Selective Prins reaction of styrenes and formaldehyde catalyzed by 2,6-Di-tert-butylphenoxy(difluoro)borane

Article abstract of DOI:10.1055/s-2002-35645

The sterically congested Lewis acid 1 was used as a catalyst in the Prins reaction of various styrenes and formaldehyde. 4-Aryl-1,3-dioxanes 5 were selectively formed as the exclusive products of the reaction with styrenes 4a-i and vinylthiophenes 4j-k. The reaction proceeded in most cases with good to excellent yields (55-99%). Styrenes which carried a strongly electron-withdrawing group (CN, CO₂Me) did not react. The reaction with β-alkylstyrenes 6 was successful for the methyl substituted substrate 6a and yielded (88%) trans-5-methyl-4-phenyl-1,3-dioxane (7a) preferentially (dr = 75:25). For steric reasons, other β-alkylstyrenes 6b-d did not react. The remarkable stereodiscrimination attained by catalyst 1 was employed in the regioselective transformation of 4-propenylstyrene (10) to dioxane 11 (83% yield).

Full text of DOI:10.1055/s-2002-35645

PAPER
2521
Selective Prins Reaction of Styrenes and Formaldehyde Catalyzed by
2,6-Di-tert-butylphenoxy(difluoro)borane
Selective Prins
h
Reaction of
S
o
tyrenes rsten Bach,* Johannes Löbel
Technische Universität München, Lehrstuhl für Organische Chemie I, Lichtenbergstr. 4, 85747 Garching, Germany
Fax +49(89)28913315; E-mail: thorsten.bach@ch.tum.de
Received 19 August 2002; revised 21 August 2002
Dedicated to Professor George A. Olah on the occasion of his 75th birthday.
We became interested in the Prins reaction because of its
high synthetic versatility.4 A double bond functionaliza-
tion can be nicely combined with a C–C-bond formation
in a single step provided there is a significant type selec-
Abstract: The sterically congested Lewis acid 1 was used as a cat-
alyst in the Prins reaction of various styrenes and formaldehyde.
4-Aryl-1,3-dioxanes 5 were selectively formed as the exclusive
products of the reaction with styrenes 4a–i and vinylthiophenes
4j–k. The reaction proceeded in most cases with good to excellent tivity for either product B, C or D. At least one stereogenic
center is formed in the course of the reaction to B or C.5
yields (55–99%). Styrenes which carried a strongly electron-with-
drawing group (CN, CO2Me) did not react. The reaction with
-
Our major focus was to find suitable conditions for the
conversion of styrenes to the corresponding 1,3-dioxanes.
Ideally, we looked for a catalytic reaction system with the
Lewis acid6 being used in substoichiometric amounts.7
Preliminary studies with BF3 as the Lewis acidic catalyst
and styrene as the alkene under various conditions re-
vealed that the chemoselectivity of the BF3-catalyzed re-
action was not sufficient. Yields remained under 50% and
many side reactions were observed. In search of less ac-
tive, but more selective catalysts, we considered the use of
sterically congested alkoxy- and aryloxyboron halides.8
Recent synthetic studies by Meller et al.9 had provided
several boron compounds, e.g. 1–3 (Figure 1), which ap-
peared interesting Lewis acids for our purpose. Whereas
diaryloxyboron fluoride 2 and dialkoxyboron fluoride 3
turned out to be not sufficiently reactive the aryloxyboron
difluoride 1 was found well suited to catalyze the Prins re-
action of styrenes. Details of the reactions conducted by
us are reported in this account.
alkylstyrenes 6 was successful for the methyl substituted substrate
6a and yielded (88%) trans-5-methyl-4-phenyl-1,3-dioxane (7a)
preferentially (dr = 75:25). For steric reasons, other -alkylstyrenes
6b–d did not react. The remarkable stereodiscrimination attained by
catalyst 1 was employed in the regioselective transformation of
4-propenylstyrene (10) to dioxane 11 (83% yield).
Keywords: carbocations, catalysis, chemoselectivity, electrophilic
additions, Lewis acids
The Prins reaction1,2 of alkenes A and formaldehyde can
proceed to a variety of products depending on the reaction
conditions (Scheme 1). Major products commonly ob-
served include 1,3-dioxanes B, 1,3-diols C and allylic al-
cohols D. Homoallylic alcohols are also accessible from
the same starting materials but they are often formed by a
mechanistically different pathway (carbonyl-ene reac-
tion).3 Additional side reactions may further complicate
the outcome of the reaction. In particular, a polymeriza-
tion of the olefin which is induced by Lewis or Brønsted
acids can severely interfere with the desired C–C-bond
formation.
t Bu
t Bu
t Bu
t Bu
t Bu
OBF2
O
O
BF
BF
t Bu
t Bu
2
2
1
2
3
Figure 1 Sterically congested Lewis acids9 with a boron atom as the
Lewis acidic center
Catalyst 1 is a liquid which can be purified by distillation
in vacuo. It can be stored at –30 °C for several weeks
without loosing its catalytic activity. Optimized reaction
conditions which we used in all Prins reaction experi-
ments included the use of paraformaldehyde [(CH2O)n] as
the formaldehyde source and 1,4-dioxane as the solvent.
A catalyst loading of 10 mol% turned out to be ideal. The
use of a lower catalyst/substrate ratio (5 mol%) led to
longer reaction times or to incomplete conversion. The se-
lectivity (type selectivity and chemoselectivity) of the cat-
alyzed reaction is remarkable. In all instances, the
styrenes 4 were converted exclusively to the 1,3-dioxanes
Scheme 1
Synthesis 2002, No. 17, Print: 02 12 2002.
Art Id.1437-210X,E;2002,0,17,2521,2526,ftx,en;Z11802SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

2522
T. Bach, J. Löbel
PAPER
5 (Scheme 2). Other side products were not observed. The
reaction temperature had to be adjusted depending on the
substituent on the styrenes (Table 1). The parent com-
pound 4a reacted at 80 °C and gave the corresponding di-
oxane 5a in 95% yield. Electron-donating substituents
with a negative Hammett constant10 [4b, p (Me) = –0.14,
4c, p (OMe) = –0.28] facilitated reactions at lower tem-
perature. The reactive vinylthiophenes 4j and 4k also re-
acted under milder conditions (75 °C) and yielded the
hitherto unknown 1,3-dioxanes 5j and 5k. Styrenes sub-
stituted with an electron-withdrawing group reacted less
readily and required higher reaction temperatures. Reac-
tions which were conducted at 100 °C with the para-sub-
Table 1 Substitution Pattern, Reaction Conditions and Yields for
the Conversion of Styrenes 4 to the Corresponding 1,3-Dioxanes 5
with Paraformaldehyde in Dioxane as the Solvent
Sub- Ar
strate
Temp
(°C)
Time
(h)a
Prod-
uct
Yield
(%)b
4a
4b
4c
4d
80
12
12
8
5a
5b
5c
5d
5e
95
97
65
88
55
80
70
O
stituted styrenes 4d and 4i [4d,
(Cl) = 0.22, 4i,
p
p
100
110
24
48
(OAc) = 0.18] serve as examples.
Cl
(CH2O)n, 1 (10 mol-%)
4e
O
O
(dioxane)
Ar
Ar
see table
Cl
O
4
5
4f
110
80
48
12
5f
81
56
Scheme 2
Cl
4g
5g
Varying the location of the chlorine substituents in the
chlorostyrenes 4d–f showed that an ortho-substituent
does not significantly alter the outcome of the reaction.
Both 2- (4f) and 4-chlorostyrene (4d) reacted smoothly to
give the corresponding products in good yields. The lower
reactivity of the meta-compound 4e is attributed to the
higher electron acceptor power of chlorine in meta-posi-
tion [ m (Cl) = 0.37]. Indeed, it appears as if the reactivity
of the electrophile, which is presumably a formaldehyde-
Lewis acid (H2CO 1) complex, is sufficient to attack sty-
renes, the substituents of which exhibit a Hammett con-
N
H
4h
110
24
5h
35
NH
O
O
O
4i
100
75
12
12
6
5i
99
80
67
4j
4k
5j
5k
stant
0.40. More deactivating substituents prohibit the
S
S
reaction completely. Accordingly, 4-cyano
(CN) = 0.71] and 4-methoxycarbonylstyrene
[
[
p
75
p
(CO2Me) = 0.44] did not react. It is unlikely that the fail-
ure of these reactions is due to a deactivation of the Lewis
acid by carbonyl complexation as other esters 4i and even
amides 4g, 4h did react. Along these lines, the unsuccess-
ful attempt to convert 4-vinylpyridine to its 1,3-dioxane
derivative is easy to understand.
a Period of time after which the reaction was complete.
b Yield of isolated product after chromatographic purification.
1-Phenylprop-1-ene (6a)11 underwent a stereoselective
Prins reaction under the typical reaction conditions. The
trans-1,3-dioxane 7a was formed in excess relative to the
cis-isomer 8a (dr = 75:25) (Scheme 3). The reaction pro-
ceeded not stereospecifically but in a stereoconvergent
fashion, i.e. the diastereomeric ratio was not dependent on
the configuration of the styrene. Experiments conducted
with pure trans-6a and with a cis/trans-mixture resulted in
identical yields and diastereoselectivities. The diastereo-
selectivity is higher than previously observed for the anal-
ogous Prins reaction promoted by Brønsted acids.12
Depending on the acid and the reaction conditions dia-
stereomeric ratios of dr = 64:36 to 37:63 have been
reported.
(CH2O)n, 1 (10 mol-%)
O
O
O
O
(dioxane)
+
Ph
Ph
Ph
88%
6a
d.r. = 75/25
7a
8a
Scheme 3
The diastereomerically pure 1,3-dioxane 7a was subjected
to the typical Prins reaction conditions. An equilibration
to compound 8a was not observed. We therefore conclude
that the products are formed in a kinetically controlled re-
action, which proceeds irreversibly to the two diastereo-
isomers. A possible explanation for the preference in
favor of 7a is based on the generally accepted mechanism
Synthesis 2002, No. 17, 2521–2526 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Selective Prins Reaction of Styrenes
2523
All reactions involving water-sensitive chemicals were carried out
in flame-dried glassware with magnetic stirring under Ar. All ex-
periments were performed in Fluka p.a. solvents. The styrenes were
either commercially available or they were prepared according to
known protocols: acetamidostryrenes 4g/h,14 vinylthiophenes 4j/
k.15 Common solvents for chromatography [Et2O, pentane (P),
EtOAc] were distilled prior to use. TLC was performed on alumi-
num sheets (0.2 mm silica gel 60 F254) with detection by UV (254
nm) or by coloration with ceric ammonium molybdate (CAM).
Flash chromatography16 was performed on silica gel 60 (Merck,
230–400 mesh) (ca. 50 g for 1 g of material to be separated) with the
indicated eluent. Melting points (uncorrected): Reichert hot bench.
IR: Perkin Elmer 1600 FT-IR. MS: Varian CH7 (EI). HRMS: Finni-
gan MAT 95S or MAT 8200. GC-MS: Agilent 6890 (GC system),
of the Prins reaction. Accordingly, the styrene is attacked
by an activated formaldehyde molecule (complex
H2CO 1) in the first reaction step. As a cyclization to a
four-membered oxetane is disfavored, a second formalde-
hyde molecule is incorporated leading to a 1,3-dioxane. In
the case of compound 6a, a potential cyclization precursor
is the chiral carbenium ion 9a. The two faces of the carbe-
nium ion are diastereotopic due to the adjacent stereogen-
ic center. A differentiation results from the size difference
of the hydrogen atom and the methyl group. The hydrogen
atom adopts the pseudoaxial position in the transition state
of the cyclization as depicted in Figure 2. The hypothesis
of a carbenium ion intermediate is in line with the ob-
served stereoconvergency of the reaction.
1
Agilent 5973 (Mass selective detector). H and 13C NMR: Bruker
AMX-250 and AV-360. 1H and 13C NMR spectra were recorded at
303 K. Chemical shifts are reported relative to tetramethylsilane as
an internal reference. The multiplicities of the 13C NMR signal were
determined by DEPT experiments.
Prins Reaction of Styrenes 4, 6a and 10; General Procedure
A high pressure reaction vessel with gas inlet was charged with
paraformaldehyde (0.45 g, 15.0 mmol), styrene 4, 6a or 10
(2.50 mmol) and 1,4-dioxane (20 mL). 2,6-Di-tert-butylphe-
noxy(difluoro)borane (1;9 0.13 mL, 0.25 mmol) was added under
Ar. The mixture was heated for the time provided in Table 1 or in
the corresponding paragraph (vide infra). After complete conver-
sion, the reaction was quenched by the addition of H2O (10 mL) and
the aqueous layer was extracted with Et2O (3 20 mL). The com-
bined organic layers were washed with brine (20 mL), dried
(Na2SO4), filtered and evaporated. The crude material was purified
by flash chromatography to give the pure 1,3-dioxane.
Figure 2 Putative intermediate 9a en route to the formation of com-
pound 7a and other -alkylstyrenes 6b–d
Due to the steric bulk of the Lewis acid 1, a potential elec-
trophilic complex H2CO 1 is sensitive towards the substi-
tution pattern in -substituted styrenes. Whereas 1-
phenylprop-1-ene (6a)11 showed reasonable reactivity
(vide supra) other styrenes 6b–d (Figure 2) did not react
at all. In this respect, the Lewis acid allows for a differen-
tiation between a methyl and an ethyl substituted styrene.
Since compound 6a reacted already significantly slower
than the unsubstituted parent styrene (4a) we attempted a
differentiation in a bifunctional substrate. To this end,
compound 10 was prepared13 as a mixture of diastereoiso-
mers (cis/trans = 36:64). Upon subjecting this bifunction-
al substrate to the catalytic reaction conditions (Scheme 4)
at 80 °C dioxane 11 was the exclusive reaction product
(diastereomeric mixture, cis/trans = 36:64). The result
supports the high selectivity, which can be achieved with
Lewis acid 1.
4-Phenyl-1,3-dioxane (5a)
Yield: 0.39 g (95%); colorless oil; Rf 0.30 (P–EtOAc, 95:5).
The analytical and spectral data were in full agreement with previ-
ously reported values.17
4-(4-Methylphenyl)-1,3-dioxane (5b)
Yield: 0.44 g (97%); colorless oil; Rf 0.28 (P–EtOAc, 95:5).
The analytical and spectral data were in full agreement with previ-
ously reported values.17
4-(4-Methoxyphenyl)-1,3-dioxane (5c)
Yield: 0.31 g (65%), colorless solid; Rf 0.12 (P–EtOAc, 95:5); mp
71 °C.
The analytical and spectral data were in full agreement with previ-
ously reported values.17
(CH2O)n, 1 (10 mol-%)
O
O
4-(4-Chlorophenyl)-1,3-dioxane (5d)
(dioxane)
Yield: 0.44 g (88%); colorless oil; Rf 0.26 (P–EtOAc, 95:5).
83%
The analytical and spectral data were in full agreement with previ-
ously reported values.17
10
11
4-(3-Chlorophenyl)-1,3-dioxane (5e)
Yield: 0.27 g (55%), yellow oil; Rf 0.17 (P–EtOAc, 95:5).
Scheme 4
IR (film): 2920 (vs, CHal), 2850 (s, CHal), 1730 (w), 1650 (m, C=C),
1435 (m), 1365 (w), 1225 (s), 1175 (s), 1120 (m), 1030 (s), 785
cm–1 (m).
1H NMR (360 MHz, CDCl3): = 1.69–1.73 (m, 1 H, CHCHH),
1.98–2.09 (m, 1 H, CHCHH), 3.81–3.89 (m, 1 H, CHHO), 4.19 (dd,
2J = 11.5 Hz, 3J = 5.0 Hz, 1 H, CHHO), 4.61 (dd, 3J = 11.4 Hz,
3J = 2.5 Hz, 1 H, CH), 4.87 (d, 2J = 6.4 Hz, 1 H, OCHHO), 5.23 (d,
2J = 6.4 Hz, 1 H, OCHHO), 7.21–7.30 (m, 3 Harom), 7.37 (s,
1 Harom).
In summary, the boron compound 1 was found to be an
effective and selective catalyst for the Prins reaction of
several styrenes. Due to its steric bulk, the catalyst allows
for a decent diastereoselectivity and a remarkable site-se-
lectivity in this reaction. Possible applications of these se-
lectivities are currently studied more closely. In addition,
chiral analogues of compound 1 are being prepared to
evaluate enantioselective variants of the Prins reaction.
Synthesis 2002, No. 17, 2521–2526 ISSN 0039-7881 © Thieme Stuttgart · New York

2524
T. Bach, J. Löbel
PAPER
3
13C NMR (90.6 MHz, CDCl3): = 33.9 (t, CHCH2), 66.7 (t, CH2O),
77.8 (d, CH), 94.1 (t, OCH2O), 123.7 (d, CHarom), 126.0 (d, CHarom),
127.9 (d, CHarom), 129.7 (d, CHarom), 134.4 (s, Carom), 143.5 (s, Car-
om).
1 Harom), 7.44 (d, J = 8.2 Hz, 1 Harom), 7.52 (s, 1 Harom), 7.72 (s,
1 Harom).
13C NMR (90.6 MHz, CDCl3): = 24.4 (q, CH3), 33.8 (t, CHCH2),
66.8 (t, CH2O), 78.3 (d, CH), 94.0 (t, OCH2O), 117.2 (d, CHarom),
119.2 (d, CHarom), 121.4 (d, CHarom), 129.0 (d, CHarom), 138.2 (s,
GC-MS (EI, 70 eV, tR 13.37 min): m/z (%) = 198 (12, [M]+), 168 (5,
[M – CH2O]+), 163 (2, [M – Cl]+), 140 (100, [M – (CH2)2OCH2]+).
Carom), 142.4 (s, Carom), 168.5 (s, CO).
HRMS (EI, 70 eV): m/z calcd for C10H11ClO2: 198.0448; found:
198.0446.
GC-MS (EI, 70 eV, tR 20.00 min): m/z (%) = 221 (19, [M]+), 179
(16, [M –C2H2O]+), 175 (23, [M – C2H2O]+), 163 (25, [M –
CH2O(CH2)2]+), 133 (38, [M – CH2O – CH3CONH]+), 121 (100,
[M – C2H2O – CH2O(CH2)2]+), 107 (9, [C7H7O]+).
4-(2-Chlorophenyl)-1,3-dioxane (5f)
Yield: 0.40g (81%); colorless oil; Rf 0.40 (P–EtOAc, 95:5).
HRMS (EI, 70 eV): m/z calcd for C12H15NO3: 221.1052; found:
IR (film): 2965 (w, CHal), 2850 (s, CHal), 1475 (m), 1370 (m), 1250
(m), 1175 (s), 1120 (s), 1025 (s), 985 (s), 755 cm–1 (s).
221.1051.
4-(4-Acetoxyphenyl)-1,3-dioxane (5i)
Yield: 0.55 g (99%); yellow solid; Rf 0.30 (P–EtOAc, 9:1); mp
75 °C.
1H NMR (360 MHz, CDCl3): = 1.84–1.94 (m, 2 H, CHCH2),
3.86–3.93 (m, 1 H, CHHO), 4.15–4.20 (m, 1 H, CHHO), 4.92 (d,
2J = 6.4 Hz, 1 H, OCHHO), 5.03 (dd, 3J = 9.6 Hz, 3J = 3.9 Hz, 1 H,
CHCH2), 5.23 (d, 2J = 6.4 Hz, 1 H, OCHHO), 7.18–7.23 (m,
1 Harom), 7.28–7.33 (m, 2 Harom), 7.60 (dd, 3J = 7.7 Hz, 4J = 1.8 Hz,
1 Harom).
IR (KBr): 2970 (m, CHal), 2785 (w, CHal), 1760 (vs, br, C=O), 1605
(m), 1500 (s), 1370 (s), 1190 (vs, br), 1080 (s), 1020 (s) 810 cm–1
(m).
13C NMR (60.9 MHz, CDCl3): = 32.7 (t, CHCH2), 66.8 (t, CH2O),
75.6 (d, CH), 94.2 (t, OCH2O), 127.3 (d, 2 CHarom), 128.6 (d,
CHarom), 129.2 (d, CHarom), 131.1 (s, Carom), 139.2 (s, Carom).
GC-MS (EI, 70 eV, tR 14.15 min): m/z (%) = 198 (7, [M]+), 168 (4,
[M – CH2O]+), 163 (2, [M – Cl]+), 152 (48, [M – OCH2O]), 140
(100, [M – (CH2)2OCH2]+), 117 (28, [M – OCH2O – Cl]+).
1H NMR (360 MHz, CDCl3): = 1.68–1.73 (m, 1 H, CHCHH),
2.00–2.12 (m, 1 H, CHCHH), 2.28 (s, 3 H, CH3), 3.82–3.89 (m,
1 H, CHHO), 4.18 (dd, J = 11.4 Hz, J = 4.8 Hz, 1 H, CHHO),
4.63 (dd, 3J = 11.1 Hz, 3J = 2.5 Hz, 1 H, CH), 4.75 (d, 2J = 6.4 Hz,
1 H, OCHHO), 5.19 (d, 2J = 6.4 Hz, 1 H, OCHHO), 7.07 (d,
3J = 8.4 Hz, 2 Harom), 7.37 (d, 3J = 8.4 Hz, 2 Harom),
13C NMR (90.6 MHz, CDCl3): = 21.1 (q, CH3), 33.9 (t, CHCH2),
66.8 (t, CH2O), 78.1 (d, CH), 94.1 (t, OCH2O), 121.5 (d, CHarom),
126.8 (d, CHarom), 139.0 (s, Carom), 150.1 (s, Carom), 169.4 (s, C=O).
2
3
HRMS (EI, 70 eV): m/z calcd for C10H11ClO2: 198.0448; found:
198.0447.
4-(4-Acetamidophenyl)-1,3-dioxane (5g)
Yield: 0.31 g (56%); colorless solid; Rf 0.28 (P–EtOAc, 3:7); mp
146 °C.
GC-MS (EI, 70 eV, tR 16.60 min): m/z (%) = 222 (11, [M]+), 180
(80, [M –C2H2O]+), 134 (21, [M – C2H2O – OCH2O]+), 122 (100,
[M – C2H2O –CH2O(CH2)2]+), 107 (8, [C7H7O]+).
IR (KBr): 3310 (s, br, NH), 1685 (s, C=O), 1605 (s), 1540 (s), 1320
(s), 1170 (s), 1080 (s), 1020 (s), 970 (s, br), 835 cm–1 (s).
HRMS (EI, 70 eV): m/z calcd for C12H14O4: 222.0892; found:
222.0891.
1H NMR (360 MHz, CDCl3): = 1.68 (d, 2J = 13.2 Hz, 1 H,
CHCHH), 1.99–2.11 (m, 1 H, CHCHH), 2.14 (s, 3 H, CH3), 3.82–
4-(3-Thiophenyl)-1,3-dioxane (5j)
Yield: 0.34 g (80%); colorless oil; Rf 0.26 (P–EtOAc, 95:5).
2
3
3.89 (m, 1 H, CHHO), 4.18 (dd, J = 11.4 Hz, J = 4.8 Hz, 1 H,
3
3
CHHO), 4.60 (dd, J = 11.4 Hz, J = 2.3 Hz, 1 H, CH), 4.88 (d,
IR (film): 3105 (w), 2960 (m, sh, CHal), 2850 (s, CHal), 2775 (s,
CHal), 1365 (m), 1170 (s), 1115 (s), 1085 (s), 1030 (s), 990 (s), 840
cm–1 (s).
2J = 6.4 Hz, 1 H, OCHHO), 5.19 (d, J = 6.4 Hz, 1 H, OCHHO),
2
7.30 (d, 3J = 8.4 Hz, 2 Harom), 7.48 (d, 3J = 8.4 Hz, 2 Harom), 7.57 (s,
1 H, NH).
1H NMR (360 MHz, CDCl3): = 1.72–1.79 (m, 1 H, CHCHH),
2.08–2.19 (m, 1 H, CHCHH), 3.79–3.87 (m, 1 H, CHHO), 4.17 (dd,
2J = 11.4 Hz, 3J = 4.8 Hz, 1 H, CHHO), 4.73 (dd, 3J = 11.1 Hz,
3J = 2.5 Hz, 1 H, CH), 4.86 (d, 2J = 6.4 Hz, 1 H, OCHHO), 5.16 (d,
2J = 6.4 Hz, 1 H, OCHHO), 7.09 (dd, 3J = 8.4 Hz, 4J = 1.1 Hz,
1 Harom), 7.22–7.24 (m, 1 Harom), 7.29 (dd, 3J = 5.0 Hz, 4J = 3.0 Hz,
1 Harom).
13C NMR (90.6 MHz, CDCl3): = 33.1 (t, CHCH2), 66.7 (t, CH2O),
74.9 (d, CH), 94.0 (t, OCH2O), 121.2 (d, CHarom), 125.6 (d, CHarom),
126.1 (s, CHarom), 142.5 (s, Carom).
13C NMR (90.6 MHz, CDCl3): = 24.6 (q, CH3), 33.8 (t, CHCH2),
66.9 (t, CH2O), 78.3 (d, CH), 94.1 (t, OCH2O), 119.9 (d, CHarom),
126.4 (d, CHarom), 137.2 (s, Carom), 137.4 (s, Carom), 168.5 (s, CO).
GC-MS (EI, 70 eV, tR 20.30 min): m/z (%) = 221 (31, [M]+), 179 (5,
[M – C2H2O]+), 163 (43, [CH2O(CH2)2]+), 121 (100, [M – C2H2O –
CH2O(CH2)2]+).
HRMS (EI, 70 eV): m/z calcd for C12H15NO3: 221.1052; found:
221.1052.
4-(3-Acetamidophenyl)-1,3-dioxane (5h)
Yield: 0.20 g (35%); yellow solid; Rf 0.36 (P–EtOAc, 3:7); mp
108 °C.
GC-MS (EI, 70 eV, tR 11.90 min): m/z (%) = 170 (12, [M]+), 140 (6,
[M – CH2O]+), 124 (78, [M – OCH2O]+), 112 (90, [M –
(CH2)2OCH2]+), 97 (15, [C5H5S]+).
IR (KBr): 3300 (s, br, NH), 2930 (w, CHal), 2860 (w, CHal), 1665
(s, C=O), 1605 (s), 1560 (s), 1445 (s), 1375 (m), 1170 (s), 1030 (s),
780 cm–1 (s).
HRMS (EI, 70 eV): m/z calcd for C8H10O2S: 170.0402; found:
170.0398.
4-(2-Thiophenyl)-1,3-dioxane (5k)
Yield: 0.21 g (67%); colorless oil; Rf 0.22 (P–EtOAc, 95:5).
1H NMR (360 MHz, CDCl3): = 1.69 (d, 2J = 13.4 Hz, 1 H,
CHCHH), 1.96–2.09 (m, 1 H, CHCHH), 2.13 (s, 3 H, CH3), 3.79–
2
3
3.87 (m, 1 H, CHHO), 4.16 (dd, J = 11.4 Hz, J = 4.8 Hz, 1 H,
IR (film): 3105 (w), 2960 (m, sh, CHal), 2850 (s, CHal), 1370 (s),
1165 (s), 1115 (s), 1085 (s), 1020 (s, br), 980 (s), 830 (m), 705
cm–1 (s, br).
1H NMR (360 MHz, CDCl3): = 1.82–1.87 (m, 1 H, CHCHH),
2.17–2.29 (m, 1 H, CHCHH), 3.81–3.88 (m, 1 H, CHHO), 4.19 (dd,
3
3
CHHO), 4.59 (dd, J = 11.1 Hz, J = 2.0 Hz, 1 H, CH), 4.85 (d,
2J = 6.4 Hz, 1 H, OCHHO), 5.16 (d, J = 6.4 Hz, 1 H, OCHHO),
7.08 (d, J = 7.5 Hz, 1 Harom), 7.27 (dd, J = 8.2 Hz, J = 7.5 Hz,
2
3
3
3
Synthesis 2002, No. 17, 2521–2526 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Selective Prins Reaction of Styrenes
2525
3
3J = 11.4 Hz, J = 4.8 Hz, 1 H, CHHO), 4.87–4.92 (m, 2 H, CH,
OCHHO), 5.16 (d, 2J = 6.4 Hz, 1 H, OCHHO), 6.97–7.02 (m,
2 Harom), 7.27 (dd, 3J = 5.0 Hz, 4J = 1.3 Hz, 1 Harom).
13C NMR (90.6 MHz, CDCl3): = 18.5 (q, CH3), 33.8 (t, CHCH2),
66.9 (t, CH2O), 78.6 (d, CH), 94.2 (t, OCH2O), 125.9 (d, CHarom
d, =CH; d, CHarom), 130.6 (d, =CH), 137.6 (s, Carom), 139.8 (s,
Carom).
GC-MS (EI, 70 eV, tR 58 (33, [M – OCH2O]+), 146 (100, [M –
CH2O(CH2)2]+), 129 (35, [M – CH3 – 2CH2O]+), 117 (52, [M –
OCH2O – CH3(CH)2]+), 91 (22, [C7H7]+).
;
13C NMR (90.6 MHz, CDCl3): = 33.8 (t, CHCH2), 66.5 (t, CH2O),
74.4 (d, CH), 94.0 (t, OCH2O), 124.0 (d, CHarom), 125.1 (d, CHarom),
126.5 (d, CHarom), 144.3 (s, Carom).
GC-MS (EI, 70 eV, tR 11.80 min): m/z (%) = 170 (49, [M]+), 138
(20, [M – S]+), 124 (72, [M – OCH2O]+), 112 (90, [M –
(CH2)2OCH2]+), 97 (100, [C5H5S]+).
HRMS (EI, 70 eV): m/z calcd for C13H16O2: 204.1150; found:
204.1142.
HRMS (EI, 70 eV): m/z calcd for C8H10O2S: 170.0402; found:
170.0399.
Acknowledgments
5-Methyl-4-phenyl-1,3-dioxane (7a/8a)
This project has been generously supported by the BASF AG (Lud-
wigshafen). We thank Drs. A. Hettche, A. Oftring, H. Reichelt, G.
Scherr, N. Wagner, E. Winkler, and C. Wulff for valuable discussi-
ons and their continuing interest in this research.
The reaction was conducted according to the general procedure with
compound 6a as the starting material. In one run diastereomerically
pure trans-6a11 was used. In another run a cis/trans-mixture of com-
pound 6a11 (dr = 52:48) was employed as the substrate. In both runs,
the product (0.39 g, 88%) was obtained as a mixture of cis- and
trans-isomers (dr = 25:75), which could be separated by flash chro-
matography; yield: 0.39 g (88%); colorless oil; Rf 0.32 (7a), 0.31
(8a) (P–EtOAc, 95:5). The analytical data were in full agreement
with previously reported values.18
References
(1) (a) Prins, H. J. Chem. Weekbl. 1919, 16, 1072; Chem. Abstr.
1919, 13, 3155. (b) Prins, H. J. Proc. Acad. Sci.
(Amsterdam) 1919, 22, 51; Chem. Abstr. 1920, 14, 1662.
(2) Reviews: (a) Arundale, E.; Mikeska, L. A. Chem. Rev. 1952,
51, 505. (b) Adams, D. R.; Bthnagar, S. P. Synthesis 1977,
661.
4-(4-Prop-1-enylphenyl)-1,3-dioxane (11)
The reaction was conducted according to the general procedure with
a cis/trans-mixture (dr = 36:64) of compound 10.13 The product
(0.59 g, 83%) was obtained as a mixture of cis/trans-isomers (dr =
36:64) which were separated by flash chromatography.
(3) Okachi, T.; Fujimoto, K.; Onaka, M. Org. Lett. 2002, 4,
1667; and references cited therein.
(4) Reviews: (a) Snider, B. B. In Comprehensive Organic
Synthesis, Vol. 2; Trost, B. M.; Fleming, I., Eds.; Pergamon:
London, 1991, 527. (b) Nubbemeyer, U. In Methoden der
Organischen Chemie (Houben-Weyl), Vol. E21c, 4th ed.;
Helmchen, G.; Hoffmann, R. W.; Mulzer, J.; Schaumann, E.,
Eds.; Thieme: Stuttgart, 1995, 2295. (c) Overman, L. E.;
Pennington, L. D. Can. J. Chem. 2000, 78, 732.
(5) For recent reports on stereoselective variants of the Prins
reaction, see the following references, and the references
cited therein: (a) Kocovsky, P.; Ahmed, G.; Srogl, J.;
Malkov, A. V.; Steele, J. J. Org. Chem. 1999, 64, 2765.
(b) Pansare, S. V.; Jain, R. P. Org. Lett. 2000, 2, 175.
(c) Ishihara, K.; Nakamura, H.; Yamamoto, H. Synlett 2000,
1245. (d) Zhang, W.-C.; Li, C.-J. Tetrahedron 2000, 56,
2403. (e) Cohen, F.; MacMillan, D. W. C.; Overman, L. E.;
Romero, A. Org. Lett. 2001, 3, 1225. (f) Lebsack, A. D.;
Overman, L. E.; Valentekovich, R. J. J. Am. Chem. Soc.
2001, 123, 4851. (g) Jaber, J. J.; Mitsui, K.; Rychnovsky, S.
D. J. Org. Chem. 2001, 66, 4679. (h) Kimura, M.; Ezoe, A.;
Tanaka, S.; Tamaru, Y. Angew. Chem. Int. Ed. 2001, 40,
3600. (i) Braddock, D. C.; Badine, D. M.; Gottschalk, T.
Synlett 2001, 1909.
cis-Isomer (cis-11)
Yellow oil; Rf 0.28 (P–EtOAc, 95:5).
IR (film): 2960 (m, br, CHal), 2850 (s, CHal), 1515 (w), 1370 (m),
1245 (m), 1170 (s), 1115 (s), 1030 (vs), 985 (s), 845 cm–1 (s).
1H NMR (360 MHz, CDCl3): = 1.70–1.74 (m, 1 H, CHCHH),
3
4
1.88 (dd, J = 7.3 Hz, J = 1.8 Hz, 3 H, CH3), 2.05–2.15 (m, 1 H,
CHCHH), 3.84–3.91 (m, 1 H, CHHO), 4.20 (dd, 2J = 11.4 Hz,
3J = 4.8 Hz, 1 H, CHHO), 4.64 (dd, 3J = 11.1 Hz, 3J = 2.5 Hz, 1 H,
CH), 4.90 (d, 2J = 6.4 Hz, 1 H, OCHHO), 5.21 (d, 2J = 6.4 Hz, 1 H,
OCHHO), 5.79 (dq, 3J = 11.6 Hz, 3J = 7.3 Hz, 1 H, = CH), 6.42
(dd, 3J = 11.6 Hz, 4J = 1.8 Hz, 1 H, = CHCH3), 7.29 (d, 3J = 8.2 Hz,
2 Harom), 7.33 (d, 3J = 8.2 Hz, 2 Harom).
13C NMR (90.6 MHz, CDCl3): = 14.6 (q, CH3), 33.8 (t, CHCH2),
66.9 (t, CH2O), 78.6 (d, CH), 94.2 (t, OCH2O), 125.6 (d, CHarom),
127.0 (d, = CH), 128.9 (d, CHarom), 129.5 (d, =CH), 137.2 (s, Carom),
139.5 (s, Carom).
GC-MS (EI, 70 eV, tR 16.40 min): m/z (%) = 204 (54, [M]+), 189 (2,
[M – CH3]+), 174 (2, [M – CH2O]+), 158 (18, [M – OCH2O]+), 146
(100, [M – CH2O(CH2)2]+), 129 (35, [M – CH3 – 2CH2O]+), 117
(58, [M – OCH2O – CH3(CH)2]+), 91 (27, [C7H7]+).
(6) Comprehensive treatment: Lewis Acids in Organic
Synthesis; Yamamoto, H., Ed.; Wiley-VCH: Weinheim,
2000.
HRMS (EI, 70 eV): m/z calcd for C13H16O2: 204.1150; found:
204.1149.
(7) For previous work related to catalytic Prins reactions of
styrenes, see: (a) Delmas, M.; Gaset, A. Synthesis 1980,
871. (b) Thioville-Cazat, J.; Tkatchenko, I. J. Chem. Soc.,
Chem. Commun. 1982, 1128. (c) Chandrasekhar, S.; Subba
Reddy, B. V. Synlett 1998, 851. (d) Aramendía, M. A.;
Borau, V.; Jiménez, C.; Marina, J. M.; Romero, F. J.;
Urbano, F. J. Catal. Lett. 2001, 73, 203.
(8) For reviews on the use of bulky designer Lewis acid
catalysts, see: (a) Saito, S.; Yamamoto, H. Pure Appl. Chem.
1999, 71, 239. (b) Saito, S.; Yamamoto, H. Chem. Commun.
1997, 1585.
trans-Isomer (trans-11)
Colorless crystals; Rf 0.27 (P–EtOAc, 95:5); mp 37 °C.
IR (film): 2960 (m, br, CHal), 2850 (s, CHal), 1515 (w), 1370 (m),
1245 (m), 1170 (s), 1115 (s), 1030 (vs), 985 (s), 845 cm–1 (s).
1H NMR (360 MHz, CDCl3): = 1.67–1.72 (m, 1 H, CHCHH),
3
4
1.88 (dd, J = 6.6 Hz, J = 1.6 Hz, 3 H, CH3), 2.03–2.15 (m, 1 H,
CHCHH), 3.82–3.90 (m, 1 H, CHHO), 4.20 (dd, 2J = 11.4 Hz,
3J = 4.8 Hz, 1 H, CHHO), 4.61 (dd, 3J = 11.3 Hz, 3J = 2.5 Hz, 1 H,
CH), 4.88 (d, 2J = 6.4 Hz, 1 H, OCHHO), 5.21 (d, 2J = 6.4 Hz, 1 H,
OCHHO), 6.24 (dq, 3J = 15.7 Hz, 3J = 6.6 Hz, 1 H, =CH), 6.40 (dd,
3J = 15.7 Hz, 4J = 1.6 Hz, 1 H, =CHCH3), 7.29 (d, 3J = 8.4 Hz,
2 Harom), 7.33 (d, 3J = 8.4 Hz, 2 Harom).
(9) v. Steuber, E.; Elter, G.; Noltemeyer, M.; Schmidt, H.-G.;
Meller, A. Organometallics 2000, 19, 5083.
Synthesis 2002, No. 17, 2521–2526 ISSN 0039-7881 © Thieme Stuttgart · New York

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T. Bach, J. Löbel
PAPER
(10) All substituent constants were taken from: Exner, O.
Correlation Analysis of Chemical Data; Plenum Press: New
York, 1988.
(14) (a) Zhuo, J.-C.; Wyler, H. Helv. Chim. Acta. 1999, 82, 1122.
(b) The same protocol was used to obtain compound4h from
3-vinylaniline.
(11) (a) The trans-compound is commercially available. (b) A
cis/trans-mixture can be obtained according to: Martles, B.
A.; Saint, C. G.; Traynor, J. R. J. Chem. Soc., Perkin Trans.
1 1986, 567.
(12) Dolby, L. J.; Wilkins, C.; Frey, T. G. J. Org. Chem. 1966, 31,
1110.
(13) Styrene 10 was obtained by Wittig reaction starting from
terephthalaldehyde, according to: Le Bigot, Y.; Delmas, M.;
Gaset, A. Synth. Commun. 1983, 13, 177.
(15) A cross-coupling protocol was used to obtain compound 4j
from 3-bromothiophene and 4k from 2-bromothiophene:
Tamao, K.; Sumitani, K.; Kiso, Y.; Zembayashi, M.;
Fujioka, A.; Komada, S.-i.; Nakajima, I.; Minato, A.;
Kumada, M. Bull. Chem. Soc. Jpn. 1976, 49, 1958.
(16) Still, W. C.; Kahn, M.; Mitra, A. J. J. Org. Chem. 1978, 43,
2923.
(17) Tateiwa, J.; Hashimoto, K.; Yamauchi, T.; Uemura, S. Bull.
Chem. Soc. Jpn. 1996, 69, 2361.
(18) Ferrand, G.; Huet, J. Bull Soc. Chim. Fr. 1973, 3122.
Synthesis 2002, No. 17, 2521–2526 ISSN 0039-7881 © Thieme Stuttgart · New York