Tandem Zn-Brook rearrangement/ene-allene carbocyclization

Article abstract of DOI:10.1002/ejoc.200900043

The addition of metalated alkynes to acylsilanes leads to the corresponding α-propargylsilanol derivatives. On addition of ZnBr₂, Zn-promoted Brook rearrangements take place to produce the propargyl/allenylzinc bromides, which undergo cyclization to give functionalized carbocycles as single diastereoisomers. Wiley-VCH Verlag GmbH & Co. KGaA.

Full text of DOI:10.1002/ejoc.200900043

FULL PAPER
DOI: 10.1002/ejoc.200900043
Tandem Zn-Brook Rearrangement/Ene-Allene Carbocyclization
Rozalia Unger,[a] Theodore Cohen,[b] and Ilan Marek*[a]
Dedicated to Professor Alain Krief
Keywords: Carbocycles / Cyclization / Ene reaction / Rearrangement / Brook rearrangement / Carbometalation
The addition of metalated alkynes to acylsilanes leads to the
corresponding α-propargylsilanol derivatives. On addition of
ZnBr2, Zn-promoted Brook rearrangements take place to pro-
duce the propargyl/allenylzinc bromides, which undergo cy-
clization to give functionalized carbocycles as single dia-
stereoisomers.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
Introduction
The ene reaction, originally described by Alder,[1] is a
powerful reaction in synthesis that has found many applica-
tions because of its highly organized transition state, which
provides all the necessary characteristics for the control of
relative and absolute configuration.[2] When both partners
are simple alkenes and are linked together so as to provide
for an intramolecular ene reaction, there is a preference for
the formation of cis-disubstituted cyclopentane[3] and trans-
disubstituted cyclohexane systems.[4] However, non-cata-
lyzed ene reactions usually require elevated temperatures,
and so the intramolecular metallo-ene reaction, in which a
metal atom is transferred instead of a hydrogen atom
(Scheme 1, path A), represents an interesting variant. Fur-
ther synthetic manipulations of the resulting organometallic
species can increase the molecular complexity. First de-
scribed in 1970,[5] the metallo-ene reaction proceeds under
milder conditions[6] and it has recently become abundantly
clear that zinc-ene cyclizations are far superior to the more
widely used magnesium-ene cyclizations.[7] Although the
ene-allene reaction, by flash vacuum pyrolysis, was origi-
nally disclosed more than 25 years ago,[8] the metallo-ene-
allene carbocyclization was developed more recently by our
group (Scheme 1, path B).[9]
Scheme 1. Ene vs. metallo-ene reactions.
lenyllithium species was observed even after the system had
been allowed to stand at room temperature for several
hours. The addition of 1 equiv. of magnesium salt to the
lithium derivative did not lead to the cyclic product either.
However, addition of 1 equiv. of ZnBr2 to the lithium deriv-
ative at –20 °C resulted in a virtually quantitative cycliza-
tion reaction after stirring at room temperature. Hydrolysis
of the reaction mixture led to the corresponding cyclopen-
tane 3 in excellent isolated yields and as a single dia-
stereoisomer (E = H, Scheme 2).
When 8-(trimethylsilyl)oct-1-en-7-yne (1) was metalated
at the propargylic position with sBuLi, either in THF or
Et2O, no cyclization reaction of the resulting propargyl/al-
To explain the stereoselectivity of the reaction, a zinc-
ene-allene transition state 2 in which the allenylzinc plays
the role of the ene moiety and fixes the cis relationship of
the two substituents was considered. When a substituent is
present on the carbon skeleton, a unique isomer is still
formed, and this was attributed to a preferred geometry in
which the substituent preferentially occupies a pseudoequa-
torial position.
[a] Mallat Family Laboratory of Organic Chemistry, Schulich Fa-
culty of Chemistry and Lise Meitner-Minerva Center for Com-
putational Quantum Chemistry, Technion – Israel Institute of
Technology
32000 Haifa, Israel
Fax: +972-4-8293709
E-mail: chilanm@tx.technion.ac.il
[b] Department of Chemistry, University of Pittsburgh
Pittsburgh, Pennsylvania 15260, USA
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R. Unger, T. Cohen, I. Marek
FULL PAPER
Scheme 2. Zn-ene-allene carbocyclization.
This strategy was extended to the stereoselective synthe-
ses of polysubstituted tetrahydrofurans[10] and pyrrolid-
ines[11] and to an efficient approach to angular and linear
triquinane skeletons,[12] as well as to zinc-yne-allene[13] car-
bocyclization reactions. However, the direct metalation of
propargylic benzyl ether 4a (R = CH2C6H5, Scheme 3) led
instantaneously to a Wittig rearrangement,[14] whereas met-
alation of 4b or 4c (R = SiEt3 or SiMe2tBu, respectively)
gave none of the cyclic product but instead a triene, presum-
ably formed through translocation of the metal and an al-
lylic proton.[15] Moreover, problems of regioselectivity may
arise when two acidic sites are present in the molecule (i.e.,
kinetic vs. thermodynamic metalation reactions, for the
metalation of 5, Scheme 3)[13] or between two nearly equiva-
lent acidic sites as in 6. Therefore, although the Zn-ene-
allene reaction is a very efficient and mild carbocyclization
reaction, we recently wondered whether it might be possible
to develop a simple synthetic solution that could overcome
these limitations.
Scheme 4. Brook vs. retro-Brook rearrangement.
of the lithium acetylide 7a to acylsilane 8,[20] no Brook re-
arrangement was detected after hydrolysis. Because the sta-
bility of the alkoxide correlates with the ion pairing capa-
bility of the counterion, the highly aggregated state and
tight ion pairing characteristics of lithium alkoxides stabi-
lize intermediates such as 9a.
Destabilization of alkoxides should therefore be achiev-
able through the addition of reagents that chelate metal
counterions, such as TMEDA. Even in the presence of
TMEDA, NMP, or crown ether, however, no Brook re-
arrangement was observed. When the hexenylmagnesium
species 7b was used as nucleophilic species, only a 7% yield
of the Brook product could be detected after hydrolysis.[21]
On the other hand, upon addition of methyl iodide to
9a, the alkylated allenic Brook product 10 was formed in
good yield. Hence, in the presence of a stoichiometric
amount of base, the Brook rearrangement does not proceed
and the equilibrium can only be switched towards the prod-
uct by the presence of an electrophile (Scheme 5). Indeed,
Brook rearrangements usually proceed when catalytic
amounts of base are utilized and the typically rapid and
essentially irreversible reaction takes place through proton-
ation of the carbanion variously by the conjugate acid, by
the starting alcohol, or by an excess of the starting alkyne
possessing an acetylenic acidic hydrogen, but never when a
stoichiometric amount of base is used.[22]
Scheme 3. Limitations of the method.
A possible solution to this problem would be to prepare
propargyl/allenyl metal species such as 2 without any met-
alation step. How might we achieve such a transformation?
However, if one desires to have a specific carbanionic
species in hand for subsequent reactions (i.e., carbometal-
ation), the addition of an external electrophilic partner rep-
resents a limitation to the wide applicability of such pro-
Results and Discussion
Fortunately, intramolecular 1,2-anionic migrations of si- cesses. Can this equilibrium be displaced towards the for-
lyl groups from carbon atoms to oxygen atoms were origi- mation of the propargyl/allenyl metal derivatives without
nally recognized and studied by A. G. Brook in the late addition of an electrophile? Considering that an additional
1950s and early 1960s (Scheme 4);[16] these rearrangements, factor for an efficient Brook rearrangement should be the
extended to [1,n]-silyl migrations (such as the retro-Brook stability of the formed organometallic species after mi-
or West rearrangements),[17] have found increasing use in gration, we hypothesized that a rearranged organozinc
organic synthesis.[18,19]
should afford extra stabilization through overlap of the
The presence of an electron-withdrawing group (such as nonbonding electrons of the oxygen atom and the filled d
an alkynyl moiety in R1 for the [1,2]-silyl migration) should orbitals of the metal with the π-antibonding orbitals of the
stabilize the developing negative charge of the carbanion carbon–carbon bonds.[23]
and then promote the migration of the silyl group from car-
When alkynylmagnesium bromides 11a–c were added to
bon to oxygen. However, in the case of the lithium salt 9a acysilanes 8a and 8b, the α-silylmagnesium carbinols 12a–c
of the α-silylpropargylic alcohol generated by the addition were formed in excellent yields (Scheme 6). After addition
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Tandem Zn-Brook Rearrangement/Ene-Allene Carbocyclization
Scheme 5. Effect on an electrophile on the Brook rearrangement.
Scheme 6. Zn-promoted Brook rearrangements.
of a solution of zinc bromide in THF, the corresponding
With an efficient Zn-promoted Brook rearrangement to
zinc derivative 13a–c underwent Brook rearrangements to hand, we turned our attention to the combined Zn-Brook
afford two product types 14 and 16 after hydrolysis as rearrangement/Zn-ene-allene cyclization reaction, starting
shown in Scheme 6 and Table 1.
with addition of compounds 11 to the ω-ene acylsilane 17.
Several representative alkynes such as 11a–c were tested in
this reaction, as described in Scheme 7 and Table 2. In all
cases, acylsilane 17 was slowly added over a period of
30 min to afford the corresponding α-alkoxypropargyl-
silanes 18a–c. Then, on addition of one equivalent of zinc
bromide, the Brook rearrangements took place to give the
corresponding propargyl/allenylzinc derivatives, which was
Table 1. Zinc-promoted Brook rearrangements.
Entry
R
Starting material
8 (n)
14/16[a]
Yield (%)[b]
1[c]
2[d]
3[d]
SiMe3
Ph
Hex
11a
11b
11c
8a (1)
8a (1)
8b (1)
1.5:1
40:1
3:1
90
85
73
[a] Ratio determined on the crude product by NMR. [b] Deter-
mined after purification by column chromatography on silica gel. immediately followed by diastereoselective Zn-ene-allene
cyclization (Scheme 7).[25]
[c] Reaction mixture was stirred at room temperature overnight.
[d] Reaction mixture was stirred at reflux overnight.
The reactions proceeded smoothly for all tested metalated
alkynes [11a (R = SiMe3), 11b (R = Ph), 11c (R = Hex),
It is not surprising that compounds 13a–c rearrange Entries 1 to 3, respectively in Table 2], although in the case
more readily than 12a–c in view of the higher bond dissoci- of 11c the cyclization could not be completed (the remaining
ation energy of the Mg–O bond (94 kcalmol–1) relative to being the hydrolyzed product obtained after the Brook re-
the Zn–O bond (68 kcalmol–1).[24] Several zinc salts were arrangement),[26] as judged from the formation of the car-
tried for the conversion of 12a to the Brook rearrangement bocycles 20a–c after hydrolysis. The formation of discrete
products 14 and 16 [ZnBr2 (90%), ZnCl2 (65%), ZnI2 organometallic species was checked by iodinolysis, as de-
(40%), Zn(OTf)2 (32%)], and zinc bromide was found to be scribed for the formation of 20d (Table 2, Entry 4). The cis
the most efficient for Brook rearrangements (zinc triflate configurations between methyl groups and alkynyl moieties
was insoluble in THF). Moreover, THF was found to be were determined by comparison with literature data for
the optimal solvent for the Brook rearrangements, because 20a[27] and assigned by analogy for all other compounds.
Et2O and DME gave poorer results (15 and 40%, respec- This unique stereochemistry can be explained in terms of a
tively).
zinc-ene-allene transition state 19 as illustrated in Scheme 7.
Eur. J. Org. Chem. 2009, 1749–1756
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R. Unger, T. Cohen, I. Marek
FULL PAPER
Scheme 7. Zn-Brook rearrangement/ene-allene cyclization.
Table 2. Tandem zinc-promoted Brook rearrangement/ene-allene
carbocyclization.
Table 3. Tandem zinc-promoted Brook rearrangement/ene-allene
carbocyclization of substituted acylsilanes 21 to afford cyclic prod-
ucts 24a–c.
Entry
R
Starting material E–X Products
dr[a]
Yield (%)[b]
Entry
R
Starting material
Product
dr[a]
Yield (%)[b]
1
2
3
4
SiMe3
Ph
Hex
11a
11b
11c
11a
H3O+
H3O+
H3O+
I2
20a
20b
20c
20d
Ͼ98:2
Ͼ98:2
Ͼ98:2
Ͼ98:2
89
70
52
60
1
2
3
SiMe3
Ph
Hex
11a
11b
11c
24a
24b
24c
1:1
1:1
1:1
73
67
62
SiMe3
[a] Ratio determined on the crude product by NMR. [b] Deter-
mined after purification by column chromatography on silica gel.
[a] Ratio determined on the crude product by NMR. [b] Deter-
mined after purification by column chromatography on silica gel.
As would expected, when acylsilane 21, possessing a sub- known to be configurationally stable,[28] and our ongoing
stituent in the allylic position, was treated with alkynylmag- research is intended to clarify this hypothesis.
nesium bromide derivatives 11a–c the two diastereoisomers
Finally, we turned our attention to carbocyclization of
22a–c were obtained, in 1:1 ratios in all cases (Scheme 8 alkynes to solve the problem of regioselectivity illustrated
and Table 3). Further, when the zinc salt was added and the in Scheme 3 for the metalation of 5 when two acidic sites
system was subjected to our tandem Zn-Brook rearrange- were present in the molecule (i.e., kinetic vs. thermo-
ment and Zn-ene-allene cyclization, pairs of cyclic isomers dynamic metalation reactions). The acylsilane 27 was there-
24a–c were obtained in good yields, also in 1:1 ratios.
fore first treated with alkynylmagnesium bromide deriva-
It is interesting to note, however, that the cyclization of tives 11a–c, and the corresponding α-propargylsilanol spe-
25, generated as described in our initial metalation ap- cies were then further treated with zinc bromide. After the
proach, leads to a single diastereoisomer 26 after hydroly- transmetalation reactions, the Brook rearrangements fol-
sis.[9] Therefore, we suggest that each diastereoisomer of the lowed by the Zn-yne-allene carbocyclizations gave, through
allenylzinc bromide 23 (with regard to the allylic stereogenic syn-carbometalation reactions, the corresponding exo-alk-
center), generated through our tandem reaction, leads to its ylidene cyclopentyl species 28a–c after hydrolysis (Scheme 9
own cyclic product 24, because allenylzinc species are and Table 4).
Scheme 8. Carbocyclization of allenylzinc species possessing allylic substituents.
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Tandem Zn-Brook Rearrangement/Ene-Allene Carbocyclization
125 MHz): δ = –4.8, 21.1, 35.0, 41.8, 128.0, 129.7, 133.8, 134.5,
246.1 ppm. FTIR (thin film): ν = 910, 997, 1081, 1162, 1253, 1350,
˜
1411, 1443, 1642, 2856, 2925, 2955 cm–1.
1-(Trimethylsilyl)hex-5-en-1-one (17): 1H NMR (CDCl3, 500 MHz):
δ = 0.16 (s, 9 H), 1.59 (quint, J = 7.5 Hz, 2 H), 1.99 (q, J = 7.0 Hz,
2 H), 2.57 (t, J = 7.2 Hz, 2 H), 4.91–4.98 (m, 2 H), 5.69–5.74 (m,
1 H) ppm. 13C NMR (CDCl3, 125 MHz): δ = –3.2, 21.1, 33.2, 47.5,
Scheme 9. Tandem Zn-Brook rearrangement/ene-yne cyclization.
115.0, 138.1, 248.3 ppm. FTIR (thin film): ν = 912, 997, 1079, 1091,
˜
Table 4. Tandem zinc-promoted Brook rearrangement/yne-allene
carbocyclization on substituted acylsilanes.
1162, 1249, 1351, 1411, 1443, 1642, 2856, 2927, 2956 cm–1.
4-Methyl-1-(trimethylsilyl)hex-5-en-1-one (21): 1H NMR (CDCl3,
300 MHz): δ = 0.15 (s, 9 H), 0.94 (d, J = 6.6 Hz, 3 H), 1.43–1.54
(m, 2 H), 2.00–2.05 (m, 1 H), 2.54 (t, J = 7.4 Hz, 2 H), 4.86–4.93
(m, 2 H), 5.50–5.62 (m, 1 H) ppm. 13C NMR (CDCl3, 75 MHz): δ
= –3.2, 20.3, 28.4, 37.5, 46.1, 113.2, 143.9, 248.3 ppm. FTIR (thin
Entry
R
Starting material Product
E/Z[a]
Yield (%)[b]
1
2
3
SiMe3
Ph
Hex
11a
11b
11c
28a
28b
28c
Ͼ99:1
Ͼ99:1
Ͼ99:1
75
63
72
[a] Ratio determined on the crude product by NMR. [b] Deter-
mined after purification by column chromatography on silica gel.
film): ν = 912, 995, 1077, 1090, 1162, 1249, 1353, 1411, 1443, 1639,
˜
2856, 2927, 2956 cm–1.
1,6-Bis(trimethylsilyl)hex-5-yn-1-one (27): 1H NMR (CDCl3,
300 MHz): δ = 0.03 (s, 9 H), 0.09 (s, 9 H), 1.60 (quint, J = 6.0 Hz,
2 H), 2.11 (t, J = 6.1 Hz, 2 H), 2.64 (t, J = 5.9 Hz, 2 H) ppm. 13C
NMR (CDCl3, 75 MHz): δ = –3.4, –3.3, 0.0, 19.0, 20.7, 46.4, 85.0,
Conclusions
In conclusion, the addition of metalated alkynes to acyl-
silanes leads to the initial formation of α-propargylsilanol
salts. Addition of ZnBr2 then promotes in situ Brook re-
arrangement followed by Zn-ene-allene (or Zn-yne-allene)
cyclization to give the corresponding polysubstituted car-
bocycles in good isolated yields and as unique diastereoiso-
mers with regard to the creation of quaternary and tertiary
stereocenters. It is remarkable that these processes involve
three successive rearrangements (Brook suprafacial, pro-
pargylic to allenylzinc and cyclization) and result in single
diastereomers of the cyclization products.
106.4, 247.2 ppm. FTIR (thin film): ν = 911, 1044, 1248, 1351,
˜
1407, 1430, 1645, 2173, 2900, 2957 cm–1.
General Procedure for the Brook Rearrangements: EtMgBr in Et2O
(1 , 1 equiv.) was added dropwise to a cold (0 °C) stirred solution
of terminal alkyne in THF. The mixture was first allowed to warm
to room temperature for 90 min and was then cooled to –78 °C for
very slow introduction of the acylsilane 8 over a period of 30 min.
After the addition was complete, the mixture was heated at reflux
for 45 min, and a solution of ZnBr2 in THF (1 , 1 equiv.) was
added at –60 °C. The reaction mixture was allowed to warm to
room temperature over several hours and the evolution was fol-
lowed by gas chromatography analyses of hydrolyzed aliquots. The
reaction mixture was then quenched at –5 °C with aqueous HCl
(1 , 10 mL) and extracted with Et2O (3ϫ10 mL). The combined
extracts were washed with saturated NaHCO3 and stirred for at
least 3 h with a few Na2S·9H2O crystals that enabled the removal
of all zinc salts before further purification. These were then re-
moved by filtration, and the organic solution was washed with
brine (2ϫ15 mL), dried with MgSO4, and concentrated to give the
mixture of propargyl alcohols 14 (after removal of the silyl moiety)
and α,β-unsaturated ketones 16.
Experimental Section
General: All reactions involving air- and moisture-sensitive com-
pounds were carried out under argon, with flamed flasks and dry,
oxygen-free solvents. Diethyl ether, tetrahydrofuran, and toluene
were distilled under argon from sodium benzophenone ketyl. nBuLi
and MeLi·LiBr were commercially obtained from Aldrich and ti-
trated under argon with isobutanol in toluene (1 ), with 1,10-
phenanthroline as indicator. All Grignard reagents were prepared
and titrated under argon with isobutanol in toluene (1 ), with
2,2Ј-biquinoline as indicator. Unless otherwise noted, commercially
available materials were used without further purification. Flash
chromatography (FC) was performed with silica gel 60 (230–
400 mesh). Thin layer chromatography was performed with pre-
coated plates (silica gel 60, 0.25 mm). All NMR spectra were re-
corded at room temperature with Bruker Avance 300 and Bruker
Avance 500 MHz instruments at operating frequencies of 300/
500 MHz (1H) or 75/125 MHz (13C), respectively. Chemical shifts
are referenced to the residual proton or carbon resonance of the
General Procedure for Desilylation: A solution of Bu4NF (1 ,
1.05 equiv.) was added at room temperature to a solution of the
corresponding silyl ether (1 mmol) in THF (3 mL). When the reac-
tion was complete, the crude mixture was concentrated under re-
duced pressure. Brine was then added, and the aqueous phase was
extracted five times with Et2O. Next, the combined organic phases
were washed once with brine, dried with MgSO4, and purified by
column chromatography (EtOAc/hexanes 5%) to give cyclic prod-
ucts as colorless liquids.
Compounds 14a and 16a were prepared by the general procedure
with trimethyl(1-oxo-3-phenylpropyl)silane (130.2 mg, 0.5 mmol),
(trimethylsilyl)acetylene (0.09 mL, 0.6 mmol), ethylmagnesium bro-
mide (0.6 mL, 0.6 mmol), and ZnBr2 (0.7 mL, 1  solution in THF,
0.7 mmol).
1
deuteriated solvent (chloroform δ = 7.24 ppm for H NMR or δ =
77.00 ppm for proton-decoupled 13C NMR) with J in Hz. All the
NMR spectroscopic data for our compounds were correlated with
data from the literature (see references cited therein).
Acylsilanes were prepared according to literature pro-
cedures.[20,22,29]
Trimethyl(1-oxo-3-phenylpropyl)silane (8a): 1H NMR (CDCl3,
300 MHz): δ = 0.15 (s, 9 H), 2.77–2.82 (m, 2 H), 2.88–2.93 (m, 2 H),
7.12–7.21 (m, 3 H), 7.22–7.27 (m, 2 H) ppm. 13C NMR (CDCl3,
Compounds 14b and 16b were prepared by the general procedure
with trimethyl(1-oxo-3-phenylpropyl)silane (130.2 mg, 0.5 mmol),
phenylacetylene (0.07 mL, 0.6 mmol), ethylmagnesium bromide
(0.6 mL, 0.6 mmol), and ZnBr2 (0.7 mL, 1  solution in THF,
0.7 mmol).
Eur. J. Org. Chem. 2009, 1749–1756
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R. Unger, T. Cohen, I. Marek
FULL PAPER
Compounds 14c and 16c were prepared by the general procedure
General Procedure for Brook Rearrangements Followed by Zinc-
with trimethyl(1-oxo-3-phenylpropyl)silane (130.2 mg, 0.5 mmol),
Ene-Allene Cyclization: A solution of EtMgBr in Et2O (1 ,
oct-1-yne (0.07 mL, 0.6 mmol), ethylmagnesium bromide (0.6 mL, 1 equiv.) was added dropwise to a cold (0 °C) stirred solution of
0.6 mmol), and ZnBr2 (0.7 mL, 1  solution in THF, 0.7 mmol).
terminal alkyne in THF. The mixture was first allowed to warm to
room temperature for 90 min and was then cooled to –78 °C for
very slow introduction of the acylsilane over a period of 30 min.
After the addition was complete, the mixture was heated at reflux
for 45 min, and a solution of ZnBr2 in THF (1 , 1 equiv.) was
added at –60 °C. The reaction mixture was either allowed to warm
to room temperature in the case of 20a or heated at 40 °C in the
cases of 20b and 20c for a few hours (the evolution was followed by
gas chromatography analyses of hydrolyzed aliquots). The reaction
mixture was then quenched at –5 °C with aqueous HCl (1 ,
10 mL) and extracted with Et2O (3ϫ10 mL). The combined ex-
tracts were washed with saturated NaHCO3, and stirred for at least
3 h with a few Na2S·9H2O crystals that enabled the removal of all
zinc salts before further purification. These were then removed by
filtration, and the organic solution was washed with brine
(2ϫ15 mL), dried with MgSO4, and concentrated to give the un-
purified cyclic product, which was further desilylated.
5-Phenyl-1-(trimethylsilyl)pent-1-yn-3-ol (14a): This compound was
obtained after purification by column chromatography as a color-
less liquid. 127.8 mg (55%). 1H NMR (CDCl3, 300 MHz): δ = 0.12
(s, 9 H), 1.68 (s, 9 H), 1.92–2.00 (m, 2 H), 2.73 (t, J = 7.8 Hz, 2
H), 4.30 (t, J = 6.6 Hz, 1 H), 7.14–7.26 (m, 5 H) ppm. 13C NMR
(CDCl3, 75 MHz): δ = –0.1, 31.4, 39.2, 62.2, 89.9, 106.4, 126.0,
128.4, 128.5, 141.3 ppm.
(E)-5-Phenyl-1-(trimethylsilyl)pent-1-en-3-one (16a): This com-
pound was obtained after purification by column chromatography
1
as a colorless liquid. 81.3 mg (35%). H NMR (C6D6, 300 MHz):
δ = 0.05 (s, 9 H), 2.52 (t, J = 7.7 Hz, 2 H), 2.90 (t, J = 7.6 Hz, 2
H), 6.42 (d, J = 19.5 Hz, 1 H), 6.88 (d, J = 19.2 Hz, 1 H), 7.02–
7.10 (m, 5 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = –1.9, 30.0,
41.0, 126.1, 128.4, 128.5, 141.2, 142.1, 147.0, 199.4 ppm. FTIR
(CHCl ): ν = 976, 1072, 1097, 1176, 1302, 1329, 1366, 1451, 1495,
˜
3
1577, 1609, 1659, 1688, 3010, 3030 cm–1. MS (GCMS): m/z calcd.
General Procedure for Desilylation: Bu4NF (1 , 1.05 equiv.) was
added at room temperature to a solution of the corresponding silyl
ether (1 mmol) in THF (3 mL). When the reaction was over the
crude mixture was concentrated under reduced pressure. Brine was
then added, and the aqueous phase was extracted five times with
Et2O. Next, the combined organic phases were washed once with
brine, dried with MgSO4, and purified by column chromatography
(EtOAc/hexanes 5%) to give the cyclic products as colorless liquids.
for C14H20OSi [M]·+ 232.4; found 232.0.
1,5-Diphenylpent-1-yn-3-ol (14b): This compound was obtained af-
ter purification by column chromatography as a yellow liquid.
4.8 mg (2%). 1H NMR (CDCl3, 300 MHz): δ = 1.94–2.00 (m, 3
H), 2.73 (t, J = 8.1 Hz, 2 H), 4.30 (t, J = 6.6 Hz, 1 H), 7.12–7.25
(m, 10 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 31.4, 39.2, 62.2,
82.7, 89.9, 126.0, 126.0, 128.1, 128.3, 128.4, 128.8, 134.3,
141.1 ppm.
cis-2-Methyl-1-[(trimethylsilyl)ethynyl]cyclopenanol (20a): This
compound was prepared by the general procedure with 1-(trimeth-
ylsilyl)hex-5-en-1-one (85 mg, 0.5 mmol), (trimethylsilyl)acetylene
(0.09 mL, 0.6 mmol), ethylmagnesium bromide (0.6 mL, 0.6 mmol),
and ZnBr2 (0.7 mL, 1  solution in THF, 0.7 mmol). After purifi-
cation by column chromatography, 87.3 mg (89%) of 20a was ob-
tained as a colorless liquid. 1H NMR (CDCl3, 300 MHz): δ = 0.15
(s, 9 H), 1.11 (d, J = 6.6 Hz, 3 H), 1.30–1.32 (m, 1 H), 1.67–1.71
(m, 2 H), 1.87–2.00 (m, 5 H) ppm. 13C NMR (CDCl3, 75 MHz): δ
= 0.0, 16.5, 20.6, 31.1, 40.8, 45.8, 78.7, 90.1, 107.3 ppm. HRMS
(C14H28OSi2, EI M·+ m/z); calcd. 263.2043; found 263.2038.
(E)-1,5-Diphenylpent-1-en-3-one (16b): This compound was ob-
tained after purification by column chromatography as a yellow
1
oil. 196.1 mg (83%). H NMR (C6D6, 300 MHz): δ = 1.43 (dt, J1
= 9.8, J2 = 1.8 Hz, 2 H), 1.90 (t, J = 9.9 Hz, 2 H), 6.50 (dd, J1 =
21.0, J2 = 0.9 Hz, 1 H), 7.17–7.33 (m, 10 H), 7.61 (dd, J1 = 20.9,
J2 = 1.0 Hz, 1 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 30.0,
42.3, 126.0, 126.0, 128.1, 128.3, 128.4, 128.8, 130.4, 134.3, 141.1,
142.5, 199.1 ppm. FTIR (CHCl ): ν = 976, 1072, 1097, 1176, 1302,
˜
3
1329, 1366, 1451, 1495, 1577, 1609, 1659, 1688, 3010, 3030 cm–1.
HRMS (EI): m/z calcd. for C17H16O [M]·+, 236.1201; found
236.1203.
trans-2-Methyl-1-(phenylethynyl)cyclopentanol (20b): This com-
pound was prepared by the general procedure with 1-(trimethyl-
silyl)hex-5-en-1-one (85 mg, 0.5 mmol), phenylacetylene (0.07 mL,
0.6 mmol), ethylmagnesium bromide (0.6 mL, 0.6 mmol), and
ZnBr2 (0.7 mL, 1  solution in THF, 0.7 mmol). After purification
by column chromatography, 70.1 mg (70%) of 20b was obtained as
1-Phenyldodec-4-yn-3-ol (14c): This compound was obtained after
purification by column chromatography as a colorless liquid.
46.5 mg (18%). 1H NMR (CDCl3, 300 MHz): δ = 0.86 (t, J =
6.9 Hz, 3 H), 1.24–1.27 (m, 4 H), 1.37–1.44 (m, 5 H), 1.46–1.64 (m,
2 H), 1.88 (quint, J = 6.9 Hz, 2 H), 2.20 (t, J = 6.9 Hz, 2 H), 2.64
(t, J = 7.7 Hz, 2 H), 4.20 (t, J = 6.3 Hz, 1 H), 7.13–7.29 (m, 5
H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 14.0, 18.9, 22.6, 25.7,
28.5, 29.0, 31.3, 36.2, 37.3, 64.6, 82.4, 88.2, 125.6, 128.2, 128.4,
142.5 ppm.
1
a colorless liquid. H NMR (CDCl3, 300 MHz): δ = 1.10 (d, J =
6.6 Hz, 3 H), 1.40–1.43 (m, 1 H), 1.56 (brs, 1 H), 1.73–1.78 (m, 2
H), 1.96–2.16 (m, 4 H), 7.27–7.43 (m, 5 H) ppm. 13C NMR
(CDCl3, 125 MHz): δ = 16.5, 20.6, 31.2, 40.9, 46.1, 78.9, 85.9, 90.6,
122.9, 128.2, 128.2, 131.6 ppm. HRMS [C14H16O, EI M·+ (– H2O)
m/z]; calcd. 182.1096; found 182.1114.
(E)-1-Phenyldodec-4-en-3-one (16c): This compound was obtained
after purification by column chromatography as a colorless liquid.
142.1 mg (55%). 1H NMR (CDCl3, 300 MHz): δ = 0.87 (t, J =
trans-2-Methyl-1-(oct-1-ynyl)cyclopentanol (20c):[25] This com-
6.7 Hz, 3 H), 1.24–1.38 (m, 6 H), 1.41–1.45 (m, 2 H), 1.93 (quint, pound was prepared by the general procedure with 1-(trimethyl-
J = 7.5 Hz, 2 H), 2.17 (dq, J1 = 7.2, J1 = 1.2 Hz, 2 H), 2.53 (t, J silyl)hex-5-en-1-one (85 mg, 0.5 mmol), oct-1-yne (0.07 mL,
= 7.4 Hz, 2 H), 2.63 (t, J = 7.2 Hz, 2 H), 6.06 (dt, J1 = 15.9, J2 =
0.6 mmol), ethylmagnesium bromide (0.6 mL, 0.6 mmol), and
1.2 Hz, 1 H), 6.72–6.82 (m, 1 H), 7.15–7.19 (m, 3 H),7.24–7.29 (m, ZnBr2 (0.7 mL, 1  solution in THF, 0.7 mmol). After purification
2 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 14.0, 22.5, 25.7, 28.0,
28.8, 31.6, 32.4, 35.2, 39.2, 125.9, 128.3, 128.5, 130.2, 141.7, 147.5,
by column chromatography, 54.2 mg (52%) of 20c was obtained as
a colorless liquid. 1H NMR (CDCl3, 300 MHz): δ = 0.87 (t, J =
6.8 Hz, 3 H), 1.01 (d, J = 6.6 Hz, 3 H), 1.23–1.27 (m, 4 H), 1.31–
1.39 (m, 2 H), 1.41–1.48 (m, 2 H), 1.51–1.57 (m, 2 H), 1.62–1.70
(m, 2 H), 1.82–1.97 (m, 3 H), 1.99–2.04 (m, 1 H), 2.20 (t, J =
6.9 Hz, 2 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 14.0, 16.3,
200.5 ppm. FTIR (CHCl ): ν = 909, 977, 1100, 1229 1261, 1370,
˜
3
1438, 1456, 1495, 1625, 1666, 1688, 2857, 2930, 2958, 3009 cm–1.
HRMS (EI): m/z calcd. for C18H26O [M]·+ 258.1984; found
258.1984.
1754
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 1749–1756

Tandem Zn-Brook Rearrangement/Ene-Allene Carbocyclization
18.7, 20.4, 22.5, 28.4, 28.7, 30.9, 31.3, 40.9, 45.6, 68.1, 78.5,
86.4 ppm.
H), 7.28–7.30 (m, 3 H), 7.42–7.43 (m, 2 H) ppm. 13C NMR
(CDCl3, 75 MHz): δ = –0.7, 22.0, 29.8, 41.4, 76.7, 84.7, 91.2, 121.6,
122.8, 128.2, 131.7, 163.3 ppm.
trans-2-(Iodomethyl)-1-[(trimethylsilyl)ethynyl]cyclopentanol (20d):[25]
This compound was prepared by the general procedure with 1-(tri-
methylsilyl)hex-5-en-1-one (85 mg, 0.5 mmol), (trimethylsilyl)-
acetylene (0.09 mL, 0.6 mmol), ethylmagnesium bromide (0.6 mL,
0.6 mmol), and ZnBr2 (0.7 mL, 1  solution in THF, 0.7 mmol),
with addition of I2 (6 equiv.) at –30 °C in THF (10 mL). The reac-
tion mixture was allowed to warm to room temperature and stirred
for an additional 2 h before the hydrolysis, and further treatment
was then performed as usual to afford 96.7 mg (60%) of 20d as a
yellow liquid. 1H NMR (CDCl3, 300 MHz): δ = 0.15 (s, 9 H), 1.40–
1.46 (m, 1 H), 1.67–1.72 (m, 2 H), 1.93–1.98 (m, 1 H), 2.11–2.15
(m, 2 H), 2.27 (s, 1 H), 2.30–2.35 (m, 1 H), 3.08 (t, J = 9.4 Hz, 1
H), 3.46 (dd, J1 = 6.1, J2 = 2.9 Hz, 1 H) ppm. 13C NMR (CDCl3,
75 MHz): δ = –0.1, 7.2, 20.0, 31.4, 42.4, 53.2, 77.7, 91.8, 105.5 ppm.
(E)-2-[(Trimethylsilyl)methylidene]-1-(oct-1-ynyl)cyclopentanol
(28c):[25] This compound was prepared by the general procedure
with 1,6-bis(trimethylsilyl)hex-5-yn-1-one (120 mg, 0.5 mmol), oct-
1-yne (0.07 mL, 0.06 mmol), ethylmagnesium bromide (0.6 mL,
0.6 mmol), and ZnBr2 (0.7 mL, 1  solution in THF, 0.7 mmol).
After purification by column chromatography, 91.4 mg (72%) of
28c was obtained as a colorless liquid. 1H NMR (CDCl3,
300 MHz): δ = 0.10 (s, 9 H), 0.87 (t, J = 3 Hz, 3 H), 1.23–1.30 (m,
5 H), 1.47–1.50 (m, 2 H), 1.51–1.56 (m, 2 H), 1.74–1.90 (m, 3 H),
1.97–1.99 (m, 1 H), 2.22 (t, J = 7.6 Hz, 2 H), 2.36–2.39 (m, 1 H),
2.49–2.50 (m, 1 H), 5.9 (t, J = 2.8 Hz, 1 H) ppm. 13C NMR
(CDCl3, 75 MHz): δ = –0.7, 14.0, 18.7, 21.8, 22.5, 28.4, 28.6, 29.7,
31.3, 41.5, 82.3, 85.5, 120.6, 163.8 ppm.
2,3-Dimethyl-1-[(trimethylsilyl)ethynyl]cyclopentanol (24a): This
compound was prepared by the general procedure with 3-methyl-1-
(trimethylsilyl)hex-5-en-1-one (92.2 mg, 0.5 mmol), (trimethylsilyl)-
acetylene (0.09 mL, 0.6 mmol), ethylmagnesium bromide (0.6 mL,
0.6 mmol), and ZnBr2 (0.7 mL, 1  solution in THF, 0.7 mmol).
After purification by column chromatography, 76.8 mg (73%) of
24a was obtained as a colorless liquid. 1H NMR (CDCl3,
300 MHz): δ = 0.15 (s, 9 H), 0.90–0.93 (m, 3 H), 0.97–1.03 (m, 3
H), 1.23–1.45 (m, 2 H), 1.58 (s, 1 H), 1.85–2.12 (m, 4 H) ppm. 13C
NMR (CDCl3, 75 MHz): δ = –0.0, 11.3, 13.6, 16.0, 19.3, 29.8, 30.1,
34.2, 39.2, 40.0, 40.6, 49.4, 53.1, 78.8, 78.9, 89.8, 90.0, 107.8,
108.3 ppm.
Acknowledgments
This research was supported by the United States–Israel Binational
Science Foundation (BSF), Jerusalem, Israel (Grant No. 2005128)
and by the Israel Science Foundation administrated by the Israel
Academy of Sciences and Humanities (78/08).
[1] K. Alder, F. Pascher, A. Schmitz, Ber. Dtsch. Chem. Ges. 1943,
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2,3-Dimethyl-1-(phenylethynyl)cyclopentanol (24b): This compound
was prepared by the general procedure with 3-methyl-1-(trimethyl-
silyl)hex-5-en-1-one
(92.2 mg,
0.5 mmol),
phenylacetylene
(0.07 mL, 0.6 mmol), ethylmagnesium bromide (0.6 mL, 0.6 mmol),
and ZnBr2 (0.7 mL, 1  solution in THF, 0.7 mmol). After purifi-
cation by column chromatography, 71.8 mg (67%) of 24b was ob-
tained as a colorless liquid. 1H NMR (CDCl3, 300 MHz): δ = 0.95–
1.03 (m, 3 H), 1.12 (d, J = 6.6 Hz, 3 H), 1.34–1.41 (m, 1 H), 1.52–
1.64 (m, 1 H), 1.95–2.01 (m, 3 H), 2.15–2.30 (m, 1 H), 7.27–7.29
(m, 3 H), 7.39–7.42 (m, 2 H) ppm. 13C NMR (CDCl3, 125 MHz):
δ = 11.5, 13.8, 16.2, 19.4, 29.9, 30.1, 34.3, 39.2, 40.1, 40.7, 49.6,
53.4, 79.0, 79.1, 85.8, 91.1, 91.7, 122.9, 128.1, 128.1, 128.2, 131.5,
131.6 ppm.
(E)-1-[2-(Trimethylsilyl)ethynyl]-2-[(trimethylsilyl)methylidene]cyclo-
pentanol (28a):[25] This compound was prepared by the general pro-
cedure with 1,6-bis(trimethylsilyl)hex-5-yn-1-one (120 mg,
0.5 mmol), (trimethylsilyl)acetylene (0.09 mL, 0.06 mmol), ethyl-
magnesium bromide (0.6 mL, 0.6 mmol), and ZnBr2 (0.7 mL, 1 
solution in THF, 0.7 mmol). After purification by column
chromatography, 99.9 mg (75%) of 28a was obtained as a colorless
1
[9] C. Meyer, I. Marek, G. Courtemanche, J. F. Normant, J. Org.
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liquid. H NMR (CDCl3, 300 MHz): δ = 0.12 (s, 9 H), 0.16 (s, 9
H), 1.76–1.79 (m, 1 H), 1.82–1.97 (m, 3 H), 2.00–2.04 (m, 1 H),
2.31–2.43 (m, 1 H), 2.49–2.56 (m, 1 H), 5.93 (t, J = 2.6 Hz, 1
H) ppm. 13C NMR (CDCl3, 75 MHz): δ = –0.7, –0.1, 22.0, 29.7,
41.2, 62.5, 89.2, 107.9, 121.6, 163.1 ppm.
[10] a) E. Lorthiois, I. Marek, C. Meyer, J. F. Normant, Tetrahedron
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(E)-2-[(Trimethylsilyl)methylidene]-1-(2-phenylethynyl)cyclopentanol
(28b):[25] This compound was prepared by the general procedure
with 1,6-bis(trimethylsilyl)hex-5-yn-1-one (120 mg, 0.5 mmol),
phenylacetylene (0.07 mL, 0.06 mmol), ethylmagnesium bromide
(0.6 mL, 0.6 mmol), and ZnBr2 (0.7 mL, 1  solution in THF,
0.7 mmol). After purification by column chromatography, 85.2 mg
(63%) of 28b was obtained as a colorless liquid. 1H NMR (CDCl3,
300 MHz): δ = 0.13 (s, 9 H), 1.84–1.95 (m, 4 H), 2.04–2.13 (m, 2
H), 2.46–2.49 (m, 1 H), 2.56–2.57 (m, 1 H), 6.02 (t, J = 2.4 Hz, 1
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Eur. J. Org. Chem. 2009, 1749–1756
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1755

R. Unger, T. Cohen, I. Marek
FULL PAPER
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Received: January 16, 2008
Published Online: March 2, 2009
1756
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 1749–1756