Prins cyclization of α-bromoethers under basic conditions

Article abstract of DOI:10.1139/cjc-2013-0337

α-Bromoethers have been found to undergo Prins-type cyclization under basic conditions and without the need to add a promoter. The products are those derived from a Markovnikov addition on the pendant alkene. However, the stereochemistry and even the structure of the products sometimes differ from those expected with the classical Lewis-acid-catalyzed Prins reaction of acetals.

Full text of DOI:10.1139/cjc-2013-0337

1193
ARTICLE
Prins cyclization of ␣-bromoethers under basic conditions
Patrice Arpin, Bryan Hill, Robin Larouche-Gauthier, and Claude Spino
Abstract: ␣-Bromoethers have been found to undergo Prins-type cyclization under basic conditions and without the need to add
a promoter. The products are those derived from a Markovnikov addition on the pendant alkene. However, the stereochemistry
and even the structure of the products sometimes differ from those expected with the classical Lewis-acid-catalyzed Prins
reaction of acetals.
Key words: Prins cyclization, bromoethers, tetrahydrofuran, tetrahydropyran.
Résumé : Il a été découvert que les ␣-bromoéthers peuvent subir une cyclization de Prins en conditions basiques sans la présence
d’un promoteur. Les produits obtenus découlent d’une addition Markovnikov de l’alcène. Cependant, la stéréochimie et même
la structure des produits obtenus diffèrent parfois de ceux obtenus dans les conditions classiques de la réaction de Prins catalysée
par un acide de Lewis.
Mots-clés : cyclization de Prins, bromoéthers, tétrahydrofuranne, tétrahydropyranne.
same reaction conditions but omitting the AIBN initiator and ob-
tained the same compound 2 in a similar yield. We noted that the
presence of Ph3SnH accelerated the Prins cyclization, as the con-
version of ␣-bromoether 1b to 2 in refluxing benzene without any
Introduction
The Prins cyclization is a powerful synthetic tool to make carbo-
or oxacycles of different ring sizes.1 They have been divided into
three types according to the substitution pattern and the rela-
tive position of the alkene with respect to the oxonium ion
additive was indeed slower (almost no conversion after 10 h, the
time required for the tin-promoted reaction to complete).
(Scheme 1).1c The path to the final Prins type III products may or
Intrigued by these observations, we surveyed the behavior of a
may not involve prior equilibrium of two oxonia−Cope interme-
number of ␣-bromoethers with and without additives. ␣-Bromoether
diates (A and B).2
5 was prepared from the corresponding methoxymethyl ether
Although this reaction has been known for a long time,3 it is
(MOM) acetal 4 by the method of Guindon9 using Me2BBr at low
now receiving an increasing amount of attention from the re-
temperature (Scheme 3). With excess potassium carbonate or
search community.1b This delay may be due, in part, to the fact
di-t-butylmethylpyridine (DTBMP), the sensitive ␣-bromoether 5
that the typically strongly Brønsted or Lewis acidic conditions
could be isolated.10 We submitted it to various reaction condi-
required for this transformation have limited its use in the syn-
tions to effect its cyclization to tetrahydrofuran 6. Simply letting
thesis of complex natural products.1 More recently, many re-
␣-bromoether 5 sit at room temperature for 7 h in dichloromethane
search groups are creating new catalysts, developing new reaction
conditions, or inventing new structural features in the substrate
effected its cyclization to bromide 6, which, given its sensitive
nature, was reduced with Ph3SnH to the isopropyl analogue 7, in
this case obtained in 44% yield for the two steps. In refluxing
benzene, the cyclization was complete in a matter of minutes and
to generate the pivotal oxocarbenium ion under milder reaction
conditions.4
Among strategies to generate the oxocarbenium ion, the Lewis-
we obtained a similar yield of 7 after reduction with Ph3SnH.
acid-promoted cleavage of an acetal precursor is frequently
Strong Lewis acids (SnCl4, TiCl4, and BCl3) or HBr promoted the
used.1,5 On a few occasions, authors have reported the generation
reaction, which could then be performed at −78 °C in these cases,
of ␣-chloro-6a,6b or ␣-bromoethers6c as intermediates between the
and again, product 7 was obtained in yields varying from 30% to
starting acetal and the oxocarbenium ion under Lewis acid
52%. Weak Lewis acids such as Me4Sn, (TMS)3SiH, and Ph3SnH
treatment.
somewhat accelerated the cyclization but did not increase the
yield of product 7 and we began to wonder if a promoter was really
necessary. We thus added excess base to see if the reaction would
proceed under basic conditions: we found that the reaction pro-
ceeded indeed in higher yield. When potassium carbonate was
used, the cyclization/reduction product 7 was isolated in 74% yield
for the two steps. With DTBMP, the two alkenes 8a and 8b were
isolated in 98% yield and a 2:1 ratio.
We report herein that ␣-bromomethyl ethers do not need any
promoter to cyclize.7 In fact, they cyclize in the absence of Brøn-
sted or Lewis acid and in the presence of excess base8 and many
cyclize at or lower than room temperature. Moreover, the product
of such cyclization may differ from the same cyclization that is
promoted by a Lewis acid starting from the corresponding alde-
hyde or acetal.
We first observed this phenomenon when we attempted the
radical cyclization of ␣-bromoether 1b (Scheme 2). Instead of the
expected product 3, resulting from a radical cyclization, we ob-
tained only the Prins cyclization product 2. Curious about this
unexpected outcome, we resubmitted the ␣-bromoether 1b to the
A one-pot procedure starting from the MOM acetal was found to
be optimal: after treatment with Me2BBr and excess potassium
carbonate or DTBMP for 15 min, the remaining boron reagent and
the dimethylboron methoxide formed were removed under high
vacuum11 and the sensitive ␣-bromoether 5 was unambiguously
Received 24 July 2013. Accepted 22 August 2013.
P. Arpin, B. Hill, R. Larouche-Gauthier, and C. Spino. Département de chimie, Université de Sherbrooke, 2500 boul. Université, Sherbrooke,
QC J1K 2R1, Canada.
Corresponding author: Claude Spino (e-mail: Claude.Spino@USherbrooke.ca).
Can. J. Chem. 91: 1193–1201 (2013) dx.doi.org/10.1139/cjc-2013-0337
Published at www.nrcresearchpress.com/cjc on 23 August 2013.

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Can. J. Chem. Vol. 91, 2013
Scheme 1. Prins cyclizations.
Scheme 2. Prins cyclization of 1.
Scheme 3. Prins cyclization of 5.
assigned by 1H NMR of an aliquot. Solvent was reintroduced and
␣-bromoether 5 in the presence of excess base cyclized (to 6 or 8a
and 8b depending on the base) within 48 h at 25 °C.
acterized in the crude mixture. The stereochemistry of 14c was
assigned by nOe experiments. The fact that the silyl group did not
eliminate under such conditions suggests a fast delivery of the
bromide ion onto the carbocation, perhaps via a tight ion pair.
Rychnovsky and co-workers also argued an intimate ion pair to
explain the unusual axially selective attack of bromide ion from
the treatment of ␣-acetoxyethers with trimethylsilyl bromide.6b,16
Indeed, axial attack of the bromide ion occurred in the cyclization
of ␣-bromoethers 15a and 15b (Table 1, entry 4). Note that if the
yield was higher using DTBMP, the ratio of 16a:16b remained 8:1
when K2CO3 was used.
The 1,1-disubstituted alkene in 17 led to a 2:2:1 mixture of tetra-
hydropyrans 18a, 18b, and 18c (Table 1, entry 5). This results
stands in contrast with the axially selective Lewis-acid-catalyzed
cyclization of a similar substrate by the group of Rychnovsky.6b
However, preference for axial attack was shown to be sensitive to
reaction conditions, and in neither case (Table 1, entries 4 and 5)
could we ascertain whether an oxonia−Cope rearrangement was
involved or not.17
Surprisingly, there are few reports of the utilization of the Prins
cyclization to make tetrahydrofuran rings, none with the stereo-
chemical relationship found in product 6 or 8.12 However, Rawal
and co-workers cyclized the phenylselenide analogue of 5 (Br =
SePh) under radical conditions and obtained 7 in 83% in a syn:anti
ratio of 2.2:1.13 The anionic cyclization of a similar compound gave
mostly (15:1) the syn tetrahydrofuran analogous to 7 in 49% yield.14
We studied three more cases of the formation of five-membered
rings using the procedure described above and potassium carbon-
ate as the base (Fig. 1; Table 1, entries 1–3). Each time, only the
tetrahydrofuran having the syn stereochemistry was obtained.
Distinctively, cyclization of allylsilanes 13a and 13b was termi-
nated by the bromide ion rather than by loss of the silyl group
(Table 1, entry 3).15 Elimination of trimethylsilyl bromide (TMSBr)
occurred upon chromatography to give the terminal alkene 14c
(Fig. 1), although products 14a and 14b were unambiguously char-
Published by NRC Research Press

Arpin et al.
1195
Fig. 1. Structures of compounds in Table 1.
the cyclization of (E,E)- and (Z,E)-1,5-dienes 21a and 21b (Fig. 2).
Polycyclization18 is expected with such dienes and this is indeed
the result we obtained using Lewis acids such as SnCl4 and
BF3·Et2O (Fig. 2; Table 2, entries 2 and 3). Strangely, the milder
Lewis acid TMSBr led to a multitude of unidentifiable products
(Table 2, entry 4) as did the stronger Lewis acid TiCl4 (Table 2, entry
5). With our conditions, starting with (E)-21a, a 92% yield of a
single diastereomer of monocyclization product 22a was isolated,
devoid of any trace of bis-cyclization products (Table 2, entry 1).
When starting from the Z isomer, 70% of a 1:5 mixture of diaste-
reomers 22a and 22b was isolated. The major diasteromer was
now the syn isomer 22b.
This initial study clearly shows that ␣-bromoethers cyclize un-
der basic conditions and that the end product may be different
from that obtained with the classic Lewis-acid-promoted cycliza-
tion of an acetal. We are now working to find a method to make
␣-bromoethers from alcohols under completely basic or neutral
conditions.
Perhaps not surprisingly, when the alkoxide from alcohol 24
(Scheme 4) was mixed with different dihalomethanes or tosylhalo-
methanes in the presence of base, only a symmetrical acetal 25
was formed (Fig. 3).19,20 Alcohol 24 reacted with Dolbier’s salt21 in
DMF at reflux temperature to give products 8a and 8b in 58%
combined yield and in a 4:1 ratio. The ammonium salt 26 was
easily prepared from the alcohol 24 and Eschenmoser’s salt. Heat-
ing it in refluxing DMF led to no reaction until lithium bromide
was added. Then, compound 8b was isolated in 67% yield. The
high temperature is a drawback in these methods. Efforts to
achieve acid-free Prins cyclization, including the use of bromo-
methyl carbene, are continuing.
We have shown that ␣-bromoethers can cyclize under basic
conditions and need no promoter to do so. The cyclization prod-
ucts are often different, structurally or stereochemically, from the
classic Lewis-acid-catalyzed reaction. Further efforts to discover
strictly neutral or basic conditions to make the ␣-bromoethers
from the corresponding alcohols are underway.
Experimental section
General considerations
Table 1. Prins cyclization of ␣-bromoethers 9, 11, 13, 15, 17, and 19
All reactions were performed under an inert atmosphere of argon
in glassware that had been flame dried. Solvents were distilled from
calcium hydride (dichloromethane, triethylamine, and pyridine) and
from potassium/benzophenone (tetrahydrofuran) prior to use.
n-Butyllithium (solution in hexanes) was titrated using the
method of Love and Jones.24 Reagents were purchased and used
without purification. Flash chromatography was performed using
silica gel (230–400 mesh) with solvents distilled prior to use. IR
spectra were recorded as a neat film of oil on NaCl pellets. NMR
spectra were recorded at 300 MHz for 1H NMR and at 75.5 MHz for
13C NMR. The following abbreviations were used: s, singlet; d,
doublet; t, triplet; q, quartet. Chemical shifts are reported in ppm
with the solvent resonance as the internal standard (CDCl3:
7.26 ppm (1H NMR) and 77.0 ppm (13C NMR)). IR spectra were
recorded on a thin layer of the product on a NaCl disk. GCMS
analyses were performed on a 30 m lengh, 25 ␮ OD, DB-5ms MSD
column coupled with a mass spectrometer.
under basic conditions.
Entry
Basea
␣-Bromoether
Product (yield)b
1
2
3
K2CO3
K2CO3
K2CO3
9
10 (66%)c
11
12a and 12b 89% (1:1)
E-13ad
14a and 14b (75%)e
Z-13b
4
5
6
DTMB
K2CO3
DTMB
E-15a
Z-15b (E:Z = 8:1)
17
16a, ␣-Me, ␣-Br
16b, ␤-Me, ?-Br (84%, a:b = 8:1)
18a, ␣-Br
18b, ␤-Br (68%, 1:1)f
20 (53%)
19
aSee text for reaction conditions.
bIsolated yields.
cBest isolated after reduction of the bromide with n-Bu3SnH.
dThe ␣-bromoether could neither be isolated nor observed in this case.
eYield of the product of elimination of Br-SiMe3, alkene 14c (Fig. 1), after
chromatography.
fAccompanied by 17% of compound 18c having an exocyclic double bond for a
total yield of 85%.
2-(Methoxymethoxy)-1,2,3,4,5,6,7,8-octahydronaphthalene (1a)
To a stirred solution of 1,2,3,4,5,6,7,8-octahydronaphthalen-2-ol
(prepared according to the method of Marshall and co-workers)22
(420 mg, 2.75 mmol) and dimethoxymethane (14 mL) were added
LiBr (240 mg, 2.76 mmol) and TsOH (53 mg, 0.28 mmol). After
2 days, both water and ethyl ether were added, the layers were
separated, and the aqueous was extracted with ethyl ether (×3).
The organics were dried over MgSO4, filtered, and concentrated.
The 6-exo-trig mode of cyclization led exclusively to the 2,5-anti-
disubstituted tetrahydropyran 20 (entry 6). A purported tertiary
bromide in the initial product presumably undergoes fast E1-type
elimination under the reaction conditions.
The difference between the cyclization of ␣-bromoethers and
the Lewis-acid-promoted cyclization of acetals is underscored in
Published by NRC Research Press

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Can. J. Chem. Vol. 91, 2013
Fig. 2. Structures of compounds in Table 2.
Table 2. Cyclization of diene-acetals 21a and 21b.
Entry Reaction conditions Yield from (E)-21a
Me2BBr, DTBMP, −78 °C to
Yield from (Z)-21b
1
22a (92%)
22b (70%) (21a:21b = 1:5)
room temperature
SnCl4, CH2Cl2, 0 °C
BF3·Et2O, CH2Cl2, 0 °C
TMSBr
2
3
4
5
23a, ␤-Me; 23b, ␣-Me; 53% (a:b = 4:1)
23a, ␤-Me; 23b, ␣-Me; 60% (a:b = 3:1)
Complex mixture
23a, ␤-Me; 23b, ␣-Me; 40% (1:1)
23a, ␤-Me; 23b, ␣-Me; 82% (1:1)
Complex mixture
TiCl4, −78 °C
Complex mixture
Complex mixture
Scheme 4. Attempted formation of ␣-bromoethers under strictly basic or neutral conditions.
(m/z, relative intensity): 196 (M+, 3), 134 (100), 135 (95), 91 (85), 79
Fig. 3. Structure of 14c and symmetrical acetal 25.
(70). HRMS calcd. for C12H20O2: 196.1463; found: 196.1459.
2-(Bromomethoxy)-1,2,3,4,5,6,7,8-octahydronaphthalene (1b)
To a cooled −78 °C solution of methoxymethyl ether 1a (75 mg,
0.382 mmol) and dichloromethane was added 1.33 mol L−1 Me2BBr
(373 ␮L, 0.5 mmol). The mixture was stirred at −78 °C for 1 h and
then the solvent was evaporated under high vacuum while the
bath was removed and the temperature slowly brought to room
temperature. The resulting 93 mg of 1b was then used without
1
further purification. H NMR (300 MHz, CDCl3) ␦ (ppm): 5.79 (s,
Purification by flash chromatography (15:1 hexanes − ethyl ace-
tate) yielded 461 mg (85%) of 1a as a clear colorless oil. H NMR
1
2H), 4.04–3.95 (m, 1H), 2.24–2.17 (m, 2H), 1.99–1.83 (m, 7H), 1.73–
1.50 (m, 5H). 13C NMR (75.5 MHz, CDCl3) ␦ (ppm): 127.8 (s), 124.5 (s),
75.9 (d), 74.8 (t), 35.3 (t), 30.0 (t), 29.6 (t), 28.1 (t), 27.1 (t), 22.7 (t). IR
(CHCl3) ␯ (cm−1): 2925, 2831, 1442, 1103, 1056, 1029. LRMS (m/z,
relative intensity): 246 (M+, 18), 244 (M+, 20). HRMS calcd. for
C11H17BrO (79Br): 244.0463; found: 244.0466.
(CDCl3, 300 MHz) ␦ (ppm): 4.70 (ABq, J = 9.6 Hz, 2H), 3.85–3.77 (m,
1H), 3.37 (s, 3H), 2.21–2.14 (m, 2H), 1.98–1.85 (m, 7H), 1.69–1.50 (m,
5H). 13C NMR (CDCl3, 75 MHz) ␦ (ppm): 127.6 (s), 125.1 (s), 94.5 (t),
72.5 (d), 55.0 (q), 36.9 (t), 30.1 (t), 29.7 (t), 28.7 (t), 28.6 (t), 22.9 (t), 22.8
(t). IR (film, cm−1): 2926, 2832, 1441, 1150, 1104, 1055, 1036. LRMS
Published by NRC Research Press

Arpin et al.
1197
Oxatricyclo 2
vacuo to give bromide 6 as an oil. The crude product was charac-
terized but unstable and thus was used in the next step (reduction)
without purification. 1H NMR (300 MHz, CDCl3) ␦ (ppm): 7.41–7.28
(m, 5H), 4.89 (dd, 1H, J = 10.4, 5.5 Hz), 4.13–4.03 (m, 2H), 2.74–2.62
(m, 1H), 2.41 (ddd, 1H, J = 12.3, 7.7, 5.5 Hz), 1.89–177 (m, 1H), 1.77 (s,
3H), 1.76 (s, 3H). 13C NMR (75 MHz, CDCl3) ␦ (ppm): 141.9 (s), 128.4
(d), 127.9 (d), 127.6 (d), 125.8 (d), 81.9 (d), 70.9 (t), 68.7 (s), 53.8 (d), 39.0
(t), 33.2 (q), 32.3 (q). IR (film, cm−1): 3026–2862, 1110, 570. LRMS (m/z,
relative intensity): 270 (60), 268 (60), 189 (45), 159 (75), 105 (100).
HRMS calcd. for C13H16O (M-HBr+): 188.1201; found: 188.1205.
To a refluxing solution of crude ␣-bromoether 1b (93 mg,
0.379 mmol) and benzene (20 mL) was added Ph3SnH (173 mg,
0.493 mmol) in benzene (2 mL) via syringe pump over 10 h. The
solvent was removed under reduced pressure and the crude mix-
ture purified by flash chromatography (25:1 hexanes − ethyl ace-
1
tate) yielding 34 mg (54%) of 2 as a volatile colorless oil. H NMR
(300 MHz, CDCl3) ␦ (ppm): 5.35–5.31 (m, 1H), 4.45 (t, J = 5.0 Hz, 1H),
3.83 (d, J = 6.6 Hz, 1H), 3.47 (d, J = 6.6 Hz, 1H), 2.52–2.43 (m, 1H), 2.07
(dd, J = 14.4, 6.3 Hz, 1H), 1.97–1.81 (m, 2H), 1.78–1.50 (m, 6H), 1.40 (dt,
J = 12.6, 6.5 207 Hz, 1H), 1.30–1.22 (m, 1H). 13C NMR (75.5 MHz,
CDCl3) ␦ (ppm): 141.3 (s), 117.7 (d), 77.8 (t), 77.3 (d), 44.6 (t), 44.3 (s),
33.9 (t), 30.8 (t), 28.7 (t), 25.2 (t), 21.2 (t). IR (CHCl3) ␯ (cm−1): 2925,
1652. LRMS (m/z, relative intensity): 164 (M+, 3), 134 (100). HRMS
calcd. for C11H16O: 164.1201; found: 164.1205.
4-Isopropyl-2-phenyltetrahydrofuran (rac-7)23
To bromide 6 (111 mg, 0.41 mmol), obtained from bromoether 5
via general procedure A, in benzene (2 mL, 0.2 mol L−1) was added
triphenyltin hydride (150 mg, 0.43 mmol) and the solution was
heated to refluxing temperature for a 12 h period. Then, the solu-
tion was cooled and concentrated in vacuo to give a white paste.
The crude product was purified by flash column chromatography
on silica gel eluting with CH2Cl2−hexanes (50:50) to give tetrahy-
drofuran 7 as a colorless oil (58 mg, 74% for 2 steps). 1H NMR
(300 MHz, CDCl3) ␦ (ppm): 7.34–7.25 (m, 5H), 4.90 (dd, 1H, J = 10.4,
5.5 Hz), 4.11 (t, 1H, J = 8.3 Hz), 3.73 (t, 1H, J = 8.3 Hz), 2.46–2.38 (m,
1H), 2.21–2.07 (m, 1H), 1.60–1.26 (m, 4H), 0.95 (d, 3H, J = 6.6 Hz), 0.92
(d, 3H, J = 6.6 Hz).
General procedure A for the preparation of ␣-bromoethers
The acetal (1.0 equiv.) was dissolved in dichloromethane
(0.2 mol L−1). Anhydrous potassium carbonate (1.2–1.5 equiv.) was
added and the solution was cooled to −78 °C. Dimethylbro-
moborane (1.1 equiv.) was then added and the solution was stirred
for 15 min, after which time the reaction mixture was concen-
trated under reduced pressure for 3 h at −78 °C and then for an
extra 3 h at room temperature to give the ␣-bromoether. Note that
some bromoethers will cyclize completely or partially during this
time.
cis-4-Isopropenyl-2-phenyltetrahydrofuran (rac-8a) and
4-isopropylidene-2-phenyltetrahydrofuran (rac-8b)
Bromoether 6, obtained from bromoether 5 via general proce-
dure B, was dissolved in dichloromethane (3 mL) at room temper-
ature. The solution was stirred for 2 days and then diethyl ether
(5 mL) was added and the solution was filtered and concentrated
in vacuo. The crude product was purified by flash column chro-
matography on silica gel eluting with EtOAc−hexanes (10:90) to
give a mixture of 8a and 8b (123 mg, 98%, ratio 2:1). Isomer 8a:
1H NMR (300 MHz, CDCl3) ␦ (ppm): 7.38–7.23 (m, 5H), 4.96 (dd, 1H,
J = 10.2, 6.1 Hz), 4.78 (2, 2H)), 4.13 (t, 1H, J = 8.3 Hz), 3.87 (t, 1H, J =
8.3 Hz), 3.16–3.04 (m, 1H), 2.45 (ddd, 1H, J = 12.1, 6.1, 6.1 Hz), 1.84–
1.73 (m, 1H), 1.76 (s, 3H). 13C NMR (75 MHz, CDCl3) ␦ (ppm): 144.4 (s),
142.8 (s), 128.4 (d), 127.3 (d), 125.7 (d), 110.6 (t), 81.6 (d), 72.1 (t), 47.3
(d), 40.4 (t), 20.7 (q). IR (film, cm−1): 3026–2862, 1110, 570. LRMS (m/z,
relative intensity): 188 (M+, 15), 158 (20), 143 (100), 105 (50). HRMS
General procedure B for the preparation of ␣-bromoethers
The acetal (1.0 equiv.) was dissolved in dichloromethane
(0.2 mol L−1). Anhydrous 2,6-di-t-butyl-4-methylpyridine (1.5 equiv.)
was added and the solution was cooled to −78 °C. Dimethylbro-
moborane (1.1 equiv.) was then added and the solution was stirred
for 15 min, after which time the reaction mixture was concen-
trated under reduced pressure for 3 h at −78 °C and then for an
extra 3 h at room temperature to give the ␣-bromoether. Note that
some bromoethers will cyclize completely or partially during this
time.
1-(Bromomethylmethoxy)-4-methyl-1-phenylpent-3-ene (5)
The reaction was performed according to general procedure A
with 1-(methoxymethoxy)-4-methyl-1-phenyl-3-pentene 4 (205 mg,
0.93 mmol), dichloromethane (5.0 mL, 0.2 mol L−1), bromodimethyl-
borane (0.10 mL, 1.02 mmol), and potassium carbonate (147 mg,
1.06 mmol) to give bromoether 5 as an oil containing some re-
maining potassium carbonate in suspension. The crude product
was used in the next step (cyclization) without purification.
Alternatively, the reaction was performed according to general
procedure B with 1-(methoxymethoxy)-4-methyl-1-phenyl-3-pentene 4
(147 mg, 0.67 mmol), dichloromethane (3.0 mL, 0.2 mol L−1),
bromodimethylborane (80 ␮L, 0.82 mmol), and 2,6-di-t-butyl-4-
methylpyridine (230 mg, 1.12 mmol) to give bromoether 5 as a paste.
The crude product was used in the next step without purification.
1H NMR (300 MHz, CDCl3) ␦ (ppm): 7.35–7.30 (m, 5H), 5.78 (d, 1H, J =
3.6 Hz), 5.32 (d, 1H, J = 3.6), 5.07 (t, 1H, J = 7.2 Hz), 4.70 (t, 1H, J =
6.9 Hz), 2.64–2.55 (m, 1H), 2.48–2.38 (m, 1H), 1.67 (s, 3H), 1.51 (s, 3H).
IR (film, cm−1): 3020, 2916, 1452, 1105, 558. LRMS (m/z, relative
intensity): 288 ((MNH4)+, 100), 286 ((MNH4)+, 100), 270 (MH+, 25),
268 (M+, 25), 206 (70), 189 (45), 171 (45). HRMS calcd. for C13H17OBr:
268.0463; found: 268.0468.
1
calcd. for C13H16O: 188.1201; found: 188.1196. Isomer 8b: H NMR
(300 MHz, CDCl3) ␦ (ppm): 7.40–7.24 (m, 5H), 4.94 (dd, 1H, J = 8.8,
6.6 Hz), 4.59 (br d, 1H, J = 12.7 Hz), 4.38 (br d, 1H, J = 12.7 Hz), 2.89
(dd, 1H, J = 15.4, 6.6 Hz), 2.46–2.38 (m, 1H), 1.68 (s, 3H), 1.61 (s, 3H).
13C NMR (75 MHz, CDCl3) ␦ (ppm): 142.2 (s), 131.7 (s), 128.3 (d), 127.4
(d), 125.9 (d), 121.4 (s), 81.3 (d), 70.3 (t), 39.0 (t), 21.5 (q), 20.6 (q). IR
(film, cm−1): 3030, 2910, 2854, 1451, 1053, 699. LRMS (m/z, relative
intensity): 188 (M+, 20), 128 (15), 104 (100), 82 (90). HRMS calcd. for
C13H16O: 188.1201; found: 188.1198.
4-(2-Bromoprop-2-yl)-2-phenethyltetrahydrofuran (rac-10)
Bromoether 9 was prepared from the corresponding MOM ac-
etal (29 mg, 0.12 mmol), potassium carbonate (30 mg, 0.22 mmol),
and dimethylbromoborane (13 ␮L, 0.13 mmol) using general pro-
cedure A. It was then dissolved in dichloromethane (1 mL) and
stirred for 2 days. The reaction mixture was concentred in vacuo.
The crude product was purified by flash column chromatography
on silica gel eluting with EtOAc−hexanes (5:95) to give bromide 10
1
as colorless oil (23 mg, 66%). H NMR (300 MHz, CDCl3) ␦ (ppm):
4-(2-Bromoprop-2-yl)-2-phenyltetrahydrofuran (rac-6)
7.32–7.16 (m, 5H), 3.91–3.82 (m, 3H), 2.82–2.62 (m, 2H), 2.50 (dddd,
1H, J = 9.9, 7.7, 7.7, 7.7 Hz), 2.10 (ddd, 1H, J = 12.1, 7.7, 5.0 Hz),
2.04–1.78 (m, 2H), 1.75 (s, 3H), 1.73 (s, 3H), 1.50 (dt, 1H, J = 9.9,
12.1 Hz). 13C NMR (75 MHz, CDCl3) ␦ (ppm): 141.9 (s), 128.4 (d), 125.8
(d), 79.5 (d), 70.1 (d), 69.2 (q), 53.5 (d), 36.9 (t), 35.9 (t), 33.1 (q), 32.6
To bromoether 5 (220 mg, 1.07 mmol), obtained from general
procedure A or B, was added dichloromethane (5 mL) at room
temperature. The solution was stirred at room temperature for
2 days and then was filtered and the filtrate was concentrated in
Published by NRC Research Press

1198
Can. J. Chem. Vol. 91, 2013
(t), 32.4 (q). IR (film, cm−1): 3026–2862, 1453, 1110, 701, 570. LRMS
(m/z, relative intensity): 298 and 296 (7), 218 (30), 117 (40), 91 (100).
HRMS calcd. for C15H21BrO: 296.0776; found: 296.0772.
2,6-di-t-butyl-4-methylpyridine was left in the solution. The solu-
tion was stirred for 2 days, filtered, and concentrated under re-
duced pressure to give a yellow oil. The crude product was purified
by flash column chromatography on silica gel eluting with
CH2Cl2−hexanes (0:100 to 50:50) to give an 8:1 mixture of the two
epimers 16a and 16b (155 mg, 84%, 8:1). Bromoethers 15a and 15b:
1H NMR (300 MHz, CDCl3) ␦ (ppm): 7.36–7.30 (m, 5H), 5.77 (d, 1H, J =
3.8 Hz), 5.95–5.44 (m, 1H), 5.37–5.28 (m, 1H), 5.31 (d, 1H, J = 3.8 Hz),
4.71 (t, 1H, J = 6.6 Hz), 2.66–2.54 (m, 1H), 2.48–2.39 (m, 1H), 1.68 (d,
3H, J = 5.0, trans isomer), 1.62 (d, 3H, J = 6.1 Hz cis isomer). IR (film,
cm−1): 3029, 2917, 1451, 1106, 701, 561. LRMS (m/z, relative inten-
sity): 254 (M+, 5), 175 (60), 107 (55), 99 (80), 81 (100). HRMS calcd. for
C12H15OBr: 254.0306; found: 254.0310. 16a: 1H NMR (300 MHz,
CDCl3) ␦ (ppm): 7.37–7.24 (m, 5H), 4.89 (dd, 1H, J = 10.4, 2.5 Hz), 4.65
(br d, 1H, J = 2.7 Hz), 3.79 (dd, 1H, J = 11.5, 4.1 Hz), 3.69 (t, 1H, J =
11.5 Hz), 2.33 (dt, 1H, J = 14.3, 2.7 Hz), 2.20 (ddd, 1H, J = 14.3, 10.4,
2.7 Hz), 2.02–1.90 (m, 1H), 0.96 (d, 3H, J = 6.6 Hz). 13C NMR (75 MHz,
CDCl3) 141.6 (s), 128.4 (d), 127.6 (d), 126.0 (d), 73.8 (d), 68.8 (t), 59.4
(d), 42.6 (t), 35.4 (d), 16.3 (q). IR (CHCl3, cm−1): 3013, 2967, 2870,
1454, 1210, 554. LRMS (m/z, relative intensity): 254 (M+, 2), 175 (100),
145 (60), 107 (90). HRMS calcd. for C12H15BrO: 254.0306; found:
254.0310. mp (°C): 58–61. 16b: 1H NMR (300 MHz, CDCl3) ␦ (ppm):
7.32–7.23 (m, 5H), 4.35 (dd, 1H, J = 12.0, 2.19 Hz), 4.11 (dd, 1H, J = 11.6,
4.4 Hz), 3.96 (dt, 1H, J = 11.6, 4.4 Hz), 3.26 (t, 1H, J = 11.6 Hz), 2.52
(ddd, 1H, J = 13.2, 4.4, 2.2 Hz), 2.22 (t, 1H, J = 13.2 Hz), 2.15–1.24 (m,
1H), 1.06 (d, 3H, J = 6.6 Hz). 13C NMR (75 MHz, CDCl3) ␦ (ppm): 140.9,
128.4, 127.9, 125.8, 80.4, 73.5, 56.1, 45.7, 40.6, 15.7. IR (CHCl3, cm−1):
3063, 3032, 2958, 2848, 1454, 1085, 1025, 700. LRMS (m/z, relative
intensity): 254 (M+, 2), 175 ((M-Br)+, 100), 145 (45), 107 (80). HRMS
calcd. for C12H15OBr: 254.0306; found: 254.0308.
4-(Bromobenz-1-yl)-2-n-butyltetrahydrofurans (rac-12a and
rac-12b)
Bromoether 11 was prepared from the corresponding MOM ac-
etal (205 mg, 0.83 mmol), potassium carbonate (140 mg,
1.01 mmol), and dimethylbromoborane (0.09 mL, 0.9 mmol) using
general procedure A. It was then dissolved in dichloromethane
(5 mL) and the solution was stirred at room temperature for 14 h.
The crude product was purified by flash column chromatography
on silica gel eluting with EtOAc−hexanes (10:90) to give 12a as a
colorless oil (109 mg 44%) and 12b (111 mg, 45%). Bromoether 11:
1H NMR (300 MHz, CDCl3) ␦ (ppm): 7.38–7.19 (m, 5H), 6.45 (d, 1H, J =
16.0 Hz), 6.19 (dt, 1H, J = 16.0, 7.1 Hz), 5.80 (s, 2H), 3.83 (qi, 1H, J =
6.0 Hz), 2.52–2.46 (m, 2H), 1.62–1.55 (m, 2H), 1.42–1.25 (m, 4H), 0.91
(t, 3H, J = 6.9 Hz). IR (film, cm−1): 3027–2860, 1454, 1111. LRMS (m/z,
relative intensity): 298 (M+, 10), 296 (M+, 10), 239 (M-C4H9+, 20), 217
(M-Br+, 60), 131 (100), 91 (95). HRMS calcd. for C15H21OBr: 296.0776;
found: 296.0772. 12a: 1H NMR (300 MHz, CDCl3) ␦ (ppm): 7.40–7.28
(m, 5H), 4.81 (d, 1H, J = 11.0 Hz), 4.10 (dd, 1H, J = 9.1, 7.4 Hz), 3.95 (dd,
1H, J = 9.1, 6.3 Hz) 3.84 (dddd, 1H, J = 9.9, 5.8, 5.8, 5.8 Hz), 3.31–3.17
(m, 1H), 1.84 (ddd, 1H, J = 17.9, 8.0, 5.5 Hz), 1.63–1.54 (m, 1H), 1.46–
1.14 (m, 5 H), 0.97 (dt, 1H, J = 12.6, 9.3 Hz), 0.86 (t, 3H, J = 6.9 Hz). 12b:
1H NMR (300 MHz, CDCl3) ␦ (ppm): 7.40–7.28 (m, 5H), 4.82 (d, 1H, J =
11.0 Hz), 3.92–3.82 (m, 1H), 3.56 (dd, 1H, J = 8.8, 8.8 Hz), 3.35 (dd, 1H,
J = 8.8, 6.3 Hz), 3.28–3.15 (m, 1H), 2.47 (ddd, 1H, J = 18.1, 7.7, 5.5 Hz),
1.72–1.49 (m, 4H), 1.42–1.27 (m, 5H), 0.91 (t, 3H, J = 6.9 Hz).
2-Cyclohexyl-4-(1-bromo-2-trimethylsilyleth-1-yl)tetrahydrofuran
(rac-14) and 2-cyclohexyl-4-ethenyl)tetrahydrofuran (rac-14c)
Bromoethers 13a and 13b were prepared from the correspond-
ing MOM acetals (143 mg, 0.50 mmol), potassium carbonate
(106 mg, 0.77 mmol), and bromodimethylborane (50 ␮L, 0.51 mmol)
according to general procedure A to give tetrahydrofurans 14a
and 14b as a paste (cyclization occurred instantaneously and bro-
moethers 13a and 13b could not be isolated or characterized). The
crude product was used in the next step without purification. The
crude product was purified by flash column chromatography on
silica gel eluting with CH2Cl2−hexanes (30:70). Upon chromatog-
raphy, elimination of TMSBr occurred to give 14c as a colorless oil
(68 mg, 75% for 2 steps). BromoTHF 14a and 14b: 1H NMR
(300 MHz, CDCl3) ␦ (ppm): 4.21–4.10 (m, 1H), 3.94–3.82 (m, 1H),
3.62–3.49 (m, 2H), 2.63–2.52 (m, 1H), 2.13–2.00 (m, 1H), 1.93 (br d,
1H, J = 12.7 Hz), 1.74−1.57 (m, 4H), 1.55–1.12 (m, 6H), 1.03–0.89 (m,
2H), 0.08 (s, 9H). IR (film, cm−1): 2927, 2853, 1449, 1248, 1041, 850.
LRMS (m/z, relative intensity): 317 ((M-CH3)+, 5), 253 (65), 185 (50),
169 (60), 139 (85), 97 (100). HRMS calcd. for C14H26BrOSi ((M-CH3)+):
317.0936; found: 317.0951. Tetrahydrofuran 14c: 1H NMR
(300 MHz, CDCl3) ␦ (ppm): 5.73 (ddd, 1H, J = 17.0, 10.2, 8.0 Hz), 5.06
(d, 1H, J = 17.0 Hz), 4.98 (dd, 1H, J = 10.2, 1.4 Hz), 3.90 (t, 1H, J =
8,2 Hz), 3.59 (ddd, 1H, J = 9.9, 7.8, 5.5 Hz), 3.48 (t, 1H, J = 8.2 Hz), 2.88
(dddd, 1H, J = 15.9, 8.8, 8.8, 8.8 Hz), 2.09 (ddd, 1H, J = 12.4, 7.8,
5.5 Hz), 1.94 (br d, 1H, J = 12.4 Hz), 1.76–1.59 (m, 4H), 1.44–1.07 (m,
5H), 0.97 (qd, 2H, J = 11.7, 3.3 Hz). 13C NMR (75 MHz, CDCl3) ␦ (ppm):
139.2 (d), 114.8 (t), 84.7 (d), 72.2 (t), 44.3 (d), 43.2 (d), 36.9 (t), 30.0 (t),
29.0 (t), 26.5 (t), 26.0 (t), 25.8 (t). IR (film, cm−1): 3077, 2924, 2852,
1642, 1079, 912. LRMS (m/z, relative intensity): 180 (M+, 15), 98 (10),
97 (100). HRMS calcd. for C12H20O: 180.1514; found: 180.1509.
2-Benzyl-4-bromo-4-methyltetrahydropyrane (rac-18)
Bromoether 17 was prepared from the corresponding MOM
acetal (137 mg, 0.62 mmol), potassium carbonate (102 mg,
0.73 mmol), and dimethylbromoborane (68 ␮L, 0.69 mmol) ac-
cording to general procedure A. Then dichloromethane (5 mL) was
added at room temperature. The solution was stirred for 2 days,
filtered, and concentrated in vacuo to give a yellow oil. The crude
product was purified by flash column chromatography on silica
gel eluting with CH2Cl2−hexanes (30:70 to 50:50) to give a mixture
of the three compounds 18a, 18b, and 18c (85%, 2:2:1). Compound
1
18a: H NMR (600 MHz, CDCl3) ␦ (ppm): 7.32–7.29 (m, 2H), 7.24–
7.22 (m, 3H), 4.02 (dddd, 1H, J = 10.6, 7.3, 5.9, 5.9 Hz), 3.94 (dd, 1H,
J = 11.7, 5.1 Hz), 3.86 (dt, 1H, J = 11.7, 2.2 Hz), 2.90 (dd, 1H, J = 13.9,
7.3 Hz), 2.70 (dd, 1H, J = 13.9, 5.9 Hz), 2.01 (d, 1H, J = 14.7 Hz), 1.93 (d,
1H, J = 14.7 Hz), 1.92 (s, 3H), 1.67 (ddd, 1H, J = 14.7, 11.7, 5.1 Hz), 1.37
(dd, 1H, J = 14.7, 10.6 Hz). 13C NMR (75 MHz, CDCl3) ␦ (ppm): 137.8 (s),
129.3 (d), 128.4 (d), 126.4 (d), 75.8 (d), 65.1 (t), 62.7 (s), 49.4 (t), 43.9 (t),
42.5 (t), 29.2 (q). IR (film, cm−1): 2959–2863, 1453, 1103, 699, 504.
LRMS (m/z, relative intensity): 270 (M+, 5), 268 (5), 205 (5), 177 (100),
97 (90). HRMS calcd. for C13H17BrO: 268.0463; found: 268.0465.
18b: 1H NMR (600 MHz, CDCl3) ␦ (ppm): 7.31–7.19 (m, 5H), 3.80 (ddd,
1H, J = 12.9, 5.1, 1.8 Hz), 3.61 (dddd, 1H, J = 12.8, 6.2, 6.2, 2.6 Hz), 3.51
(dt, 1H, J = 12.9, 2.2 Hz), 2.88 (dd, 1H, J = 13.9, 7.0 Hz), 2.66 (dd, 1H,
J = 13.9, 6.2 Hz), 2.50 (dt, 1H, J = 12.8, 5.1 Hz), 2.21 (t, 1H, J = 13.2 Hz),
2.08 (ddd, 1H, J = 13.2, 3.7, 1.8 Hz), 1.88 (s, 3H). 13C NMR (75 MHz,
CDCl3) ␦ (ppm): 138.0 (s), 129.3 (d), 128.4 (d), 126.4 (d), 74.7 (d), 65.1
(t), 62.7 (s), 49.4 (t), 43.9 (t), 42.5 (t), 29.2 (q). IR (film, cm−1): 2959–
2863, 1453, 1103, 699, 504. LRMS (m/z, relative intensity): 270 (2),
268 (M+, 2), 205 (15), 177 (95), 97 (100), 83 (20). HRMS calcd. for
C13H17BrO: 268.0463; found: 268.0465. 18c: 1H NMR (300 MHz,
CDCl3) ␦ (ppm): 7.33–7.20 (m, 5H), 4.72 (d, 1H, J = 1.9 Hz), 4.67 (d, 1H,
J = 1.9 Hz), 4.08 (ddd, 1H, J = 11.0, 5.8, 1.3 Hz), 3.50 (dddd, 1H, J = 12.6,
6.6, 6.6, 2.2 Hz), 3.37 (td, 1H, J = 11.0, 2.7 Hz), 2.94 (dd, 1H, J = 13.7,
6.6 Hz), 2.73 (dd, 1H, J = 13.7, 6.6 Hz) 2.32 (br dt, 1H, J = 12.6, 5.8 Hz),
2.25–1.99 (m, 3H). 13C NMR (75 MHz, CDCl3) ␦ (ppm): 144.4 (s), 138.3
(d), 129.3 (d), 128.2 (d), 126.2 (d), 108.6 (t), 79.5 (d), 68.7 (t), 42.8 (t),
40.6 (t), 35.1 (t). IR (film, cm−1): 3067, 3027, 2939, 2846, 1654, 1093.
4-Bromo-5-methyl-2-phenyltetrahydropyrane (rac-16a and
rac-16b)
Bromoethers 15a and 15b were prepared from the corresponding
MOM acetals (149 mg, 0.72 mmol), 2,6-di-t-butyl-4-methylpyridine
(256 mg, 1.24 mmol), and bromodimethylborane (85 ␮L,
0.87 mmol) according to general procedure B. Then dichlorometh-
ane (5 mL) was added at room temperature and the excess of
Published by NRC Research Press

Arpin et al.
1199
LRMS (m/z, relative intensity): 188 (1), 128 (5), 115 (5), 103 (5), 97 (100),
91 (60), 69 (30), 41 (20). HRMS calcd. for C13H16O: 188.1201; found:
188.1208.
7.7 Hz), 1.96–1.79 (m, 1H), 1.75 (s, 3H). 13C NMR (75 MHz, CDCl3) ␦
(ppm): 146.7 (s), 145.6 (s), 142.4 (s), 128.4 (d), 127.6 (d), 125.8 (d), 109.7
(t), 106.4 (t), 81.2 (d), 72.9 (t), 43.5 (t), 39.5 (d), 35.5 (t), 28.6 (t), 22.5 (q).
IR (film, cm−1): 3069, 2940, 2847, 1649, 1452, 1096, 890, 699. LRMS
(m/z, relative intensity): 242 (M+, 10), 214 (15), 136 (40), 107 (75), 105
(75), 77 (100). HRMS calcd. for C17H22O: 242.1671; found: 242.1662.
121.
5-(Propen-1-yl)-2-phenyltetrahydropyrane (rac-20)
Bromoether 19 was prepared from the corresponding MOM
acetal (153 mg, 0.653 mmol), 2,6-di-t-butyl-4-methylpyridine
(246 mg, 1.12 mmol), and bromodimethylborane (80 ␮L, 0.82 mmol)
in dichloromethane (3.5 mL) according to general procedure B. To
bromoether 19 containing the excess potassium carbonate was
added dichloromethane (2 mL) at room temperature. The solution
was stirred for 2 days and then was filtered and concentrated
under reduced pressure. The crude product was purified by
flash column chromatography on silica gel eluting with EtOAc−
hexanes (6:94) to give 20 as a colorless oil (70 mg, 53%). Bromoether
19: 1H NMR (300 MHz, CDCl3) ␦ (ppm): 7.37–7.30 (m, 5H), 5.77 (d, 1H,
J = 3.3 Hz), 5.30 (d, 1H, J = 3.3 Hz), 5.10 (t, 1H, J = 6.6 Hz), 4.70 (q, 1H,
J = 6.4 Hz), 2.10–1.88 (m, 2H), 1.85–1.62 (m, 2H), 1.68 (s, 3H), 1.56 (s,
3H). IR (film, cm−1): 3031, 2919, 1451, 1106, 701, 558. LRMS (m/z,
relative intensity): 282 (M+, 5), 254 (15), 199 (80), 173 (80), 145 (85),
105 (100). HRMS calcd. for C14H19BrO: 282.0619; found: 282.0622.
4a,6-Dimethyl-3-phenyl–3,4,4a,5,8,8a-hexahydro-1H-isochromene
(rac-23a and 23b)
Method A
To a solution of diene (E)-21a (15 mg, 0.055 mmol) and sodium
carbonate (15 mg, 0.14 mmol) in dichloromethane (1 mL) at 0 °C
was added SnCl4 (10 ␮L, 0.13 mmol). Water was then added, the
organic layer was separated, and the aqueous phase was extracted
twice with dichloromethane. The combined organic layers were
dried with anhydrous magnesium sulfate, filtered, and evapo-
rated in vacuo. The crude product was purified by flash column
chromatography on silica gel eluting with PhMe−hexanes (50:50)
to give bicyclic compounds 23a and 23b as a colorless oil (7 mg,
53%, 3.7:1).
1
20: H NMR (300 MHz, CDCl3) ␦ (ppm): 7.37–7.25 (m, 5H), 4.82 (s,
1H), 4.74 (s, 1H), 4.31 (dd, 1H, J = 11.0, 2.2 Hz), 4.16 (ddd, 1H, J = 11.0.
3.8, 2.2 Hz), 3.43 (t, 1H, J = 11.0 Hz), 2.32 (broad dt, 1H, J = 11.0,
3.8 Hz), 2.05–1.91 (m, 2H), 1.77 (s, 3H), 1.70–1.62 (m, 2H). 13C NMR
(75 MHz, CDCl3) ␦ (ppm): 146.1 (s), 142.9 (s), 128.3 (d), 127.3 (d), 125.8
(d), 110.1 (t), 80.0 (d), 72.7 (t), 43.2 (d), 33.9 (t), 29.4 (q), 21.7 (t). IR
(film, cm−1): 3028–2857, 1453, 1092, 700. LRMS (m/z, relative inten-
sity): 202 (M+, 15), 146 (10), 104 (100), 77 (15). HRMS calcd. for
C14H18O: 202.1358; found: 202.1361.
Method B
To a solution of diene (E)-21a (15 mg, 0.055 mmol) in dichlo-
romethane (1 mL) at 0 °C was added BF3·OEt2 (10 ␮L, 0.12 mmol).
Water was then added, the organic layer was separated, and the
aqueous phase was extracted twice with dichloromethane. The
combined organic layers were dried with anhydrous magnesium
sulfate, filtered, and evaporated in vacuo. The crude product was
purified by flash column chromatography on silica gel eluting
with PhMe−hexanes (50:50) to give bicyclic compound 23a and
5-(3-Methylbut-3-enyl)-4-methylene-2-phenyltetrahydro-2H-pyran
(rac-22a)
1
23b as a colorless oil (8 mg, 60%, 2.9:1). Compound 23a: H NMR
(300 MHz, CDCl3) ␦ (ppm): 7.37–7.22 (m, 5H), 5.38 (br s, 1H), 4.63
(dd, 1H, J = 11.5, 2.7 Hz), 3.83 (dd, 1H, J = 11.5, 3.8 Hz), 3.50 (t, 1H, J =
11.5 Hz), 1.93–1.74 (m, 4H), 1.69–1.42 (m, 3H), 1.64 (s, 3H), 1.04 (s, 3H).
13C NMR (75 MHz, CDCl3) ␦ (ppm): 143.1 (s), 132.2 (s), 128.2 (d), 127.3
(d), 125.8 (d), 119.1 (d), 75.7 (d), 68.8 (t), 48.6 (t), 46.1 (t), 39.0 (d), 31.5
(s), 24.1 (t), 24.0 (q), 16.1 (q). IR (film, cm−1): 3031, 2925, 1725, 1452,
1073, 700. LRMS (m/z, relative intensity): 242 (M+, 100), 121 (50), 93
(70). HRMS calcd. for C17H22O: 242.1671; found: 242.1665.
Bromoether 58 was prepared from acetal (E)-21a (51 mg,
0.19 mmol), di-t-butylmethylpyridine (52 mg, 0.25 mmol), and bro-
modimethylborane (20 ␮L, 0.20 mmol) according to general pro-
cedure B. It was then dissolved in dichloromethane (1 mL) at room
temperature. The solution was stirred 15 h and diethyl ether was
added. The solution was filtered and concentrated in vacuo to give
a yellow oil. The crude product was purified by flash column
chromatography on silica gel eluting with PhMe−hexanes (50:50)
to give 22a as a colorless oil (47 mg, 62%). 1H NMR (300 MHz, CDCl3)
␦ (ppm): 7.39–7.28 (m, 5H), 4.89 (s, 1H), 4.79 (s, 1H), 4.76 (s, 1H), 4.74
(s, 1H), 4.33 (dd, 1H, J = 11.0, 2.8 Hz), 4.22 (dd, 1H, J = 11.0, 5.2 Hz), 3.20
(t, 1H, J = 11.0 Hz), 2.51 (dd, 1H, J = 13.2, 2.8 Hz), 2.35 (t, 1H, J =
12.4 Hz), 2.35–2.27 (m, 1H), 2.12 (t, 2H, J = 7.8 Hz), 1.89–1.75 (m, 1H),
1.76 (s, 3H), 1.38 (dq, 1H, J = 13.7, 7.8 Hz). 13C NMR (75 MHz, CDCl3)
␦ (ppm): 148.1 (s), 145.6 (s), 142.2 (s), 128.4 (d), 127.6 (d), 125.8 (d),
110.2 (t), 106.4 (t), 81.6 (d), 73.6 (t), 44.5 (t), 41.6 (d), 35.1 (t), 25.5 (t),
22.4 (q). IR (film, cm−1): 3081, 2940, 1649, 1452, 1099, 889, 698. LRMS
(m/z, relative intensity): 242 (M+, 15), 214 (20), 136 (60), 121 (65), 107
(100), 79 (90). HRMS calcd. for C17H22O: 242.1671; found: 242.1662.
Bis(4-methyl-1-phenylpent-3-enyloxy)methane (25)
To a solution of alcohol 24 (100 mg, 0.570 mmol) in THF (5 mL)
was added a 30% suspension of sodium hydride in mineral oil
(25 mg, 0.63 mmol). After 30 min, chloroiodomethane was added
(0.25 mL, 3.4 mmol) and the reaction mixture was stirred over-
night at room temperature. The solution was filtered, rinced with
diethyl ether, and concentrated under reduced pressure. The
crude product was purified by flash column chromatography on
silica gel eluting with EtOAc−hexanes (5:95) to give mixture of
diastereomers of 25 as a colorless oil (25 mg, 40%, 1:1). Separation
of the two diastereomers for the purpose of characterization was
possible upon further column chromatography, although the ste-
reochemical assignment was not possible. Similar results were
obtained with other dihalomethanes or halo(toluenesulfonyloxy)
methanes. Diastereoisomer 25a: 1H NMR (300 MHz, CDCl3) ␦
(ppm): 7.34–7.22 (m, 10H), 5.23 (t, 2H, J = 7.1 Hz), 4.73 (dd, 2H, J = 7.1,
6.0 Hz), 4.40 (s, 2H), 2.61–2.51 (m, 2H), 2.44–2.35 (m, 2H), 1.72 (s, 6H),
1.57 (s, 6H). 13C NMR (75 MHz, CDCl3) ␦ (ppm): 141.6 (s), 133.7 (s),
128.2 (d), 127.5 (d), 127.1 (d), 120.4 (d), 90.0 (t), 77.39 (d), 36.8 (t), 25.8
(q), 17.9 (q). IR (film, cm−1): 3030, 2915, 1452, 1097, 1060, 1024, 701.
LRMS (m/z, relative intensity) 295.1 ((M-C5H9)+, 5), 189.1 (10), 159.1
(100), 117.1 (35). HRMS calcd. for C20H32O2 ((M-C5H9)+): 295.1698;
found: 295.1695. 25b: 1H NMR (300 MHz, CDCl3) ␦ (ppm): 7.36–7.17
(m, 10H), 4.94 (t, 2H, J = 7.1 Hz), 4.78 (d, 1H, J = 7.1 Hz), 4.50 (t, 3H, J =
7.1 Hz), 2.39–2.21 (m, 4H), 1.61 (s, 6H), 1.42 (s, 6H). 13C NMR (75 MHz,
CDCl3) ␦ (ppm): 142.3 (s, 133.7 (s), 128.1 (d), 127.3 (d), 126.8 (d), 119.8
5-(3-Methylbut-3-enyl)-4-methylene-2-phenyltetrahydro-2H-pyran
(rac-22b)
Bromoether 58 was prepared from acetal (Z)-21b (53 mg,
0.19 mmol), di-t-butylmethylpyridine (52 mg, 0.25 mmol), and bro-
modimethylborane (20 ␮L, 0.20 mmol) according to general pro-
cedure B. Then, it was dissolved in dichloromethane (1 mL) at
room temperature. The solution was stirred for 15 h and diethyl
ether was then added. The solution was filtered and concentrated
in vacuo to give a yellow oil. The crude product was purified by
flash column chromatography on silica gel eluting with PhMe−
hexanes (50:50) to give 22a and 22b as a colorless oil (47 mg, 60%, 1:5).
Compound 22b: 1H NMR (300 MHz, CDCl3) ␦ (ppm): 7.40–7.28 (m,
5H), 4.83 (s, 2H), 4.74 (s, 1H), 4.72 (s, 1H), 4.30 (dd, 1H, J = 11.3, 3.0 Hz),
4.06 (d, 1H, J = 11.6 Hz), 3.72 (dd, 1H, J = 11.3, 2.8 Hz), 2.49–2.39 (m,
1H), 2.32 (dd, 1H, J = 13.7, 2.8 Hz), 2.22–2.17 (m, 1H), 2.01 (t, 2H, J =
Published by NRC Research Press

1200
Can. J. Chem. Vol. 91, 2013
(d), 91.9 (t), 78.7 (d), 36.2 (t), 25.7 (q), 17.7 (q). IR (film, cm−1): 3029,
2913, 2856, 1453, 1062, 1019, 700. LRMS (m/z, relative intensity):
295.1 ((M-C5H9)+, 5), 189.1 (10), 159.1 (100), 117.1 (35). HRMS calcd. for
C20H32O2 ((M-C5H9)+): 295.1698; found: 295.1704.
(3) (a) Hanschke, E. Chem. Ber. 1955, 88, 1053. doi:10.1002/cber.19550880718; (b)
Stapp, P. R. J. Org. Chem. 1969, 34, 479. doi:10.1021/jo01255a001.
(4) For example, see: (a) Chio, F. K.; Warne, J.; Gough, D.; Penny, M.; Green, S.;
Coles, S. J.; Hursthouse, M. B.; Jones, P.; Hassall, L.; McGuire, T. M.;
Dobbs, A. P. Tetrahedron 2011, 67, 5107. doi:10.1016/j.tet.2011.05.019; (b)
Hu, X.-H.; Liu, F.; Loh, T.-P. Org. Lett. 2009, 11, 1741. doi:10.1021/ol900196w; (c)
Tadpetch, K.; Rychnovsky, S. D. Org. Lett. 2008, 10, 4839. doi:10.1021/
ol8019204; (d) Matsumoto, K.; Fujie, S.; Ueoka, K.; Suga, S.;
Yoshida, J.-I. Angew. Chem. Int. Ed. 2008, 47, 2506. doi:10.1002/anie.
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2000, 56, 2403. doi:10.1016/S0040-4020(00)00152-6; (h) Yang, J.;
Viswanathan, G. S.; Li, C. J. Tetrahedron Lett. 1999, 40, 1627. doi:10.1016/S0040-
4039(99)00027-1; (i) Zhang, W. C.; Viswanathan, G. S.; Li, C. J. Chem. Commun.
1999, 291. doi:10.1039/A808960D; (j) Udding, J. H.; Tuijp, K. C. J. M.;
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1993. doi:10.1021/jo00087a011.; (k) Semeyn, C.; Blaauw, R. H.; Hiemstra, H.;
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(5) For the synthesis of acetoxy acetals, see: (a) Dahanukar, V. H.;
Rychnovsky, S. D. J. Org. Chem. 1996, 61, 8317; (b) Kopecky, D. J.;
Rychnovsky, S. D. J. Org. Chem. 2000, 65, 191.
(6) (a) Blumenkopf, T. A.; Bratz, M.; Castañeda, A.; Look, G. C.; Overman, L. E.;
Rodriguez, D.; Thompson, A. S. J. Am. Chem. Soc. 1990, 112, 4386. doi:10.1021/
ja00167a041; (b) Berger, D.; Overman, L. E.; Renhowe, P. A. J. Am. Chem. Soc.
1997, 119, 2446. doi:10.1021/ja964080b; (c) Jasti, R.; Vitale, J.; Rychnovsky, S. D.
J. Am. Chem. Soc. 2004, 126, 9904. doi:10.1021/ja046972e.
(7) The unassisted solvolysis of ␣-bromoethers, which were observed but not
isolated, was proposed by Rychnovsky and co-workers to initiate Prins cy-
clizations. See ref. 6b. For an interesting synergetic effect between nonpro-
moting Lewis acids and a Bronsted acid, see: Borkar, P.; Van De Weghe, P.;
Reddy, B. V. S.; Yadav, J. S.; Grée, R. Chem. Commun. 2012, 48, 9316. doi:10.
1039/c2cc35052a.
(8) Substoechiometric amounts of 2,6-di-t-butylpyridine or N,O-bis(trimethyl-
silyl)acetamide have been added to the reaction mixture consisting of SnCl4
and a MOM-protected alkenol. While the additive increased the yield of
Prins product, the yield remained low at 38% and 35%, respectively. See ref.
6a. Rychnovsky and co-workers added 0.2 equiv. of lutidine to their reaction
mixture containing the Lewis acid. See ref. 6b.
(9) (a) Guindon, Y.; Yoakim, C.; Morton, H. E. J. Org. Chem. 1984, 49, 3912. doi:
10.1021/jo00195a007; (b) Guindon, Y.; Bernstein, M. A.; Anderson, P. C.
Tetrahedron Lett. 1987, 2225. doi:10.1016/S0040-4039(00)96086-6; (c)
Guindon, Y.; Ogilvie, W. W.; Bordeleau, J.; Cui, W. L.; Durkin, K.; Gorys, V.;
Juteau, H.; Lemieux, R.; Liotta, D.; Simoneau, B.; Yoakim, C. J. Am. Chem. Soc.
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doi:10.1016/0040-4039(91)80056-C.
Formation of THF 8a and 8b via Dolbier’s salt
To a solution of alcohol 24 (236 mg, 1.34 mmol) in DMF was
added KH (80 mg, 2.0 mmol) and 18-C-6 (52 mg, 0.2 mmol). After
stirring the suspension for 1 h at room temperature, Dolbier’s salt
(535 mg, 2.70 mmol) was added and the resulting solution was
stirred at reflux temperature for 24 h. The reaction mixture was
cooled to room temperature and poured into a mixture of diethyl
ether and brine. The organic phase was separated and the aqueous
phase was extracted thrice with diethyl ether. The combined or-
ganic phases were dried with anhydrous magnesium sulfate,
evaporated in vacuo, and the residue was purified by flash column
chromatography on silica gel eluting with EtOAc−hexanes (10:90)
to give a mixture of 8a and 8b (146 mg, 58%, ratio 4:1).
Formation of THF 8b via the quaternary ammonium salt
To a mixture of NaH (30 mg (60% dispersion in oil, 0.738 mmol)
in dry DMF (3 mL) was added alcohol 24 (100 mg, 0.567 mmol) at
0 °C under argon. The resulting mixture was then stirred for 1 h at
room temperature and Eschenmoser’s salt (157 mg, 0.815 mmol)
was added. The reaction mixture was stirred 16 h at room temper-
ature. After that, Me3OBF4 (109 mg, 0.738 mmol) was added and
the mixture was stirred for 18 h at room temperature (monitored
by 1H NMR). LiBr (148 mg, 1.70 mmol) was then added to the reac-
tion mixture and the resulting solution was stirred at 150 °C for
15 h (monitored by 1H NMR). DMF was then removed in vacuo and
the residue was mixed with EtOAc and water. The layers were
separated and the aqueous phase was extracted twice with diethyl
ether. The combined organic phases were dried over magnesium
sulfate and evaporated in vacuo. The crude product was purified
by silica gel column chromatography eluting with EtOAc−hexanes
(0:100 to 2:98) to give 8b as a colorless oil.
Supplementary material
(10) Overman and co-workers isolated an ␣-bromoether by the same method
and used it to make a mixed acetal. See ref. 6b.
Supplementary material is available with the article through
the journal Web site at http://nrcresearchpress.com/doi/suppl/
10.1139/cjc-2013-0337.
(11) Me2BBr: bp 32 °C, Me2BOMe: 24 °C. Each time, careful analysis by 1H NMR
confirmed the absence of these two reagents.
(12) For example, see: (a) Shin, C.; Chavre, S. N.; Ae, N. P.; Joo, H. C.; Hun, Y. K.;
Moon, H. C.; Jung, H. C.; Yong, S. C. Org. Lett. 2005, 7, 3283. doi:10.1021/
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1991, 113, 5365. doi:10.1021/ja00014a031; (d) Gasparski, C. M.;
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doi:10.1016/S0040-4039(00)01571-9.
(13) Rawal, V. H.; Singh, S. P.; Dufour, C.; Michoud, C. J. Org. Chem. 1993, 58, 7718.
doi:10.1021/jo00079a016.
(14) Broka, C. A.; Wen, J. L.; Sheng, T. J. Org. Chem. 1988, 53, 1336. doi:10.1021/
jo00241a047.
(15) To the best of our knowledge, this phenomenon has not been reported
elsewhere for a Prins cyclization. For other examples, see: (a) Bélanger, G.;
O'Brien, G.; Larouche-Gauthier, R. Org. Lett. 2011, 13, 4268. doi:10.1021/
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Indukuri, K.; Gogoi, P. Chem. Lett. 2011, 40, 1176. doi:10.1246/cl.2011.1176; (d)
Zurwerra, D.; Gertsch, J.; Altmann, K.-H. Org. Lett. 2010, 12, 2302. doi:10.1021/
ol100665m; (e) Lolkema, L. D. M.; Hiemstra, H.; Semeyn, C.;
Speckamp, W. N. Tetrahedron 1994, 50, 7115. doi:10.1016/S0040-4020(01)
85238-8.
(17) (a) Rychnovsky, S. D.; Marumoto, S.; Jaber, J. J. Org. Lett. 2001, 3, 3815. doi:
10.1021/ol0168465; (b) Jasti, R.; Rychnovsky, S. D. Org. Lett. 2006, 8, 2175.
doi:10.1021/ol0606738; (c) Al-Mutairi, E. H.; Crosby, S. R.; Darzi, J.;
Hughes, R. A.; Simpson, T. J.; Smith, R. W.; Willis, C. L.; Harding, J. R.;
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(18) Sutherland, J. K. Comprehensive Organic Synthesis, Vol. 3; Trost, B. M., Fleming,
I., Eds.; Pergamon Press: Oxford, UK, 1991.
Acknowledgements
We thank the Université de Sherbrooke and the Natural Sci-
ences and Engineering Research Council of Canada for financial
support.
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