Ti-Catalyzed Synthesis of Exocyclic Allenes on Oxygen Heterocycles

Article abstract of DOI:10.1002/ejoc.201601444

A general method for the straightforward synthesis of exocyclic allenes on five-, six-, seven-, and eight-membered oxygen heterocycles is described. A Barbier-type titanocene(III)-catalyzed cyclization of propargyl halides with a pendant carbonyl group is

Full text of DOI:10.1002/ejoc.201601444

A Journal of
Accepted Article
Title: Ti-Catalyzed Synthesis of Exocyclic Allenes on Oxygenated
Heterocycles
Authors: Natalia Muñoz-Padial, Carmen Hernández-Cervantes, Juan
Muñoz-Bascón, Esther Roldan-Molina, Mireya García-
Martínez, Ana Belén Ruiz-Muelle, Antonio Rosales, Míriam
Álvarez-Corral, Manuel Muñoz Dorado, Ignacio Rodriguez-
Garcia, and J. Enrique Oltra
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the VoR from the journal website shown below when it is published
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content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201601444
Link to VoR: http://dx.doi.org/10.1002/ejoc.201601444
Supported by

European Journal of Organic Chemistry
10.1002/ejoc.201601444
FULL PAPER
Ti-Catalyzed Synthesis of Exocyclic Allenes on Oxygenated
Heterocycles
[
a]
[b]
[a]
[a]
Natalia M. Padial, Carmen Hernández-Cervantes, Juan Muñoz-Bascón, Esther Roldan-Molina,
Mireya García-Martínez,[b] Ana Belén Ruiz-Muelle,[b] Antonio Rosales, Míriam Álvarez-Corral,
[c]
[b]
Manuel Muñoz-Dorado,[b] Ignacio Rodríguez-García * and J. Enrique Oltra. *
[b]
[a]
6
Abstract: A general method for the straightforward synthes is of
exocyclic allenes on oxygenated five-, six-, seven- and eight-
membered heterocycles is described. A Barbier-type titanocene(III)
catalyzed cyclization of propargyl halides w ith a pendant carbonyl
group is the key step of the process. This reaction is compatible w it h
many functional groups and can be performed under smooth neutral
and mild conditions at room temperature.
non-toxic and eco-friendly. Moreover, based on our previous
observations, w e deemed that the Ti-catalyzed synthesis of
oxygenated heterocycles bearing an exocyclic allene could be
easily achieved by using the titanocene-regenerating agent 1,
7
developed in our laboratory, to close the catalytic cycle depicted
in Scheme 1.
Introduction
For many years, allenes w ere considered highly unstable
compounds or chemical curiosities for theoretical calculations.
Now adays, how ever, many natural products containing the allene
group are know n and, in many cases, they possess this peculiar
1
unsaturated system on an exocyclic location. In addition, allenes
can be considered now as common building blocks in synthetic
2
organic chemistry. Due to the increasing versatility of allenes in
pharmacy and contemporary chemistry, the number of methods
3
for allene preparation is in continuous expansion. In this context,
w e have recently reported the Barbier-type cyclization of
2
propargyl halides catalyzed by [Cp TiCl] (Nugent-RajanBabu
4
reagent). This novel C-C bond forming reaction directly gave
Scheme 1. Anticipated catalytic cycle for the Ti-catalyzed synthesis of
oxygenated heterocycles bearing an exocyclic allene.
carbocycles and N-heterocycles w ith an exocyclic allene group
5
and w ith ring sizes ranging from five to seven members. Now , we
have extended this method to the straightforw ard synthesis of
oxygen-containing heterocycles bearing an exocyclic allene motif .
To check our hypothesis, w e treated ketone 2 w ith commercial
Cp
mixture of TMSCl and 2,4,6-collidine, to allow the formation of 1.
As expected, an acceptable 65% yield of the
vinylidenetetrahydrofuran product 15 w as obtained (Table 1, entry
).
Subsequently, w e checked the method for the synthesis of six-
membered oxygenated heterocycles. Thus, treatment of
aldehyde 3 under the above mentioned conditions gave the
vinylidene hydroxychromane derivative 16 w ith a good 92% yield
(Table 1, entry 2).
2 2
TiCl in substoichiometric amount (0.2 equiv.), Mn dust and a
8
Results and Discussion
Titanium is a relatively inexpensive metal, one of the most
abundant on the Earth crust, and many titanium derivatives are
1
[
[
[
a]
b]
c]
N. M. Padial, J. Muñoz-Bascón, E. Roldan-Molina, J. E. Oltra.
Department of Organic Chemistry, Faculty of Sciences.
University of Granada. 18071-Granada, Spain
E-mail: joltra@ugr.es
C. Hernández-Cervantes, M. García-Martínez, A. B. Ruiz-Muelle, M.
Álvarez-Corral, M. Muñoz-Dorado, I. Rodríguez-García.
Organic Chemistry, ceiA3. University of Almería. 04120-Almería, Spain.
E-mail: irodrigu@ual.es
In
a
similar manner, titanocene(III)-catalyzed cyclization of
aldehydes 4-7 provided halogenated
dihalogenated
vinylidenechromane derivatives 17-20 in yields ranging from a
84% to a 96% (Table 1, entries 3-6), confirming that the method
is compatible w ith both aryl chlorides and aryl bromides. It should
be noted that 17 and 18 w ere obtained as the trimethylsilyl ether
derivatives of the expected alcohols, in accordance w ith the
catalytic cycle depicted in Scheme 1. Moreover, secondary
A. Rosales.
Department of Chemical and Environmental Engineering, EPS.
University of Sevilla. 41011-Sevilla, Spain.
Supporting information for this article are available on the WWW under
http://dx.doi.org/10.1002/ejoc.xxxxx
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European Journal of Organic Chemistry
10.1002/ejoc.201601444
FULL PAPER
alcohols 16-20 might be easily transformed into chromone
analogs by simple oxidation.
Table 1. Ti-catalyzed 5-, 6-, 7- and 8-cyclizations to oxygenated
heterocycles with exocyclic allenes
Titanocene(III)-catalyzed cyclization of ketone 8 lead to tertiary
alcohol 21 w ith an excellent 94% yield (Table 1, entry 7). In a
similar manner, Ti-catalyzed cyclization of aromatic ketones 9-12
gave vinylidenechromane derivatives 22-25 w ith yields ranging
from 57% to 66% (Table 1, entries 8-11). Despite of the moderate
yields obtained in these cyclizations, it should be noted that in all
of these reactions relatively unstable tertiary and benzylic
alcohols in α-position of an allene group w ere obtained,
underlying the mild experimental conditions of the method.
Synthesis of fluorinated benzopyran 23 (entry 9) also confirms
that the method is compatible w ith aryl fluorides.
[
a]
Entry
Substrate
Product
Yield [%]
Ti(III)-catalyzed
cyclization
of
aldehyde
13
gave
vinylidenebenzoxepane derivative 26. To the best of our
know ledge, this is the first synthesis of an exocyclic allene on an
oxygenated seven-membered heterocycle reported so far.
Eight-membered rings are considered as medium-size ones.
Cyclization reactions leading to this kind of rings are generally
9
hindered by both enthalpy and entropy factors. Nevertheless,
Ti(III)-catalyzed cyclization of aldehyde 14 gave an excellent 95%
yield of vinylidenebenzoxocane derivative 27. This is the first
synthesis of an exocyclic allene on an eight-membered ring
described to date, suggesting the potential usefulness of our
method for the synthesis of medium-size rings. This
unprecedented result may be rationalized if the mechanism
depicted in Scheme 2 is accepted.
Scheme 2. Hypothetical mechanism for the titanocene(III)-catalyzed cyclizat io n
of 14 to 27.
It is know n that titanocene(III)-catalyzed cyclizations of propargyl
halides take place in three steps: i) generation of a propargyl
radical, ii) formation of an organometallic Ti(IV) complex and (iii)
5
intramolecular nucleophylic attack to the carbonyl group. In this
w ay, formation of eight-membered ring 27 might proceed as
depicted in scheme 2.
[
a] Free alcohol can also coexist with a lesser amount of the corresponding
2
First, Cp TiCl w ould abstract the chlorine atom of 14 to give
TMS ether, which can easily be converted into the alcohol by treatment with
tetrabutylammonium fluoride. Only the TMS ether was detected.
propargyl radical 28 (Scheme 2). Second, this radical w ould be
b)
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European Journal of Organic Chemistry
10.1002/ejoc.201601444
FULL PAPER
trapped by an additional Cp
2
TiCl species to generate the alkyl-
211.3 (C), 85.5 (C), 80.9 (C), 69.7 (CH2), 58.4 (CH2), 51.0 (CH2), 26.2
+
(CH3). HRMS (TOF MS ES+) calc. for C10H17O3 [M+H] : 185,1178; found
Ti(IV) organometallic intermediate 29. In this key intermediate,
coordination betw een titanium and the carbonyl oxygen closes a
large-size tw elve-membered ring in spite of unfavorable entropic
1
85,1153.
1
0
1-(4-Chlorobut-2-ynyloxy)-3,3-dimethylbutan-2-one (2). To a solution
of compound 2a (500 mg, 2.71 mmol) in Et2O (30 mL), one drop of DMF
and SOCl2 (20 mL) were added. Themixture wasstirred for 3 h, and then
it was poured into a mixture of water-ice (40 mL) andAcOEt (60 mL). The
organic layer was washed with aqueous KHCO3 solution and with brine,
dried over anhydrous Na SO . The solvent was removed and 538.3 mg
factors. Moreover, it is possible that the flat o-disubstituted
benzene ring could exert some template effect, facilitating the
cyclization to 29 by diminishing the entropy of the process. Finally,
intramolecular nucleophilic attack to the carbonyl group, w ith
concomitant extrusion of the allene moiety, w ould provide the
eight-membered oxy-titanium ring 30, w hich in the presence of
the titanocene-regenerating agent 1, w ould give product 27.
2
1
4
(98%) of 2 wasobtained. H NMR (300 MHz, CDCl3) δ:4.41 (br s, 2H), 4.31
1
3
(br s, 2H), 4.15 (br s, 2H), 1.16 (s, 9H). C NMR (75 MHz, CDCl3, DEPT)
δ: 211.1 (C), 82.0 (C), 81.7 (C), 69.6 (CH2), 58.3 (CH2), 42.9 (C), 30.2
(
CH2), 26.2 (CH3). HRMS (TOF MS ES+) calc. for C10H16ClO2 [M+H]+:
2
03,0839; found203,0835.
Conclusions
4
-(4-Hydroxybut-2-ynyloxy)butan-2-one (8a). But-3-en-2-one (1 g,
2
In conclusion, w e have demonstrated that the Cp TiCl-catalyzed
1
4.26 mmol) was added to a mixture of but-2-yne-1,4-diol (1.23 g, 14.26
cyclization of propargyl halides can also be used for the
straightforw ard synthesis of exocyclic allenes on oxygenated five-,
six-, seven- and eight-membered heterocycles. The reaction
presumably follow s the catalytic cycle depicted in Scheme 1. The
present results, together w ith those previously described for
carbocycles and nitrogen-containing heterocycles, suggest that
this procedure might became a general and convenient method
for the synthesis of exocyclic allenes.
mmol) and DBU (4.57 mg, 0.03 mmol) in MeCN (43 mL) at room
temperature. The mixture was stirred for 48h. The solvent was removed
and the residue was submitted to flash chromatography (hexane/AcOEt
1
6
:4) to give 1.78 g (80%) of product 8a. H NMR (300 MHz, CDCl3) δ: 4.31
(
t, J = 1.7 Hz, 2H), 4.17 (t, J = 1.7 Hz, 2H), 3.77 (t, J = 6.2 Hz, 2H), 2.70 (t,
J = 6.2 Hz, 2H), 2.19 (s, 3H). 13C NMR (75 MHz, CDCl3, DEPT) δ: 176.0
C), 84.5 (C), 81.4 (C), 64.6 (CH2), 58.3 (CH2), 50.9(CH2), 43.2 (CH2), 30.3
(
+
(CH3). HRMS (TOF MS ES+) calc. for C8H13O3 [M+H] : 157,0865; found
1
57,0886.
4
-(4-Chlorobut-2-ynyloxy)butan-2-one (8). To a solution of compound
Experimental Section
8a (500 mg, 3.2 mmol) in Et2O (30 mL), one drop of DMF and SOCl2 (24
mL) were added. The mixture wasstirred for 3 h, and then it was poured
into a mixture of water-ice (50 mL) and AcOEt (70 mL). The organic layer
was washed with aqueous KHCO3 solution and with brine, dried over
anhydrous Na2SO4. The solvent was removed and 547.5 mg (98%) of 8
General experimental details. All reactionswere performed under argon
atmosphere, using oven-dried glassware in all cases. Dichloromethane
was distilled from NaH under argon. THF was distilled from
Na/benzophenone under argon, and in all experiments involving
titanocene (III) was deoxygenated prior to use. Dry distilled DMF was
bought from Sigma-Aldrich supplier. NMR spectra were recorded on a
1
was obtained. H NMR (300 MHz, CDCl3) δ: 4.21 (t, J = 1.8 Hz, 2H), 4.19
(
t, J = 1.8 Hz, 2H), 3.78 (t, J = 6.2 Hz, 2H), 2.73 (t, J = 6.2 Hz, 2H), 2.20
(
s, 3H). 13C NMR (75 MHz, CDCl3, DEPT) δ: 206.7 (C), 82.3 (C), 81.2 (C),
1
65.0 (CH2), 58.5 (CH2), 43.4 (CH2), 30.4 (CH3), 30.3 (CH2). HRMS (TOF
Bruker Avance DPX 300 spectrometer, operatingat 300 MHz for H NMR
+
1
3
MS ES+) calc. for C8H12ClO2 [M+H] : 175,0526; found 175,0551.
and 75 MHz for C NMR, on a Varian Unity Inova operating at 300 MHz
1
13
for H NMR and 75 MHz for C NMR, and on a Varian Direct Drive
operating at 400MHz for H NMR and 100 MHz for 13C NMR, in CDCl3 as
solvent. Chemical shifts(δ) are expressed in ppm and couplingconstants
1
1-Allyl-2-(4-chlorobut-2-ynyloxy)benzene (13a). K2CO3 (1.5134 g, 11
mmol) and 1,4-dichlorobut-2-yne (1.8 mL, 17.5 mmol) were added to a
solution of 2-allylphenol (1.5 mL,11 mmol) inacetone(19 mL). Themixture
was refluxed for 48 h. The reaction was quenched with HCl 5% (15 mL)
and extracted with Et2O. The organic layer was washed with saturated
brine, dried over anhydrous MgSO4. After filtration, the solvent was
evaporated under reducepressure. Compound 13a(1.3933 g,6.32mmol,
(J) in hertzs (Hz). Chemical shifts are reported using CDCl3 as internal
reference. IR Spectra were recordedwith a Bruker Alpha spectrometer and
a Mattson Satellite FTIR. Mass spectra were recorded in a Waters Xevo
by LC-QTof-MS and in a Bruker Autoflex by electrospray ionization.
Analytical TLC wasperformed on 0.2 mm DC-Fertigfolien Alugram®Xtra
Sil G/UV254 silica gel plates. Flash chromatography was performed on
silicagel 60(0.04 - 0.06 mm).
-1
57%) was obtainedasa colorlessoil. IR (film) v (cm ): 1638, 1598,1263,
1
1018. H NMR (300 MHz, CDCl3) δ (ppm) 7.28-6.95(4H, m), 6.02 (1H, ddt,
J= 6.9 Hz, 10.2 Hz, 16.8 Hz), 5.09 (2H, m), 4.78 (2H, t, J= 1.8 Hz), 4.19
1
3
(
1
2H, t, J= 1.8 Hz), 3.43 (2H, m). C NMR (75 MHz, CDCl3, DEPT) δ (ppm)
55.25 (C), 136.75 (CH), 130.01 (CH), 129.24 (C), 127.20 (CH), 121.52
CH), 115.54 (CH2), 112.02 (CH), 81.68 (C), 81.03 (C), 56.19 (CH2), 34.16
Synthesis of substrates 2, 8, 13, 14,
(
(
1
-(4-Hydroxybut-2-ynyloxy)-3,3-dimethylbutan-2-one
(2a). To
a
+
CH2), 30.00 (CH2). HRMS (QTof): calc. for C13H14ClO [M+1] 221.0733;
solution of but-2-yne-1,4-diol (1 g, 11.63 mmol) in dry DMF (30 mL) at 0
ºC, NaH 95 % (279 mg, 11.63 mmol) in dry DMF (5 mL) was added
dropwise. The mixturewasstirred for 1h, then1-bromo-3,3-dimethylbutan-
found 221.0727.
2
-(2-(4-Chlorobut-2-ynyloxy)phenyl)acetaldehyde (13). A 250 mL two-
2
-one (2.29 g, 12.79 mmol) wasadded and the mixture wasstirred for 4 h
necked round-bottomed flaskwas charged with a mixture of 13a (1 g, 4.5
mmol) and CH2Cl2 (100 mL). The flask was placed in a cooling bath
at room temperature. AqueousKHSO4 saturated solution wasadded and
the mixture extracted with Et2O. The ethereal solution was washed with
brine and dried over anhydrous Na2SO4. The solvent was removed and
the residue wassubmitted to flash chromatography (hexane/AcOEt85:15)
(acetone/dry ice) at -78ºC, anda calcium chloride drying tube wasused in
one of the necks. Then O3 was bubbled for 20 minutes until blue color
appeared. N2 was bubbled for 5 min. and Me2S (343 µL, 4.5 mmol) was
added. The mixture was stirred for 20 h, then the solvent was removed.
The crude residue was purified by chromatography (gradient
1
to give 985.6 mg (46%) of product 2a. H NMR (300 MHz, CDCl3) δ:4.42
s, 2H), 4.31 (s, 4H), 1.18 (s, 9H). 1 C NMR (75 MHz, CDCl3, DEPT) δ:
3
(
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European Journal of Organic Chemistry
10.1002/ejoc.201601444
FULL PAPER
hexane:AcOEt from 7:3 to 6:4). Compound 13 (0.1577 g, 0.7 mmol, 16%)
was obtained asa colorless oil. H NMR (300 MHz, CDCl3) δ (ppm) 9.72
2H), 4.88 (t, J = 2.0 Hz, 2H), 3.92 (t, J = 2.0 Hz, 2H). 13C NMR (75 MHz,
CDCl3, DEPT) δ: 189.3(CH), 159.7 (C), 135.7 (CH), 128.5 (CH), 125.5(C),
121.6 (CH), 113.2 (CH), 83.3 (C), 80.6 (C, C), 56.6 (CH2,), 13.5 (CH2).
1
(
1H, t, J= 2.1 Hz), 7.35-6.98 (4H, m), 4.78 (2H, t, J= 1.8 Hz), 4.16 (2H, t,
J= 1.8 Hz), 3.70 (2H, d, J= 2.1 Hz). 13C NMR (75 MHz, CDCl3, DEPT) δ
ppm) 199.90 (CH), 155.56(C), 131.49(CH), 128.86 (CH), 121.79 (CH,C),
+
HRMS (QTof): calc. for C11H10BrO2 [M+1] : 252.9864, 254.9844 ; found
252.9857, 254.9840.
(
1
12.05 (CH), 82.16 (C), 81.10 (C), 56.11 (CH2), 45.28 (CH2), 30.07 (CH2).
+
HRMS (QTof): calc. for C12H12ClO2 [M+1] 223.0526; found 222.0520
2-((4-Bromobut-2-yn-1-yl)oxy)-5-chlorobenzaldehyde (4). Reaction of
+
[
M+1] .
5
-chloro-2-hydroxybenzaldehyde (500 mg, 3.76 mmol) with 1,4-
dibromobut-2-yne in THF according to the general procedure A afforded
1
2
-(3-Hydroxypropyl)phenol (14a). To a solution of NaBH4 (0.395 g, 10
532 mg (59%) of product 4, isolated asa white solid. mp 73.2-75.3 ºC. H
mmol) in THF (6 mL), 3,4-dihydrochromen-2-one (841 µL, 6.7 mmol) was
added. The mixture was refluxed for 2 h, then, it was cooled until room
temperature and aqueous NH4Cl saturated solution (5 mL) was added
dropwise for 10 min. The mixture wasstirred for 4 h. It was extracted with
AcOEt and the organic layer was dried over anhydrous MgSO4. After
filtration, the solvent was evaporated under reduce pressure. Compound
NMR (300 MHz, CDCl3) 10.41 (s, 1H), 7.82 (d, J = 2.8 Hz, 1H), 7.53 (dd,
J = 8.9, 2.8 Hz, 1H), 7.07 (d, J = 8.9 Hz, 1H), 4.90 (t, J = 2.0 Hz, 2H), 3.93
1
3
(t, J = 2.0 Hz, 2H). δ: C NMR (75 MHz, CDCl3, DEPT) δ: 188.1 (CH),
158.1 (C), 135.2 (CH), 128.2 (CH), 127.5 (C), 126.4 (C), 114.9 (CH), 83.8
(C), 80.1 (C), 57.0 (CH2), 13.3 (CH2). HRMS (QTof): calc. for C11H9BrClO2
+
[M+1] : 286.9474, 288.9454; found286.9365, 288.9449.
1
4a (0.6754 g, 66%) was obtained asa colorless oil. Spectral data are in
1
1
agreement withliterature values.
5
-Bromo-2-((4-bromobut-2-yn-1-yl)oxy)benzaldehyde (5). Reaction of
5
-bromo-2-hydroxybenzaldehyde (500 mg, 2.98 mmol) with 1,4-
3
-(2-(4-Chlorobut-2-ynyloxy)phenyl)propan-1-ol (14b). K2CO3 (0.6081
dibromobut-2-yne in DMF according to the general procedure A afforded
g, 4.4 mmol) and 1,4-dichlorobut-2-yne(714 µL, 7.1 mmol) were addedto
a solution of 14a (0.6754 g, 4.4 mmol) in acetone (4.5 mL). The mixture
was refluxed for 24 h. The reaction was quenched with HCl 5% (15 mL)
and extracted with Et2O. The organic layer was washed with saturated
brine, dried over anhydrous MgSO4. After filtration, the solvent was
evaporated under reduce pressure and purified by column
460 mg (56%) of product 5, isolated asa white solid. mp 65.1-67.3 ºC. IR
-1
1
(film) v (cm ): 2877, 1684, 1472, 1003, 742, 620. H NMR (300 MHz,
CDCl3) δ: 10.37 (s, 1H), 7.94 (d, J = 2.6 Hz, 1H), 7.65 (dd, J = 8.9, 2.6 Hz,
1H), 7.00 (d, J = 8.9 Hz, 1H), 4.88 (t, J = 2.0 Hz, 2H), 3.92 (t, J = 2.0 Hz,
1
3
2H). C NMR (75 MHz, CDCl3, DEPT) δ: 188.0 (CH), 158.6 (C), 138.1
(CH), 131.2 (CH), 126.7 (C), 115.3 (CH), 114.6 (C), 83.8 (C), 80.1 (C),
+
chromatography (gradient hexane:AcOEt from 9:1 to 65:35). Compound
56.9 (CH2), 13.4 (CH2). HRMS (QTof): calc. for C11H9Br2O2 [M+1] :
1
1
4b (0.5521 g, 2.3 mmol, 52%) was obtained as a colorless oil. H NMR
332.8949; found332.8922.
(300 MHz, CDCl3) δ (ppm) 7.24-6.93 (4H, m), 4.79 (2H, s), 4.19 (2H, s),
3
.65 (2H, t, J= 6.3 Hz), 2.75 (2H, t, J= 7.5 Hz), 1.88 (2H, q, J= 6.9 Hz).
5-bromo-2-(4-bromobut-2-ynyloxy)-3-methylbenzaldehyde
(6).
+
HRMS (QTof): calc. C13H15ClO2 238.0761; found238.0757 [M+1] .
Reaction of compound 6b (215 mg, 1 mmol) with 1,4-dibromobut-2-yne in
THF according to the general procedure A afforded product 6 (51%),
-1
3
-(2-(4-Chlorobut-2-ynyloxy)phenyl)propanal (14). To a suspension of
PCC (1.0184 g, 4.6 mmol) in CH2Cl2 (20 mL), a solutionof 14b (0.5520 g,
.3 mmol) inCH2Cl2 (15 mL) wasadded dropwise. The mixture wasstirred
isolated as a light yellow-green oil. IR (film) v (cm ): 2870, 2254, 1685,
1
1470, 1208, 1120,1003, 726. H NMR (400 MHz, CDCl3) δ: 10.30 (s, 1H),
2
7.81 (d, J= 2.5 Hz,1 H), 7.58 (d, J= 2.2Hz, 1H), 4.72 (t, J= 2.0Hz, 2H), 3.84
1
3
for 1 h, then Et2O (40 mL) was added and it was stirred for another hour.
(t, J= 2.0Hz, 2H), 2.34 (s, 3H). C NMR (100 MHz, CDCl3) (DEPT) δ: 188.8
(CH), 157.6 (C), 139.7 (CH), 135.0(C), 131.6(C), 129.0(CH), 118.3(C),
84.6 (C), 80.4 (C), 62.5 (CH2), 15.7 (CH3), 13.2(CH2). HRMS (QTOF ES+):
The whole was filtered on silica gel. Compound 14 (0.4412 g, 1.9 mmol,
8
2
-1
1%) was obtainedasa colorlessoil. IR (film) v (cm ): 3065, 2928,2725,
1
+
252, 1720, 1600. H NMR (300 MHz, CDCl3) δ (ppm) 9.83 (1H, t, J= 1.5
calculated for C12H11Br2O2 [M+H] : 344.9121, 346.9100,348.9080; found:
Hz), 7.28-6.93 (4H, m), 4.78 (2H, t, J= 1.8Hz), 4.18 (2H, t, J= 1.8 Hz), 2.98
2H, t, J= 7.5 Hz), 2.75 (2H, m). 13C NMR (75 MHz, CDCl3, DEPT) δ (ppm)
02.30 (CH), 155.34 (C), 130.20 (CH), 129.21 (C), 127.58 (CH), 121.51
CH), 111.79 (CH), 81.92 (C), 81.44 (C), 55.91 (CH2), 43.82 (CH2), 30.17
CH2), 23.32 (CH2). HRMS (QTof): calc. C13H13ClO2 236.0604; found
344.9117, 346.9097, 348.9086.
(
2
5
-Bromo-2-(4-bromobut-2-ynyloxy)-3-tert-butylbenzaldehyde
(7).
(
(
Reaction of compound 7b (257 mg, 1 mmol) with 1,4-dibromobut-2-yne in
THF according to the general procedure A afforded product 7 (58%),
+
2
36.0610 [M+1] .
-1
isolated as a light yellow-green oil. IR(film) v (cm ): 2872, 2250, 1687,
1
1
471, 1203, 1121, 1005,725. H NMR (400 MHz, CDCl3) δ 10.23 (s, 1H),
Synthesis of substrates 3, 4, 5, 6, 7, 9, 10, 11, 12. General procedure
for SN2 reactions. Salicylaldehyde or 2-hydroxyacetophenone
derivatives (1 equiv) were added to a stirred mixture of sodium hydride,
0 % dispersion in mineral oil, (1.2 equiv.) indry DMF (3 mL/mmol) or THF
3 mL/mmol) at 0º C. Then, 15-crown-5 (1.2 equiv.) was added. After 15
7.80 (d, J = 2.6 Hz, 1H), 7.66 (d, J = 2.6 Hz, 1H), 4.71 (t, J = 2.1 Hz, 2H),
1
3
A
3.89 (t, J = 2.1 Hz, 2H), 1.41 (s, 9H). C NMR (100 MHz, CDCl3) (DEPT)
δ: 188.4 (CH), 159.1 (C), 146.6 (C), 136.3 (CH), 131.8 (C), 130.5 (CH),
117.8 (C), 84.5 (C), 80.3 (C), 65.2 (CH2), 35.16(C), 30.7(CH3), 13.2 (CH2).
6
(
+
HRMS (QTOF ES+): calculated for C15H17Br2O2 [M+H] : 388.9575,
min, 1,4-dibromobut-2-yne(1.2 equiv) wasadded quickly and themixture
stirred for 12h. at room temperature. AqueousNaHCO3 saturated solution
was added and the mixture extracted withEt2O.Theethereal solution was
washed with brine and dried over anhydrous MgSO4. The solvent was
removed and the residue was submitted to flash chromatography
386.9595, 390.9554; found:388.9580, 386.9593, 390.9551.
1
-(2-((4-Bromobut-2-yn-1-yl)oxy)phenyl)ethanone (9). Reaction of 2-
hydroxyacetophenone (570 µL, 3.67 mmol) with 1,4-dibromobut-2-yne in
THF according to the general procedure A afforded 503 mg (51%) of
(hexane/Et2O mixtures) to give the corresponding product.
-1
product 9, isolated asa white solid.mp 39.8-41ºC. IR (film) v (cm ): 3002,
1
2
249, 1688, 1291, 1003, 754. H NMR (300 MHz, CDCl3) δ: 7.72 (dd, J =
2
-((4-Bromobut-2-yn-1-yl)oxy)benzaldehyde (3). Reaction
of
7.9, 1.9 Hz, 1H), 7.49 – 7.43 (m, 1H), 7.06 – 7.02 (m, 2H), 4.85 (t, J = 2.0
Hz, 2H), 3.92 (t, J = 2.0 Hz, 2H), 2.62 (s, 3H). 13C NMR (75 MHz, CDCl3,
DEPT) δ: 199.4 (C), 156.7 (C), 133.4 (CH), 130.4 (CH), 129.1 (C), 121.6
(CH), 113.2 (CH), 82.9 (C), 80.9 (C), 56.5 (CH2), 31.8 (CH3), 13.6 (CH2).
salicylaldehyde (600 µL, 4.13 mmol) with 1,4-dibromobut-2-yne in THF
according to the general procedure A afforded 533 mg(51%) of product3,
isolated as a white solid. mp 46.5-47.6 ºC. IR (film) v (cm ): 2871, 2252,
-1
1
+
1
684, 1474, 1208, 1121, 1000, 728. H NMR (300 MHz, CDCl3) δ: 10.46
HRMS (QTof): calc. for C12H12BrO2 [M+1] : 287.0021, 269.0000; found
(s, 1H), 7.84 (dd, J = 7.8, 1.8 Hz, 1H), 7.59 – 7.53 (m, 1H), 7.10 – 7.05(m,
287.0010, 268.9992.
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201601444
FULL PAPER
1
-(2-((4-Bromobut-2-yn-1-yl)oxy)-4-fluorophenyl)ethanone
Reaction of 4-fluoro-2-hydroxyacetophenone (500 mg, 3.18 mmol) with
,4-dibromobut-2-yne in THF according to the general procedure A
afforded 352 mg (39%) of product 10, isolated asa white solid. mp 58.8-
(10).
6-Chloro-4-trimethylsilyloxy-3-vinylidenechromane (17). Reaction of
2-((4-bromobut-2-yn-1-yl)oxy)-5-chlorobenzaldehyde (4) (100 mg, 0.348
mmol) according to the general procedure B afforded 86 mg (0.32 mmol,
1
-1
92%) of product 17, isolated ascolorlessoil. IR (film) v (cm ): 2956, 1962,
-1
1
1
6
0.3 ºC. IR (film) v (cm ): 3019, 1664, 1584, 1419, 1221, 1010, 827. H
NMR (300 MHz, CDCl3) δ: 7.86 – 7.80 (m, 1H), 6.80 – 6.74 (m, 2H), 4.87
t, J = 2.0 Hz, 2H), 3.94 (t, J = 2.0 Hz, 2H), 2.62 (s, 3H). 13C NMR (75 MHz,
CDCl3, DEPT) δ: 197.6 (C), 164.2 (C), 158.3 (C), 132.7 (CH), 125.1 (C),
1479, 1226, 1037,838,723. H NMR (300 MHz, CDCl3) δ: 7.20 – 7.13(m,
2H), 6.80 (d, J = 8.7 Hz, 1H), 5.12 (s, 1H), 4.98 – 4.97 (m, 2H), 4.78 (dt, J
= 11.4, 2.8 Hz, 1H), 4.63 (dd, J = 11.4, 0.9 Hz, 1H), 0.24 (s, 9H). 13C NMR
(75 MHz, CDCl3, DEPT) δ: 204.5 (C), 152.7 (C), 129.3 (CH), 128.9 (CH),
126.0 (C), 125.4 (C), 118.4 (CH), 96.8 (C), 77.5 (CH2), 66.0 (CH), 64.5
(
1
08.5 (CH), 100.9 (CH), 83.5 (C), 80.0 (C), 56.7 (CH2), 31.8 (CH3), 13.2
+
+
(CH2). HRMS (QTof): calc. for C12H11BrFO2 [M+1] : 284.9926, 286. 9906;
(CH2), 0.3 (CH3). HRMS (Qtof): calc. for C14H18ClO2Si [M+1] : 281.0759;
found 284.9924,286.9900.
found 281.0703.
1
-(2-((4-Bromobut-2-yn-1-yl)oxy)-5-chlorophenyl)ethanone
Reaction of 5-chloro-2-hydroxyacetophenone (500 mg, 2.90 mmol) with
,4-dibromobut-2-yne in THF according to the general procedure A
afforded 410 mg (47%) of product 11, isolated asa white solid. mp 74.3-
(11).
6-Bromo-4-trimethylsilyloxy-3-vinylidenechromane (18). IR (film) v
(cm ):2956, 1962, 1476, 1224, 998, 843, 815, 613. 1H NMR (300 MHz,
CDCl3) δ: 7.33 – 7.27 (m, 2H), 6.74 (d, J = 8.7 Hz, 1H), 5.12 (s, 1H), 4.97
– 4.96 (m, 2H), 4.77 (dt, J = 11.4, 2.8 Hz, 1H), 4.62 (dd, J = 11.4, 0.9 Hz,
1H), 0.24 (s, 9H). 13C NMR (75 MHz, CDCl3, DEPT) δ: 204.5 (C), 153.2
(C), 132.1 (CH), 131.8 (CH), 126.7 (C), 118.8 (CH), 112.6 (C), 96.9 (C),
77.4 (CH2), 66.1 (CH), 64.5 (CH2), 0.2 (CH3). HRMS (Qtof): calc. for
-1
1
-1
1
7
9.6 ºC. IR (film) v (cm ): 2885, 2256, 1670, 1473, 1180, 902, 640. H
NMR (300 MHz, CDCl3) δ: 7.83 (d, J = 2.6 Hz, 1H), 7.55 (dd, J = 8.8, 2.6
Hz, 1H), 6.95 (d, J = 8.8 Hz, 1H), 4.85 (t, J = 2.0 Hz, 2H), 3.92 (t, J = 2.0
Hz, 2H), 2.61 (s, 3H). 13C NMR (75 MHz, CDCl3, DEPT) δ: 197.8 (C), 155.6
+
C14H18BrO2Si [M+1] :325.0254; found 325.0224.
(C), 135.8 (CH), 133.0 (CH), 130.5 (C), 115.1 (CH), 114.2 (C), 83.4 (C),
8
0.3 (C), 56.8 (CH2), 31.7 (CH3), 13.3 (CH2). HRMS (QTof): calc. for
6
-Bromo-3-vinylidenechroman-4-ol (18a). To a solution of 18 (65mg,
+
C12H11BrClO2 [M+1] : 300.9631, 302.9610; found300.9621, 302.9602.
0.20 mmol) in THF (1 mL), 0.6 mL of n-Bu NF (1 M in THF) were added.
4
The reaction mixture was stirred under reflux for 12 h. Then, the solvent
was removed under reduced pressure and the residue was dissolved in
Et2O, washed with brine, dried over MgSO4 and filtered. The solvent was
again removed. Compound 18a (43mg, 0.17 mmol, 85%) was obtained
after purification by flash chromatography SiO2 (hexane/Et2O 4:6). IR (film)
1
-(5-Bromo-2-((4-bromobut-2-yn-1-yl)oxy)phenyl)ethanone
Reaction of 5-bromo-2-hydroxyacetophenone (500 mg, 2.28 mmol) with
,4-dibromobut-2-yne in THF according to the general procedure A
afforded 347 mg (44%) of product 12, isolated asa white solid. mp 78.3-
(12).
1
-1
1
-1
1
8
1.2 ºC. IR (film) v (cm ): 3001, 2243, 1664, 1476, 1205, 1003, 806. H
v (cm ): 3358, 2921, 1961, 1478, 1001, 750. H NMR (300 MHz, CDCl3)
δ: 7.55 (d, J = 2.5 Hz, 1H), 7.32 (dd, J = 8.8, 2.5 Hz, 2H), 6.77 (d, J = 8.8
Hz, 1H), 5.21 (s, 1H), 5.07 (dd, J = 4.2, 2.0 Hz, 2H), 4.78 (dd, J = 11.8, 2.4
NMR (300 MHz, CDCl3) δ: 7.84 (d, J = 2.6 Hz, 1H), 7.56 (dd, J = 8.8, 2.6
Hz, 1H), 6.95 (d, J = 8.8 Hz, 1H), 4.86 (t, J = 2.0 Hz, 2H), 3.93 (t, J = 2.0
1
3
13
Hz, 2H), 2.62 (s, 3H). C NMR (75 MHz, CDCl3, DEPT) δ: 197.87 (C),
55.60 (C), 135.82 (CH), 133.05 (CH), 130.49 (C), 115.13 (CH), 114.26
C), 83.41 (C), 80.29 (C), 56.76 (CH2), 31.70 (CH3), 13.31 (CH2). HRMS
Hz, 1H), 4.68 – 4.63 (m, 1H). C NMR (75 MHz, CDCl3, DEPT) δ: 204.00
1
(
(C), 153.30 (C), 132.45 (CH), 131.53 (CH), 126.07 (C), 118.84 (CH),
113.03 (C), 97.33 (C), 78.88 (CH2), 64.91 (CH2), 64.85 (CH). HRMS
+
+
(QTof): calc. for C12H11Br2O2 [M+1] : 346.9105; found 346.9126.
(QTof): calc. for C12H11BrO2 [M+1] : 252.9859; found 252.9849.
General experimentalprocedure B for the Ti(III) mediated cyclization.
6-Bromo-8-methyl-3-vinylidenechroman-4-ol (19).
Reaction of
[
TiCp2Cl2] (0.2equiv.) and Mndust (8 equiv.) are placed in a Schlenkflask
compound 6 (173 mg, 0.5 mmol) according to the general procedure B
afforded 134 mg (0.475mmol, 95%) of product 19, isolated as a light
under an Ar atmosphere. Then, carefully deoxygenated,dry THF (20 mL)
isadded and thered suspension isstirred at room temperature until it turns
lime green (after about 15 min). Next, a mixture of Me3SiCl (4 equiv.) and
-1
brown-green oil. IR (film) v (cm ): 3230, 2922, 2005, 1731, 1646, 1251,
1
1193, 1097, 933, 843, 734, 591. H NMR (400 MHz, CDCl3) δ: 7.37 (d, J=
2
,4,6-collidine (7 equiv.) in THF is added. Finally, a solution of the
2.5 Hz, 1H), 7.20 (d, J= 2.2 Hz, 1H), 5.18 (br s, 1H), 5.05 (br s, 2H), 4.78
substrate (1 equiv.) in THF (2 mL) is added dropwise over a period of 15
min and the mixture stirred for another 6 h. The reaction isquenched with
(dt, J= 11.7, 2.5 Hz ,1H), 4.68 (dt, J= 11.7, 1.4 Hz, 1H), 2.17 (s, 3H).13
C
NMR (100 MHz, CDCl3) (DEPT) δ: 203.9 (C), 151.4 (C), 133.2(CH), 129.1
2
N HCl and the organic solvent removed invacuo. The residue isdiluted
(CH), 128.7 (C), 125.2 (C), 112.4 (C), 97.2 (C), 78.9(CH2), 65.1 (CH), 64.8
-
in Et2O, washed with brine, dried (anhydrous MgSO4) and the solvent
evaporated. Products were always purified by silica gel flash column
chromatography (hexane/Et2O mixtures).
(CH2), 15.8 (CH3). HRMS (QTOF ES-): calculated for C12H10BrO2 [M-H]:
264.9869, 266.9884; found:264.9868, 266.9876.
6
-Bromo-8-tert-butyl-3-vinylidenechroman-4-ol (20). Reaction of
3
-(tert-Butyl)-4-vinylidenetetrahydrofuran-3-ol (15). Reaction of
compound 7 (100 mg, 0.26 mmol) according to the general procedure B
afforded 68 mg (84%) of product 20,isolatedasa light brown-greenoil. IR
compound 2 (150 mg, 0.74 mmol) according to the general procedure B
afforded 80.9 mg (65%) of product 15, isolated as colorless oil. 1H NMR
-1
(film) v (cm ): 3166, 2954, 1974,1730, 1431, 1252,1214, 1157, 1001, 871,
1
(300 MHz, CDCl3) δ: 5.06 (ddd, J = 11.0, 4.6, 3.8 Hz, 1H), 4.94 (ddd, J =
846, 733, 645, 519. H NMR (400 MHz, CDCl3) δ: 7.41 (d, J= 2.5 Hz, 1H),
1
4
1.0, 4.7, 3.9 Hz, 1H), 4.58 (dt, J = 11.9, 3.8 Hz, 1H), 4.37 – 4.29 (m, 1H),
7.30 (d, J= 2.5 Hz, 1H), 5.18 (br s, 1H), 5.06 (br s, 2H), 4.73 (dt, J= 11.8,
2.6 Hz, 1H), 4.68(dt, J= 11.8, 1.8 Hz, 1H), 1.35(s, 9H). C NMR (100 MHz,
13
13
.01 (dd, J = 9.7, 0.4 Hz, 1H), 3.77 (d, J = 9.6 Hz, 1H), 1.06 (s, 9H).
C
NMR (75 MHz, CDCl3, DEPT) δ: 199.8 (C), 106.2 (C), 85.7 (C), 80.7(CH2),
CDCl3) (DEPT) δ: 203.6 (C), 152.2 (C), 140.7 (C), 129.8 (CH), 129.4 (CH),
7
7.0 (CH2), 70.2 (CH2), 25.3 (CH3). HRMS (QTOF ES+): calc. for C10H17O
126.8 (C), 113.2 (C), 97.7 (C), 79.3 (CH2), 65.2 (CH), 64.4 (CH2), 35.01
(C), 29.5 (CH3). HRMS (QTOF ES-): calculated for C15H16BrO2 [M-H]:
+
-
[
M+H] : 169,1229; found 169,1235.
3
07.0339, 309.0318; found:307.0344, 309.0325
3
-Vinylidenechroman-4-ol (16) Reaction of 2-((4-Bromobut-2-yn-1-
yl)oxy)benzaldehyde (3) (100 mg, 0.395 mmol) according to the general
procedure B afforded 63 mg(92%) of product 16, isolatedascolorlessoil.
Data corresponds to that quoted in theliterature.12
Tetrahydro-4-methyl-3-vinylidene-2H-pyran-4-ol (21). Reaction of
compound 8 (150 mg, 0.68 mmol) according to the general procedure B
afforded 90.3 mg (94%) of product 21, isolated as colorless oil. 1H NMR
(300 MHz, CDCl3) δ: 4.93 (d, J = 10.6 Hz, 1H), 4.88 (dd, J = 11.0, 2.1 Hz,
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201601444
FULL PAPER
1
H), 4.38 (dt, J = 12.1, 2.6 Hz, 1H), 4.15 (d, J = 12.1 Hz, 1H), 3.97 – 3.90
3,4,5,6-tetrahydro-4-trimethylsilyloxi-3-vinylidene-2H-
(
m, 1H), 3.79 (dt, J = 11.6, 4.4 Hz, 1H), 1.86 – 1.73 (m, 2H), 1.42 (s, 3H).
benzo[b]oxocine (27). Reaction of compound 14 (100 mg, 0.42 mmol)
1
3
C NMR (75 MHz, CDCl3, DEPT) δ: 201.6 (C), 104.3(C), 78.4 (CH2), 67.9
C), 66.9 (CH2), 64.7 (CH2), 40.1 (CH2), 27.98 (CH3). HRMS (ES): m/z calc.
according to the general procedure B afforded 109 mg (0.40 mmol, 95%)
-1
(
of product 27 isolatedascolorlessoil. IR (film) v (cm ): 2928, 2865, 1953,
+
1
for C8H13O2 [M+H] : 141.0916; found 141.0922.
1490, 1215, 1037, 984. H NMR (300 MHz, CDCl3) δ (ppm) 7.35-7.03 (4H,
m), 4.64 (1H, m), 4.54 (2H, m), 4.50 (1H, m), 4.33 (1H, m), 2.91 (1H, m),
2.67 (1H, m), 1.93 (2H, m), 0.14 (9H, s). 13C NMR (75 MHz, CDCl3, DEPT)
δ (ppm) 206.93 (C), 156.01 (C), 137.07 (C), 129.95 (CH), 127.64 (CH),
4
-Methyl-3-vinylidenechroman-4-ol (22). Reaction of 1-(2-((4-bromobut-
-yn-1-yl)oxy)phenyl)ethanone (9) (45 mg, 0.168 mmol) according to the
2
1
24.54 (CH), 121.78 (CH), 103.61 (C), 76.33 (CH2), 74.92 (CH2), 71.87
general procedure B afforded 20 mg (0.106 mmol, 63%) of product 22,
isolated ascolorless oil. IR (film) v (cm ): 3431, 2927, 1961, 1484, 1219,
-1
(CH), 40.30 (CH ), 26.26 (CH ), 0.05 (CH ). HRMS (QTof): calc. for
2
2
3
+
006, 727 1H NMR (300 MHz, CDCl3) δ: 7.57 (dd, J = 7.8, 1.7 Hz, 1H),
C16H23O2Si [M+1] :275.1467; found 275.1475.
1
7
6
1
.21 (ddd, J = 8.2, 7.2, 1.7 Hz, 1H), 7.00 (ddd, J = 7.8, 7.2, 1.3 Hz, 1H),
.86 (dd, J = 8.2, 1.3 Hz, 1H), 5.11 (t, J = 2.1 Hz, 2H), 4.79 (dt, J = 11.9,
.9 Hz, 1H), 4.79 (dt, J = 11.9,2.2 Hz, 1H), 1.76 (s, 3H). 13C NMR (75 MHz,
Acknowledgements
CDCl3, DEPT) δ: 202.8 (C), 153.5 (C), 129.1 (CH), 128.9 (C), 126.5 (CH),
1
21.3 (CH), 117.0 (CH), 103.4 (C), 80.0 (CH2), 77.2 (C), 65.9 (CH2), 29.6
+
We w ould like to thank the financial support received from the
Spanish MINECO (Projects CTQ2015-70724-R and CTQ2011-
(CH3). HRMS (QTof): calc. for C12H13O2 [M+1] : 189.0910; found189.0900.
24443) and from "Junta de Andalucía" (Project P10-FQM-6050).
7
-Fluoro-4-methyl-3-vinylidenechroman-4-ol (23). Reaction of 1-(2-((4-
bromobut-2-yn-1-yl)oxy)-4-fluorophenyl)ethanone (10) (100 mg, 0.351
E. Roldan-Molina and C Hernandez-Cervantes to the Spanish
Ministery of Education for theirs FPU grants (FPU14/01472 and
AP2009-1266), and N. M. Padial to Junta de Andalucía for her
grant. A. Rosales acknow ledges University of the Sevilla for his
position as professor.
mmol) according to the general procedure B afforded 47 mg (0.21 mmol,
-
1
6
1
1
4
0%) of product 23, isolated ascolorlessoil. IR (film) v (cm ): 2852, 1597,
1
259, 1021, 703. H NMR (300 MHz, CDCl3) δ: 7.52 (dd, J = 8.8, 6.5 Hz,
H), 6.70 (m, 1H), 6.56 (dd, J = 10.1, 2.5 Hz, 1H), 5.11 (m, 2H), 4.82 –
.69 (m, 2H), 1.73 (s, 3H). C NMR (75 MHz, CDCl3) δ 202.8 (C), 164.5
1
3
(C), 161.2 (C), 127.8 (CH), 108.4 (CH), 103.7 (CH), 112.9 (C), 103.0 (C),
8
0.2 (CH2), 67.1 (C), 66.1 (CH2), 29.6 (CH3). HRMS (QTof): calc. for
Keywords:Titanium; heterocycles; exocyclic allenes; titanocene
+
C12H11FO2 [M+1] : 206,0743; found 206.0453.
catalyzed cyclizations; oxygenated heterocycles.
6
-Chloro-4-methyl-3-vinylidenechroman-4-ol (24). Reactionof 1-(2-((4-
[
[
1]
2]
A. Hoffmann-Röder, N. Krause, Angew. Chem. 2004, 116, 1216–1236;
Angew. Chem. Int. Ed. 2004, 43, 1196-1216.
bromobut-2-yn-1-yl)oxy)-5-chlorophenyl)ethanone (11) (70 mg, 0.232
mmol) according to the general procedure B afforded 30 mg (57%) of
product 24, isolated as colorless oil. IR (film) v (cm ): 3390, 2982, 1961,
For a recent review on the use of allenes in asymmetric synthesis and
natural product syntheses, see: S. Yu. S. Ma, Angew. Chem. 2012, 124,
-1
1
1
1
476, 1239, 1003, 806. H NMR (300 MHz, CDCl3) δ: 7.67 (d, J = 2.5 Hz,
H), 7.28 (dd, J = 8.7, 2.5 Hz, 1H), 6.73 (d, J = 8.7 Hz, 1H), 5.13 – 5.11
3128–3167; Angew. Chem. Int. Ed. 2012, 51, 3074-3112.
[
3]
a) For an extensive survey on allene synthesis: Modern Allene Chemistry,
Vol. 1 (Eds.: N. Krause and S. K. Hashmi). Wiley -VCH, Weinheim, 2004.
For recent reviews on the preparation of allenes: b) M. Periasamy, N.
Sanjeevakumar, M. Dalai, R. Gurubrahamam, P. O. Reddy, Org. Lett.
(
m, 2H), 4.77 (dt, J = 12.0, 2.0 Hz, 1H), 4.71(dt, J = 12.0,2.3 Hz, 1H), 1.73
s, 3H). 13C NMR (75 MHz, CDCl3, DEPT) δ: 202.7 (C), 152.7 (C), 131.9
CH), 131.0, (C), 129.2 (CH), 118.8 (CH), 113.1 (C), 103.0(C), 80.3 (CH2),
(
(
6
7.3 (C), 66.0 (CH2), 29.7 (CH3). HRMS (QTof): calc. for C12H12ClO2
2012, 14, 2932-2935; c) R. K. Neff, D. E. Frantz, ACS Catal. 2014, 4,
+
[
M+1] : 223.0520; found223.0510.
519−528; d) D. Tejedor, G. Méndez-Abt, L. Cotos, F. García-Tellado,
Chem. Soc. Rev., 2013, 42, 458-471; e) S. Yua, S. Ma, Chem. Commun. ,
2011, 47, 5384–5418.
6
-Bromo-4-methyl-3-vinylidenechroman-4-ol (25). Reaction of 1-(5-
bromo-2-((4-bromobut-2-yn-1-yl)oxy)phenyl)ethanone (12) (100 mg,
.289 mmol) accordingto the general procedure B afforded51 mg (66%)
[4]
[7]
a) T. V. RajanBabu, W. A. Nugent, J. Am. Chem. Soc. 1994, 116, 986-
997; and cited work; b) A. Rosales, I. Rodríguez-García, J. Muñoz-
Bascón, E. Roldan-Molina, N. M. Padial, L. P. Morales, M. García-Ocaña,
J. E. Oltra, Eur. J. Org. Chem. 2015, 4567-4592.
0
1
of product 25, isolated ascolorlessoil. H NMR (300 MHz, CDCl3) δ: 7.67
d, J = 2.4 Hz, 1H), 7.28 (dd, J = 8.7, 2.4 Hz, 1H), 6.73 (d, J = 8.7 Hz, 1H),
(
5
2
1
.13 (t, J = 2.0 Hz, 2H), 4.77 (dt, J = 12.0, 1.9 Hz, 1H), 4.71 (dt, J = 12.0,
J. Muñoz-Bascón, C. Hernández-Cervantes, N. M. Padial, M. Álvarez-
Corral, A. Rosales, I. Rodríguez-García, J. E. Oltra, Chem., Eur. J. 2014,
1
3
.3 Hz, 1H) 1.73 (s, 3H). C NMR (75 MHz, CDCl3, DEPT) δ: 202.7 (C),
52.6 (C), 131.9 (CH), 130.9 (C), 129.3(CH), 118.8 (CH), 113.3 (C), 102.8
20, 801-810.
(
C), 80.4 (CH2), 67.3 (C), 66.0 (CH2), 29.7 (CH3). HRMS (QTof): calc. for
[6]
[7]
D. J. Ramón, M. Yus, Chem. Rev. 2006, 106, 2126-2208.
+
C12H12ClO2 [M+1] : 267.0015; found267.0013.
A. F. Barrero, A. Rosales, J. M. Cuerva, J. E. Oltra, Org. Lett. 2003, 5,
1935-1938.
2
,3,4,5-tetrahydro-4-trimethylsilyloxi-3-vinylidenebenzo[b]oxepine
26). Reaction of compound 13 (40 mg, 0.18 mmol) according to the
general procedure B afforded 38 mg (0.15 mmol 83%) of product 26,
[8]
In order to reuse the excess of 2,4,6-collidine and Mn dust, a simple
filtration and acid-base extraction allowed us to recover both materials.
E. L. Eliel, S. H. Wilen, M. P. Doyle, Basic Organic Stereochemistry, John
Wiley & Sons, New York, 2001, pp 429-433.
(
[9]
-1
isolated ascolorless oil. IR (film) v (cm ): 3065, 2923, 2857, 1958, 1489,
226, 1044, 988. 1H NMR (300 MHz, CDCl3) δ (ppm) 7.23-6.98 (4H, m),
.85 (2H, m), 4.62 (1H, dt, J= 1.8 Hz, 12.3 Hz), 4.52 (1H, m), 4.45 (1H, dt,
J= 0.9 Hz, 12.3 Hz), 3.06 (2H, m), 0.11 (9H, s). C NMR (75 MHz, CDCl3,
DEPT) δ (ppm) 206.36 (C), 159.32 (C), 131.78 (CH), 129.80 (C), 127.76
[10]
It is generally accepted that in large rings there are neither Baeyer strain
nor transannular strain (see Ref . 9).
1
4
1
3
[11] A. Gridnev; C.A. Simoneau, S.D. Allen, J.J. Farmer, A.S. Godleski. PCT
Int. Appl. 2012075277, 2012.
(CH), 123.51 (CH), 120.78 (CH), 104.57 (C), 77.15 (CH2), 70.69 (CH2),
[12] H.Y. Kang, Y.T. Kim, Y.K. Yu, J.H. Cha, Y.S. Cho, H.Y. Koh. Synlett 2004,
6
9.41 (CH), 42.62 (CH2), -0.10 (CH3). HRMS (QTof): calc. for C15H21O2Si
45-48.
+
[
M+1] : 261.1311; found261.1320.
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European Journal of Organic Chemistry
10.1002/ejoc.201601444
FULL PAPER
Entry for the Table of Contents
FULL PAPER
Key Topic* Exocyclic Allenes.
a
Natalia M. Padial, Carmen Hernández-
b
a
Cervantes, Juan Muñoz-Bascón,
a
Esther Roldan-Molina, Mireya García-
b
b
Martínez, Ana Belén Ruiz-Muelle,
Antonio Rosales, Míriam Álvarez-
Corral, Manuel Muñoz Dorado, Ignacio
Rodríguez-García, * J. Enrique Oltra. *
c
b
b
Synthesis of exocyclic allenes on oxygenated 5-, 6-, 7- and 8-membered
heterocycles can be achieved through a Barbier-type titanocene(III) catalyzed
cyclization of propargyl halides w ith a pendant carbonyl group.
b
a
Page No. – Page No.
Ti-Catalyzed Synthesis of Exocyclic
Allenes on Oxygenated Heterocycles
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