Catalytic Alkynylation of Cyclic Acetals and Ketals Enabled by Synergistic Gold(I)/Trimethylsilyl Catalysis

Article abstract of DOI:10.1021/acs.joc.7b01828

A completely regioselective and challenging gold(I)-catalyzed ring-opening of cyclic 1,3-dioxolanes and dioxanes by trimethylsilyl alkynes to set diol-derived propargyl trimethylsilyl bis-ethers is reported. This unprecedented and not trivial transformation does not operate with the catalytic methodologies recently reported for catalytic alkynylation of acyclic acetals/ketals, and is uniquely enabled by the application of a recently introduced synergistic gold(I)-silicon catalysis concept capable of producing simultaneously catalytic amounts of two key players, a silicon-based Lewis superacid and a nucleophilic gold acetylide.

Full text of DOI:10.1021/acs.joc.7b01828

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Note
Catalytic Alkynylation of Cyclic Acetals and Ketals
Enabled by Synergistic Gold(I)/Trimethylsilyl Catalysis
Matheo Berthet, Olivier Songis, Catherine Taillier, and Vincent Dalla
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01828 • Publication Date (Web): 16 Aug 2017
Downloaded from http://pubs.acs.org on August 17, 2017
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The Journal of Organic Chemistry
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Catalytic Alkynylation of Cyclic Acetals and Ketals Enabled
by Synergistic Gold(I)/Trimethylsilyl Catalysis
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Mathéo Berthet, Olivier Songis, Catherine Taillier and Vincent Dalla*
UNIHAVRE, FR 3032, URCOM EA 3221, 76600 le Havre, 25 rue Philippe Lebon, BP 540, 76058ꢀF Le Havre, France.
Supporting Information Placeholder
Scheme 1. Current state-of-the-art for catalytic alkynylation of
acyclic acetals, for TiCl4-mediated alkynylation of cyclic acetals
and examples of bioactive compounds bearing a functionalized
propargylic diol skeleton
ABSTRACT: A completely regioselective and challenging
gold(I)ꢀcatalyzed ringꢀopening of cyclic 1,3ꢀdioxolanes and dioxꢀ
anes by trimethylsilyl alkynes to set diolꢀderived propargyl trimeꢀ
thylsilyl bisꢀethers is reported. This unprecedented and not trivial
transformation does not operate with the catalytic methodologies
recently reported for catalytic alkynylation of acyclic aceꢀ
tals/ketals, and is uniquely enabled by the application of a recently
introduced synergistic gold(I)ꢀsilicon catalysis concept capable of
producing simultaneously catalytic amounts of two key players, a
siliconꢀbased Lewis superacid and a nucleophilic gold acetylide.
a) Alkynylation of acyclic acetals : catalysis and terminal alkynes
O
O
O
LAu(I), Zn(II), Cu(I)/L* + LA
catatyst
R1
H +
R1
R2
R2
b) Alkynylation of cyclic acetals : stoichiometric in metal and TMS alkynes
OH
lit. 2a, 7
O
R1
TMS
+
> 1 equiv TiCl4
O
O
R1
R2
R2
Taken separately, the incorporation of an alkynyl group into
organic molecules1 and the transformations of acetals under an
acidic activation mode2 are foundational to modern organic chemꢀ
istry. In addition to the stimulating academic challenge of conꢀ
fronting these two topics, the great synthetic utility of the exꢀ
pected propargyl ether products has prompted several research
groups to develop new strategies to enable highly effective SN1
alkynyl transfers from acetals.3 To tackle the strong current deꢀ
mand in developing safer, atomꢀeconomical and sustainable
methodologies, catalytic approaches for these transformations
constitute an emerging research theme. Accordingly, a few numꢀ
ber of methodologies enabling the direct and catalytic alkynylaꢀ
tion of acyclic acetals and ketals by CꢀH activation of terminal
alkynes,4ꢀ5 including impressive enantioselective variants by
Watson and coꢀworkers,6 were reported quite recently (Scheme 1,
a). Similar transformations of cyclic acetals and ketals have been
comparatively much less studied. As far as we are aware, only a
handful of papers have been reported, and all mention use of
trimethylsilyl alkynes and more than one equivalent of the strong
Lewis acid TiCl4 as a mediator (Scheme 1, b).2a,7 One of the most
plausible reasons accounting for the absence of catalytic variants
is the energetic cost associated with the ringꢀopening of cyclic
acetals, which combined with the weak nucleophilicity of terminal
and TMS alkynes8, renders a catalytic transformation particularly
defiant.9 In addition to the inherent challenge of accommodating
cyclic acetals/ketals to catalytic alkynylation, the potential synꢀ
thetic value of the diol monoꢀpropargylic ether products, which
comprise a number of important molecular targets (Scheme 1, c)
on one hand,10ꢀ11 while constituting a promising and yet so far
underꢀappreciated platform for further elaborations on the other
hand, is also noteworthy. Whereas the targeted compounds could
in principle also be accessible by the addition of a metallic acetyꢀ
lide on protected hydroxy aldehydes/ketones, the latter are availaꢀ
ble by relatively lengthy routes from the corresponding diols, and
thus our approach planning the use of easily available aceꢀ
tals/ketals (most of them being commercially available)
c) Examples of bioactive compounds containing a diol-derived propargylic
ether moiety
OH
F
O
N
S
O
HN
O
O
O
O
N
N
N
human serotonin transporter inhibitor activities
PI3K/mTOR inhibitor activities
establishes an additional improvement besides the catalytic asꢀ
pect. These considerations prompted us to tackle the challenge of
developing the first catalytic alkynylation of cyclic acetals and
ketals. To reach this goal we sought to exploit a synergistic
gold(I)ꢀsilicon catalysis concept recently introduced.12ꢀ14 The
latter is characterized by two interlaced catalytic cycles capable of
producing in situ and simultaneously small amounts of a siliconꢀ
based Lewis superacid dedicated to the activation of a proꢀ
electrophile, and a gold alkynylide intended for trapping the reꢀ
sulting intermediate promptly due to an improved nucleophilicity
compared with the parent alkynylsilane. We have launched this
concept by reporting the first catalytic alkynylation of N,Oꢀ
acetals.15ꢀ16 Assuming that our approach is transposable to a wider
range of transformations, and thus bears the potential to become a
truly general catalytic alkynylation methodology, we next identiꢀ
fied the non trivial and challenging alkynylative ringꢀopening of
cyclic acetals/ketals as new platform (Scheme 2).17 We now reꢀ
port the successful realization of these ideas to provide diol monoꢀ
propargylic ethers with perfect regiocontrol and moderate diaꢀ
stereocontrol.
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Scheme 2. Synergistic gold(I)-silicon catalysis concept (left), and
synthetic applications (right)
this problem, and delivered the product 4b in an excellent yield
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2
3
4
from a reaction run at 50°C over 18h (Table 1, entries 12ꢀ14).
Finally, the alkynylation of 2b, which slightly differs from its
counterpart 2a by one methyl substituent, succeeded in much
milder reaction conditions.
5
6
7
Table 1. Optimization of the reaction conditions for the alkynyla-
tion of model acetals 2a and 2b
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NMR Yield
of 3 (%) [a]
Yield of
4 (%) [b]
Entry
Solvent T (°C)
t (h)
To validate our working hypothesis, we began this study by
testing the different methodologies recently reported for the cataꢀ
lytic alkynylation of the more reactive acyclic acetals,4ꢀ6 and as
we had anticipated none of them was capable of promoting any
conversion of the cyclic substrates (Scheme 3).
1
C6D6
85
85
50
85
85
85
85
85
50
r.t
3
100
100
97
92
81 [c]
2
C6D6
5
3
C6D6
24
18
24
48
1
75
4
CDCl3
CHCl3
CDCl3
C6D6
100
ꢀ
92
Scheme 3. Absence of reactivity of common cyclic acetals using
catalytic alkynylation procedures described for acyclic acetals4
5
75
49 [d]
6
70
7
70
58
8
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
1 h 30
6
48
37
9
70
51
10
11
12
13
4 d
21
5 h 30
18
55
30 [e]
38
50
85
50
ꢀ
62
57 [d]
90 [d]
92 [d],[f]
100
To initiate the optimization study of the projected synergistic
gold(I)ꢀsilicon catalytic alkynylation reaction, we chose the nonꢀ
substituted acetal 2a as a model reaction partner. 2a was first
reacted with 1.9 equivalents of trimethyl(phenylethynyl)silane 1a
in the presence of 1 mol % of IPrAuNTf2 in deuterated benzene at
85°C (Table 1, entry 1). To our delight, a rapid disappearance of
2a was observed, resulting in a clean and total conversion into the
TMSꢀether 3a. A brief survey of less toxic solvents was undertakꢀ
en from which chloroform appeared to be a safer alternative (Taꢀ
ble 1, entries 4ꢀ5). Moreover, we verified that the reaction did not
occur without the gold preꢀcatalyst or by directly employing
phenylacetylene (Scheme 1).4ꢀ5 These observations are particularꢀ
ly revealing of the decisive and unique ability of the association
TMSꢀalkynesꢀgold(I) triflate/triflimidate catalysts to promote
difficult alkynylation reactions, thus supplying an additional
credit to our concept of synergistic catalysis. By using the accordꢀ
ant IPr gold(I) triflate catalyst, the conversion remained incomꢀ
plete even after 48h (Table 1, entry 6). This result indicates that
the stronger Lewis acidity of the TMSNTf2 catalyst is essential for
an efficient alkynylation of 2a. The evaluation of the second
model acetal substrate, the monoꢀsubstituted component 2b,
revealed a markedly different behavior. The dioxolane 2b, being
the progenitor of a more stabilized oxonium intermediary, disꢀ
played superior reactivity as well as sensitivity, as demonstrated
by shorter reaction time, poor NMR and isolated yields of 4b
under varying reaction conditions using gold(I)ꢀtriflimidate cataꢀ
lysts (Table 1, entries 7ꢀ11). The latter family seems unsuitable to
promote this reaction in an efficient fashion, due to the extreme
reactivity of the ancillary TMSNTf2 Lewis acid catalyst which
most likely causes decomposition of 2b or of its oxocarbenium
ion. Accordingly, shifting to the IPrAuCl/AgOTf catalyst system
which generates in situ the softer TMSOTf Lewis acid12 solved
14
CDCl3
50
18
100
[a] NMR yield related to the internal standard 1ꢀbromo,4ꢀnitrobenzene.
[b] Yield of isolated product. [c] Using 1.5 equiv. of trimethylsilylphenylaꢀ
cetylene. using 1 mol% of IPrAuCl and 1 mol% of AgOTf. [e] Using
[d]
1 mol% of JohnPhosꢀAuNTf2. [f] Reaction executed from 3.8 mmoles of
2b instead of 0.224 mmol for all the other experiments in Table 1.
With such flexible and fully adaptable reaction conditions in
hand and a more global comprehension of the reaction parameꢀ
ters, we then examined the substrate scope and functional group
tolerance of the reaction (Scheme 4).
This gold(I)ꢀcatalyzed alkynylation mostly focuses on unbiased
and thus challenging acetals/ketals devoid of any aromatic or
mesomeric stabilizing substituent at the anomeric carbon. In these
cases, the method is effective for preparing a wide range of monoꢀ
propargyloxyꢀ1,2ꢀdiols (1,3ꢀdioxolane series, see 4c-e and 4j-m)
and 1,3ꢀdiols (case of 1,3ꢀdioxane, see 4f) in moderate to excelꢀ
lent yields, which were optimized and varied depending on the
structural pattern, and thus the inherent stability and sensitivity, of
the alkyne/acetal combinations used. Of particular note, the
TBDPSꢀprotected alkynol derivative 1c (TBDPS = tertꢀbutyl
dimethyl silyl) exhibited an exquisite reactivity with 2a to deliver
the target product 4k in 85% yield. In contrast, masking the alcoꢀ
hol by a benzoate ester of greater Lewis base properties (alkyne
1d) altered the reactivity somehow, leading to only 36% yield of
the alkynylated compounds 4l.
Acetals/ketals bearing a πꢀstabilizing phenyl substituent, includꢀ
ing the more classical acyclic benzaldehyde dimethyl acetal and
dioxolanes with branching substituents on the 4/5 positions, exꢀ
pectedly appeared to be highly reactive substrates to furnish the
propargylic methyl ether product 4i and the diol derivatives 4g
and 4h within short reaction times (< 3h) and in good yields (73ꢀ
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The Journal of Organic Chemistry
78%). The facile access to 4i points out that our method is comꢀ
bility to combine both alkynylation and transprotection in a seꢀ
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plementary of a related alkynylation of aldehydes published by
Gonzales et al.13 In the latter case, the harsh reaction conditions
required for the alkynyl transfer to the aldehyde function makes
inevitable a second SN1ꢀtype alkynylation of the primary proparꢀ
quential oneꢀpot procedure was thus investigated. We were deꢀ
lighted to observe that after full conversion towards the TMSꢀ
alcohol ascertained by analytical monitoring, the catalytic transꢀ
protection was successfully achieved across diverse TMSꢀ
alkynes/acetals(ketals) combinations, and furnished the desired
esters in decent to good yields (Scheme 5).19 As hoped, this esteriꢀ
fication was highly useful to increase the stability of sensitive
materials such as hexyne and TMSꢀalkyne products and therefore
enhanced the chemical space of this alkynylative method. As a
representative example, we improved the yield from 39% for the
alcohol 4m (see Scheme 4) to 63% for its ester 5e. Furthermore,
while their ancillary alcohols could not be isolated, the transꢀ
protected products 5c and 5d were obtained in 47% and 36%
yields, respectively. The preparation of product 5f starting from
the branched acetal 2h illustrates an additional utility of this transꢀ
protection method, which basically enabled to unambiguously
confirm the structure of 4h (creation of a primary versus a secꢀ
ondary alcohol function) and hence the complete regioselectivity
of the alkynylation event.
gylic OTMS ether intermediate, finally delivering
a bisꢀ
alkynylated compound where the ether function was destroyed.
Scheme 4. Scope of the catalytic alkynylation of dioxolanes and
dioxanes
9
R4
(
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R3
O
R4
n
OH
)
n
(
)
O
IPrAuNTf2 (1 mol %)
CDCl3
R
R3
R
TMS
O
R2
4a-m
1a-e
(1.9 equiv.)
2a-i
R1
R1 R2
Reactions of cyclic acetals 2a-i with alkynylsilane 1a (R = Ph)
2a (R1, R2 = H)
2b (R1 = Me, R2 = H)
Ph
O
O
2c (R1, R2 = Me)
O
O
O
O
O
O
MeO OMe
R1 R2 2d (R1 = CH2Br, R2 = H)
2f
rac-2g
2h
2i
Ph
Ph
OH
Ph
2e (R1, R2 = C5H10
)
OH
OH
OH
O
O
O
O
R
Ph
Ph
Ph
Scheme 5. Scope of the sequential one-pot alkynylation of acetals
and trans-protection into benzoate derivatives
Br
4a (R=H), 92%
(18h, 85°C)
4c
22%
4d
34%
4e
87%
4b (R=Me), 90%
(18h, 85°C)[a]
(2h, 85°C)
(3h30, 85°C)
(18h, 20°C)
R
*
OH
*
O
O
O
OH
Ph
Me
Ph
Ph
Ph
Ph
4f
87%
4g (R=Me), 78% (d:r 75:25)[b]
4i
73%
(3h, 50°C)[c]
(1h30, 85°C)
(3h30, 85°C)
4h (R=H), 76% (d:r 85:15)[b]
(3h, 85°C)
Reactions of acetal 2a with alkynylsilanes 1b-e
TMS
RO
TMS
O
TMS
1c (R=TBDPS)
1d (R=Bz)
S
1b
1e
OH
OH
OH
O
O
S
RO
4j
66%
4m
39%
4k (R=TBDPS), 85%
(18h, 85°C)
(18h, 50°C)
(40h, 50°C)
4l (R=Bz), 36%
(18h, 85°C)
Based
on
our
recently
introduced
synergistic
[a] IPrAuCl and AgOTf (1mol % each) were used as the catalyst system. [b] The in situ desilylation was
effected with TBAF instead of HCl. [c] 1.2 equiv. (instead of 1.9 equiv.) of trimethylsilylphenylacetylene
were used.
gold(I)/trimethylsilyl catalysis concept, this paper deals with the
first catalytic alkynylation of cyclic acetals and ketals. The reportꢀ
ed reaction is assumed to be a difficult transformation which
completely failed when the variety of catalytic methodologies
recently reported for the direct use of terminal alkynes in conjuncꢀ
tion with acyclic acetals and ketals were tested. Our preliminary
results therefore show that the synergistic assistance of a gold
acetylide nucleophile and a silylium Lewis superacid is essential
for the methodology to succeed on one hand, and moreover that
the method displays a promising scope. This alkynylation producꢀ
es functionalized TMS ethers which can be easily desilylated to
give the corresponding alcohols under different mild hydrolytic
conditions. Complementarily, we have also developed a oneꢀpot,
biꢀcatalytic alkynylation/desilylative esterification sequence that
produces robust benzoates, enabling yield enhancements or even
obtention of products which otherwise could not be isolated.
As for the alkynylation of (rac)ꢀ(4R,5R)ꢀ4,5ꢀdimethylꢀ2ꢀphenyl
acetal 2g and its stereochemically undefined congener (rac)ꢀ4ꢀ
methylꢀ2ꢀphenyl (d.r 45:55) 2h, the alcohol products 4g and 4h
were isolated in a good yield of 78%, provided that an alternative
in situ desilylation mediated by TBAF is applied due to the acidꢀ
sensitivity of the benzylic/propargylic ether adducts. In addition to
be obtained in good yield and d.r., compound 4h also resulted
from a completely regioselective reaction for the primary alcohol
(vide infra).
As briefly mentioned above, in some specific cases our alkynylꢀ
ation resulted in unsatisfactory outputs, since we were occasionalꢀ
ly not even able to isolate products. Driven by the idea of transꢀ
forming these sensitive hydroxylic reaction products 4 into more
robust derivatives, thus improving the efficacy of the process, we
sought to apply oneꢀpot derivatizations of the alkynylation prodꢀ
ucts as a way to solve the problem. Some years ago, our group
was involved in the development of an efficient Oꢀsilyl into Oꢀ
benzoyl interconversion mediated by benzoyl fluoride and catalytꢀ
ic DMAP.18 This highly selective transprotection that occurred in
mild conditions and was compatible with a large range of funcꢀ
tional groups, was particularly useful to accomplish a deprotecꢀ
tion/reprotection through a oneꢀpot twoꢀstep sequence. The possiꢀ
EXPERIMENTAL SECTION
General information. Unless otherwise specified, started reaꢀ
gents and deuterated solvent were purchased from commercial
sources and used without further purification (SigmaꢀAldrich®,
Fisher scientific®, TCI®). All solvents were dried and freshly
distilled prior to use, taking precaution to exclude moisture by
refluxing over CaH2. All reactions were performed under argon
inert atmosphere. All glass apparatus was oven dried and cooled
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under vacuum before use. Thin layer chromatography (TLC) was
δ 166.6, 133.0, 130.4, 129.7, 128.5, 105.9, 85.5, 63.8, 28.0, 16.9,
0.2; IR (neat, cmꢀ1): 3065, 2960, 2899, 2176, 1719, 1603, 1585,
1482, 1315, 1269, 1249, 1176, 1113, 1070, 1028; HRMS (ESIꢀ
TOF) m/z: [M+H]+ calcd. for C15H21O2Si: 261.1311, found:
261.1313; Rf: 0.75 (cHx/EtOAc 8:2).
1
2
3
4
5
6
7
8
performed on preꢀcoated sheets of silica gel 60 with fluorescent
indicator UV254 (Merck). Detection was accomplished by irraꢀ
diation with a UV lamp and by an ethanolic solution of pꢀ
anisaldehyde. Chromatographic separations were achieved on
silica gel columns (Kieselgel 60, 40–63 ꢁm, Merck) typically
using a cyclohexane/ethyl acetate eluent system typically using a
cyclohexane/ethyl acetate or nꢀpentane/Et2O eluent system. Flash
chromatography purifications were performed on Interchim Puriꢀ
flash® (Puriflash® columns 50µ) typically using a cyclohexꢀ
ane/ethyl acetate eluent system. In all cases, distilled solvents
were used as eluents for column chromatography. NMR spectra
were recorded on a Bruker AvanceTM 300 spectrometer. 1H
NMR spectra were recorded at 300 MHz and data are reported as
General procedure A. IPrAuNTf2 (0.00118 mmol) and 1ꢀ
bromo,4ꢀnitrobenzene (internal standard, 0.059 mmol) were
charged in a dry NMR tube under Argon. CDCl3 (0.5 mL), trimeꢀ
thylsilyl alkyne (0.224 mmol) and acetal (0.118 mmol) were then
added. The tube was sealed under argon atmosphere and the
reaction mixture was stirred for t hours at T °C. Conversions were
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1
determined by H NMR experiments. After full conversion into
followed: chemical shift (δ) in ppm, multiplicity (s = singlet, d =
the TMS protected alcohol, a 4.0 M solution of HCl in 1,4ꢀ
dioxane (0.2 mL) was added and the mixture was stirred for 20
minutes. The mixture was then directly purified by flash chromaꢀ
tography using cHx/EtOAc 8:2 solvent to afford the desired alcoꢀ
hol.
doublet, t = triplet, b = broad, m = multiplet), coupling constants J
in Hz and integration. 13C NMR spectra were recorded at 75 MHz
using broadband proton decoupling and data are reported as folꢀ
lowed: chemical shift (δ) in ppm. High resolution mass spectra
(HRMS) were measured on a Agilent 6530 QꢀTof MS system.
The QꢀTOF MS instrument was operated under the following
condition: Ion source ESI+ Agilent Jet Stream or APCI both in
positive ionization mode. FTꢀIR spectra were recorded with a
PerkinꢀElmer Frontier.
2-((3-phenylprop-2-yn-1-yl)oxy)ethanol (4a) According to the
general procedure A for 18h at 85°C and starting with trimethylsiꢀ
lylphenylacetylene 1a and 1,3ꢀdioxolane 2a, the title compound
1
4a was obtained as a yellowish oil in 92% yields (19.1 mg). H
NMR (300 MHz, CD2Cl2) δ 7.37 (m, 2H), 7.25 (m, 3H), 4.33 (s,
2H), 3.72ꢀ3.63 (m, 2H), 3.60ꢀ3.57 (m, 2H); 13C NMR (75 MHz,
CD2Cl2) δ 131.6, 128.5, 128.35, 122.5, 86.0, 85.1, 71.3, 61.7,
59.0; IR (neat, cmꢀ1): 3399, 2926, 2854, 2238, 1489, 1352, 1104,
1068, 1027; HRMS (ESIꢀTOF) m/z: [M+H]+ calcd. for C11H13O2:
177.0916, found: 177.0913; Rf: 0.14 (cHx/EtOAc 8:2).
Synthesis of starting material
The preparation of trimethoxy(phenylethynyl)silane was achieved
followed the procedure described by M. Nakajima et al.20 Spectral
data were consistent with those previously reported. The preparaꢀ
tion of tertꢀbutyldimethyl(phenylethynyl)silane was achieved
followed the procedure described by W. Uhl et al.21 Spectral data
were consistent with those previously reported. The preparation of
tertꢀbutyldiphenyl((5ꢀ(trimethylsilyl)pentꢀ4ꢀynꢀ1ꢀyl)oxy)silane 1c
was achieved followed the procedure described by Z. Hou et al.22
Spectral data were consistent with those previously reported. The
preparation of 1,4ꢀdioxaspiro[4.5]decane 2e was achieved folꢀ
lowed the procedure described by M. Benohoud et al.23 Spectral
data were consistent with those previously reported. The preparaꢀ
tion of (rac)ꢀ(4R,5R)ꢀ4,5ꢀdimethylꢀ2ꢀphenyl acetal 2g was
achieved followed the procedure described by J.A. Soderquist et
al.24 Spectral data were consistent with those previously reported.
The preparation of (rac)ꢀ4ꢀmethylꢀ2ꢀphenyl (d.r 45:55) 2h was
achieved followed the procedure described by N. Yasukawa et
al.25 Spectral data were consistent with those previously reported.
The preparation of cisꢀ(2S,5S)ꢀ2,5ꢀdiphenylꢀ1,3ꢀdioxolanꢀ4ꢀone
9a was achieved followed the procedure described by Y.Q Liu et
al.26 Spectral data were consistent with those previously reported.
The preparation of 1,4ꢀdioxaspiro[4.5]decanꢀ2ꢀone 9b was
achieved followed the procedure described by Y. Fall et al.27
Spectral data were consistent with those previously reported.
2-((4-phenylbut-3-yn-2-yl)oxy)ethanol (4b) According to the
general procedure A (using 1 mol% of IPrAuCl and 1 mol% of
AgOTf as catalysts), for 18h at 50°C and starting with trimethylsiꢀ
lylphenylacetylene 1a and 2ꢀmethylꢀ1,3ꢀdioxolane 2b, the title
compound 4b was obtained as a yellowish oil in 90% yields (20.2
1
mg). H NMR (300 MHz, CD2Cl2) δ 7.47 (s, 2H), 7.37 (s, 3H),
4.48 (q, 1H, J=6.6 Hz), 3.97ꢀ3.84 (m, 1H), 3.77 (t, 2H, J=4.6 Hz),
3.68ꢀ3.52 (m, 1H), 2.07 (b, 1H), 1.55 (d, 3H, J=6.6 Hz); 13C NMR
(75 MHz, CDCl3) δ 131.6, 128.4, 128.3, 122.6, 89.0, 84.8 70.0,
66.1, 61.8, 21.9; IR (neat, cmꢀ1): 3405, 2932, 2864, 2234, 1489,
1328, 1107, 1105; HRMS (ESIꢀTOF) m/z: [M+H]+ calcd. for
C12H15O2: 191.1072, found: 191.1074; Rf: 0.16 (cHx/EtOAc 8:2).
2-((2-methyl-4-phenylbut-3-yn-2-yl)oxy)ethanol (4c) According
to the general procedure A for 2h at 85°C and starting with trimeꢀ
thylsilylphenylacetylene 1a and 2,2ꢀdimethylꢀ1,3ꢀdioxolane 2c,
the title compound 4c was obtained as a yellowish oil in 22%
1
yields (5.3 mg). H NMR (300 MHz, CD2Cl2) δ 7.36ꢀ7.32 (m,
2H), 7.29ꢀ7.20 (m, 3H), 3.63 (s, 4H), 1.47 (s, 6H); 13C NMR (75
MHz, CD2Cl2) δ 131.5, 128.3, 128.3, 122.7, 91.2, 84.0, 70.7, 65.4,
62.1, 28.6; IR (neat, cmꢀ1): 3410, 2931, 2871, 2231, 1490, 1277,
1153, 1051; HRMS (ESIꢀTOF) m/z: [M+Na]+ calcd. for
C13H16O2Na: 227.1048, found: 227.1044; Rf: 0.22 (cHx/EtOAc
8:2).
5-(trimethylsilyl)pent-4-yn-1-yl benzoate (1l) Under argon atꢀ
mosphere, 5ꢀ(trimethylsilyl)pentꢀ4ꢀynꢀ1ꢀol (1.0 mmol) and
DMAP (0.1 mmol) were diluted in 10 mL of anhydrous dichloroꢀ
methane. Benzoyl chloride (5.0 mmol) was then added dropwise.
After stirring at room temperature for 5h, the reaction mixture was
diluted with dichloromethane and washed with a 1.0 M aqueous
solution of HCl (x2) and with a 0.1 M aqueous solution of Naꢀ
HCO3 (x2). The combined organic layers were dried over MgSO4,
filtered and concentrated under vacuum. The residue was purified
on silica gel (nꢀpentane/Et2O 9:1) to afford the desired product as
2-((1-bromo-4-phenylbut-3-yn-2-yl)oxy)ethanol (4d) According
to the general procedure A for 24h at 85°C and starting with
trimethylsilylphenylacetylene 1a and 2,2ꢀdimethylꢀ1,3ꢀdioxolane
2d, the title compound 4d was obtained as a yellowish oil in 34%
1
yields (10.8 mg). H NMR (300 MHz, CD2Cl2) δ 7.43ꢀ7.35 (m,
2H), 7.29ꢀ7.24 (m, 3H), 4.50 (dd, 1H, J=7.0 Hz, J=5.0 Hz), 3.89ꢀ
3.80 (m, 1H), 3.71ꢀ3.68 (m, 2H), 3.58 (m, 3H); 13C NMR (75
MHz, CD2Cl2) δ 131.7, 128.9, 128.4, 121.8, 87.0, 85.0, 70.6, 70.0,
61.6, 34.3; IR (neat, cmꢀ1): 3393, 2925, 2869, 2230, 1490, 1220,
1
a colorless oil in quantitative yield (260.4 mg). H NMR (300
MHz, CDCl3) δ 8.04 (d, 2H, J=8.4 Hz), 7.56 (t, 1H, J=7.4 Hz),
7.44 (t, 1H, J=7.5 Hz), 4.41 (t, 2H, J=6.3 Hz), 2.42 (t, 2H, J=7.1
Hz), 2.04ꢀ1.95 (m, 2H), 0.14 (s, 9H); 13C NMR (75 MHz, CDCl3)
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The Journal of Organic Chemistry
1102; HRMS (ESIꢀTOF) m/z: [M+Na]+ calcd. for C12H13BrO2Na:
1026; HRMS (ESIꢀTOF) m/z: [M+Na]+ calcd. for C15H18O4Na:
1
290.9997, found: 291.0001; Rf: 0.26 (cHx/EtOAc 8:2).
285.1102, found: 285.1102; Rf: 0.10 (cHx/EtOAc 8:2).
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7
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2-((1-(phenylethynyl)cyclohexyl)oxy)ethan-1-ol (4e) According
to the general procedure A for 18h at 50°C and starting with
trimethylsilylphenylacetylene 1a and 1,4ꢀdioxaspiro[4.5]decane
2e, the title compound 4e was obtained as a colorless oil in 87%
2-((1-(hex-1-yn-1-yl)cyclohexyl)oxy)ethan-1-ol (4m) According
to the general procedure A for 24h at 85°C and starting with hexꢀ
1ꢀynꢀ1ꢀyltrimethylsilane 1e and 1,4ꢀdioxaspiro[4.5]decane 2e, the
title compound 4m was obtained as a colorless oil in 39% yields
1
1
yields (25.1 mg). H NMR (300 MHz, CDCl3) δ 7.45ꢀ7.42 (m,
(10.3 mg). H NMR (300 MHz, CDCl3) δ 3.74ꢀ.372 (m, 2H),
2H), 7.31ꢀ7.29 (m, 3H), 3.78 (s, 4H), 2.14 (b, 1H), 2.03ꢀ1.98 (m,
2H), 1.71ꢀ1.53 (m, 7H), 1.42ꢀ1.26 (m, 1H); 13C NMR (75 MHz,
CDCl3) δ 131.2, 128.4, 128.3, 123.0, 90.6, 86.4, 74.4, 64.5, 62.4,
37.4, 25.6, 23.0; IR (neat, cmꢀ1): 3429, 2933, 2858, 2222, 1490,
1444, 1302, 1090, 1056, 968; HRMS (ESIꢀTOF) m/z: [M+Na]+
calcd. for C16H20O2Na: 267.1361, found: 267.1364; Rf: 0.23
(cHx/EtOAc 8:2).
3.69ꢀ3.68 (m, 2H), 2.22 (t, 2H, J=6.8 Hz), 2.10 (b, 1H), 1.88ꢀ1.80
(m, 2H), 1.64ꢀ1.37 (m, 11H), 1.35ꢀ1.17 (m, 1H), 0.91 (t, 3H,
J=7.1 Hz); 13C NMR (75 MHz, CDCl3) δ 86.8, 81.3, 71.1, 64.1,
62.4, 37.7, 31.1, 25.6, 23.1, 22.1, 18.5, 13.7; IR (neat, cmꢀ1):
3425, 2932, 2859, 2234, 1729, 1448, 1090; HRMS (ESIꢀTOF)
m/z: [M+Na]+ calcd. for C14H24O2Na: 247.1674, found: 247.1674;
Rf: 0.34 (cHx/EtOAc 8:2).
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15
16
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18
19
20
21
22
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27
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3-((3-phenylprop-2-yn-1-yl)oxy)propan-1-ol (4f) According to
the general procedure A for 3h at 50°C and starting with trimeꢀ
thylsilylphenylacetylene 1a and 1,3ꢀdioxane 2f, the title comꢀ
pound 4f was obtained as a colorless oil in 87% yields (19.5 mg).
1H NMR (300 MHz, CDCl3) δ 7.45ꢀ7.43 (m, 2H), 7.32ꢀ7.30 (m,
3H), 4.38 (s, 2H), 3.82ꢀ3.75 (m, 4H), 1.93ꢀ1.86 (m, 2H), 1.25 (b,
1H); 13C NMR (75 MHz, CDCl3) δ 131.9, 128.6, 128.4, 122.7,
86.5, 85.0, 68.9, 61.6, 59.2, 32.2; IR (neat, cmꢀ1) 3374, 2931,
2873, 2237, 1599, 1490, 1442, 1356, 1257, 1083, 1051; HRMS
(ESIꢀTOF) m/z: [M+Na]+ calcd. for C12H14O2Na: 213.0892,
found: 213.0889; Rf: 0.20 (cHx/EtOAc 8:2).
General procedure B. IPrAuNTf2 (0.00118 mmol) and 1ꢀ
bromo,4ꢀnitrobenzene (internal standard, 0.059 mmol) were
charged in a dry NMR tube under Argon. CDCl3 (0.5 mL), trimeꢀ
thylsilyl alkyne (0.224 mmol) and cyclic acetal (0.118 mmol)
were then added. The tube was sealed under argon atmosphere
and the reaction mixture was stirred for t hours at T °C. Converꢀ
1
sions were determined by H NMR experiments. After full conꢀ
version into the TMS protected alcohol, a 1.0 M solution of TBAF
in THF (0.130 mmol) was added and the mixture was stirred for
40 minutes. The mixture was then directly purified by flash chroꢀ
matography (cHx/EtOAc 1:0 ꢀ 8:2) to afford the desired alcohol.
2-((3-(thiophen-2-yl)prop-2-yn-1-yl)oxy)ethan-1-ol (4j) Accordꢀ
ing to the general procedure A for 18h at 85°C and starting with
trimethylsilylthiophenylacetylene 1b and 1,3ꢀdioxolane 2a, the
title compound 4j was obtained as a colorless oil in 66% yields
3-((1,3-diphenylprop-2-yn-1-yl)oxy)butan-2-ol (4g) According to
the general procedure B for 1h30 at 85°C and starting with trimeꢀ
thylsilylphenylacetylene 1a and (4R,5R)ꢀ4,5ꢀdimethylꢀ2ꢀphenylꢀ
1,3ꢀdioxolane 2g, the title compound 4g was obtained as a colorꢀ
less oil in 78% yields (25.8 mg) (d.r 75:25 D1/D2). 1H NMR (300
MHz, CDCl3) D1/D2: δ 7.60ꢀ7.57 (m, 2H, D1+D2), 7.49ꢀ7.47 (m,
2H, D1+D2), 7.42ꢀ7.39 (m, 3H, D1+D2), 7.34ꢀ7.32 (m, 3H,
D1+D2), 5.49 (s, 0.25H, D2), 5.47 (s, 0.75H, D1), 3.88ꢀ3.80 (m,
0.25H, D2), 3.71ꢀ3.62 (m, 1.25H, D1+D2), 3.61ꢀ3.52 (m, 1H),
2.62 (b, 1.25H, D1+D2), 1.30 (d, 2.5H, J=6.1 Hz, D1), 1.25 (d,
0.75H, J=4.1 Hz, D2), 1.23 (d, 0.75H, J=4.3 Hz, D2), 1.17 (d,
2.5H, J=6.2 Hz); 13C NMR (75 MHz, CDCl3) D1/D2: δ 139.1
(D1), 139.1 (D2), 131.9 (D2), 131.8 (D1), 128.9 (D1), 128.8 (D1),
128.7 (D2), 128.7 (D1), 128.6 (D2), 128.5 (D2), 128.4 (D1),
127.5 (D2), 126.9 (D2), 122.7 (D1), 122.5 (D2), 88.1 (D1), 87.8
(D2), 87.2 (D1), 87.1 (D2), 80.1 (D1), 78.8 (D2), 72.0 (D1), 71.3
(D1), 71.2 (D2), 70.2 (D2), 18.8 (D2), 18.7 (D1), 16.9 (D1), 15.6
(D2); IR (neat, cmꢀ1) 3429, 3063, 3033, 2975, 2876, 2226, 1953,
1718, 1599, 1490, 1451, 1380, 1270, 1176, 1158, 1059, 1028,
917, 756; HRMS (ESIꢀTOF) m/z: [M+H]+ calcd. for C19H21O2:
281.1542, found: 281.1549; Rf: 0.28 (D1), 0.26 (D2) (cHx/EtOAc
8:2).
1
(14.2 mg). H NMR (300 MHz, CDCl3) δ 7.27ꢀ7.26 (m, 1H),
7.25ꢀ7.22 (m, 1H), 6.97 (dd, 1H, J= 3.8 Hz, J=4.9 Hz), 4.44 (s,
2H), 3.81ꢀ3.78 (m, 2H), 3.72ꢀ3.69 (m, 2H), 1.25 (b,1H); 13C NMR
(75 MHz, CDCl3) δ 132.7, 127.6, 127.1, 122.5, 88.9, 80.0, 71.4,
61.9, 59.4; IR (neat, cmꢀ1): 3412, 2926, 2856, 2221, 1709, 1357,
1347, 1190, 1104, 1066, 1023; HRMS (ESIꢀTOF) m/z: [M+H]+
calcd. for C9H11O2S: 183.0479, found: 183.0474; Rf: 0.07
(cHx/EtOAc 8:2).
2-((6-((tert-butyldiphenylsilyl)oxy)hex-2-yn-1-yl)oxy)ethan-1-ol
(4k) According to the general procedure A for 28h at 85°C and
starting with tertꢀbutyldiphenyl((5ꢀ(trimethylsilyl)pentꢀ4ꢀynꢀ1ꢀ
yl)oxy)silane 1c and 1,3ꢀdioxolane 2a, the title compound 4k was
obtained as a colorless oil in 85% yields (39.8 mg). 1H NMR (300
MHz, CDCl3) δ 7.68ꢀ7.65 (m, 4H), 7.43ꢀ7.35 (m, 6H), 4.16 (t, 2H,
J=2.1 Hz), 3.76ꢀ3.72 (m, 4H), 3.61ꢀ3.58 (m, 2H), 2.42ꢀ2.36 (m,
2H), 1.81ꢀ1.73 (m, 2H), 1.26 (b, 1H), 1.05 (s, 9H); 13C NMR (75
MHz, CDCl3) δ 135.7, 134.0, 129.7, 127.8, 87.1, 76.0, 71.0, 62.5,
61.9, 59.1, 31.6, 27.0, 19.4, 15.5; IR (neat, cmꢀ1): 3384, 2931,
2857, 2240, 1713, 1590, 1428, 1104, 1067; HRMS (ESIꢀTOF)
m/z: [M+Na]+ calcd. for C24H32O3SiNa: 419.2018, found:
419.2019; Rf: 0.12 (cHx/EtOAc 8:2).
2-((1,3-diphenylprop-2-yn-1-yl)oxy)propan-1-ol (4h) According
to the general procedure B for 3h at 85°C and starting with trimeꢀ
thylsilylphenylacetylene 1a and (rac)ꢀ4ꢀmethylꢀ2ꢀphenylꢀ1,3ꢀ
dioxolane 2h (d.r 45:55), the title compound 4h was obtained as a
colorless oil in 76% yields (23.4 mg) (d.r 85:15 D1/D2). 1H NMR
(300 MHz, CDCl3) D1/D2 δ 7.61ꢀ7.58 (m, 2.6H, D1+D2), 7.50ꢀ
7.47 (m, 2.8H, D1+D2), 7.41ꢀ7.39 (m, 3.9H, D1+D2), 7.34ꢀ7.32
(m, 3.9H, D1+D2), 5.51 (s, 1H, D1), 5.46 (d, 0.15H, J=2.5 Hz,
D2), 4.22ꢀ4.11 (m, 0.3H, D2), 3.99ꢀ3.92 (m, 1H, D1), 3.75 (dd,
0.3H, J=3.0 Hz, J=9.4 Hz, D2), 3.66 (dd, 1H, J=2.7 Hz, J=11.3
Hz, D1), 3.58ꢀ3.52 (m, 1H, D1), 3.43ꢀ3.37 (m, 0.15H, D2), 2.03
(b, 1H, D1), 1.70 (b, 0.2H, D2),1.27 (d, 3H, J=6.4 Hz, D1), 1.19
(d, 0.45H, J=6.4 Hz, D2); 13C NMR (75 MHz, CDCl3) δ 139.2
(D1), 139.1 (D2), 131.9 (D2), 131.9 (D1), 128.8 (D1), 128.8 (D2),
128.7 (D1), 128.6 (D2), 128.4 (D2), 128.4 (D1), 127.6 (D1), 88.0
(D1), 87.7 (D2), 87.3 (D2), 87.2 (D1), 75.1 (D1), 74.7 (D2), 71.2
6-(2-hydroxyethoxy)hex-4-yn-1-yl benzoate (4l) According to the
general procedure
A for 24h at 85°C and starting 5ꢀ
(trimethylsilyl)pentꢀ4ꢀynꢀ1ꢀyl benzoate 1d and 1,3ꢀdioxolane 2a,
the title compound 4l was obtained as a colorless oil in 36%
1
yields (11.1 mg). H NMR (300 MHz, CDCl3) δ 8.03 (d, 2H,
J=7.3 Hz), 7.56 (t, 1H, J=7.4 Hz), 7.43 (t, 2H, J=7.5 Hz), 4.42 (t,
2H, J=6.2 Hz), 4.16 (s, 2H), 3.75 (t, 2H, J=4.2 Hz), 3.62 (t, 2H,
J=4.7 Hz), 2.42 (t, 2H, J=7.0 Hz), 2.08 (b, 1H), 2.03ꢀ1.94 (m,
2H); 13C NMR (75 MHz, CDCl3) δ 166.7, 133.1, 130.3, 129.7,
128.5, 85.8, 76.8, 71.1, 63.7, 61.9, 59.0, 27.9, 15.8; IR (neat, cmꢀ
1): 3426, 2930, 2858, 2223, 1715, 1602, 1452, 1270, 1109, 1069,
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(D1), 70.3 (D2), 66.7 (D2), 66.4 (D1), 30.3 (D2), 27.0 (D2), 17.1
1H); 13C NMR (75 MHz, CDCl3) δ 166.8, 132.9, 131.8, 130.5,
(D1), 16.0 (D2); IR (neat, cmꢀ1) 3414, 3063, 3033, 2971, 2929,
2224, 1952, 1718, 1599, 1573, 1490, 1453, 1443, 1378, 1304,
1278, 1140, 1028, 1003, 989, 915, 755; HRMS (ESIꢀTOF) m/z:
[M+Na]+ calcd. for C18H18O2Na: 289.1205, found: 289.1206; Rf:
0.11 (cHx/EtOAc 8:2).
129.8, 128.4, 128.4, 128.3, 123.0, 90.6, 86.3, 74.5, 64.7, 61.7,
37.4, 25.6, 23.0; IR (neat, cmꢀ1): 2934, 2858, 2221, 1717, 1602,
1490, 1451, 1271, 1090, 1069, 1027; HRMS (ESIꢀTOF) m/z:
[M+Na]+ calcd. for C23H24O3Na: 371.1623, found: 371.1620; Rf:
0.36 (nꢀpentane/Et2O 9:1).
1
2
3
4
5
6
7
8
9
General Procedure C. IPrAuNTf2 (0.00118 mmol) and 1ꢀ
bromo,4ꢀnitrobenzene (internal standard, 0.059 mmol) were
charged in a dry NMR tube under Argon. CDCl3 (0.5 mL), pheꢀ
nyltrimethylsilyl alkyne 1a (0.142 mmol) and cyclic acetal 2m
(0.118 mmol) were then added. The tube was sealed under argon
atmosphere and the reaction mixture was stirred for t hours at
T°C. Conversions were determined by 1H NMR experiments.
After full conversion, the mixture was then directly purified by on
silica gel (nꢀpentane/Et2O 98:2 ꢀ 90:10).
2-((3-(trimethylsilyl)prop-2-yn-1-yl)oxy)ethyl benzoate (5c)
According to the general procedure D for 24h at 85°C and starting
with 1,2ꢀbis(trimethylsilyl)ethyne 1f and 1,3ꢀdioxolane 2a, the
title compound 5c was obtained as a yellowish oil in 47% yields
1
(15.3 mg). H NMR (300 MHz, CDCl3) δ 8.07 (d, 2H, J = 7.1
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14
15
16
17
18
19
20
21
22
23
24
25
26
27
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29
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32
33
34
35
36
37
38
39
40
41
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47
48
49
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52
53
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59
60
Hz), 7.56 (t, 1H, J = 6.7 Hz), 7.44 (t, 3H, J = 7.5 Hz), 4.50 (t, 2H,
J = 4.7 Hz), 4.25 (s, 2H), 3.89 (t, 2H, J = 4.8 Hz), 0.17 (s, 9H);
13C NMR (75 MHz, CDCl3) δ 166.7, 133.2, 130.2, 129.9, 128.5,
101.2, 92.0, 67.8, 64.1, 59.3, 0.06; IR (neat, cmꢀ1): 3425, 2978,
2913, 1716, 1603, 1585, 1484, 1453, 1337, 1253, 1116, 1099,
1071, 1023; HRMS (ESIꢀTOF) m/z: [M+Na]+ calcd. for
C15H20O3SiNa: 299.1079, found: 299.1080; Rf: 0.11 (nꢀ
pentane/Et2O 95:5).
(3-methoxyprop-1-yne-1,3-diyl)dibenzene (4i) According to the
general procedure C for 3h at 50°C and starting with trimethylsiꢀ
lylphenylacetylene 1a and (dimethoxymethyl)benzene 2i, the title
compound 4i was obtained as a colorless oil in 76% yields (14.4
1
mg). H NMR (300 MHz, CDCl3) δ 7.61ꢀ7.58 (m, 2H), 7.52ꢀ7.49
3-(hept-2-yn-1-yloxy) propyl benzoate (5d) According to the
general procedure D for 18h at 85°C and starting with hexꢀ1ꢀynꢀ1ꢀ
yltrimethylsilane 1e and 1,3ꢀdioxane 2f, the title compound 5d
was obtained as a yellowish oil in 36% yields (11.7 mg). 1H NMR
(300 MHz, CDCl3) δ 8.04 (d, 2H, J = 7.8 Hz), 7.55 (t, 1H, J = 7.2
Hz), 7.43 (t, 2H, J = 7.7 Hz), 4.42 (t, 2H, J = 6.3 Hz), 4.14 (s,
2H), 3.66 (t, 2H, J = 6.2 Hz), 2.19 (t, 2H, J = 6.8 Hz), 2.11ꢀ2.02
(m, 2H), 1.50ꢀ1.32 (m, 4H), 0.89 (t, 3H, J = 7.0 Hz); 13C NMR
(75 MHz, CDCl3) δ 166.7, 133.0, 130.5, 129.7, 128.5, 87.2, 75.9,
66.4, 62.3, 58.9, 30.8, 29.2, 22.1, 18.6, 13.7; IR (neat, cmꢀ1):
3387, 2959, 2933, 2873, 2239, 1717, 1602, 1585, 1452, 1272,
1096, 1070; HRMS (ESIꢀTOF) m/z: [M+H]+ calcd. for C17H23O3:
275.1647, found: 275.1647; Rf: 0.51 (cHx/EtOAc 8:2).
(m, 2H), 7.44ꢀ7.37 (m, 3H), 7.35ꢀ7.32 (m, 3H), 5.33 (s, 1H), 3.51
(s, 3H); 13C NMR (75 MHz, CDCl3) δ 138.7, 131.9, 128.7, 128.6,
128.4, 127.7, 122.7, 87.9, 86.8, 73.7, 56.1; IR (neat, cmꢀ1): 3063,
3033, 2930, 2901, 2820, 2221, 1599, 1490, 1453, 1444, 1329,
1186, 1073; HRMS (ESIꢀTOF) m/z: [M+Na]+ calcd. for
C16H14ONa: 245.0942, found: 245.0934; Rf: 0.18 (nꢀpentane/Et2O
98:2).
General Procedure D. IPrAuNTf2 (0.00118 mmol) was charged
in a dry tube under Argon. CDCl3 (0.5 mL), trimethylsilyl alkyne
1 (0.224 mmol) and acetal 2 (0.118 mmol) were then added. The
tube was sealed under argon atmosphere and the reaction mixture
was stirred for t hours at T °C. After a full conversion into the
1
TMS protected alcohol 3 was observed by H NMR analysis, the
2-((1-(hex-1-yn-1-yl)cyclohexyl)oxy)ethyl benzoate (5e) Accordꢀ
ing to the general procedure D for 24h at 85°C and starting with
hexꢀ1ꢀynꢀ1ꢀyltrimethylsilane 1e and 1,4ꢀdioxaspiro[4.5]decane 2e,
the title compound 5e was obtained as a yellowish oil in 63%
reaction mixture was placed at room temperature to add PhCOF
(0.177 mmol) and DMAP (0.0118 mmol). After stirring at room
temperature until disappearance of the TMS protected alcohol
intermediate 3 (18hꢀ24h) the reaction mixture was directly puriꢀ
fied by flash chromatography using cHx/EtOAc 1:0 ꢀ 8:2 gradiꢀ
ent to afford the desired benzoate derivatives 5a-e.
1
yields (28.4 mg). H NMR (300 MHz, CDCl3) δ 8.07 (d, 2H, J =
7.1 Hz), 7.55 (t, 1H, J = 7.4 Hz), 7.43 (t, 3H, J = 7.5 Hz), 4.47 (t,
2H, J = 4.9 Hz), 3.90 (t, 2H, J = 5.0 Hz), 2.19 (t, 2H, J = 6.8 Hz),
1.88ꢀ1.82 (m, 2H), 1.69ꢀ1.60 (m, 2H), 1.60ꢀ1.56 (m, 2H), 1.52ꢀ
1.35 (m, 7H), 1.33ꢀ1.26 (m, 1H), 0.89 (t, 3H, J = 7.1 Hz); 13C
NMR (75 MHz, CDCl3) δ 166.8, 133.0, 130.1, 129.8, 128.4, 86.6,
81.3, 74.2, 64.8, 61.4, 37.6, 31.1, 25.6, 23.0, 22.1, 18.5, 13.7; IR
(neat, cmꢀ1): 2933, 2859, 2232, 1720, 1603, 1451, 1271, 1176,
1091, 1069; HRMS (ESIꢀTOF) m/z: [M+Na]+ calcd. for
C21H28O3Na: 351.1936, found: 351.1935; Rf: 0.56 (cHx/EtOAc
8:2).
2-((3-phenylprop-2-yn-1-yl)oxy)ethyl benzoate (5a) According to
the general procedure D for 18h at 85°C and starting with trimeꢀ
thylsilylphenylacetylene 1a and 1,3ꢀdioxolane 2a, the title comꢀ
9
pound 5a was obtained in mixture with BzOꢀCH2ꢀCH2ꢀOBz
1
(ratio 9:1) as a yellowish oil in 85% yields (28.1 mg). H NMR
(300 MHz, CDCl3) δ 8.08 (d, 2H, J=7.2 Hz), 7.55 (t, 1H, J=7.3
Hz), 7.44ꢀ7.39 (m, 5H), 7.32ꢀ7.30 (m, 3H), 4.67 (s, 0.45H, BzOꢀ
CH2ꢀCH2ꢀOBz), 4.54 (t, 2H, J=4.6 Hz), 4.48 (s, 2H), 3.96 (t, 2H,
J=4.8 Hz); 13C NMR (75 MHz, CDCl3) δ 166.6, 166.5, 134.6,
133.2, 133.1, 131.9, 130.7, 130.1, 129.9, 129.8, 129.0, 128.6,
128.5, 128.4, 128.4, 122.6, 86.7, 84.8, 69.1, 67.8, 64.1, 62.8
(BzOꢀCH2ꢀCH2ꢀOBz), 59.2; IR (neat, cmꢀ1): 3063, 2925, 2238,
1717, 1601, 1490, 1451, 1269, 1093, 1070, 1027; HRMS (ESIꢀ
TOF) m/z: [M+Na]+ calcd. for C18H16O3Na: 303.0997, found:
303.0996; Rf: 0.45 (cHx/EtOAc 8:2).
2-((1,3-diphenylprop-2-yn-1-yl)oxy)propyl benzoate (5f) Accordꢀ
ing to the general procedure D for 24h at 85°C and starting with
trimethylsilylphenylacetylene 1a and (rac)ꢀ4ꢀmethylꢀ2ꢀphenylꢀ
1,3ꢀdioxolane (d.r 55:45) 2h, the title compound 5f was obtained
in mixture with BzOꢀCH2(CH3)ꢀCH2ꢀOBz (ratio 4:1) as a yellowꢀ
1
ish oil in 70% yields (30.6 mg). H NMR (300 MHz, CDCl3) δ
8.07 (d, 2H, J=7.7 Hz), 7.61ꢀ7.55 (m, 2H), 7.48ꢀ7.44 (m, 5H),
7.35ꢀ7.31 (m, 6H), 5.64 (s, 1H), 4.48 (dd, 1H, J=7.0 Hz, J=15.0
Hz), 4.36 (dd, 2H, J=5.9 Hz, J=9.4 Hz), 1.39 (d, 3H, J=5.8 Hz);
13C NMR (75 MHz, CDCl3) δ 166.5, 139.1, 133.1, 131.9, 130.2,
128.9, 128.6, 128.5, 128.4, 128.3, 127.6, 122.6, 87.5, 87.5, 71.9,
71.2, 68.0, 18.1; IR (neat, cmꢀ1) 3064, 3033, 2978, 2250, 1717,
1601, 1490, 1451, 1315, 1270, 1110, 1026, 907, 756, 729; HRMS
(ESIꢀTOF) m/z: [M+Na]+ calcd. for C25H22O3Na: 393.1467,
found: 393.1468; Rf: 0.46 (cHx:EtOAc 8:2).
2-((1-(phenylethynyl)cyclohexyl)oxy)ethyl benzoate (5b) Accordꢀ
ing to the general procedure D for 18h at 85°C and starting with
trimethylsilylphenylacetylene 1a and 1,4ꢀdioxaspiro[4.5]decane
2e, the title compound 5b was obtained as a yellowish oil in 66%
1
yields (27.1 mg). H NMR (300 MHz, CDCl3) δ 8.07 (d, 2H, J =
7.2 Hz), 7.54 (t, 1H, J = 7.4 Hz), 7.42ꢀ7.37 (m, 4H), 7.31ꢀ7.28 (m,
3H), 4.52 (t, 2H, J = 4.9 Hz), 4.00 (t, 2H, J = 4.9 Hz), 2.04ꢀ1.98
(m, 2H), 1.77ꢀ1.69 (m, 4H), 1.66ꢀ1.52 (m, 3H), 1.43ꢀ1.27 (m,
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lylsilanes: (a) Motokura, K.; Yoneda, H.; Miyaji, A.; Sakamoto,
ASSOCIATED CONTENT
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Y.; Baba, T. Catal. Sci. Technol. 2011, 1, 470. (b) Motokura, K.;
Yoneda, H.; Miyaji, A.; Baba, T. Green Chem. 2010, 12, 1373. (c)
Spafford, M. J.; Christensen, J. E.; Huddle, M. G.; Lacey, J. R.;
Mohan, R. S. Aust. J. Chem. 2008, 61, 419. ꢀ by silyl enol ethers:
(d) Kinugasa, M.; Harada, T.; Oku, A. J. Org. Chem. 1996, 61,
6772. and ꢀby TMSꢀCN: (e) Sauer, D.; Schneller, S. J. Org.
Chem. 1990, 55, 5535. (f) Kirchmeyer, S.; Mertens, A.; Arꢀ
vanaghi, M.; Olah, G. Synthesis 1983, 498.
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
Optimization studies and NMR spectra are included in the Supꢀ
porting Information file (file type, i.e., PDF).
AUTHOR INFORMATION
[10] Brinkø, A.; Larsen, M. T.; Koldsø, H.; Besenbacher, L.;
Kolind, A.; Schiøtt, B.; Sinning, S.; Jensen, H. H. Bioorg. Med.
Chem. 2016, 24, 2725.
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vincent.dalla@univꢀlehavre.fr
[11] Lv, X.; Ying, H.; Ma, X.; Qiu, N.; Wu, P.; Yang, B.; Hu, Y.
Eur. J. Med. Chem. 2015, 99, 36.
Notes
[12] For the use of gold catalysis in general, see: (a) Dyker, G.
Angew Chem. Int. Ed. 2000, 39, 4237. (b) Hashmi, A. S. K. Chem.
Rev. 2007, 107, 3180. (c) HoffmannꢀRöder, A.; Krause, N. Org.
Biomol. Chem. 2005, 3, 387. (d) Zhang, D.ꢀH.; Tang, X.ꢀY.; Shi,
M. Acc. Chem. Res. 2014, 47, 913. (e) Pflästerer, D.; Hashmi, A.
S. K. Chem. Soc. Rev. 2016, 45, 1331.
The authors declare no competing financial interests.
ACKNOWLEDGMENT
This work was supported by the "région HauteꢀNormandie" and
the “Fonds Européen de Développement Régional” (FEDER
catalyse HN0001397) for funding the postꢀdoctoral fellowships of
O. S. and M. B. The authors dedicated this work to our friend and
colleague Dr Vincent Levacher.
[13] For some reviews on gold catalysis dealing with gold acetyꢀ
lides : (a) Li, C.ꢀJ. Acc. Chem. Res. 2010, 43, 581, (b) de Haro, T.;
Nevado, C. Synthesis 2011, 2530.
[14] In gold catalysis other alkynylation strategies rely on oxidaꢀ
tive protocols and are limited to the alkynylation of arenes and
heteroarenes: (a) Brand, J. P.; Waser, J. Chem. Soc. Rev. 2012, 41,
4165, (b) de Haro, T.; Nevado, C. J. Am. Chem. Soc., 2010, 132,
1512.
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