Ring-opening of cyclic ethers with carbon-carbon bond formation by Grignard reagents

Article abstract of DOI:10.1016/j.tet.2014.05.026

The ring-opening of cyclic ethers with concomitant C-C bond formation was studied with a number of Grignard reagents. The transformation was performed in a sealed vial by heating to ～160 °C in an aluminum block or at 180 °C in a microwave oven. Good yields of the product alcohols were obtained with allyl- and benzylmagnesium halides when the ether was tetrahydrofuran or 3,3-dimethyloxetane. Lower yields were obtained with substituted tetrahydrofurans while no ring-opening was observed with tetrahydropyran. Only highly reactive allyl and benzyl Grignard reagents participated in the transformation while no reaction occurred with other alkylmagnesium halides.

Full text of DOI:10.1016/j.tet.2014.05.026

Tetrahedron xxx (2014) 1e5
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Ring-opening of cyclic ethers with carbonecarbon bond formation
by Grignard reagents
*
Stig Holden Christensen, Torkil Holm, Robert Madsen
Department of Chemistry, Technical University of Denmark, 2800 Kgs. Lyngby, Denmark
a r t i c l e i n f o
a b s t r a c t
Article history:
The ring-opening of cyclic ethers with concomitant CeC bond formation was studied with a number of
Grignard reagents. The transformation was performed in a sealed vial by heating to w160 ꢀC in an
aluminum block or at 180 ꢀC in a microwave oven. Good yields of the product alcohols were obtained
with allyl- and benzylmagnesium halides when the ether was tetrahydrofuran or 3,3-dimethyloxetane.
Lower yields were obtained with substituted tetrahydrofurans while no ring-opening was observed with
tetrahydropyran. Only highly reactive allyl and benzyl Grignard reagents participated in the trans-
formation while no reaction occurred with other alkylmagnesium halides.
Received 13 February 2014
Received in revised form 28 April 2014
Accepted 12 May 2014
Available online xxx
Keywords:
CeC bond formation
Cyclic ether
Ó 2014 Elsevier Ltd. All rights reserved.
Grignard reagent
Nucleophilic substitution
Ring-opening
1. Introduction
Very recently, we conducted a study on the reversibility of the
Grignard addition reaction.7 By performing crossover experiments
Formation of the carbonecarbon bond is at the cornerstone of
organic synthesis and is often achieved by the reaction of a carbon
nucleophile with a suitable electrophile. A number of functional
groups can serve as the electrophile, but ethers (other than epox-
ides) are usually deemed too unreactive for this transformation. In
fact, key nucleophilic substitution and addition reactions such as
alkylations with lithium species, the Grignard reaction, the Wittig
olefination, and reactions with organocopper reagents are often
performed in ethereal solvents.1 However, ethers are not always
completely unreactive toward carbon nucleophiles.2 Cyclic ethers
larger than oxiranes undergo ring-opening with concomitant CeC
bond formation with allylsilanes in the presence of a Lewis acid.3
The same transformation can be carried out with organolithium
reagents both in the presence and in the absence of a Lewis acid.2a,4
Grignard reagents are also known to cleave ethers with formation
of a CeC bond, but the reaction is sluggish and has found little
synthetic use.2b,5 The most successful example is the rather special
reaction between tritylmagnesium bromide and THF, which pro-
duces 5,5,5-triphenylpentan-1-ol in 94% yield after reflux in ben-
zene.6 The transformation is presumably facilitated by the
unusually strong coordination between the Grignard reagent and
THF.6
it was revealed that the addition of benzylmagnesium halides to
ketones is in fact a reversible reaction.7 The studies were performed
at 140 ꢀC in THF solution and small amounts of a byproduct from
ring-opening of THF with the Grignard reagent were observed.
Therefore, we decided to investigate this ring-opening in further
detail in order to develop a more synthetically useful protocol. This
transformation complements the established synthesis of primary
alcohols from Grignard reagents and ethylene oxide.8 Herein, we
report a full account on the ring-opening of cyclic ethers with si-
multaneous CeC bond formation by Grignard reagents.
2. Results and discussion
p-Methylbenzylmagnesium chloride was chosen as the
Grignard reagent for the initial studies and a 0.62 M solution in THF
was prepared from p-methylbenzyl chloride and magnesium.
Heating this solution to 140 ꢀC in a sealed vial in an aluminum block
produced the desired ring-opening product in a rather clean but
also very slow reaction (Table 1, entry 1). To achieve a shorter re-
action time the temperature was raised to 150 ꢀC, which gave 79%
isolated yield after 97 h (entry 2). Further increase in temperature
resulted in a shorter reaction time, but without significantly im-
proving the yield (entries 3 and 4). Several Lewis acids were in-
vestigated as additives in an attempt to improve this result, but in
all cases a lower yield was obtained (entries 5e8). Other Lewis acids
* Corresponding author. Tel.: þ45 4525 2151; fax: þ45 4593 3968; e-mail ad-
dress: rm@kemi.dtu.dk (R. Madsen).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.05.026
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2
S.H. Christensen et al. / Tetrahedron xxx (2014) 1e5
Table 1
Table 2
Synthesis of 5-(p-methylphenyl)pentan-1-ol
Ring-opening of THF with Grignard reagents
Entry
Additive
Temp (ꢀC)
Time (h)
Pressurea (bar)
Yieldb (%)
1
2
3
4
5
6
7
8
d
140
150
160
170
170
160
160
140
180
180
180
200
200
200
260
97
41.5
41
d
82
79
70
82
69
60
40
69
60
75
36
49
48
60
Entry RMgX
BnMgBrb
Method Time (h)
Product
Yielda (%)
61
d
d
d
d
d
CuIc
d
1
2
3
4
5
6
7
8
A
B
A
B
A
B
A
B
114
16
90
16
95
24
97
20
41
d
MgBr2$Et2Oc
38.5
41.5
260
16
24
16
16
16
16
d
c
BiCl3
CuBr2
d
d
65
70
86
40
35
61
68
c
d
9d
10d
11d
12d
13d
14d
13/16
13/20
11/14
15/19
15/18
15/20
BnMgClc
d
Mesitylenee
Decalenee
Tetralenee
Biphenyle
a
p-MeOBnMgCld
m-MeOBnMgCld
Values show start and final pressure.
Isolated yield.
5% of the Lewis acid added.
b
c
d
Performed in 10 mL sealed vial in a microwave oven with 2.5 mL of the Grignard
solution in THF.
e
0.5 mL of the co-solvent added.
such as LiCl, AlCl3, TiCl4, CuBr, FeCl2, FeCl3, and InCl3 gave inferior
yields (results not shown).
Since the transformation requires a high temperature in a closed
vial it was also decided to perform the reaction in a microwave
oven. Furthermore, the instrument allows for the internal pressure
to be measured where a maximum of 20 bar is permitted. This gave
a yield of 75% after heating to 180 ꢀC for 24 h at which time the
pressure limit was reached (entries 9 and 10). Attempts to improve
the reaction by using high-boiling co-solvents and higher temper-
ature only led to lower yields (entries 11e14). Thus, the ring-
opening of THF with a Grignard reagent can be performed in
good yield by using both conventional heating and a microwave
oven. As a result, it was decided to study the substrate scope of the
transformation under both conditions where a temperature of
150 ꢀC was selected for the conventional heating and 180 ꢀC under
the microwave conditions.
The ring-opening of THF with benzylmagnesium bromide gave
a moderate yield of 5-phenylpentan-1-ol (Table 2, entries 1 and 2).
Notably, the yield increased significantly by using the corre-
sponding chloride reagent (entries 3 and 4), which correlates with
the known observation that alkylmagnesium chlorides are more
reactive in the Grignard addition reaction than the bromide coun-
terparts.9 The experiment in entry 3 was performed with a ma-
nometer attached to the vial, which showed an internal pressure of
6 bar during conventional heating. An electron-donating group
lowered the yield significantly especially when then the group was
placed in the para-position (entries 5e8). Besides benzylic Grignard
reagents, the ring-opening could also be performed with allyl-
magnesium chlorides (entries 9e11). On the contrary, alkyl
9
B
24
66
79
34
10f
A
11
12
B
24
50
CyMgBrg
A
237
w1
13
Ph(CH2)3MgBrc
A
233
w1
a
Isolated yield.
b
c
d
e
f
0.49 M solution in THF.
0.68 M solution in THF.
0.25 M solution in THF.
2.3 M solution in THF.
Heated at 120 ꢀC.
g
1.13 M solution in THF.
methyltetrahydrofuran and the mixture was subjected to both
conventional heating at 160 ꢀC and microwave heating at 180 ꢀC
(Scheme 1). However, in both cases a poor yield was obtained al-
though the transformation was regioselective for attack at the least
substituted ether position. The same regioselectivity was observed
in the ring-opening of 2-methyltetrahydrofuran by alkyllithium
reagents.4c
Grignard
reagents
such
as
cyclohexyl-
and
3-
phenylpropylmagnesium bromide only furnished trace amounts
of the desired product (entries 12 and 13). This observation is also
in accordance with the previously observed reactivity difference
between Grignard reagents since allyl- and benzylmagnesium ha-
lides are more reactive in the addition reaction than other alkyl
reagents.9,10 Overall, the best results are obtained with allyl- and
benzylmagnesium chloride and in both cases similar yields are
obtained for the two modes of heating.
Scheme 1. Ring-opening of 2-methyltetrahydrofuran.
Then, tetrahydropyran was investigated as a substrate and
a 0.74 M solution of benzylmagnesium bromide was prepared in
this solvent. However, no ring-opening occurred when this mixture
was heated in an aluminum block at 170 ꢀC. The lower reactivity of
Following these results it was then decided to investigate
the ring-opening with other cyclic ethers. First, a 0.98 M solution
of
benzylmagnesium
chloride
was
prepared
in
2-
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S.H. Christensen et al. / Tetrahedron xxx (2014) 1e5
3
Table 3
tetrahydropyran was also observed in the reported ring-opening
Ring-opening of cyclic ethers with benzyl- and allylmagnesium halidesa
with alkyllithium reagents where a higher temperature was re-
quired for the six-membered ether than for THF.4c The benzyl
Grignard solution in tetrahydropyran was also subjected to mi-
crowave heating, but due to the lower polarity of the solvent it was
not possible to reach the desired temperature of 180 ꢀC in this case.
Consequently, tetrahydropyran is stable under the reaction condi-
tions and it may therefore be possible to use this ether as a co-
solvent for ring-opening of more valuable cyclic substrates.
To investigate this scenario, 2.5 mL of benzylmagnesium chlo-
ride in tetrahydropyran was mixed with 0.5 mL of 3,3-
dimethyloxetane. It turned out that this mixture was sufficiently
polar to be heated in a microwave oven at 180 ꢀC. Due to the higher
reactivity of the four-membered ether, the ring-opened product
could now be obtained in only 4 h (Table 3, entry 1). With p-
methylbenzylmagnesium chloride the same transformation pro-
ceeded in good yield in only 1 h (entry 2). Attempts to ring-open
THF in the mixture with tetrahydropyran were less successful and
only afforded 40% yield of 5-phenylpentan-1-ol (entry 3). Two
other five-membered ethers were also studied and gave the ring-
opening products in moderate yields (entries 4 and 5). The prod-
uct stereochemistry in entry 4 indicates that the reaction proceeds
by coordination of magnesium to oxygen followed by an SN2 attack
on carbon.2 No reaction occurred with phthalan and N-methyl-
pyrrolidinone at 200 ꢀC (entries 6 and 7). As a result, the ring-
opening in tetrahydropyran solution seems to be limited to
highly reactive cyclic ethers such as 3,3-dimethyloxetane. This
ether was also reacted with allylic Grignard reagents and the ring-
opened products were isolated in good yields (entries 8 and 9). In
these cases, the reaction could be performed with THF as the co-
solvent and a more modest temperature of 120 ꢀC.
Entry
1c
Ether
Temp (ꢀC) Time (h) Product
Yieldb (%)
69
180
4
2d
180
1
78
40
3c
190
24
4c
200
200
25
24
44
49
In summary, we have optimized the ring-opening of cyclic
ethers with Grignard reagents to produce primary alcohols. Good
yields were obtained with allyl- and benzylmagensium halides
when the ether is THF or 3,3-dimethyloxetane. Neither alkyl
Grignard reagents nor tetrahydropyran afforded any of the desired
products while low to moderate yields were obtained with
substituted tetrahydrofurans. The reactivity of the Grignard re-
agents in the transformation correlated with the reactivity in the
Grignard addition reaction to ketones.
5c
6c
7c
200
200
20
20
d
d
0
0
3. Experimental section
3.1. General methods
8e
9f
120
120
0.5
84
67
The allylic Grignard reagents were purchased from Sigma-
eAldrich and used as received. The remaining Grignard reagents
were prepared in a three-neck round-bottom flask by slow addition
of the halide to a magnesium suspension in freshly distilled THF
under an argon atmosphere. The base concentration was de-
termined by quenching 1.0 mL of the solution in H2O followed by
addition of a few drops of phenolphthalein and then titrating with
nitric acid until a color shift from pink to colorless occurred.11 THF
was distilled from sodium and benzophenone. Magnesium turn-
ings were dried under high vacuum while glassware was dried in an
oven at 185 ꢀC. NMR spectra were recorded on a Varian Mercury
300 spectrometer with residual solvent signals as reference.
Melting points were measured by Stuart SMP30 Melting Point
Apparatus and are uncorrected. Mass spectrometry was performed
by direct inlet on a Shimadzu GCMS-QP5000 instrument. Solvents
used for chromatography were of HPLC grade. Thin layer chroma-
tography was performed on aluminum plates coated with silica gel
60. Visualization was done by dipping into a solution of KMnO4
(1%), K2CO3 (6.7%), and NaOH in H2O, or a solution of H2SO4 (10%) in
H2O, followed by heating with a heatgun. Flash chromatography
0.5
a
2.5 mL of the Grignard reagent in tetrahydropyran was mixed with 0.5 mL of the
ether and then heated in a microwave oven.
b
Isolated yield.
c
With 0.66 M solution of benzylmagnesium bromide in tetrahydropyran.
With 0.62
d
M
solution of p-methylbenzylmagnesium chloride in
tetrahydropyran.
e
With 2.3
M solution of allylmagnesium bromide in THF (instead of
tetrahydropyran).
f
With 0.48 M solution of methallylmagnesium bromide in THF (instead of
tetrahydropyran).
was performed with a Personal Chemistry Emry Optimizer reactor.
The pressure with conventional heating was measured by attaching
a Keller LEO Record Monometer through a SyTracks H-cap spacer to
the reaction vial. High resolution mass spectra were recorded on an
Agilent 1100 LC system, which was coupled to a Micromass LCT
was performed with silica gel 60 (35e70 mm). Microwave heating
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4
S.H. Christensen et al. / Tetrahedron xxx (2014) 1e5
orthogonal time-of-flight mass spectrometer equipped with a lock
mass probe.
1.68e1.53 (m, 4H), 1.45e1.33 (m, 2H); dC (75 MHz, CDCl3) 157.7,
134.8, 129.3, 113.8, 62.9, 55.3, 35.0, 32.7, 31.6, 25.4; nmax (film) 3337,
2931, 2856, 1612, 1510, 1462, 1299, 1242, 1176, 1034, 810 cmꢁ1; MS
m/z 194 [Mþ]; HRMS (ESI) calcd for C12H17O [MꢁH2OþH]þ m/z
177.1279, found 177.1273. NMR data are in accordance with litera-
ture values.14
3.2. General procedure for ring-opening of THF by Grignard
reagents with conventional heating
The solution of the Grignard reagent in THF (10.0 mL) was added
to a screw-top heavy wall vial (20 mL) under an argon atmosphere
and the vial was sealed. The reaction mixture was heated in an
aluminum block with a lid to the indicated temperature for the
time stated. The mixture was allowed to cool to ambient temper-
ature, diluted with Et2O and quenched with H2O. The organic phase
was washed with saturated aqueous NH4Cl and H2O. The organic
layer was dried with MgSO4, filtered, concentrated, and purified by
flash column chromatography.
3.8. 5-(m-Methoxyphenyl)pentan-1-ol (Table 2, entries 7 and 8)
Isolated as a colorless oil. Rf 0.29 (EtOAc/heptane 1:2); dH
(300 MHz, CDCl3) 7.20 (dd, J¼8.9, 7.6 Hz, 1H), 6.83e6.69 (m, 3H),
3.80 (s, 3H), 3.63 (t, J¼6.6 Hz, 2H), 2.61 (t, J¼7.7 Hz, 2H), 1.76e1.54
(m, 5H), 1.47e1.33 (m, 2H); dC (75 MHz, CDCl3) 159.7, 144.4, 129.3,
121.0, 114.3, 111.0, 63.0, 55.3, 36.1, 32.8, 31.3, 25.5; nmax (film) 3337,
2932, 2857, 1601, 1584, 1487, 1453, 1436, 1257, 1151, 1042, 776,
694 cmꢁ1; MS m/z 194 [Mþ]. NMR data are in accordance with
literature values.15
3.3. General procedure for ring-opening of THF by Grignard
reagents with microwave heating
3.9. Hept-6-en-1-ol (Table 2, entry 9)
The solution of the Grignard reagent in THF (4.0 mL) was added
to a microwave vial (10 mL) under an argon atmosphere and the
vial was sealed. The reaction was heated by microwave irradiation
to the indicated temperature for the time stated. The mixture was
cooled to ambient temperature, diluted with Et2O, and quenched
with H2O. The organic phase was washed with saturated aqueous
NH4Cl and H2O. The organic layer was dried with MgSO4, filtered,
concentrated, and purified by flash column chromatography.
Isolated as a colorless oil. Rf 0.41 (Et2O/pentane 1:2); dH
(300 MHz, CDCl3) 5.80 (ddt, J¼16.9, 10.2, 6.7 Hz, 1H), 5.10e4.79 (m,
2H), 3.75e3.47 (m, 2H), 2.26e1.92 (m, 2H), 1.70e1.22 (m, 7H); dC
(75 MHz, CDCl3) 139.0, 114.5, 63.1, 33.8, 32.7, 28.8, 25.4; nmax (film)
3331, 3077, 2929, 2858,1641,1458,1053, 993, 908 cmꢁ1; MS m/z 115
[MþHþ]; HRMS (ESI) calcd for C7H15O [MþH]þ m/z 115.1117, found
115.1123. NMR data are in accordance with literature values.16
3.4. General procedure for ring-opening of cyclic ethers by
Grignard reagents in tetrahydropyran
3.10. 6-Methylhept-6-en-1-ol (Table 2, entries 10 and 11)
Isolated as a colorless oil. Rf 0.30 (Et2O/pentane 1:1); dH
(300 MHz, CDCl3) 4.83e4.52 (m, 2H), 3.64 (t, J¼6.6 Hz, 2H), 2.02 (t,
J¼7.3 Hz, 2H), 1.80e1.25 (m, 9H); dC (75 MHz, CDCl3) 146.1, 109.9,
63.1, 37.9, 32.8, 27.4, 25.5, 22.5; nmax (film) 3331, 3074, 2932, 2859,
1649, 1449, 1374, 1052, 884 cmꢁ1; MS m/z 128 [Mþ]; HRMS (ESI)
calcd for C8H17O [MþH]þ m/z 129.1274, found 129.1278. NMR data
are in accordance with literature values.17
The solution of the Grignard reagent in tetrahydropyran
(2.5 mL) was mixed with the cyclic ether (0.50 mL) in a microwave
vial (10 mL) under an argon atmosphere and the vial was sealed.
The reaction mixture was heated by microwave irradiation to the
indicated temperature for the time stated. The mixture was cooled
to ambient temperature, diluted with Et2O, and quenched with
H2O. The organic phase was washed with saturated aqueous NH4Cl
and H2O. The organic layer was dried with MgSO4, filtered, con-
centrated, and purified by flash column chromatography.
3.11. 6-Phenylhexan-2-ol (Scheme 1)
Isolated as a colorless oil. Rf 0.23 (EtOAc/heptane 1:4); dH
(300 MHz, CDCl3) 7.32e7.15 (m, 5H), 3.79 (hex, J¼6.2 Hz, 1H), 2.63
(t, J¼7.7 Hz, 2H), 1.69e1.31 (m, 7H), 1.18 (d, J¼6.2 Hz, 3H); dC
(75 MHz, CDCl3) 142.7, 128.5, 128.4, 125.8, 68.2, 39.3, 36.0, 31.6,
25.6, 23.6; nmax (film) 3346, 3062, 3026, 2930, 2857, 1603, 1495,
1453, 1373, 1155, 1127, 1092, 1064, 930, 744, 697 cmꢁ1; MS m/z 178
[Mþ]; HRMS (ESI) calcd for C12H17 [MꢁH2OþH]þ m/z 161.1325,
found 161.1323. 1H NMR data are in accordance with literature
values.18
3.5. 5-(p-Tolyl)pentan-1-ol (Table 1)12
Isolated as a colorless oil. Rf 0.21 (CH2Cl2); dH (300 MHz, CDCl3)
7.14 (br s, 4H), 3.65 (t, J¼6.6 Hz, 2H), 2.64 (t, J¼7.6 Hz, 2H), 2.38 (s,
3H), 2.32 (s, 1H), 1.78e1.56 (m, 4H), 1.52e1.35 (m, 2H); dC (75 MHz,
CDCl3) 139.5, 135.0, 129.0, 128.3, 62.7, 35.5, 32.6, 31.5, 25.5, 21.0;
nmax (film) 3332, 3018, 2929, 2857, 1515, 1457, 1048, 804 cmꢁ1; MS
m/z 178 [Mþ]; HRMS (ESI) calcd for C12H17 [MꢁH2OþH]þ m/z
161.1325, found 161.1326.
3.12. 2,2-Dimethyl-4-phenylbutan-1-ol (Table 3, entry 1)
3.6. 5-Phenylpentan-1-ol (Table 2, entries 1e4)
Isolated as a colorless oil. Rf 0.33 (EtOAc/heptane 1:4); dH
(300 MHz, CDCl3) 7.42e7.07 (m, 5H), 3.38 (s, 2H), 2.71e2.44 (m,
2H), 1.67e1.52 (m, 2H), 1.50 (s, 1H), 0.97 (s, 6H); dC (75 MHz, CDCl3)
143.3, 128.5 (3C), 128.4, 125.8, 71.9, 41.0, 35.4, 30.6, 23.9; nmax (film)
3579, 3062, 3026, 2652, 2867, 1603, 1496, 1472, 1454, 1388, 1364,
1047, 1031, 762, 736, 697 cmꢁ1; MS m/z 178 [Mþ]; HRMS (ESI) calcd
for C12H17 [MꢁH2OþH]þ m/z 161.1325, found 161.1324. NMR data
are in accordance with literature values.19
Isolated as a colorless oil. Rf 0.21 (CH2Cl2); dH (300 MHz, CDCl3)
7.37e6.95 (m, 5H), 3.51 (t, J¼6.6 Hz, 2H), 2.53 (t, J¼7.7 Hz, 2H), 1.90
(s, 1H), 1.70e1.40 (m, 4H), 1.40e1.18 (m, 2H); dC (75 MHz, CDCl3)
142.6, 128.5, 128.3, 125.7, 62.8, 36.0, 32.6, 31.3, 25.5; nmax (film)
3333, 3026, 2931, 2857,1603,1585,1495,1453,1050, 744, 696 cmꢁ1
;
MS m/z 164 [Mþ]. NMR data are in accordance with literature
values.13
3.7. 5-(p-Methoxyphenyl)pentan-1-ol (Table 2, entries 5 and 6)
3.13. 2,2-Dimethyl-4-(p-tolyl)butan-1-ol (Table 3, entry 2)
Isolated as a colorless oil. Rf 0.29 (EtOAc/heptane 1:2); dH
(300 MHz, CDCl3) 7.10 (d, J¼8.5 Hz, 2H), 6.83 (d, J¼8.5 Hz, 2H), 3.79
(s, 3H), 3.62 (t, J¼6.5 Hz, 2H), 2.56 (t, J¼6.5 Hz, 2H), 1.69 (s, 1H),
Isolated as a colorless oil. Rf 0.29 (EtOAc/heptane 1:5); dH
(300 MHz, CDCl3) 7.11 (br s, 4H), 3.38 (d, J¼4.8 Hz, 2H), 2.65e2.47
(m, 2H), 2.33 (s, 3H), 1.72e1.43 (m, 3H), 0.97 (s, 6H); dC (75 MHz,
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S.H. Christensen et al. / Tetrahedron xxx (2014) 1e5
5
CDCl3) 140.2,135.2,129.2,128.3, 71.9, 41.2, 35.4, 30.1, 23.9, 21.1; nmax
(film) 3354, 3004, 2952, 2867, 1514, 1471, 1364, 1046, 1021,
808 cmꢁ1; MS m/z 192 [Mþ]; HRMS (ESI) calcd for C13H19
[MꢁH2OþH]þ m/z 175.1487, found 175.1481. NMR data are in ac-
cordance with literature values.19
883 cmꢁ1; MS m/z 142 [Mþ]; HRMS (ESI) calcd for C9H19O [MþH]þ
m/z 143.1430, found 143.1431. 1H NMR data are in accordance with
literature values.23
Supplementary data
3.14. trans-4-Benzylcyclohexan-1-ol (Table 3, entry 4)
1H and 13C NMR spectra of all compounds. Supplementary data
associated with this article can be found in the online version, at
http://dx.doi.org/10.1016/j.tet.2014.05.026.
Isolated as a colorless oil. Rf 0.29 (EtOAc/heptane 1:2); dH
(300 MHz, CDCl3) 7.46e7.00 (m, 5H), 3.55 (ddd, J¼10.7, 7.5, 3.3 Hz,
1H), 2.50e2.44 (m, 2H), 2.04e1.83 (m, 2H), 1.78e1.67 (m, 2H),
1.59e1.36 (m, 2H),1.34e1.11 (m, 2H),1.11e0.85 (m, 2H); dC (75 MHz,
CDCl3) 141.2, 129.2, 128.3, 125.9, 71.2, 43.4, 38.9, 35.6, 31.1; nmax
(film) 3259, 2924, 2852, 1450, 1369, 1083, 1043, 744, 697 cmꢁ1; MS
m/z 190 [Mþ]. NMR data are in accordance with literature values.20
References and notes
1. (a) Gu, Y.; Tian, S.-K. Top. Curr. Chem. 2012, 327, 197e238; (b) Yoshika, N.; Na-
kamura, E. Chem. Rev. 2012, 112, 2339e2372; (c) Monrad, R. N.; Madsen, R.
€
Tetrahedron 2011, 67, 8825e8850; (d) Gessner, V. H.; Daschlein, C.; Strohmann,
C. Chem.dEur. J. 2009, 15, 3320e3334; (e) Seyferth, D. Organometallics 2009, 28,
1598e1605; (f) Zweifel, G. S.; Nantz, M. H. Modern Organic SynthesisdAn In-
troduction; W.H. Freeman: New York, NY, 2007; pp 273e358.
3.15. 2-(3-Phenylpropyl)phenol (Table 3, entry 5)
2. (a) Maercker, A. Angew. Chem., Int. Ed. Engl. 1987, 26, 972e989; (b) Trofimov, B.
A.; Korostova, S. E. Russ. Chem. Rev. 1975, 44, 41e55.
3. (a) Oku, A.; Homoto, Y.; Harada, T. Chem. Lett. 1986, 1495e1498; (b) Carr, S. A.;
Weber, W. P. J. Org. Chem. 1985, 50, 2782e2785.
4. (a) Dalko, P. I.; Langlois, Y. J. Org. Chem. 1998, 63, 8107e8117; (b) Imai, T.;
Muramoto, T.; Tsuji, T. Chem. Lett. 1995, 355e356; (c) Chou, T.-S.; Hung, S.-H.;
Cheng, C.-C. J. Chin. Chem. Soc. 1990, 37, 629e631.
5. Combs, C. S., Jr.; Willis, T. C.; Giles, R. D.; Stephens, W. D. J. Org. Chem. 1971, 36,
2027e2029.
6. Jensen, F. R.; Bedard, R. L. J. Org. Chem. 1959, 24, 874e875.
7. Christensen, S. H.; Holm, T.; Madsen, R. Tetrahedron 2014, 70, 1478e1483.
8. (a) Schrumpf, G.; Gratz, W.; Meinecke, A.; Fellenberger, K. J. Chem. Res. 1982,
162e163; (b) Huston, R. C.; Langham, C. C. J. Org. Chem. 1947, 12, 90e95; (c)
Huston, R. C.; Agett, A. H. J. Org. Chem. 1941, 6, 123e133.
Isolated as a colorless oil. Rf 0.25 (EtOAc/heptane 1:5); dH
(300 MHz, CDCl3) 7.36e6.90 (m, 7H), 6.79 (td, J¼7.4, 1.2 Hz, 1H),
6.66 (dd, J¼7.9, 1.0 Hz, 1H), 4.54 (s, 1H), 2.74e2.46 (m, 4H),
2.01e1.75 (m, 2H); dC (75 MHz, CDCl3) 153.5, 142.4, 130.3, 128.6,
128.5, 128.2, 127.3, 125.9, 121.0, 115.4, 35.7, 31.3, 29.6; nmax (film)
3530, 3061, 3026, 2932, 2858, 1591, 1495, 1453, 1328, 1235, 1170,
1096, 1043, 747, 697 cmꢁ1; MS m/z 212 [Mþ]; HRMS (ESI) calcd for
C
15H17O [MþH]þ m/z 213.1274, found 213.1274. 1H NMR data are in
accordance with literature values.21
3.16. 2,2-Dimethylhex-5-en-1-ol (Table 3, entry 8)
9. Holm, T. Acta Chem. Scand. Ser. B 1983, 37, 567e584.
10. Osztrovszky, G.; Holm, T.; Madsen, R. Org. Biomol. Chem. 2010, 8, 3402e3404.
11. Gilman, H.; Gartledge, F. K. J. Organomet. Chem. 1964, 2, 447e454.
12. Collins, R. F.; Davis, M. J. Chem. Soc. 1961, 1863e1879.
13. Lebel, H.; Ladjel, C. J. Organomet. Chem. 2005, 690, 5198e5205.
14. Yan, C.-S.; Peng, Y.; Xu, X.-B.; Wang, Y.-W. Chem.dEur. J. 2012, 18, 6039e6048.
15. Conrad, J. C.; Kong, J.; Laforteza, B. N.; MacMillan, D. W. C. J. Am. Chem. Soc.
2009, 131, 11640e11641.
16. Zaed, A. M.; Swift, M. D.; Sutherland, A. Org. Biomol. Chem. 2009, 7, 2678e2680.
17. Buffet, M. F.; Dixon, D. J.; Edwards, G. L.; Ley, S. V.; Tate, E. W. J. Chem. Soc., Perkin
Trans. 1 2000, 1815e1827.
Isolated as a colorless oil. Rf 0.32 (Et2O/pentane 1:5); dH
(300 MHz, CDCl3) 5.81 (ddt, J¼16.8, 10.1, 6.5 Hz, 1H), 5.00 (ddd,
J¼17.1, 3.5, 1.6 Hz,1H), 4.95e4.88 (m, 1H), 3.30 (s, 2H), 2.15e1.92 (m,
2H), 1.69 (s, 1H), 1.42e1.21 (m, 2H), 0.87 (s, 6H); dC (75 MHz, CDCl3)
139.6, 114.1, 71.9, 37.9, 35.2, 28.5, 23.9; nmax (film) 3348, 3074, 2955,
2934, 2870, 1641, 1473, 1364, 1037, 992, 906 cmꢁ1; MS m/z 128
[Mþ]; HRMS (ESI) calcd for C8H16O [MþH]þ m/z 129.1274, found
129.1273. 1H NMR data are in accordance with literature values.22
18. Ponzano, S.; Bertozzi, F.; Mengatto, L.; Dionisi, M.; Armirotti, A.; Romeo, E.;
Berteotti, A.; Fiorelli, C.; Tarozzo, G.; Reggiani, A.; Duranti, A.; Tarzia, G.; Mor,
M.; Cavalli, A.; Piomelli, D.; Bandiera, T. J. Med. Chem. 2013, 56, 6917e6934.
ꢀ
19. Beaulieu, L.-P. B.; Roman, D. S.; Vallee, F.; Charette, A. B. Chem. Commun. 2012,
3.17. 2,2,5-Trimethylhex-5-en-1-ol (Table 3, entry 9)
8249e8251.
20. Holland, H. L.; Morris, T. A.; Nava, P. J.; Zabic, M. Tetrahedron 1999, 55,
7441e7460.
Isolated as a colorless oil. Rf 0.31 (Et2O/pentane 1:5); dH
(300 MHz, CDCl3) 4.82e4.56 (m, 2H), 3.32 (s, 2H), 2.05e1.88 (m,
2H), 1.73 (s, 3H), 1.50 (s, 1H), 1.47e1.27 (m, 2H), 0.88 (s, 6H); dC
(75 MHz, CDCl3) 146.8, 109.5, 72.0, 36.8, 35.1, 32.2, 23.9, 22.8; nmax
(film) 3355, 3074, 2938, 2917, 2870, 1649, 1472, 1448, 1051, 1033,
21. Lewin, G.; Bert, M.; Dauguet, J. C.; Dolley, J.; Le Menez, P.; Schaeffer, C.; Gui-
namant, J. L.; Volland, J. P. Bull. Soc. Chim. Fr. 1991, 128, 939e944.
22. Mudryk, B.; Cohen, T. J. Org. Chem. 1989, 54, 5657e5659.
23. Little, R. D.; Muller, G. W.; Venegas, M. G.; Carroll, G. L.; Bukhari, A.; Patton, L.;
Stone, K. Tetrahedron 1981, 37, 4371e4383.
Please cite this article in press as: Christensen, S. H.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.05.026