.8 (Cq ), 141.9 (Cq ), 128.1 (2CH), 127.4
(CH), 126.3 (2CH), 108.8 (CH), 107.9 (CH), 70.5 (CH), 43.4 (CH2 ), 29.0 (3CH3 ), 25.8 (CH3 ),
18.3 (Cq ), −5.0 (2CH3 ); HRMS (ESI+ ) m/z calcd for C20 H28 NaO3 Si [M+Na]+ : 367.1705,
found 367.1697.
1-[5-[(tert-Butyl-dimethyl-silanyloxy)-phenyl-methyl]-furan-2-yl]-3-phenoxy-propan-
2-one (4f).
The crude product obtained from the alcohol 3f (0.345 g, 0.79 mmol) and DMP (0.501 g,
clohexane/EtOAc 95/5) to give a colorless oil (103 mg, 0.24 mmol, 30% yield). Rf 0.69
840, 758 cm−1 ; 1 H NMR (400 MHz, CDCl3 ) δ 7.39 (2H, d, J = 8.0 Hz), 7.23-7.35 (5H, m), 6.99
(1H, t, J = 8.0 Hz), 6.81 (2H, d, J = 8.7 Hz), 6.14 (1H, d, J = 3.2 Hz), 6.01 (1H, d, J = 3.2 Hz),
5.73 (1H, s), 4.56 (2H, s), 3.85 (1H, s), 0.90 (9H, s), 0.04 (3H, s), 0.03 (3H, s); 13 C NMR
(100 MHz, CDCl3 ) δ 202.0 (Cq ), 157.6 (Cq ), 157.0 (Cq ), 146.3 (Cq ), 141.9 (Cq ), 129.6, 128.1,
127.4, 126.3, 121.7, 114.6 (10CH), 109.2 (CH), 107.9 (CH), 72.0 (CH2 ), 70.5 (CH), 39.3 (CH2 ),
25.8 (3CH3 ), 18.3 (Cq ), −5.0 (2CH3 ); HRMS (ESI+ ) m/z calcd for C26 H32 NaO4 Si [M+Na]+ :
459.1962, found 459.1957.
3.2.4. General Protocol for Silylated Alcohol Deprotection

Procedure with TBAF reagent: A solution of TBAF (1.0 M in THF, 1.5 equivalent) at
room temperature was added to a solution of silylated alcohol 4 (1 equivalent) in anhydrous
THF (2 mL/mmol of silylated alcohol). The reaction mixture was followed by TLC and
stopped when starting material completely disappeared (1 or 2 h). A saturated solution
of NH4 Cl (2 mL/mmol of silylated alcohol) was added. The reaction mixture was then
extracted with EtOAc (3 × 1 mL/mmol of silylated alcohol). The organic phases were dried
Molecules 2024, 29, 5474 11 of 16
over MgSO4 , filtrated and concentrated under reduced pressure. The crude product was
purified by column chromatography to afford product 5.
Procedure with Et3 N.3HF reagent: A solution of Et3 N.3HF (1.5 equivalent) at room
temperature was added to a solution of the silylated alcohol 4 (1 equivalent) in anhydrous
acetonitrile (1.25 mL/mmol of silylated alcohol). The reaction mixture was followed by
TLC and stopped when starting material completely disappeared (1 or 2 h). A saturated
solution of NaHCO3 (2 mL/mmol of silylated alcohol) was added. The reaction mixture
was then extracted with CH2 Cl2 (3 × 1 mL/mmol of silylated alcohol). The organic phases
were dried over MgSO4 , filtrated and concentrated under reduced pressure. The crude
product was purified by column chromatography to afford product 5.
1-[5-(1-Hydroxy-propyl)-furan-2-yl]-propan-2-one (5a).
The crude product obtained from the silylated alcohol 4a (0.332 g, 1.12 mmol) and
TBAF (1.65 mL, 1.65 mmol, 1.5 equivalent) was purified by column chromatography on
silica gel (cyclohexane/EtOAc 95/5) to give a colorless oil (81 mg, 0.44 mmol, 40% yield).
1026, 1048, 966, 795 cm−1 ; 1 H NMR (400 MHz, CDCl3 ) δ 6.19 (1H, d, J = 3.1 Hz), 6.14 (1H, d,
J = 3.1 Hz), 4.56 (1H, dd, J = 6.8, 6.8 Hz), 3.70 (2H, s), 2.17 (3H, s), 1.70–1.90 (2H, m), 0.95
(3H, t, J = 7.3 Hz); 13 C NMR (100 MHz, CDCl3 ) δ 204.2 (Cq ), 156.4 (Cq ), 147.6 (Cq ), 108.8
(CH), 107.0 (CH), 69.1 (CH), 43.3 (CH2 ), 29.2 (CH3 ), 28.8 (CH2 ), 9.9 (CH3 ); HRMS (ESI+ )
m/z calcd for C10 H14 NaO3 [M+Na]+ : 205.0835, found 205.0834.
1-[5-(1-Hydroxy-2-methyl-propyl)-furan-2-yl]-propan-2-one (5b).
The crude product obtained from the silylated alcohol 4b (1.28 g, 4.12 mmol) and
Et3 N.3HF (1.0 mL, 6.18 mmol, 1.5 equivalent) was purified by column chromatography on
silica gel (cyclohexane/EtOAc 95/5) to give a yellow oil (521 mg, 2.65 mmol, 64 % yield).
1361, 1298, 1242, 1212, 1067, 1022 cm−1 ; 1 H NMR (400 MHz, CDCl3 ) δ 6.19 (1H, d, J = 3.1
Hz), 6.14 (1H, d, J = 3.1 Hz), 4.33 (1H, d, J = 7.3 Hz), 3.69 (2H, s), 2.16 (3H, s), 2.08 (1H,
octuplet, J = 6,8 Hz), 1.88–2.02 (1H, bs), 1.01 (3H, d, J = 6.8 Hz), 0.86 (3H, d, J = 6.8 Hz); 13 C
NMR (100 MHz, CDCl3 ) δ 204.1 (Cq ), 155.9 (Cq ), 147.4 (Cq ), 108.8 (CH), 107.6 (CH), 73.5
(CH), 43.3 (CH2 ), 33.2 (CH), 29.1 (CH3 ), 18.7 (CH3 ), 18.2 (CH3 ); HRMS (ESI+ ) m/z calcd for
C11 H16 NaO3 [M+Na]+ : 219.0988, found 219.0992.
1-[5-(1-Hydroxy-3-methyl-butyl)-furan-2-yl]-propan-2-one (5c).
The crude product obtained from the silylated alcohol 4c (0.695 g, 2.14 mmol) and
silica gel (cyclohexane/EtOAc 95/5) to give a yellow oil (273 mg, 1.30 mmol, 61% yield). Rf
0.43 (PE/EtOAc 6/4); IR (neat) ν 3435, 2959, 2925, 2873, 2854, 1719, 1599, 1514, 1469, 1391,
1361, 1223, 1160, 1071, 1022 cm−1 ; 1 H NMR (400 MHz, CDCl3 ) δ 6.16 (1H, d, J = 3.1 Hz),
6.11 (1H, d, J = 3.1 Hz), 4.69 (1H, dd, J = 5.7, 5.7 Hz), 3.68 (2H, s), 2.16 (3H, s), 1.60–1.80
(4H, m), 0.93 (3H, d, J = 6.2 Hz), 0.91 (3H, d, J = 6.2 Hz); 13 C NMR (100 MHz, CDCl3 ) δ
204.2 (Cq ), 156.9 (Cq ), 147.5 (Cq ), 108.8 (CH), 106.8 (CH), 65.9 (CH), 44.4 (CH2 ), 43.2 (CH2 ),
29.1 (CH3 ), 24.6 (CH), 23.0 (CH), 22.1 (2CH3 ); HRMS (ESI+ ) m/z calcd for C12 H18 NaO3
[M+Na]+ : 233.1148, found 233.1140.
1-[5-(1-Hydroxy-pent-4-enyl)-furan-2-yl]-propan-2-one (5d).
The crude product obtained from the silylated alcohol 4d (1.16 g, 3.60 mmol) and
Et3 N.3HF (0.89 mL, 5.39 mmol, 1.5 equivalent) was purified by column chromatography
on silica gel (cyclohexane/EtOAc 90/10) to give a yellow oil (440 mg, 2.11 mmol, 59%
yield). Rf 0.20 (cyclohexane/EtOAc 7/3); IR (neat) ν 3406, 3078, 2977, 2925, 2858, 1715,
1644, 1562, 1361, 1242, 1212, 1164, 1067, 1015 cm−1 ; 1 H NMR (400 MHz, CDCl3 ) δ 6.20 (1H,
d, J = 3.2 Hz), 6.14 (1H, d, J = 3.2 Hz), 5.83 (1H, ddt, J = 17.3, 10.3, 6.6 Hz), 5.05 (1H, dm,
J = 17.2 Hz), 4.99 (1H, dm, J = 10.4 Hz), 4.67 (1H, t, J = 6.8 Hz), 3.70 (2H, s), 2.07–2.28 (2H,
m), 2.18 (3H, s), 1.93 (3H, td, J = 7.1, 7.1 Hz); 13 C NMR (100 MHz, CDCl3 ) δ 204.0 (Cq ), 156.3
(Cq ), 147.7 (Cq ), 137.8 (CH), 115.2 (CH2 ), 108.9 (CH), 107.1 (CH), 67.2 (CH), 43.3 (CH2 ), 34.5
(CH2 ), 29.8 (CH2 ), 29.2 (CH3 ); HRMS (ESI+ ) m/z calcd for C12 H16 NaO3 [M+Na]+ : 231.0992,
found 231.0990.
Molecules 2024, 29, 5474 12 of 16
1-[5-(Hydroxy-phenyl-methyl)-furan-2-yl]-propan-2-one (5e).
The crude product obtained from the silylated alcohol 4e (3.38 g, 9.81 mmol) and
silica gel (cyclohexane/EtOAc 95/5) to give a colorless oil (1.97 g, 8.56 mmol, 87% yield).
1357, 1160, 963, 724, 702 cm−1 ; 1 H NMR (400 MHz, CDCl3 ) δ 7.27-7.43 (5H, m), 6.11 (1H, d,
J = 3.2 Hz), 6.03 (1H, d, J = 3.2 Hz), 5.76 (1H, s), 3.66 (2H, s), 2.85 (1H, bs), 2.12 (3H, s); 13 C
NMR (100 MHz, CDCl3 ) δ 204.2 (Cq ), 155.7 (Cq ), 148.2 (Cq ), 140.7 (Cq ), 128.3 (2CH), 127.9
(CH), 126.5 (2CH), 108.9 (CH), 108.5 (CH), 69.9 (CH), 43.1 (CH2 ), 29.2 (CH3 ); HRMS (ESI+ )
m/z calcd for C14 H14 NaO3 [M+Na]+ : 253.0835, found 253.0829.
1-[5-(Hydroxy-phenyl-methyl)-furan-2-yl]-3-phenoxy-propan-2-one (5f).
The crude product obtained from the silylated alcohol 4f (1.03 g, 2.36 mmol) and
Et3 N.3HF (0.65 mL, 4.0 mmol, 1.7 equivalent) was purified by column chromatography on
silica gel (cyclohexane/EtOAc 9/1) to give a colorless oil (658 mg, 2.04 mmol, 86% yield).
1058, 1016 cm−1 ; 1 H NMR (400 MHz, CDCl3 ) δ 7.25–7.45 (7H, m), 7.00 (1H, t, J = 7.3 Hz),
6.84 (2H, dd, J = 8.7, 1.0 Hz), 6.17 (1H, d, J = 3.1 Hz), 6.05 (1H, d, J = 3.1 Hz), 5.78 (1H,
s), 4.59 (2H, s), 3.91 (2H, s), 2.43 (1H, bs); 13 C NMR (100 MHz, CDCl3 ) δ 202.3 (Cq ), 157.6
(Cq ), 155.8 (Cq ), 147.0 (Cq ), 140.6 (Cq ), 129.7, 128.5, 128.1, 126.6, 121.8, 114.5 (10CH), 109.4
(CH), 108.7 (CH), 72.2 (CH2 ), 70.1 (CH), 39.1 (CH2 ); HRMS (ESI+ ) m/z calcd for C20 H18 KO4
[M+K]+ : 361.0842, found 361.1036.
3.2.5. General Protocol for Oxime Formation

NH2 OH.HCl (4 eq.) and pyridine (4 eq.) were added to a solution of ketone 5
(1 equivalent) in ethanol (5 mL/mmol of ketone). After heating 1h at reflux, the reac-
tion mixture was diluted with water (5 mL/mmol of ketone) and then extracted with
EtOAc (3 × 5 mL/mmol of ketone). The organic phases were dried over MgSO4 , filtrated
and concentrated under reduced pressure. The crude product was purified by column
chromatography to afford products 6 and 7.
1-[5-(1-Ethoxy-propyl)-furan-2-yl]-propan-2-one oxime (7a).
The crude product obtained from the ketone 5a (191 mg, 1.049 mmol), NH2 OH.HCl
(292 mg, 4.20 mmol, 4 equivalent) and pyridine (0.34 mL, 4.20 mmol, 4 equivalent) give a
mixture which was purified by column chromatography on silica gel (cyclohexane/EtOAc
8/2) to give a colorless oil (81.1 mg, 0.36 mmol, 34% yield) as an inseparable 9:1 mixture
of E:Z oximes 7a. Rf 0.34 (cyclohexane/EtOAc 6/4); IR (neat) ν 3292, 2971, 2931, 2876,
1666, 1556, 1368, 1149, 1096, 968 cm−1 ; 1 H NMR (400 MHz, CDCl3 ) Major E-7a-oxime δ
8.82 (1H, bs), 6.16 (1H, d, J = 3.1 Hz), 6.05 (1H, d, J = 3.1 Hz), 4.12 (1H, t, J = 7.0 Hz), 3.51
(2H, s), 3.32-3.51 (2H, m), 1.88 (3H, s), 1.74–1.91 (2H, m), 1.16 (3H, t, J = 7.0 Hz), 0.89 (3H, t,
J = 7.4 Hz); characteristic signals of minor Z-7a-oxime δ 3.75 (2H, s), 1.82 (3H, s); 13 C NMR
(100 MHz, CDCl3 ) Major E-7a-oxime δ 155.3 (Cq ), 154.5 (Cq ), 150.0 (Cq ), 108.2 (CH), 107.6
(CH), 76.4 (CH), 64.0 (CH2 ), 34.8 (CH2 ), 27.3 (CH2 ), 15.2 (CH3 ), 13.1 (CH3 ), 10.1 (CH3 );
characteristic signals of minor Z-7a-oxime δ 154.9 (Cq ), 154.2 (Cq ), 149.6 (Cq ), 108.4 (CH),
107.7 (CH), 27.5 (CH2 ), 19.3 (CH3 ); HRMS (ESI+ ) m/z calcd for C12 H19 NNaO3 [M+Na]+ :
248.1257, found 248.1263; calcd for C12 H19 KNO3 [M+K]+ : 264.0997, found 264.0981.
1-[5-(1-Ethoxy-2-methyl-propyl)-furan-2-yl]-propan-2-one oxime (7b) and 7-isobutylidene-
3-methyl-1,6-dioxa-2-aza-spiro [4.4]nona-2,8-diene (6b).
The crude product obtained from the ketone 5b (280 mg, 1.43 mmol), NH2 OH.HCl
(397 mg, 5.71 mmol, 4 equivalent) and pyridine (0.46 mL, 5.71 mmol, 4 equivalent) was
purified by column chromatography on silica gel (cyclohexane/EtOAc 99/1 to 90/10)
to give a yellow oil (44 mg, 0.18 mmol, 13% yield) as an inseparable 77:15:8 mixture of
E-7b:Z-7b:6b. Rf 0.61 (cyclohexane/EtOAc 6/4); IR (neat) ν 3253, 2962, 2929, 2873, 1674,
1559, 1473, 1387, 1372, 1238, 1156, 1093, 1015 cm−1 ; 1 H NMR (400 MHz, CDCl3 ) Major
oxime E-7b δ 8.46 (1H, bs), 6.14 (1H, d, J = 3.1 Hz), 6.05 (1H, d, J = 3.0 Hz), 3.81 (1H, d,
J = 8.0 Hz), 3.51 (2H, s), 3.32 and 3.45 (2H, 2dq, J = 9.2, 7.0 Hz), 2.03–2.10 (1H, m), 1.87 (3H,
Molecules 2024, 29, 5474 13 of 16
s), 1.15 (3H, t, J = 7.0 Hz), 1.01 (3H, d, J = 6.6 Hz), 0.77 (3H, d, J = 6.6 Hz); characteristic
signals of minor oxime Z-7b δ 3.75 and 3.76 (2H, 2s), 1.81 (3H, s); characteristic signals of
bicyclic spiro compound 6b 6.27 (1H, d, J = 5.6 Hz), 5.92 (1H, d, J = 5.6 Hz), 4.44 (1H, d,
J = 9.2 Hz), 3.13 (1H, dd, J = 18.1, 1.1 Hz), 3.02 (1H, d, J = 18.1 Hz), 2.75 (1H, d sept., J = 9.2,
6.7 Hz), 2.07 (3H, s); 13 C NMR (100 MHz, CDCl3 ) Major oxime E-7b δ 155.4 (Cq ), 154.1 (Cq ),
149.9 (Cq ), 108.7 (CH), 107.6 (CH), 80.9 (CH), 64.4 (CH2 ), 34.8 (CH2 ), 32.5 (CH), 19.1 (CH3 ),
18.7 (CH3 ), 15.1 (CH3 ), 13.0 (CH3 ); characteristic signals of minor oxime Z-7b δ 155.0 (Cq ),
153.9 (Cq ), 149.5 (Cq ), 108.9 (CH), 107.7 (CH), 27.5 (CH2 ), 19.3 (CH3 ); characteristic signals
of bicyclic spiro compound 6b 156.6 (Cq ), 130.1 (CH), 126.5 (CH), 118.4 (Cq ), 111.3 (CH),
46.7 (CH2 ), 25.3 (CH), 13.4 (CH3 ). HRMS of oximes 7b (ESI+ ) m/z calcd for C13 H21 NNaO3
[M+Na]+ : 262.1414, found 262.1408.
1-[5-(1-Ethoxy-3-methyl-butyl)-furan-2-yl]-propan-2-one oxime (7c).
The crude product obtained from the ketone 5c (272.5 mg, 1.3 mmol), NH2 OH.HCl
(361 mg, 5.2 mmol, 4 equivalent) and pyridine (0.42 mL, 5.2 mmol, 4 equivalent), giving a
mixture of 7c and 6c, was purified by column chromatography on silica gel (PE/EtOAc
85/15) to give a yellow oil (45.7 mg, 0.18 mmol, 14% yield) as an inseparable 87:13 mixture
of E and Z oximes 7c. Rf 0.49 (PE/EtOAc 7/3); IR (neat) ν 3320, 2959, 2929, 2873, 1469, 1369,
1171, 1089 cm−1 ; 1 H NMR (400 MHz, CDCl3 ) Major oxime 7c δ 8.56 (1H, bs), 6.16 (1H, d,
J = 3.1 Hz), 6.05 (1H, d, J = 3.1 Hz), 4.27 (1H, dd, J = 8.0, 6.1 Hz), 3.51 (2H, s), 3.45 (1H, dq,
J = 9.2, 7.0 Hz), 3.36 (1H, dq, J = 9.2, 7.0 Hz), 1.88 (3H, s), 1.75–1.84 (1H, m), 1.55–1.71 (2H,
m), 1.15 (3H, t, J = 7.0 Hz), 0.91 (3H, d, J = 6.5 Hz), 0.89 (3H, d, J = 6.5 Hz); characteristic
signals of minor oxime 7c δ 3.75 and 3.76 (2H, 2s), 1.82 (3H, s); 13 C NMR (100 MHz, CDCl3 )
δ 155.3 (Cq ), 154.8 (Cq ), 150.0 (Cq ), 108.1 (CH), 107.6 (CH), 73.1 (CH), 63.9 (CH2 ), 43.2 (CH2 ),
34.8 (CH2 ), 24.6 (CH), 22.8 (CH3 CH), 22.3 (CH3 ), 15.2 (CH3 ), 13.1 (CH3 ); HRMS (ESI+ ) m/z
calcd for C14 H23 NNaO3 [M+Na]+ : 276.1576, found 276.1570.
3-Methyl-7-(3-methyl-butylidene)-1,6-dioxa-2-aza-spiro [4.4]nona-2,8-diene (6c).
Compound 6c was obtained in the same experiment as 7c and purified by column
chromatography on silica gel (CH/EtOAc 90/10) to give a yellow oil (37.7 mg, 0.18 mmol,
14% yield). Rf 0.47 (PE/EtOAc 7/3); 1 H NMR (400 MHz, CDCl3 ) δ 6.31 (1H, d, J = 5.5 Hz),
5.94 (1H, d, J = 5.5 Hz), 4.60 (1H, t, J = 7.7 Hz), 3.14 and 3.02 (2H, 2d, J = 18.2 Hz), 2.08 (3H,
s), 2.04–2.06 (2H, m), 1.55–1.68 (1H, m), 0.90 (3H, d, J = 6.7 Hz), 0.89 (3H, d, J = 6.6 Hz); 13 C
NMR (100 MHz, CDCl3 ) δ 156.6 (Cq ), 155.4 (Cq ), 129.9 (CH), 126.5 (CH), 118.4 (Cq ), 102.7
(CH), 46.7 (CH2 ), 34.4 (CH2 ), 28.7 (CH), 22.3 (CH3 ), 22.2 (CH3 ), 13.4 (CH3 ); HRMS (ESI+ )
m/z calcd for C12 H17 NNaO2 [M–H2 O+Na]+ : 230.1151, found 230.1142.
1-[5-(1-Ethoxy-pent-4-enyl)-furan-2-yl]-propan-2-one oxime (7d) and 3-Methyl-7-
pent-4-enylidene-1,6-dioxa-2-aza-spiro [4.4]nona-2,8-diene (6d).
The crude product obtained from the ketone 5d (394 mg, 1.89 mmol), NH2 OH.HCl
purified by column chromatography on silica gel (cyclohexane/EtOAc 99/1) to give a
yellow oil (62 mg, 0.25 mmol, 13% yield) as an inseparable 65:26:9 mixture of E-7d:Z-7d:6d.
1372, 1335, 1160, 1067, 1089 cm−1 ; 1 H NMR (400 MHz, CDCl3 ) Major oxime E-7d δ 8.54
(1H, bs), 6.16 (1H, d, J = 3.1 Hz), 6.05 (1H, d, J = 3.1 Hz), 5.80 (1H, ddt, J = 17.3, 10.3, 6.3
Hz), 5.01 (1H, dq, J = 17.3, 1.7 Hz), 4.96 (1H, dq, J = 10.4, 1.5 Hz), 4.22 (1H, t, J = 7.0 Hz),
3.51 (2H, s), 3.45 (1H, dq, J = 9.3, 7.0 Hz), 3.36 (1H, dq, J = 9.3, 7.0 Hz), 2.03–2.16 (1H, m),
1.80–2.03 (1H, m), 1.88 (3H, s), 1.60 (3H, t, J = 7.0 Hz); characteristic signals of minor oxime
Z-7d δ 3.75 (2H, d, J = 1.8 Hz), 1.82 (3H, s); characteristic signals of bicyclic spiro compound
6d δ 6.30 (1H, d, J = 5.6 Hz), 5.95 (1H, d, J = 5.6 Hz), 4.58 (1H, t, J = 7.4 Hz), 3.15 (1H, d,
J = 18.1 Hz), 3.03 (1H, d, J = 18.1 Hz), 13 C NMR (100 MHz, CDCl3 ) Major oxime E-7d δ
155.3 (Cq ), 154.4 (Cq ), 150.2 (Cq ), 138.0 (CH), 114.9 (CH2 ), 108.3 (CH), 107.7 (CH), 74.1 (CH),
64.1 (CH2 ), 34.8 (CH2 ), 33.4 (CH2 ), 29.8 (CH2 ), 15.2 (CH3 ), 13.1 (CH3 ); characteristic signals
of minor oxime Z-7d δ 154.9 (Cq ), 154.1 (Cq ), 149.7 (Cq ), 138.0 (CH), 108.4 (CH), 107.7 (CH),
74.1 (CH), 64.0 (CH2 ), 27.5 (CH2 ); characteristic signals of bicyclic spiro compound 6d δ
129.8 (CH), 126.8 (CH), 102.8 (CH), 46.7 (CH2 ); HRMS of oximes 7d (ESI+ ) m/z calcd for
Molecules 2024, 29, 5474 14 of 16
C14 H21 NNaO3 [M+Na]+ : 274.1414, found 274.1417; HRMS of bicyclic spiro compound 6d
(ESI+ ) m/z calcd for C12 H16 NO2 [M+H]+ : 206.1176, found 206.1178.
7-Benzylidene-3-methyl-1,6-dioxa-2-aza-spiro [4.4] nona-2,8-diene (6e).
The crude product obtained from the ketone 5e (500 mg, 2.17 mmol), NH2 OH.HCl
purified by column chromatography on silica gel (cyclohexane/EtOAc 90/10) to give
a white solid (354 mg, 1.56 mmol, 72% yield). Rf 0.41 (cyclohexane/EtOAc 6/4); mp
113.5–115.0 ◦ C; IR (neat) ν 3104, 3052, 2985, 2925, 2858, 1652, 1599, 1391, 1369, 1339, 1179,
1108, 940, 844, 825 cm−1 ; 1 H NMR (400 MHz, CDCl3 ) δ 7.60 (2H, dd, J = 7.2, 1.3 Hz), 7.29
(2H, t, J = 7.5 Hz), 7.16 (1H, tt, J = 7.3, 1.2 Hz), 6.45 (1H, d, J = 5.5 Hz), 6.08 (1H, dd, J = 5.5,
0.7 Hz), 5.51 (1H, s), 3.25 (1H, dq, J = 18.3, 1.1 Hz), 3.13 (1H, dq, J = 18.3, 0.6 Hz), 2.11
(2CH), 128.3 (2CH), 127.5 (CH), 126.3 (CH), 119.9 (Cq ), 103.3 (CH), 47.0 (CH2 ), 13.4 (CH3 );
HRMS (ESI+ ) m/z calcd for C14 H14 NO2 [M+H]+ : 228.1025, found 228.1019; m/z calcd for
C14 H13 NNaO2 [M+Na]+ : 250.0844, found 250.0847.
7-Benzylidene-3-phenoxymethyl-1,6-dioxa-2-aza-spiro [4.4]nona-2,8-diene (6f).
The crude product obtained from the ketone 5f (191 mg, 0.59 mmol), NH2 OH.HCl
(164.7 mg, 2.37 mmol, 4 equivalent) and pyridine (0.2 mL, 2.4 mmol, 4 equivalent) was
purified by column chromatography on silica gel (cyclohexane/EtOAc 7/3) to give a
colorless oil (118 mg, 0.369 mmol, 62% yield). Rf 0.52 (cyclohexane/EtOAc 7/3); 1 H NMR
(400 MHz, CDCl3 ) δ 7.55 (2H, dd, J = 7.9, 0.7 Hz), 7.25-7.35 (4H, m), 7.16 (1H, t, J = 7.4 Hz),
7.04 (1H, t, J = 7.4 Hz), 6.99 (2H, dd, J = 8.7, 0.9 Hz), 6.48 (1H, d, J = 5.5 Hz), 6.09 (1H,
dd, J = 5.5, 0.7 Hz), 5.53 (1H, s), 4.97 and 4.93 (2H, 2d, J = 13.0 Hz), 3.349 and 3.347 (2H,
2d, J = 18.5 Hz); 13 C NMR (100 MHz, CDCl3 ) δ 157.7 (Cq ), 157.5 (Cq ), 155.1 (Cq ), 135.0
(Cq ), 131.6 (CH), 129.7 (2CH), 128.6 (2CH), 128.3 (2CH), 127.0 (CH), 126.5 (CH), 121.9 (CH),
120.2 (Cq ), 114.8 (2CH), 103.9 (CH), 62.9 (CH2 ), 43.6 (CH2 ); HRMS (ESI+ ) m/z calcd for
C20 H18 NO3 [M–H2 O+H]+ : 320.1281, found 320.1280; calcd for C20 H18 NNaO3 [M+Na]+ :
342.1101, found 342.1103.
4. Conclusions
Oximation of ketofurfuryl alcohols in ethanol with hydroxylamine hydrochloride in
the presence of pyridine led, in most cases, to an oxime along with a spiroisoxazoline. The
oxime/spiroisoxazoline product ratio depended mainly on the nature of the substituent
attached to the furfuryl alcohol moiety (i.e., R1 ). If the substituent was a phenyl group,
only the spiroisoxazoline presenting a dihydrofurane moiety including a phenyl methy-
lene group was obtained (yield up to 72%), suggesting an important stabilisation by a
mesomeric effect. The suggested formation of spiranic derivatives involved an in situ
oximation/dehydration/SN ’ cascade reaction.
This original pathway, giving access to new pharmacophores, prompted us to further
study rearrangement from furyloximes.
Supplementary Materials: The following supporting information can be downloaded at: https:
//www.mdpi.com/article/10.3390/molecules29225474/s1, Figures S1–S10: NMR spectra of silylated
alcohols 2a–e; Figures S11–S22: NMR spectra of compounds 3a–f; Figures S23–S34: NMR spectra of
compounds 4a–f; Figures S35–S46: NMR spectra of keto alcohols 5a–f; Figures S47–S54: NMR spectra
of compounds 7a–d; Figures S55–S67 NMR spectra of compounds 6c,e and f.
Author Contributions: Conceptualization, C.S.; validation, M.Y.L. and C.S.; investigation, C.C.;
writing—original draft preparation, C.S.; writing—review and editing, M.Y.L. and C.S.; visualization,
C.S.; supervision, C.S. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Data Availability Statement: Data are contained within the article and Supplementary Materials.
Molecules 2024, 29, 5474 15 of 16
Acknowledgments: The authors would like to thank the Ministère de l’Enseignement Supérieur et de
la Recherche and the CNRS for their financial support. They also wish to extend thanks to Alexandre
Benard and Patrick Daubias for his contribution to the HRMS analysis.
Conflicts of Interest: The authors declare no conflicts of interest.
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Abstract: Oximation of substituted ketofurfuryl alcohols in the presence of hydroxylamine hydro-

Keywords: spiro compound; dihydroxazole; isoxazoline; furfural; oxime; cascade reaction;

Citation: Cuyamendous, C.; Laurent,

Molecules 2024, 29, x. https://doi.org/10.3390/xxxxx www.mdpi.com/journal/molecules

TBSO OEt EtOH, rt eq. 2

Molecules 2024, 29, 5474 3 of 16

3.1. General Scheme

3.2. Synthesis and Characterization

3.2.2. General Protocol for Epoxide Opening

3.2.3. General Protocol for Alcohol Oxidation to Ketone

3.2.4. General Protocol for Silylated Alcohol Deprotection

3.2.5. General Protocol for Oxime Formation

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