A Practical Synthesis of Valuable Strained Eight-Membered-Ring Derivatives for Click Chemistry

Article abstract of DOI:10.1002/ejoc.201800139

A convenient and cost-effective synthetic access to cyclooctyne and trans-cyclooctene derivatives is described. A cyclopropanation step using copper powder in place of Rh₂(OAc)₄ as catalyst and a symmetric diazomalonate resulted in a drastic decrease in the overall cost of the synthesis. Further derivatizations allowed us to characterize, for the first time, the structure of a BCN analogue by X-ray crystallography, and to obtain a library of derivatives that could potentially be useful for applications in metal-free click chemistry.

Full text of DOI:10.1002/ejoc.201800139

A Journal of
Accepted Article
Title: A practical synthesis of valuable strained 8-membered ring
derivatives for click chemistry
Authors: Sabrina Bernard, Ramar Arun Kumar, Karine Porte, Pierre
Thuéry, Frédéric Taran, and Davide Audisio
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800139
Link to VoR: http://dx.doi.org/10.1002/ejoc.201800139
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10.1002/ejoc.201800139
European Journal of Organic Chemistry
FULL PAPER
A practical synthesis of valuable strained 8-membered ring
derivatives for click chemistry
Sabrina Bernard,[a] Ramar Arun Kumar,[a, b] Karine Porte,[a] Pierre Thuéry,[c] Frédéric Taran[a] and
Davide Audisio*[a]
Abstract: A convenient and cost-effective synthetic access to
cyclooctyne and trans-cyclooctene derivatives is described.
strain conferred by the sp2-hybridized carbons. This phenomenon
can also account for the reactivity order of DIBAC (a.k.a. DBCO
or ADIBO) ca. 10 times more reactive than the first generation.
BARAC derivatives (Scheme 1a) have shown remarkable
reactivity with azides, but a challenging synthetic access has
hampered their popularization.6 One interesting exception to the
(di)benzoannulated cyclooctyne rule is provided by BCN. Its
excellent reactivity is induced by ring fusion of cyclooctyne to
cyclopropane, leading to the typical bicyclo[6.1.0]non-4-yne
structure. Reaction rate constants of BCN with aliphatic azides
are in the same range of the second generation DIBO (Scheme
1a).5
A
cyclopropanation step using copper powder in lieu of Rh2(OAc)4 as
catalyst and a symmetric diazomalonate enabled to drastically reduce
the overall cost of the synthesis. Further derivatizations allowed to
characterize, for the first time, the structure of a BCN analogue by X-
ray crystallography and obtain a library of derivatives potentially useful
for applications in metal free click chemistry.
Introduction
Since the advent of click chemistry, a new golden age for
cyclooctyl derivatives has emerged.1 In the past, cyclooctynes
have been largely overlooked by organic practitioners and were
considered a mere curiosity with low synthetic value. Wittig and
Krebs have first observed their remarkable reactivity with azides
in 1961,2 but the attention has been raised only in 2004 by the
seminal work of C. Bertozzi.3 For the first time, it was shown that
this strained reagent with a bent geometry of a triple bond is an
ideal partner for [3+2] cycloaddition with azides, thus avoiding the
employment of copper in click chemistry and enabling the use of
strain promoted transformations for bioorthogonal applications.
Over the last decade, countless scientific advancements in this
field have been reported.4 In particular, in order to accelerate the
rate of the cycloaddition, a great deal of attention was paid to find
the ideal balance between ring strain and stability of the
cyclooctyne derivatives. In 2016, Dommerholt et al. have reported
a comprehensive review on the functionalization of cyclooctynes.5
According to their definition, cyclooctynes can be recognized in
two classes: an earlier generation of aliphatic, with rather low
reactivity, and (di)benzoannulated cyclooctynes. To the first
generation belong OCT and improved derivatives such as MOFO
and DIFO bearing propargylic fluorine atoms (Scheme 1a). In the
second generation of (di)benzoannulated cyclooctynes, an
enhancement of the reactivity is caused by the increase in ring
[a]
Service de Chimie Bio-organique et Marquage DRF-JOLIOT-SCBM,
CEA, Université Paris-Saclay, 91191 Gif-sur-Yvette (France).
E-mail: davide.audisio@cea.fr
http://joliot.cea.fr/drf/joliot/Pages/Entites_de_recherche/medicament
s_technologies_sante/scbm.aspx
[b]
[c]
SRM Research Institute, Department of Chemistry, SRM University,
Kattankulathur, Kancheepuram 603203 (D.t.), India
NIMBE, CEA, CNRS, Universitꢀ Paris-Saclay, 91191 Gif-sur-Yvette
(France).
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201800139
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Scheme 1 a) Common cyclooctyne and trans-cyclooctene reagents for click
reactions; reaction rate constants with aliphatic azides (M-1 s-1) according to ref
5; b) Synthetic routes to functionalized BCN and TCO derivatives.
with diazo derivative in the literature.12,13 When, 1,5-COD and
readily available diazomalonate 2 were reacted in presence of
catalytic amounts of copper powder (25 mol%) the desired
cyclopropyl product was isolated in 67% yield. The protocol turned
out to be highly reliable and could be easily performed on a 5 gram
scale. It is worth mentioning, that the use of diazomalonate in
place of the diazoacetate has the sharp advantage to avoid
tedious regioisomer separation.14
Among the myriad structures reported, only a few have received
practical attention and are nowadays commonly found in
bioorthogonal applications. The most common examples of
cyclooctynes, regularly found in the literature for application in
click and biorthogonal chemistries, are those commercially
available: DIBAC7 and endo-BCN8 (Scheme 1a). Besides
cyclooctynes, trans-cyclooctene (TCO) derivatives have also
found large applications in chemical biology. TCOs have shown
exquisite reactivity with tetrazines by means of an inverse electron
demand Diels-Alder (IEDDA) process.9 In particular,
conformationally strained s-TCO (Scheme 1a) was reported to be
one of the most reactive dienophiles for this ligation.10
Due to the cis-cyclopropyl ring fusion, which forces the TCO to
adopt a ‘half-chair’ conformation higher in energy, s-TCO was
shown to be a remarkable handle for biological applications
including protein bioconjugation and in vivo chemistry.
Recently, our group has reported a novel click and release
transformation using imino-sydnones and strained alkynes, which
enabled the access to a novel technology for proteins trans
tagging under bioorthogonal conditions.11 This original
transformation was discovered through a large screening of
mesoionic libraries in presence of cyclooctynes with more than
hundred reactions performed. One major technical limitation we
faced in our approach was the small amounts of strained alkynes
available for the screening, discovery and optimization of the hit
reactions. Despite their broad interest, DIBAC, endo-BCN and
TCOs are expensive and can be purchased only on milligram
scale amounts therefore limiting their practical synthetic use.
Scheme 2 Cheap synthesis of cyclooctyne 4 and trans-cyclooctene 5.
The methyl esters were readily converted into the desired
cyclooctene 3 in 76% yield. Further bromination (67% yield) and
elimination (43% yield) afforded the strained alkyne 4.
Interestingly with the current synthetic route, 4 can be obtained
on 0.5 gram scale in a straightforward and cost-effective
manner.15
We next investigated the derivatization of intermediate 3 to the
corresponding trans-cyclooctene 5. s-TCO is classically prepared
according to the same procedure as BCN and the tedious isomer
separation in part reduced the appeal of this compound and its
derivatives.16 Following the photochemical procedure described
by the Fox group,17 to our delight 3 could be smoothly converted
to 5 in 62 % yield.
With a cost-effective approach to 4 and 5 secured, we next
investigated the possible derivatizations of the diol motif present
in these molecules. Van Delft previously described the
preparation of 4 using Rh catalysis and showed that its treatment
with triphosgene delivers the cyclic carbonate 6, which was further
opened upon treatment with an amine at elevated temperature
(Scheme 3).18 To develop more practical and reactive derivatives
we envisaged the preparation of sulfoxide, phosphonate and
boronate cyclooctyne derivatives.
In this contribution, we describe a divergent synthetic route
allowing the modular and scalable preparation of cyclooctyne and
trans-cyclooctene derivatives (Scheme 1b), which enable to
drastically reduce the overall cost of the synthetic process. This
novel protocol should help the democratization of such useful
reagents for click and bioorthogonal chemistry and are currently
utilized in our group for discovery of new strained promoted
transformations.
Results and Discussion
According to the original procedure described by van Delft, BCN
is prepared from 1,5-cyclooctadiene by means of a rhodium
acetate catalysed cyclopropanation in presence of ethyl
diazoacetate.8 In the reaction, a 2:1 mixture of endo:exo isomers
is formed and, after
a delicate column chromatography
purification, the desired endo product is isolated in 50% yield
(Scheme 1b). Rh2(OAc)4 is a very effective catalyst which enables
the cyclopropanation to take place under mild reaction conditions
but its cost is a limitation to the development of scalable
processes.
Copper catalysis is a desirable and cheaper alternative to rhodium
and it has found large applications in cyclopropanation of olefins
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10.1002/ejoc.201800139
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different aldehydes 11a-g under acidic conditions delivered the
corresponding acetals 12a-g in good yields (76-96%).
Interestingly, spirocyclic scaffold 12 is chiral, and a racemic
mixture of enantiomers is formed during the reaction. Compounds
12 were subsequently converted into the desired cycloalkynes
following the classical bromination/elimination procedure. BCN
analogues 13 were isolated in 13% to 39% yield over two steps.
It is worth noting, that spiro compounds 13 are unique examples
of chiral cyclooctyne structures (Scheme 4).
Scheme 3 Functionalization of cyclooctyne 4.
When 4 was reacted with phenylphosphonic dichloride with an
excess of triethylamine the corresponding phosphonate 7 was
isolated in 42% yield after column chromatography (Scheme 3).
The boronic esters 8a-b could be isolated in 74 and 33% yield by
mixing 4 with the corresponding boronic acid under dehydrating
conditions.19 It is worth mentioning, that compound 8b showed
moderate stability on silica and the diol 4 was regenerated during
the purification. Cyclic sulphite 9 was obtained upon thionyl
chloride treatment of diol 4 with thionyl chloride and Et3N at 0 °C
in dichloromethane. Spirocyclic compound 9 is particularly
intriguing, bearing a six and three membered rings further fused
with a strained cyclooctyne. Its unconventional structure could be
unambiguously confirmed by single-crystal X-ray diffraction
(Figure 1). A large number of cyclooctynes have been described
to date, nevertheless X-ray crystallography data are available
only for a limited number of them.20 In particular, for BCN
derivatives, we are aware of only a single report describing the
cobalt-hexacarbonyl-protected alkyne, where the geometry of the
molecule differs largely from regular BCN.21 As depicted in Figure
1, the crystal structure of 9 shows that the length of the triple bond,
1.190(4) Å, is in agreement with previous literature reports. On
the other hand, the C(sp)–C(sp)–C(sp3) angles of 153.4(3)° and
155.5(3)° are rather interesting and smaller than those in classic
cyclooctynes such as DIMAC (157.53(16)°, 157.00(17)°), MOFO
(159.9(2)°, 155.33(17)°), DIFO2 (150.64(14)°, 161.96(14)°).20
The presence of the fused cyclopropyl ring renders the angles of
the triple bond closer to strained BARAC derivatives (153.02(16),
153.07(16)°).20 On the other side of the molecule, the cyclic
sulphite adopts a chair conformation with the exocyclic S=O in
axial position.22
Scheme 4 Acetal functionalization of diol 3.
Not surprisingly, 12e and 12g bearing a fragile ester moiety were
not stable under the strong basic conditions required for the
double elimination step. Despite our attempts to modify
parameters such as the base (LDA, LiHMDS), the number of
equivalents of base, temperature and time of the reaction, we
were unable to obtain these derivatives. On the other hand, the
conversion of acetals 12b, 12e, 12f and 12g into the
corresponding TCOs 14 was achieved, albeit in moderate yields.
The isomerization procedure was found compatible with the
presence of an ester function (compound 14e). In all cases, a 1:1
mixture of diastereoisomers was obtained. 8-membered rings
derivatives 13 and 14 possess useful handles for further
derivatizations and could be highly interesting in the contest of
biomolecule and materials functionalization.
With a handful of derivatives synthesized, we next turned our
attention to their reactivity. Compound 4 has been previously
shown to react with azides with kinetic values very close to those
of the parent BCN.18 Due to our longstanding interest with
sydnone chemistry, we decided to investigate the reactivity of
BCN, 4 and 13f with N-phenylsydnone 15.24 We recently reported
sydnones as unconventional dipoles for [3+2]-cycloadditions with
strained cyclooctynes, such as BCN, under remarkably mild
conditions. As shown in scheme 5, the second order rate
constants are in the same range of values as commercially
available BCN, between 0.028 and 0.058 M-1sec-1.
Figure 1 Molecular structure of 9 (side and top views). Displacement ellipsoids
are drawn at the 40% probability level; hydrogen atoms are omitted for clarity.
We then decided to investigate other derivatizations of the 1,3-
diol moiety. Recently, TCO functionalized acetals were shown to
be suitable partners for site-specific protein labelling16 and
pretargeted in vivo PET imaging.23 The combination of 3 with
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10.1002/ejoc.201800139
European Journal of Organic Chemistry
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60 F254 plates (Merck). Unless otherwise noted, all other commercially
available reagents and solvents (Aldrich) were used without further
purification.
Dimethyl 2-diazomalonate (2).26 Dimethyl malonate (5.86 g, 44.3 mmol,
1
eq.), triethylamine (9.16 mL, 72.2 mmol, 1.5 eq.) and 4-
acetamidobenzenesulfonyl azide (9.00 g, 45.7 mmol, eq.) were
1
dissolved in acetonitrile (120 mL) at room temperature. After stirring the
resulting mixture overnight, the suspension was filtered through a frit
funnel and the solvent was removed under reduced pressure. The crude
product was partitioned between dichloromethane (150 mL) and water
(150 mL) and the two layers (aqueous and organic) filtered through a frit
funnel again. The two layers were separated and the aqueous layer was
extracted with dichloromethane (150 mL). The combined organic layers
were dried over MgSO4 and concentrated under reduced pressure.
Filtration over a plug of silica eluting with EtOAc/heptane (1/1), 300 mL,
afforded dimethyl 2-diazomalonate (2) as pale yellow oil) (6.32 g, 90%
yield). The crude product was used for the next step without further
purification. The spectral data (1H NMR) was consistent with literature
report.26 1H-NMR (400 MHz, CDCl3): δ 3.85 (s, 6H) ppm.
Scheme 5 Rate constant of the reactions at RT in DMSO/PBS
(10mM) (8:2) between N-phenylsydnone.
On the other hand, the reaction rate of stable TCO 517,25 with
commercially available 3,6-diphenyl-1,2,4,5-tetrazine was not
surprisingly very fast. UV measurements showed the
disappearance of the reagent within few seconds in a very similar
fashion compared to s-TCO (see supporting information for
further details).
(Z)-dimethyl bicyclo[6.1.0]non-4-ene-9,9-dicarboxylate.13 Copper
powder (0.5 g, 8 mmol, 0.3 eq.) was added into the 1,5-cyclooctadiene (27
mL, 221 mmol, 6.5 eq.) under argon atmosphere. The suspension was
heated to 130 °C and dimethyl 2-diazomalonate (2) (5.0 g, 31.6 mmol, 1
eq.) was added dropwise through automatic syringe pump for 1 hour and
the reaction mixture was stirred at the same temperature overnight. After
overnight stirring, the reaction mixture was cooled down to room
temperature. The crude reaction mixture was directly loaded to column
chromatography and eluted first with 100% heptane until remove excess
of cyclooctadiene and then eluted from 7 % to 10 % EtOAc in heptane to
afford (Z)-dimethyl bicyclo[6.1.0]non-4-ene-9,9-dicarboxylate as colorless
oil (4.970 g, 66 %). The spectral data (1H NMR) was consistent with
literature report.13 1H-NMR (400 MHz, CDCl3): δ 5.61–5.59 (m, 2H), 3.77–
3.74 (m, 3H), 3.73–3.70 (m, 3H), 2.36–2.17 (m, 2H), 2.12-2.07 (m, 4H),
2.06–1.82 (m, 2H), 1.73–1.71 (m, 2H) ppm.
Conclusions
In conclusion, we have reported an efficient and cost-effective
synthesis of cyclooctyne
4 and trans-cyclooctene 5. The
originality of this approach is the utilization of inexpensive copper
powder as an effective catalyst for the cyclopropanation and the
employment of a symmetric diazomalonate. The current method
enables to obtain significant amounts of desired compounds in a
much convenient manner compared to what is described in the
literature. In addition, a number of useful derivatives were
obtained and the unusual structure of the spirocyclic scaffold
could be determined by X-ray diffraction. Discovery research
using such strained alkynes and TCOs are currently undergoing
in our laboratory. We believe this practical and low-cost approach
might encourage new efforts and discoveries in the exciting field
of strain promoted click chemistry.
(Z)-bicyclo[6.1.0]non-4-ene-9,9-diyldimethanol (3).8b To a suspension
of LiAlH4 (0.865 g, 22.8 mmol, 1.8 eq.) in Et2O (75 mL) was added
dropwise at 0 °C a solution of (Z)-dimethyl bicyclo[6.1.0]non-4-ene-9,9-
dicarboxylate (3.0 g, 12.6 mmol, 1 eq.) in Et2O (75 mL) under argon
atmosphere. Then, the reaction mixture was stirred for 2 hours at room
temperature. Again the reaction mixture cooled to 0 °C and water was
added very carefully with constant stirring until the grey solid had turned
into white. Then MgSO4 (12 g) was added, the solid was filtered off and
washed thoroughly with Et2O (600 mL). The filtrate was concentrated in
vacuo. The crude product was recrystallized from EtOAc to afford 3 as a
white crystalline solid (1.62 g, 70%). Crude product also can be used for
the next step without further purification. The spectral data (1H NMR) was
consistent with reported one.8b 1H NMR (400 MHz, CDCl3): δ 5.64–5.57 (m,
2H), 3.85 (d, J = 5.1 Hz, 2H), 3.55 (d, J = 5.0 Hz, 2H), 2.63–2.60 (m, 2H),
2.41–2.33 (m, 2H), 2.12–1.99 (m, 4H), 1.69–1.60 (m, 2H), 0.92–0.85 (m,
2H) ppm.
Experimental Section
General Methods. FT-ATR-IR spectra were recorded on a Perkin-Elmer
UAR Two Spectrum spectrometer and are reported as wavelength
numbers (cm-1). 1H NMR (400 MHz), 13C NMR (100 MHz) were measured
on a Brucker Avance 400 MHz spectrometer. Chemical shifts are reported
in parts per million (ppm, δ) downfield from residual solvents peaks and
coupling constants are reported as Hertz (Hz). Splitting patterns are
designated as singlet (s), doublet (d), triplet (t), broad singlet (br. s).
Splitting patterns that could not be interpreted or easily visualized are
designated as multiplet (m). Electrospray mass spectra were obtained
using an ESI-Quadripole autopurify, Waters (pompe 2545, mass: ZQ2000)
mass Spectrometer. Silica gel 60H (40-63 µm) manufactured by Merck
(Germany) was used for general chromatography unless otherwise
specified. Thin-layer chromatographies were done on pre-coated silica gel
(4R,5R)-4,5-dibromobicyclo[6.1.0]nonane-9,9-diyl-dimethanol.8b The
dimethanol-cyclooctene 3 (2.3 g, 12.6 mmol, 1 eq.) was dissolved in dry
dichloromethane(80 mL). At 0 °C a solution of Br2 (839 µL, 16.4 mmol, 1.3
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10.1002/ejoc.201800139
European Journal of Organic Chemistry
FULL PAPER
eq.) in dry dichloromethane (15 mL) was added dropwise until the yellow
color of Br2 persisted. The reaction mixture was quenched with 10 %
solution of Na2S2O3 and extracted with dichloromethane (2 x 100mL). The
organic layer was dried over MgSO4 and concentrated in vacuo. The crude
product was recrystallized from dichloromethane to afford (4R,5R)-4,5-
dibromobicyclo[6.1.0]nonane-9,9-diyl-dimethanol as a white solid (2.870 g,
67%). Crude product also can be used for the next step without further
purification. The spectral data (1H NMR) was consistent with reported
one.8b 1H-NMR (400 MHz, CDCl3): δ 4.86–4.78 (m, 2H), 3.91–3.59 (m, 2H),
3.59–3.50 (m, 2H), 2.73–2.63 (m, 2H), 2.36–2.00 (m, 4H), 1.99–1.93 (m,
2H), 1.69–1.58 (m, 2H), 1.12–1.00 (m, 2H) ppm.
2.31 (m, 2H), 2.15–2.20 (m, 2H), 2.04–2.09 (m, 1H), 1.87–2.00 (m, 2H),
1.11 (dddd, J = 12.9 Hz, J = 12.6 Hz, J = 11.2 Hz, J = 7.1 Hz, 1H), 0.84
(dtd, J = 14.1 Hz, J = 12.4 Hz, J = 2.5 Hz, 1H), 0.67 (ddd, J = 13.0 Hz, J =
8.8 Hz, J = 3.0 Hz, 1H), 0.55 (ddd, J = 12.3 Hz, J = 8.8 Hz, J = 4.5 Hz, 1H)
ppm; 13C-NMR (100 MHz, CDCl3): δ 138.3, 131.3, 73.8, 63.1, 34.7, 33.6,
30.1, 28.0, 27.1, 25.3, 24.2 ppm; IR (cm-1) 3298, 2926, 1382, 1024, 1003,
972; HRMS (ESI) m/z: [M+Na]+ Calcd for C11H18NaO2: 205.1199; found:
205.1199; Mp. 138 °C.
2'-phenylspiro[bicyclo[6.1.0]non[4]yne-9,5'-[1,3,2]
dioxaphosphinane] 2'-oxide (7). To a stirred solution of Et3N (62 µL, 4.0
eq., 0.444 mmol) and (bicyclo[6.1.0]non-4-yne-9,9-diyl)dimethanol 4 (20
mg, 0.111 mmol, 1.0 eq.) in dichloromethane (2 ml) was added drop-wise
phenylphosphonic dichloride (16 µL, 0.111 mmol, 1 eq.) at 0 °C under a
nitrogen atmosphere. The mixture was allowed to warm at room
temperature. After 2 hours, the mixture was washed with water (20 mL)
and the aqueous layer was extracted with dichloromethane (3 x 10 mL)
and the combined organic extract was washed with brine, dried in Na2SO4
and concentrated in vacuo. The crude was purified though flash
chromatography (100% dichloromethane to 96% dichloromethane : 4%
EtOAc) to afford the desired product 7 as a white powder (14 mg, 0.046
mmol, 42%). 1H-NMR (400 MHz, CDCl3): δ 7.84-7.79 (m, 2H), 7.58 (td, J
= 14.9 Hz, 1.4 Hz, 1H), 7.52-7.47 (m, 2H), 4.59 (t, J = 10.4 Hz, 1H), 4.39
(t, J = 10.4 Hz, 1H), 4.22 (t, J = 10.4 Hz, 1H), 3.97(t, J = 10.4 Hz, 1H), 2.44
(dd, J = 13.5, 1.9 Hz, 2H), 2.37-2.24 (m, 4H), 1.64-1.54 (m, 2H), 1.28-1.01
(m, 2H) ppm; 13C-NMR (100 MHz, CDCl3): δ 132.8 (d, JC-P = 3.2 Hz, 1C),
131.6 (d, JC-P = 10.9 Hz, 2C), 128.6 (d, JC-P = 14.2 Hz, 2C), 127.0 (d, JC-P
= 192 Hz, 1C), 98.4, 98.0, 76.2 (d, JC-P = 5.9 Hz, 1C), 67.3 (d, JC-P = 5.9
Hz, 1C), 28.8, 28.5, 26.5 , 26.3, 25.1 (d, JC-P = 7.9 Hz, 1C), 20.9, 20.8 ppm;
31P-NMR (161 MHz, CDCl3): δ 16.2 ppm; IR (cm-1) 2922, 1439, 1255, 1131,
1016, 993, 790, 519; LCMS (ESI) m/z [M+H]+ 303.1, [2M+H]+ 605.3.
HRMS (ESI) m/z: [M+H]+ Calcd C17H20O3P: 303.1145; found: 303.1144;
Bicyclo[6.1.0]non-4-yne-9,9-diyldimethanol (4).8b To a solution of the
dibromide cyclooctane dimethanol (2.3 g, 6.76 mmol, 1 eq.) in dry THF
(115 mL) was added dropwise at 0 °C a solution of tBuOK (42 mL, 1 M in
THF, 42.0 mmol, 6.2 eq.). Then the solution was refluxed for 2 hours. After
cooling down to room temperature the mixture was quenched with a
saturated NH4Cl solution and extracted with dichloromethane. The organic
layer was dried over MgSO4 and concentrated in vacuo. The residue was
purified by column chromatography on silica gel eluting 100% EtOAc to
afford dimethanol-cyclooctyne 4 as a white solid (520 mg, 43%). The
spectral data (1H NMR) was consistent with reported one.8b 1H-NMR (400
MHz, CDCl3): δ 3.89 (s, 2H), 3.64 (s, 2H), 2.33–2.17 (m, 8H), 1.69–1.60
(m, 2H), 0.89–0.82 (m, 2H) ppm.
General procedure A to isomerize cis-alkene to trans-alkene. The (Z)-
cyclooctene (0.55 mmol, 1 eq.) and methyl benzoate (1.1 mmol, 2 eq.)
were dissolved in a mixture ether/dichloromethane (13/1, 20 mL) in a
quartz flask that was equipped with a magnetic stirrer. The quartz flask
was placed in a Rayonnet® (10 UV lamp 254 nm) connected to a column
(Isco, 40 g) and a Berthold HPLC pump via PTFE tubing. The setup used
for the general photolysis was described inhere.17 The bottom of the
column was packed with dry silica (60-250 mesh, 2 cm) and the top of the
column was packed with silver nitrate impregnated silica (3.1 g). The
column was flushed with the mixture ether/dichloromethane (13/1). The
flow rate was 10 mL/min. The lamp was turned on at 254 nm and photolysis
of the stirring mixture was carried out for 13 hours. The column was
washed with additional solvent for 30 min and then dried by a stream of
compressed air. The column was emptied into an Erlenmeyer flask and
the silica gel was stirred with ammonium hydroxide (40 mL) and
dichloromethane (40 mL) for 5 min. The silica gel was filtered and the
filtrate cake was washed with additional ammonium hydroxide (40 mL) and
dichloromethane (40 mL). The filtrate was transferred to a separatory
funnel. The organic layer was separated and the aqueous layer was
washed with dichloromethane (2x50 mL). The combined organic layers
were dried over MgSO4, filtered and concentrated. The product purified by
column chromatography with the adapted eluant to provide the desired
trans-cyclooctene product.
2'-phenylspiro[bicyclo[6.1.0]non[4]yne-9,5'-[1,3,2]dioxaborinane]
(8a). In a flame dried flask, (bicyclo[6.1.0]non-4-yne-9,9-diyl)dimethanol
(4) (20 mg, 0.111 mmol, 1.0 eq.), phenylboronic acid (13 mg, 0.111 mmol,
1.0 eq.) and MgSO4 (99.9% purity, 150 mg) were stirred in dry THF (1 mL)
at room temperature. After 2 hours, the reaction mixture was diluted in
EtOAc, filtered through Celite and concentrated under vacuum. The
residue was subjected to flash column chromatography (heptane/EtOAc
9/1) to yield the desired product (22 mg, 0.083 mmol, 74%). 1H-NMR (400
MHz, CDCl3): δ 7.77 (d, J = 7.8 Hz, 2H), 7.42 (t, J = 7.0 Hz, 1H), 7.36-7.33
(m, 2H), 4.13 (s, 2H), 3.89 (s, 2H), 2.30-2.20 (m, 6H), 1.63-1.58 (m, 2H),
0.97-0.94 (m, 2H) ppm; 13C-NMR (100 MHz, CDCl3): δ 133.9 (2C), 130.8,
127.8 (2C), 98.7 (2C), 72.5, 62.8, 29.0 (2C), 26.5, 26.0 (2C), 21.3 (2C), the
quaternary carbon (C-B) missing, ppm; 11B-NMR (128 MHz, CDCl3): δ 31.8
ppm; IR (cm-1) 2915, 1440, 1301, 1246, 1143, 1104, 907, 729, 699, 643.
Methyl (Z)-4-(spiro[bicyclo[6.1.0]non[4]yne-9,5'-[1,3,2]dioxaborinan]-
4-en-2'-yl)benzoate (8b). The alkyne diol 4 (12 mg, 0.067 mmol, 1 eq.),
4-methoxycarbonylphenylboronic acid (12.0 mg, 0.066 mmol, 1eq.) and
MgSO4 (80 mg) were stirred in dry THF (1 mL) at room temperature for 1.5
hours. The reaction mixture was diluted with ethyl acetate, filtered through
celite and concentrated under vacuum. The crude was purified by
chromatography column eluting with heptane/EtOAc (1:1) to afford the
(E)-bicyclo[6.1.0]non-4-ene-9,9-diyldimethanol (5). Compound 5 was
obtained in 62% yield, as a white powder (65.2 mg) starting from cis-
isomer 3 (100 mg, 0.55 mmol) using the general procedure A and purified
by column chromatography eluting 100% EtOAc. 1H-NMR (400 MHz,
CDCl3): δ 5.88 (ddd, J = 16.8 Hz, J = 9.3 Hz, J = 6.3 Hz, 1H), 5.19 (ddd,
J = 16.8 Hz, J = 10.6 Hz, J = 3.9 Hz, 1H), 3.75 (qd, J = 12.0 Hz, J = 2.4
Hz, 2H), 3.61 (qd, J = 11.5 Hz, J = 2.4 Hz, 2H), 2.32–3.39 (m, 1 H), 2.24–
1
product as a white powder (7.2 mg, 33%). H-NMR (400 MHz, CDCl3): δ
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800139
European Journal of Organic Chemistry
FULL PAPER
8.00 (d, J = 7.2 Hz, 2H), 7.84 (d, J = 7.2 Hz, 2H), 4.14 (s, 2H), 3.92 (s, 3H),
3.90 (s, 2H), 2.34–2.21 (m, 6H), 1.70–1.58 (m, 2H), 1.01–0.94 (m, 2H)
ppm; 13C-NMR (100 MHz, CDCl3): δ 167.3, 133.6 (2C), 131.7, 128.4 (2C),
98.4 (2C), 72.3, 62.8, 52.0, 27.3 (2C), 26.2, 25.8 (2C), 21.0 (2C) ppm, note:
one quaternary carbon missing; IR (cm-1) 2917, 2850, 1722, 1426, 1347,
1322, 1304, 1275, 1249, 1144, 1115, 1022, 711, 642; Mp. 123–125 °C.
starting from dimethanol-cyclooctene 3 (100.0 mg, 0.55 mmol) and
butyraldehyde (59.0 µL, 0.66 mmol) using the general procedure B and
purified by column chromatography eluting heptane/EtOAc (96/4). 1H NMR
(400 MHz, CDCl3): δ 5.63–5.52 (m, 2H), 4.53 (t, J = 5.2 Hz, 1H), 4.05 (d,
J = 11.4 Hz, 1H), 3.90 (d, J = 11.8 Hz, 1H), 3.76 (dd, J = 11.8 Hz, J = 2.4
Hz, 1H), 3.06 (dd, J = 11.2 Hz, J = 2.3 Hz, 1H), 2.28–2.37 (m, 2H), 2.18–
1.98 (m, 3H), 1.83–1.69 (m, 2H), 1.62–1.57 (m, 2H), 1.45–1.34 (m, 3H),
0.99–0.93 (m, 1H), 0.90 (t, J = 7.4 Hz, 3H), 0.60–0.67 (m, 1H) ppm; 13C
NMR (100 MHz, CDCl3): δ 129.7, 129.0, 102.5, 76.4, 67.4, 36.9, 27.6, 27.1,
26.5, 24.3, 22.8, 22.3, 22.0, 17.4, 13.9 ppm; IR (cm-1): 2957.9, 2931.0,
2870.9, 2833.2, 1655.1, 1455.7, 1377, 1139.63, 1097.3, 1013.1, 935.3;
LCMS (ESI) m/z [M+Na]+ 259.2; HRMS (ESI) m/z: [M+H+] Calcd for
C15H25O2 237.1849; found: 237.1850.
(Z)-spiro[bicyclo[6.1.0]non[4]yne-9,5'-[1,3,2]dioxathian]-4-ene
2'-
oxide (9). To a solution of the alkyne-diol 4 (10.0 mg, 0.056 mmol, 1 eq.)
and triethylamine (17 µL, 0.12 mmol, 2.2 eq.) in dry dichloromethane (1
mL) was added dropwise thionyl chloride (9.1 µL, 0.11 mmol, 2 eq.) at 0 °C.
The reaction was stirred for 20 minutes (TLC completion) and was
quenched at 0 °C with water. The phases were separated and the organic
phase was washed with a saturated solution of hydrogenocarbonate
sodium, dried over magnesium sulfate and concentrated under vacuum.
The product was purified by column chromatography eluting with a mixture
of heptane/EtOAc (95:5) to afford the desired product as a white powder
(1R,8S,Z)-2'-pentylspiro[bicyclo[6.1.0]non[4]ene-9,5'-[1,3]dioxane]
(12b). Compound 12b was obtained in 89% yield, 25.8 mg (pale yellow oil)
starting from dimethanol-cyclooctene 3 (20.0 mg, 0.11 mmol) and hexanal
(16.2 µL, 0.13 mmol) using the general procedure B and purified by column
chromatography eluting heptane/EtOAc (95/5). 1H-NMR (400 MHz,
CDCl3): δ 5.63–5.52 (m, 2 H), 4.52 (t, J = 5.3 Hz, 1H), 4.05 (d, J = 11.3
Hz, 1 H), 3.91 (d, J =11.8 Hz, 1H), 3.76 (dd, J = 11.8 Hz, J = 2.4 Hz, 1H),
3.06 (dd, J = 11.3 Hz, J = 2.4 Hz, 1H), 2.38–2.28 (m, 2H), 2.19–1.98 (m, 3
H), 1.91–1.69 (m, 2H), 1.63–1.58 (m, 2H), 1.44–1.33 (m, 3H), 1,31–1.23
(m, 4H), 0.99–0.93 (m, 1H), 0.86 (t, J = 7.0 Hz, 3H), 0.67–0.61 (m, 1H)
ppm; 13C-NMR (100 MHz, CDCl3): δ 129.7, 129.0, 102.7, 76.4, 67.4, 34.2,
31.7, 27.6, 27.1, 26.5, 24.3, 23.8, 22.8, 22.5, 22.3, 22.0, 14.0 ppm; IR (cm-
1) 2953, 2929, 2859, 2836, 1140, 1104, 1016; HRMS (ESI) m/z: [M+H]+
Calcd for C17H29O2 265.2162; found: 265.2158.
1
(6.4 mg, 51%). H-NMR (400 MHz, CDCl3): δ 5.26 (d, J = 11.4 Hz, 1H),
5.18 (d, J = 11.9 Hz, 1H), 3.62 (dd, J = 11.9 Hz, J = 2.4 Hz, 1H), 2.99 (dd,
J = 11.3 Hz, J = 2.4 Hz, 1H), 2.56 (ddt, J = 13.3 Hz, J = 3.2 Hz, J = 2.9 Hz,
1H), 2.43–2.34 (m, 1H), 2.32–2.18 (m, 3H), 2.17–2.11 (m, 1H), 1.72 (qd, J
= 12.7 Hz, J = 4.1 Hz, 1H), 1.51–1.40 (m, 1H), 1.1 (ddd, J = 12.6 Hz, J =
9.0 Hz, J = 3.2 Hz, 1H), 0.74 (ddd, J = 12.9 Hz, J = 9.0 Hz, J = 3.2 Hz, 1H)
ppm; 13C-NMR (100 MHz, CDCl3): δ 98.6, 97.9, 67.1, 58.9, 29.3, 28.1, 27.2,
25.1, 24.4, 20.8 (2C) ppm; IR (cm-1) 2919, 2851, 1455, 1184, 982, 953,
936, 715, 680; HRMS (ESI) m/z: [M+Na]+ Calcd C11H14NaO3S 249.0556;
found: 249.0554; Mp. 99–101 °C.
2-(2-oxoethoxy)ethyl benzoate (11g). In a flame dried flask, ethylene
glycol monobenzoate synthesized according to the litterature27 (688.8 mg,
3.28 mmol, 1 eq.) and Dess-Martin periodinane (1.67 g, 3.93 mmol, 1.2
eq.) were stirred at room temperature in dichloromethane (53 mL) for 3
hours. The reaction was quenched with sodium thiosulfate (2.4 eq.) in a
saturated solution of hydrogenocarbonate (30 mL). The mixture was
separated and the aqueous phase was extracted with dichloromethane (2
x 50 mL). The combined organic layers were dried over magnesium sulfate,
filtered and concentrated under vacuum. The residue was suspended in
ether and filtered through celite to give the desired product as a colorless
oil (264.4 mg, 37%). 1H-NMR (400 MHz, CDCl3): δ 9.75 (s, 1H), 8.07–8.05
(m, 2H), 7.60–7.56 (m, 1H), 7.47–7.44 (m, 2H), 4.55–4.53 (m, 2H), 4.20 (s,
2H), 3.93–3.91 (m, 2H) ppm; 13C-NMR (100 MHz, CDCl3): δ 200.1, 166.4,
133.1, 129.6 (3C), 128.4 (2C), 76.5, 69.8, 63.8 ppm; IR (cm-1) 3443, 2952,
2879, 1716, 1584, 1452, 1315, 1273, 1177, 1109, 1071, 1028, 712; HRMS
(ESI) m/z: [M+H]+ Calcd C11H13O4 209.0808; found: 209.0807;
(Z)-2'-heptylspiro[bicyclo[6.1.0]nonane-9,5'-[1,3]dioxan]-4-ene (12c).
Compound 12c was obtained in 92% yield, 148.9 mg (pale yellow oil)
starting from dimethanol-cyclooctene 3 (100.0 mg, 0.55 mmol) and octanal
(103.0 µL, 0.66 mmol) using the general procedure B and purified by
column chromatography eluting heptane/EtOAc (97/3). 1H NMR (400 MHz,
CDCl3): δ 5.65–5.55 (m, 2H), 4.54 (t, J = 5.3 Hz, 1H), 4.08 (d, J = 11.4 Hz,
1H), 3.93 (d, J = 11.9 Hz, 1H), 3.78 (dd, J = 11.9 Hz, J = 2.5 Hz, 1H), 3.09
(dd, J = 11.4 Hz, J = 2.5 Hz, 1H), 2.39–2.30 (m, 2H), 2.21–2.00 (m, 3H),
1.85–1.72 (m, 2H), 1.66–1.60 (m, 2H), 1.46–1.35 (m, 3H), 1.31–1.24 (m,
8H), 1.02–0.96 (m, 1H), 0.87 (t, J = 7.0 Hz, 3H), 0.70–0.63 (m, 1H) ppm;
13C NMR (100 MHz, CDCl3): δ 129.7, 129, 102.7, 76.4, 67.4, 35, 31.7, 29.4,
29.2, 27.6, 27.1, 26.5, 24.3, 24.1, 22.8, 22.6, 22.3, 22.0, 14.0 ppm; IR (cm-
1): 2952, 2924, 2856, 1457, 1377, 1141, 1107, 1016, 940; LCMS (ESI) m/z
[M+Na]+ 315.3; HRMS (ESI) m/z: [M+H]+ Calcd for C19H33O2 293.2475;
found: 293.2475.
General procedure B for acetal derivatives 12. The dimethanol-
cyclooctene 3 (1 eq.) and the desired aldehyde (1.2 eq.) were solubilized
in THF (10 mL). Paratoluenesulfonic acid monohydrate (0.1 eq.) was
added. The resulting mixture was stirred at room temperature overnight.
The reaction mixture was diluted with chloroform and washed with a
saturated solution of sodium hydrogenocarbonate. The organic phase was
dried over MgSO4 and concentrated. The product was purified by column
chromatography eluting with adapted eluant to give the desired product.
(Z)-2'-nonylspiro[bicyclo[6.1.0]nonane-9,5'-[1,3]dioxan]-4-ene (12d).
Compound 12d was obtained in 81% yield, 70.6 mg (pale yellow oil)
starting from dimethanol-cyclooctene 3 (50.0 mg, 0.27 mmol) and
decylaldehyde (62.0 µL, 0.33 mmol) using the general procedure B and
purified by column chromatography eluting heptane/EtOAc (97/3). 1H NMR
(400 MHz, CDCl3): δ 5.64–5.53 (m, 2H), 4.53 (t, J = 5.2 Hz, 1H), 4.07 (d,
J = 11.3 Hz, 1H), 3.92 (d, J = 11.8 Hz, 1H), 3.77 (dd, J = 11.8 Hz, J = 2.4
Hz, 1H), 3.07 (dd, J = 11.4 Hz, J = 2.4 Hz, 1H), 2.39-2.30 (m, 2H), 2.20–
2.00 (m, 3H), 2.40–2.30 (m, 2H), 1.84–1.71 (m, 2H), 1.67–1.61 (m, 2H),
1.45–1.34 (m, 3H), 1.30–1.24 (m, 12H), 1.01–0.95 (m, 1H), 0.86 (t, J = 6.8
Hz, 3H), 0.69–0.62 (m, 1H) ppm; 13C NMR (100 MHz, CDCl3): δ 129.7,
(Z)-2'-propylspiro[bicyclo[6.1.0]nonane-9,5'-[1,3]dioxan]-4-ene (12a).
Compound 12a was obtained in 87% yield, 112.7 mg (pale yellow oil)
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800139
European Journal of Organic Chemistry
FULL PAPER
129.0, 102.7, 76.4, 67.4, 35.0, 31.8, 29.5, 29.4 (2C), 29.2, 27.6, 27.1, 26.5,
24.3, 24.1, 22.8, 22.6, 22.3, 22.0, 14.0 ppm; IR (cm-1): 2951, 2922, 2853,
1456, 1376, 1139, 1109, 1015, 937; LCMS (ESI) m/z [M+H]+ 321.3. HRMS
(ESI) m/z: [M+Na]+ Calcd for C21H37O2 321.2788; found: 321.2788.
(0.150 M). At 0 °C a solution of Br2 (1.3 eq.) in dry dichloromethane (1.0 M)
was added dropwise until the yellow color of Br2 persisted. The reaction
mixture was quenched with 10 % solution of Na2S2O3 and extracted with
dichloromethane (2 x 100 mL). The organic layer was dried over MgSO4
and concentrated in vacuo. The crude product was directly engaged in the
next step without further purification. To a solution of the crude in dry THF
(0.60 M) was added dropwise at 0 °C a solution of tBuOK (1 M in THF, 3
eq.). Then the solution was refluxed for 2 hours except otherwise indicated.
After cooling down to room temperature the mixture was quenched with a
saturated NH4Cl solution and extracted with duchloromethane. The
organic layer was dried over MgSO4 and concentrated in vacuo. The
residue was purified by column chromatography on silica gel to afford
desired alkyne.
Ethyl 5-((1R,8S,Z)-spiro[bicyclo[6.1.0]non[4]ene-9,5'-[1,3]dioxan]-2'-
yl)pentanoate (12e). Compound 12e was obtained in 79% yield, 140.8 mg
(pale yellow oil) starting from dimethanol-cyclooctene 3 (100.0 mg, 0.55
mmol) and ethyl 6-oxohexanoate (104.2 mg, 0.66 mmol) using the general
procedure
B
and purified by column chromatography eluting
heptane/EtOAc (95/5). 1H-NMR (400 MHz, CDCl3): δ 5.65–5.53 (m, 2H),
4.54 (t, J = 5.3 Hz, 1H), 4.10 (q, J = 7.2 Hz, 2H), 4.06 ( d, J = 11.3 Hz, 1H),
3.91 (d, J = 11.8 Hz, 1H), 3.76 (dd, J = 11.8 Hz, J = 2.4 Hz, 1H), 3.06 (dd,
J = 11.3 Hz, J = 2.4 Hz, 1H), 2.38–2.26 ( m, 4H), 2.19–1.99 (m, 3H), 1.83–
1.70 (m, 2H), 1.68–1.59 (m, 4H), 1.47–1.36 (m, 3H), 1.24 (t, J = 7.2 Hz,
3H), 1.00–0.94 (m, 1H), 0.68–0.62 (m, 1H) ppm; 13C-NMR (100 MHz,
CDCl3): δ 173.6, 129.7, 129.0, 102.3, 76.3, 67.4, 60.1, 34.5, 34.2, 27.6,
27.1, 26.5, 24.7, 24.3, 23.7, 22.8, 22.3, 22.0, 14.2 ppm; IR (cm-1) 1732,
1139, 1013; HRMS (ESI) m/z: [M+H]+ Calcd for C19H31O4 323.2217; found:
323.2217.
2'-propylspiro[bicyclo[6.1.0]nonane-9,5'-[1,3]dioxan]-4-yne
(13a).
Compound 13a was obtained in 24% yield, 23.1 mg (white solid) starting
from acetal 12a (178.7 mg, 0.42 mmol) using the general procedure C and
purified by column chromatography eluting heptane/EtOAc (97/3). 1H NMR
(400 MHz, CDCl3): δ 4.54 (t, J = 5.2 Hz, 1H), 4.10 (d, J = 11.3 Hz, 1H),
3.92 (d, J = 11.8 Hz, 1H), 3.79 (dd, J = 11.8 Hz, J = 2.4 Hz, 1H), 3.13 (dd,
J = 11.3 Hz, J = 2.4 Hz, 1H), 2.50–2.45 (m, 1H), 2.34–2.10 (m, 4H), 2.07–
2.02 (m, 1H), 1.69–1.56 (m, 3H), 1.44–1.34 (m, 3H), 0.95–0.91 (m, 1H),
0.89 (t, J = 7.4 Hz, 3H), 0.62–0.56 (m, 1H) ppm; 13C NMR (100 MHz,
CDCl3): δ 102.6, 99.0, 98.1, 76.6, 67.3, 36.9, 29.7, 28.2, 27.7, 24.1, 23.0,
21.1, 21, 17.4, 13.9 ppm; IR (cm-1) 2959, 2924, 2848, 1456, 1377, 1139,
1097, 1014, 938; LCMS (ESI) m/z [M+H]+ 235.1; HRMS (ESI) m/z:
[M+Na]+ Calcd C15H22O2 235.1693; found: 235.1692; Mp. 66–67 °C.
4-((1R,8S,Z)-spiro[bicyclo[6.1.0]non[4]ene-9,5'-[1,3]dioxan]-2'-
yl)butan-1-ol (12f). Compound 12f was obtained in 96% yield, 84.9 mg
(yellow oil) starting from dimethanol-cyclooctene 3 (57.5 mg, 0.315 mmol)
and 6-hydroxypentanal, synthesized as described in the literature,28 (44.0
mg, 0.38 mmol) using the general procedure B and purified by column
chromatography eluting heptane/EtOAc (1/1). 1H-NMR (400 MHz, CDCl3):
δ 5.63–5.52 (m, 2H), 4.54 (t, J = 5.2 Hz, 1H), 4.05 (d, J = 11.6 Hz, 1H),
3.91 (d, J = 11.8 Hz, 1H), 3.76 (dd, J = 11.8 Hz, J = 2.4 Hz, 1H), 3.61 (t, J
= 6.4 Hz, 2H), 3.06 (dd, J = 11.6 Hz, J = 2.4 Hz, 1H), 2.37–2.29 (m, 2H),
2.18–1.98 (m, 3H), 1.83–1.51 (m, 7H), 1.44–1.32 (m, 5H), 0.98–0.92 (m,
1H), 0.66–0.61 (m, 1H) ppm; 13C-NMR (100 MHz, CDCl3): δ 129.7, 129.0,
102.5, 76.3, 67.4, 62.9, 34.9, 32.6, 27.6, 27.1, 26.5, 25.6, 24.3, 23.9, 22.8,
22.3, 22.0 ppm; IR (cm-1) 3402, 1139, 1041, 1011; HRMS (ESI) m/z:
[M+H]+ Calcd for C17H29O3 281.2111; found: 281.2113.
(1R,8S)-2'-pentylspiro[bicyclo[6.1.0]non[4]yne-9,5'-[1,3]dioxane]
(13b). Compound 13b was obtained in 32% yield, 7.1 mg (colorless oil)
starting from acetal 12b (30.80 mg, 0.117 mmol) using the general
procedure
C
and purified by column chromatography eluting
heptane/EtOAc (97/3). 1H-NMR (400 MHz, CDCl3): δ 4.54 (t, J = 5.2 Hz,
1H), 4.11 (d, J = 11.4 Hz, 1H), 3.92 (d, J = 11.8 Hz, 1H), 3.80 (dd, J = 11.8
Hz, J = 2.5 Hz, 1H), 3.13 (dd, J = 11.4 Hz, J = 2.5 Hz, 1H), 2.48 (dq, J =
11.3 Hz, J = 3.0 Hz, 1H), 2.35–2.08 (m, 4H), 2.05 (dq, J = 13.3 Hz, J = 3.0
Hz, 1H), 1.70–1.58 (m, 3H), 1.45–1.34 (m, 3H), 1.30–1.23 (m, 4H), 0.93
(ddd, J = 12.5 Hz, J = 8.9 Hz, J = 3.4 Hz, 1H), 0.86 (t, J = 6.9 Hz, 3H), 0.60
(ddd, J = 12.8 Hz, J = 8.9 Hz, J = 3.4 Hz, 1H) ppm; 13C-NMR (100 MHz,
CDCl3): δ 102.8, 99.1, 98.1, 76.8, 67.3, 34.9, 31.7, 29.8, 28.3, 27.7, 24.1,
23.8, 23.0, 22.5, 21.1, 21.0, 14.0 ppm; IR (cm-1) 2954, 2926, 2850, 1139,
1015; HRMS (ESI) m/z: [M+H]+ Calcd for C17H27O2 263.2006; found:
263.2007.
2-(((1R,8S,Z)-spiro[bicyclo[6.1.0]nonane-9,5'-[1,3]dioxan]-4-en-2'-
yl)methoxy)ethyl benzoate (12g). Compound 12g was obtained in 35%
yield, as a transparent oil (64.5 mg) starting from dimethanol-cyclooctene
3 (89.6 mg, 0.492 mmol) and aldehyde 11g (122.9 mg, 0.590 mmol) using
the general procedure B except that the reaction was heated at 50 °C and
purified by column chromatography eluting heptane/EtOAc (85/15). 1H-
NMR (400 MHz, CDCl3): δ 8.06 (d, J = 7.8 Hz, 2H), 7.56 (t, J = 7.4 Hz,
1H), 7.44 (d, J = 7.8 Hz, 2H), 5.65–5.61 (m, 2H), 4.81 (t, J = 4.6 Hz, 1H),
4.49 (t, J = 4.8 Hz, 2H), 4.11 (d, J = 11.3 Hz, 1H), 3.96 (d, J = 11.9 Hz, 1H),
3.88 (t, J = 4.9 Hz, 2H), 3.81 (dd, J = 11.9 Hz, J = 2.2 Hz, 1H), 3.64 (ddd,
J = 12.2 Hz, J = 9.4 Hz, J = 4.8 Hz, 2H), 3.11 (dd, J = 11.4 Hz, J = 2.2 Hz,
1H), 2.38–2.31 (m, 2H), 2.20–2.00 (m, 3H), 1.86–1.70 (m, 2H), 1.46–1.36
(m, 1H), 1.02–0.96 (m, 1H), 0.71–0.65 (m, 1H) ppm; 13C-NMR (100 MHz,
CDCl3): δ 166.5, 132.9, 130.0, 129.7 (3C), 129.1, 128.3 (2C), 100.3, 76.3,
72.7, 69.7, 67.4, 64.1, 27.6, 27.0, 26.5, 24.3, 22.9, 22.3, 22.1 ppm; IR (cm-
1) 2931, 2860; HRMS (ESI) m/z: [M+H]+ Calcd for C22H29O5 373.2010;
found: 373.2006.
2'-heptylspiro[bicyclo[6.1.0]nonane-9,5'-[1,3]dioxan]-4-yne
(13c).
Compound 13c was obtained in 13% yield, 14.1 mg (colorless oil) starting
from acetal 12c (145 mg, 0.32 mmol) using the general procedure C and
purified by column chromatography eluting heptane/EtOAc (98/2). 1H NMR
(400 MHz, CDCl3): δ 4.54 (t, J = 5.2 Hz, 1H), 4.10 (d, J = 11.4 Hz, 1H),
3.92 (d, J = 11.8 Hz, 1H), 3.80 (dd, J = 11.8 Hz, J = 2.4 Hz, 1H), 3.13 (dd,
J = 11.4 Hz, J = 2.4 Hz, 1H), 2.51–2.45 (m, 1H), 2.35–2.11 (m, 4H), 2.08–
2.03 (m, 1H), 1.70–1.57 (m, 3H), 1.45–1.33 (m, 3H), 1.29–1.23 (m, 8H),
0.96–0.90 (m, 1H), 0.85 (t, J = 7.0Hz, 3H), 0.62–0.56 (m, 1H) ppm; 13C
NMR (100 MHz, CDCl3): δ 102.8, 99.0, 98.1, 76.7, 67.3, 35.0, 31.7, 29.8,
29.4, 29.2 (2C), 28.2, 27.7, 24.1, 22.9, 22.6, 21.1, 21.0, 14.0 ppm; IR (cm-
General procedure C for bicyclo[6.1.0]non[4]ene derivatives 13. The
corresponding acetal 12 (1 eq.) was dissolved in dry dichloromethane
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10.1002/ejoc.201800139
European Journal of Organic Chemistry
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1) 2951, 2922, 2850, 1456, 1376, 1138, 1108, 1015, 918; HRMS (ESI) m/z:
[M+H]+ Calcd for C19H31O2 291.2319; found: 291.2324;
heptane/EtOAc (95/5). Both diastereoisomers were not separated. 1H-
NMR (400 MHz, CDCl3): δ 5.90–5.78 (m, 2H), 5.20–5.09 (m, 2H), 4.52–
4.50 (m, 2H), 4.12 (q, J = 7.2 Hz, 4H), 4.08 (dd, J = 11.7 Hz, J = 1.7 Hz,
2H), 3.79 (dd, J = 11.8 Hz, J = 3.5 Hz, 2H), 3.65 (dd, J = 11.8 Hz, J = 2.3
Hz, 1H), 3.60 (dd, J = 11.7 Hz, J = 2.3 Hz, 1H), 3.10 (dd, J = 11.3 Hz, J =
2.4 Hz, 2H), 2.46–2.18 (m, 10H), 2.04–1.80 (m, 6H), 1.65–1.60 (m, 8H),
1.46–1.35 (m, 4H), 1.23 (t, J = 7.2 Hz, 6H), 1.14–1.04 (m, 1H), 0.92–0.81
(m, 2H), 0.77–0.70 (m, 1H), 0.62–0.48 (m, 2H), 0.44–0.38 (m, 1H), 0.30–
0.22 (m, 1H) ppm; 13C-NMR (100 MHz, CDCl3): δ 173.6, 138.7, 137.9,
131.8, 130.8, 102.4, 102.3, 67.1, 67.0, 60.2 (2C), 35.2, 34.5, 34.2 (2C),
33.4, 33.3, 33.0, 28.3, 27.6, 27.0, 26.9, 26.6, 26.1, 24.8 (2C), 23.7,
23.6(2C), 23.5, 22.1, 21.1, 14.2 (2C), (2 peaks underneath CDCl3 peak),
quaternary carbons missing, ppm; IR (cm-1) 2953, 2927, 2855, 1731, 1455,
1404, 1376, 1138, 1102, 1056, 1016, 985, 939; HRMS (ESI) m/z: [M+H]+
Calcd for C19H31O4 323.2217; found: 323.2217.
2'-nonylspiro[bicyclo[6.1.0]nonane-9,5'-[1,3]dioxan]-4-yne
(13d).
Compound 13d was obtained in 18% yield, 12.1 mg (colorless oil) starting
from acetal 12d (90.0 mg, 0.19 mmol) using the general procedure C and
purified by column chromatography eluting heptane/EtOAc (97/3). 1H NMR
(400 MHz, CDCl3): δ 4.54 (t, J = 5.1 Hz, 1H), 4.10 (d, J = 11.4 Hz, 1H),
3.92 (d, J = 11.9 Hz, 1H), 3.80 (dd, J = 11.9 Hz, J = 2.5 Hz, 1H), 3.13 (dd,
J = 11.4 Hz, J = 2.5 Hz, 1H), 2.51–2.46 (m, 1H), 2.36–2.12 (m, 4H), 2.08–
2.03 (m, 1H), 1.69–1.58 (m, 3H), 1.45–1.34 (m, 3H), 1.29–1.23 (m, 12H),
0.96–0.90 (m, 1H), 0.85 (t, J = 7.0 Hz, 3H), 0.63–0.56 (m, 1H) ppm; 13C
NMR (100 MHz, CDCl3): δ 102.8, 99.0, 98.1, 76.6, 67.3, 35.0, 31.8, 29.8,
29.5 (4C), 29.2, 28.2, 27.7, 24.1, 23.0, 22.6, 21.1, 21.0, 14.1 ppm; IR (cm-
1) 2951, 2921, 2851, 1729, 1465, 1376, 1138, 1111, 1015, 938; HRMS
(ESI) m/z: [M+H]+ Calcd for C21H35O2 319.2632; found: 319.2631;
(E)-4-(spiro[bicyclo[6.1.0]non[4]ene-9,5'-[1,3]dioxan]-2'-yl)butan-1-ol
(14f). Compound 14f was obtained in 46% yield, 52.0 mg (pale yellow oil)
starting from the isomer 12f (112 mg, 0.40 mmol) using the general
4-((1R,8S)-spiro[bicyclo[6.1.0]non[4]yne-9,5'-[1,3]dioxan]-2'-yl)butan-
1-ol (13f). Compound 13f was obtained in 30% yield, 8.3 mg (pale yellow
oil) starting from acetal 12f (88.0 mg, 0.314 mmol) using the general
procedure C but only heated for 30 min and purified by column
chromatography eluting heptane/EtOAc (1/1). 1H-NMR (400 MHz, CDCl3):
δ 4.57 (t, J = 5.2 Hz, 1H), 4.13 (d, J = 11.3 Hz, 1H), 3.94 (d, J = 11.8 Hz,
1H), 3.82 (dd, J = 11.9 Hz, J = 2.5 Hz, 1H), 3.63 (t, J = 6.5 Hz, 2H), 3.15
(dd, J = 11.3 Hz, J = 2.5 Hz, 1H), 2.50 (dq, J = 13.4 Hz, J = 3.1Hz, 1H),
2.38–2.15 (m, 4H), 2.04 (dq, J = 13.4 Hz, J = 3.1Hz, 1H), 1.73–1.54 (m,
6H), 1.48–1.36 (m, 5H), 0.95 (ddd, J = 12.7 Hz, J = 8.8 Hz, J = 3.2 Hz, 1H),
0.62 (ddd, J = 12.7 Hz, J = 8.8 Hz, J = 3.2 Hz, 1H) ppm; 13C-NMR (100
MHz, CDCl3): δ 102.6, 99.1, 98.1, 67.3, 62.9, 53.4, 34.9, 32.6, 29.7, 28.2,
27.7, 25.6, 24.1, 23.8, 23.0, 21.1, 21.0 ppm; IR (cm-1) 3424, 2927, 2852,
1723, 1456, 1404, 1377, 1137, 1040, 1011, 937; MS (ESI) m/z [M+H]+
279.4; HRMS (ESI) m/z: [M+H]+ Calcd for C17H27O3 279.1955; found:
279.1953.
procedure
A
and purified by column chromatography eluting
heptane/EtOAc (1/1). Both diastereoisomers were not separated. 1H-NMR
(400 MHz, CDCl3): δ 5.93–5.80 (m, 2H), 5.22–5.09 (m, 2H), 4.55 (m, 2H),
4.10 (dd, J = 11.2 Hz, J = 1.4 Hz, 2H), 3.81 (dd, J = 11.9 Hz, J = 3.6 Hz,
2H), 3.69–3.60 (m, 6H), 3.12 (dd, J = 11.2 Hz, J = 2.4 Hz, 2H), 2.46–2.19
(m, 6H), 2.04–1.79 (m, 6H), 1.65–1.52 (m, 8H), 1.45–1.34 (m, 8H), 1.31–
1.23 (m, 2H), 1.16–1.05 (m, 1H), 0.94–0.82 (m, 2H), 0.79–0.73 (m, 1H),
0.65–0.50 (m, 2H), 0.47–0.40 (m, 1H), 0.32–0.25 (m, 1H) ppm; 13C-NMR
(100 MHz, CDCl3): δ 138.8, 137.9, 131.9, 130.8, 102.6, 102.5, 67.1, 67.0,
62.85 (2C), 35.2, 34.8 (2C), 33.4, 33.3, 33.0, 32.6 (2C), 28.3, 27.6, 27.0,
26.9, 26.6, 26.1, 25.6 (2C), 23.8 (2C), 23.7, 23.5, 22.1, 21.1, (2 peaks
underneath CDCl3 peak) ppm; IR (cm-1) 3415, 2927, 2853, 1136, 1013;
HRMS (ESI) m/z: [M+H]+ Calcd for C17H29O3 281.2111; found: 281.2113.
(E)-2-(spiro[bicyclo[6.1.0]nonane-9,5'-[1,3]dioxan]-4-en-2'-
ylmethoxy)ethyl benzoate (14g). Compound 14g was obtained in 8%
yield, as a colorless oil (5.3 mg) starting from the isomer 12g (64.8mg, 0.17
(E)-2'-pentylspiro[bicyclo[6.1.0]non[4]ene-9,5'-[1,3]dioxane]
(14b).
Compound 14b was obtained in 9% yield, 8.6 mg (pale yellow oil) starting
from the isomer 12b (100 mg, 0.378 mmol) using the general procedure A
and purified by column chromatography eluting heptane/EtOAc (95/5).
Both diastereosiomers were not separated. 1H-NMR (400 MHz, CDCl3): δ
5.93–5.80 (m, 2H), 5.22–5.10 (m, 2H), 4.55–4.51 (m, 2H), 4.10 (dd, J =
11.2 Hz, J = 1.5 Hz, 2H), 3.82 (dd, J = 11.9 Hz, J = 3.6 Hz, 2H), 3.66 (dd,
J = 21.1 Hz, J = 2.5 Hz, 1H), 3.63 (dd, J = 20.7 Hz, J = 2.5 Hz, 1H), 3.13
(dd, J = 11.2 Hz, J = 2.4 Hz, 2H), 2.47–2.19 (m, 6H), 2.05–1.81 (m, 6H),
1.65–1.59(m, 4H), 1.42–1.35 (m, 4H), 1.32–1.25 (m, 8H), 1.16–1.08 (m,
1H), 0.91–0.83 (m, 8H), 0.79–0.73 (m, 1H), 0.65–0.50 (m, 2H), 0.46–0.40
(m, 1H), 0.31–0.24 (m, 1H) ppm; 13C-NMR (100 MHz, CDCl3): δ 138.8,
137.9, 131.9, 130.8, 102.8, 102.7, 67.1, 67.0, 35.2, 34.9, 33.4, 33.3, 33.0,
31.7 (2C), 28.3, 27.6, 27.0, 26.9, 26.6, 26.1, 23.8 (2C), 23.5, 22.5 (2C),
22.1, 21.0, 14.0 (2C), (2 peaks underneath CDCl3 peak), quaternary
carbons missing, ppm; IR (cm-1) 2951, 2926, 2854, 1137, 1016; HRMS
(ESI) m/z: [M+H]+ Calcd for C17H29O2 265.2162; found: 265.2158.
mmol) using the general procedure
A and purified by column
chromatography eluting heptane/EtOAc (8/2). Both diastereoisomers were
not separated. 1H-NMR (400 MHz, CDCl3): δ 8.03 (d, J = 8.0 Hz, 4H), 7.53
(t, J = 7.4 Hz, 2H), 7.41 (t, J = 7.4 Hz, 4H), 5.89–5.77 (m, 2H), 5.19–5.07
(m, 2H), 4.77–4.74 (m, 2H), 4.45 (d, J = 4.5 Hz, 4H), 4.11 (dd, J = 11.2 Hz,
J = 2.0 Hz, 2H), 3.86–3.81 (m, 6H), 3.70–3.58 (m, 6H), 3.13 (dd, J = 11.4
Hz, J = 2.2 Hz, 2H), 2.43–2.16 (m, 6H), 2.02–1.77 (m, 6H), 1.13–1.02 (m,
1H), 0.90–0.79 (m, 2H), 0.77–0.70 (m, 1H), 0.63–0.50 (m, 2H), 0.47–0.39
(m, 1H), 0.30–0.24 (m, 1H) ppm; 13C-NMR (100 MHz, CDCl3): δ 166.5,
138.7, 137.9, 132.9, 131.9, 130.9, 130.0, 129.7 (2C), 128.3 (2C), 100.4,
72.6, 69.7, 67.1, 67.0, 64.1, 35.2, 33.4, 33.3, 33.0, 28.3, 27.6, 27.0, 26.9,
26.6, 26.1, 23.8, 23.5, 22.2, 21.2, (2 peaks underneath CDCl3 peak) ppm;
IR (cm-1) 2924, 2852, 1719, 1452, 1273, 1273, 1136, 1115, 1071, 1055,
713; HRMS (ESI) m/z: [M+H]+ Calcd for C22H29O5 373.2010; found:
373.2006.
(E)-ethyl
5-(spiro[bicyclo[6.1.0]non[4]ene-9,5'-[1,3]dioxan]-2'-
yl)pentanoate (14e). Compound 14e was obtained in 19% yield, 8.6 mg
(pale yellow oil) starting from the isomer 12e (70 mg, 0.21 mmol) using the
general procedure A and purified by column chromatography eluting
Acknowledgements
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10.1002/ejoc.201800139
European Journal of Organic Chemistry
FULL PAPER
This work was supported by the French Research National
Agency (ANR-14-CE06-0004). The authors thank Elodie Marcon,
Céline Chollet and David-Alexandre Buisson (DRF-JOLIOT-
SCBM, CEA) for the excellent analytical support.
E. V. Dehmlow, M. Birkhahn, Tetrahedron 1988, 44, 4363–4370. c) D. L.
Christenson, C. J. Tokar, W. B. Tolman, Organometallics 1995, 14, 2148-
2150. d) S. T. Handy, A. Ivanow Inorg. Chim. Acta 2009, 362, 4468-4471.
[14] During the submission of the manuscript, the group of Fox reported a
different approach attempting to solve this synthetic issue: J. G. K.
O’Brien, S. R. Chintala, J. M. Fox, J. Org. Chem. 2017, DOI
10.1021/acs.joc.7b02329.
Keywords: cyclooctyne • trans-cyclooctene • click chemistry •
strain promoted • sydnones
[15] Though compound 4 is stable for months at -20 °C, as a precautionary
measure, we prefer to store multigrams amounts of the precursors rather
than the alkyne 4.
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Entry for the Table of Contents (Please choose one layout)
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8-membered ring synthesis
Sabrina Bernard, Ramar Arun Kumar,
Karine Porte, Pierre Thuéry, Frédéric
Taran, Davide Audisio*
Page No. – Page No.
Text for Table of Contents
A scalable and cheap synthetic
approach to valuable strained 8-
membered ring derivatives for click
chemistry
A convenient and cost-effective synthetic access to cyclooctyne and trans-cyclooctene derivatives is described. A
cyclopropanation step using copper powder in lieu of Rh2(OAc)4 as catalyst and a symmetric diazomalonate enabled to
drastically reduce the overall cost of the synthesis.
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