LiClO4-Activated stereo- and regioselective alkylation of aldehydes

Article abstract of DOI:10.1016/j.tet.2003.11.039

Aldehydes undergo an unusual and very mild alkylation by LiClO ₄-activation in the presence of acids. This new methodology enables the inclusion of a broad range of aldehydes as well as tertiary alcohols. Regio- and stereoselectivity observed during this reaction will be discussed.

Full text of DOI:10.1016/j.tet.2003.11.039

Tetrahedron 60 (2004) 993–999
LiClO4-Activated stereo- and regioselective alkylation
of aldehydes
*
M. Markert, I. Buchem, H. Kru¨ger and R. Mahrwald
¨ ¨
Institut fur Chemie der Humboldt-Universitat zu Berlin, Brook-Taylor-Str. 2, 12 489 Berlin, Germany
Received 23 July 2003; revised 3 October 2003; accepted 7 November 2003
Abstract—Aldehydes undergo an unusual and very mild alkylation by LiClO4-activation in the presence of acids. This new methodology
enables the inclusion of a broad range of aldehydes as well as tertiary alcohols. Regio- and stereoselectivity observed during this reaction will
be discussed.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
1 equiv. titanium(IV)-alkoxide). The distribution of
products observed in this reaction is given in Table 1.
C–C bond formation processes are of great interest, in
particular regio- and stereoselective transformations. The
catalytic execution of these reactions are the focus of
attention. The simple alkylation of carbonyl compounds
mediated by LiClO4 is not described so far.
A high regioselectivity is observed during this reaction by
using unsymmetrical substituted tertiary titanium(IV)-
alkoxides. The attack of the aldehyde takes place at the
highest substituted b-carbon atom of the titanium(IV)-
alkoxide used (entries 2, 3 and 6, Table 1). One exception
represents the formation of tetrahydropyranols 2e and 4e
and diol 5e (entry 5, Table 1). This product arose from an
alkylation at the methyl group instead at the expected
benzylic carbon atom.
Recently we described an unusual addition of aldehydes to
tertiary titanium(IV)-alkoxides in the presence of
a-hydroxy acids by activation of LiClO4.1 During our
ongoing studies in this field we were able to obtain suitable
crystals for X-ray structure analysis of compounds 1d, 2b
and 4g (Table 1).2 Careful comparison of NMR data of these
compounds (chemical shifts, coupling constants and NOE-
experiments) with the NMR data of other compounds
obtained during this work, resulted in a revision of the
proposed structure to surprisingly appear as substituted
tetrahydropyranols 1–4 (Table 1) in contrast to the earlier
proposals (syn- and anti-triols 1a–c and 2a–c in Ref. 1). In
addition, the previously described diols 51 were also
observed.
The substituents at C-2 and C-6 are syn-configured
(diequatorial) in every tetrahydropyranol isolated. They
differ only in the configuration at C-4, the tertiary carbon
atom. The observed rigid syn-configuration of the sub-
stituents and the high regioselectivity of the attack of the
aldehydes are the sources for the formation of meso-
configurated tetrahydropyranols during this transformation.
In the reactions of aldehydes with titanium(IV)-alkoxides
bearing three or two equivalent substituents the attack of the
aldehydes may occur at two equivalent a-carbon atoms.
meso-Configurated compounds can be formed. This is true
for substituted tetrahydropyranols in the a, c, g, and i series
(entries 1, 3 (1c, 2c), 7, 9, 11 (1c, 2c), 13 and 15 in Table 1).
Diols 5a, 5b, 5e and 5g were isolated with a high degree of
anti-selectivity. syn-Configurated diols could not be
detected.
2. Results and discussion
In order to explore the scope and limitation of substrates in
these reactions, a series of tertiary titanium(IV)-alkoxides
(Tia–h, entries 1–8 in Table 1) were reacted with
benzaldehyde using standard conditions (10 equiv. of
aldehyde, 10 equiv. dry LiClO4, 1 equiv. tartaric acid,
During our studies we observed this described reaction even
when using tertiary alcohols instead of the corresponding
tertiary titanium(IV)-alkoxides (Ha–h, entries 9–15 in
Table 1). A comparison of product distribution of these two
procedures is shown in Table 1 (entries 1–8 titanium(IV)-
Keywords: Alkylation; Aldehydes; C–C coupling; Regioselectivity;
Diastereoselectivity.
*
Corresponding author. Tel.: þ49-30-20938397; fax: þ49-30-20936940;
e-mail address: rainer.mahrwald@rz.hu-berlin.de
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.11.039

994
M. Markert et al. / Tetrahedron 60 (2004) 993–999
Table 1. Product distribution (in %) in reactions of benzaldehyde with titanium(IV)-alkoxides, respectively tertiary alcohols in the presence of 1 equiv. LiClO4
and 10 mol% p-toluenesulfonate
Entry
Compound
X
R1
R2
R3
Overall-yield (%)
1
2
3
4
5
1
2
3
4
5
6
7
8
a
b
c
d
e
f
g
h
a
b
c
e
g
h
i
Ti
Ti
Ti
Ti
Ti
Ti
Ti
Ti
H
H
H
H
H
H
H
H
Me
Me
Ph
H
H
H
H
H
Me
Ph
H
H
H
H
H
H
Me
H
46
55
77
76
52
22
58
—
58
62
61
48
53
38
46
17
32
21
83
—
—
—
—
50
17
40
—
—
—
—
50
17
32
17
8
100
—
—
50
66
10
33
—
100
—
—
17
42
—
—
—
33
—
—
17
20
—
40
—
100
—
17
5
33
17
—
—
60
—
34
—
—
—
—
—
—
—
—
Me
Me
H
H
iPr
—
32
—
33
—
—
—
30
67
60
—
—
H
a
Cl
H
Me
Me
H
H
H
H
H
9
10
11
12
13
14
15
H
a
H
H
Cl
H
b
a
R1¼R3: –(CH2)3–.
b
R1¼R3: –(CH2)2–.
alkoxides Tia–h and entries 9–15 tertiary alcohols Ha–h).
Higher stereoselectivities were observed by using tertiary
titanium(IV)-alkoxides in these reactions. a-Halogen sub-
stituted tertiary alcohols react with aldehydes to give the
tetrahydropyranole 2h. In contrast to that the corresponding
titanium(IV)-alkoxide does not react with benzaldehyde
under the described conditions (compare entries 8 and 14,
Table 1).
Scheme 2.
low (15–30%). Further investigations in this field led us to a
more powerful and catalytic reagent system. Same regio-
and stereoselectivities of products were found by using
LiClO4 in the presence of 10 mol% ethyl p-toluenesul-
fonate. Under these conditions the products of reaction of
tertiary alcohols with aldehydes were isolated in good yields
(50–70%, Table 1). It is assumed that under these reactions
conditions hydrolysis occurs and toluenesulfonic acid acts
as the real agent, as comparative reactions with toluene-
sulfonic acid showed.
Allyl alcohols react with benzaldehyde under these standard
conditions as well. 1-Hydroxy-3-methyl-2-butene and the
tertiary alcohol 2-hydroxy-2-methyl-3-butene were trans-
formed into the tetrahydropyranol 6 by a stereoselective and
convergent synthesis (Scheme 1).
Based on these results, an elimination–addition reaction
mechanism can be assumed. This consideration involves an
electrophilic attack by a LiClO4-activated aldehyde onto an
olefin formed intermediately by elimination from tertiary
titanium(IV)-alkoxides or tertiary alcohols. The suggestion
of such a Prins-type mechanism7 was supported by the
comparative reaction of isobutene (the elimination product
of tertiary butanol) with benzaldehyde in the presence of
LiClO4 and a-hydroxy acids. The same compounds were
isolated as in the corresponding reaction of benzaldehyde
with Ti(OtBu)4. A proposed reaction mechanism based on
these results is shown in Scheme 3.
Scheme 1. Reaction conditions: tartaric acid, LiClO4, rt.
There are two explanations for this unexpected result at that
time. The formation of isoprene (the elimination product of
the two isomeric allyl alcohols) and the subsequent
alkylation lead to the product 6 (Scheme 2). Alternatively,
a rearrangement of the two isomeric allyl alcohols during
this transformation could explain these identical results.
The yields of the products obtained by using these standard
conditions (10 equiv. of aldehyde, 10 equiv. dry LiClO4,
1 equiv. tartaric acid, 1 equiv. titanium(IV)-alkoxide) are
Two main products are possible. The one, which predomi-
nates, depends on the olefin and the reaction conditions.

M. Markert et al. / Tetrahedron 60 (2004) 993–999
995
perchlorates (e.g., NaClO4, Mg(ClO4)2, Al(ClO4)3, KClO4,
Et4NClO4). On the other hand LiClO4 does not act as a
dehydrating agent only. This alkylation is not observed in
comparative experiments with other dehydrating reagents
(molecular sieves, Drierite, Na2SO4 etc.). No reactions were
observed by using LiClO4·10H2O in these reactions.
In order to demonstrate the broad applicability of this new
and promising transformation, aliphatic aldehydes were
reacted with tert-butanol and 1-methyl-cyclopentanol. The
expected tetrahydropyranols 7, 8 and 9 were isolated in
lower yields in comparison with reactions of benzaldehyde.
An overview of products observed during these reactions is
given in Table 2 and Scheme 4.
Herein we described a very simple and effective alkylation
of aldehydes by LiClO4-activation. Nevertheless, there still
are several questions remaining, e.g. the role of LiClO4, the
enantioselective execution of this reaction, or the extension
of this reaction to secondary alcohols. In any event, we are
convinced that this extremely mild and easy alkylation is a
useful method for the preparation of tertiary alcohols.8,9
Scheme 3. Proposed reaction mechanism.
3. Experimental
Zwitterionic structure C is starting point for a further
alkylation of the olefin B resulting in the formation of the
substituted tetrahydro pyranoles. Diols 5 were formed by
hydration of structure C.
3.1. General procedures
All reactions were performed using oven-dried glassware
under an atmosphere of dry argon. Toluene was distilled,
dried and stored over molecular sieve (3A). Ti(OiPr)4
purchased from Merck chemical company was used without
prior purification. Aldehydes were distilled before use.
Purification of products was accomplished using flash
chromatography according to the method of Still.10
LiClO4 was dried at 120 8C in vacuo for 10 h.
The real role of LiClO4 is not clear up to now. This reaction
is observed only in the presence of dry LiClO4. No reactions
were observed with the use of other metal salts and
Table 2. Product distribution in reactions of aliphatic aldehydes with
tertbutanol
1H NMR and 13C NMR spectra were recorded at 300 and
75 MHz in CDCl3, respectively using a AC-300 spec-
trometer. Chemical shifts are given in ppm. Thin layer
chromatography was performed out using Merck Silica Gel
60 F254 TLC plates.
The stereodescriptors a (axial) and e (equatorial) were used
for the characterization of configuration. The description of
configuration by CIP-rules is not sufficient for the
characterization of the meso-configurated tetrahydro
pyranols.
Entry
R1
Compound
Overall-yield (%)
7
8
1
2
3
4
Me
Et
nPr
isoPr
a
b
c
36
26
35
36
—
—
50
—
100
100
50
Yields are related to the amount of titanium(IV)-alkoxides
or alcohols used and are not optimized.
d
100
Scheme 4. Reaction conditions: p-toluenesulfonate, LiClO4, rt.

996
M. Markert et al. / Tetrahedron 60 (2004) 993–999
3.2. Preparation of titanium(IV)-alkoxides (Tia–Tih)
3.3.4. 3e,4e-Dimethyl-2e,6e-diphenyl-tetrahydropyran-
4a-ol (1b). 200 mg 1b (17.7%) as a colourless oil
(procedure A); IR (neat) nmax 3788, 3639, 1654, 1544,
The titanium(IV)-alkoxides were prepared by a procedure
given in Ref. 11. 100 mmol of the corresponding alcohol
were dissolved under inert conditions in 50 ml of anhydrous
toluene. 7.5 ml (25 mmol) of Ti(OiPr)4 were carefully
added at room temperature. The resulting solution was
heated and isopropanol was removed by azeotropic distilla-
tion of toluene. Resulting residue was dried in vacuo at
room temperature and was used without further purification.
1458, 1378, 1217, 1079 cm21
;
1H NMR d¼7.40–7.10
(10H, m, CHPh), 4.90 (1H, dd, J¼2.6, 11.3 Hz, H2), 4.45
(1H, d, J¼10.2 Hz, H6), 1.89 (1H, dd, J¼2.6, 13.9 Hz, H5),
1.77 (1H, dd, J¼11.3, 13.9 Hz, H5), 1.70 (1H, dq, J¼10.17,
6.8 Hz, H3), 1.23 (3H, s, C(OH)CH3), 0.68 (3H, d,
J¼6.8 Hz, –CH3); 13C NMR d¼142.8, 141.5, 128.2,
128.2, 128.1, 127.6, 127.6, 125.8, (CHPh), 81.7, 75.0,
70.4, (C2, C4, C6), 48.2, 45.1, (C3, C5), 29.0, 9.6, (2£–
CH3); HRMS: calcd for C19H22O2: 282.1620. Found:
282.1620.
1
Using this procedure, the H NMR spectra do not contain
any typical signals of the starting Ti(OiPr)4.
3.3. General procedure of alkylation
3.3.5. 3e,4a-Dimethyl-2e,6e-diphenyl-tetrahydropyran-
4e-ol (2b). 100 mg 2b (8.9%) as colourless crystals
(procedure A); mp 102–103 8C (hexane/ethylacetate); IR
(neat) nmax 3413, 2973, 1718, 1603, 1495, 1450, 1381, 1271,
Procedure A. Alkylation of aldehydes with titanium(IV)-
alkoxides (Tia–Tih): 1.1 g LiClO4 (10 mmol) were dis-
solved in 1.0 ml benzaldehyde (10 mmol). 1.0 mmol of the
corresponding titanium(IV)-alkoxide was added after
10 min stirring at rt. 200 mg ethyl p-toluenesulfonate
(1 mmol) were added. The reactions were monitored by
thin layer chromatography. At the end of the reaction the
resulting mixtures were stirred for 24 h at rt and then
extracted by diethylether and successively by saturated aq.
NH4Cl- and NaHCO3-solution. The organic layers were
separated, dried (Na2SO4) and the solvent was removed in
vacuo. The residue was purified by column
chromatography.
1210, 1100, 1069, 1021 cm21
;
1H NMR d¼7.40–7.10
(10H, m, CHPh), 4.56 (1H, dd, J¼2.3, 10.7 Hz, H6), 4.12
(1H, d, J¼10.2 Hz, H2), 1.98 (1H, dd, J¼2.3, 12.8 Hz, H5),
1.83 (1H, dd, J¼10.7, 12.8 Hz, H5), 1.78 (1H, dq, J¼6.8,
10.2 Hz, H3), 1.50 (3H, s, –CH3), 0.80 (3H, d, J¼6.8 Hz,
–CH3); 13C NMR d¼140.9, 140.7, 128.4, 128.3, 127.9,
127.5 127.4, 125.9, (CHPh), 83.7, 77.3, 71.7, (C2, C4, C6),
50.3, 47.8, (C3, C5), 20.7, 10.1, (2£–CH3); HRMS: calcd
for C19H22O2 282.1620. Found: 282.1620.
3.3.6. 3a,4a-Dimethyl-2e,6e-diphenyl-tetrahydropyran-
4e-ol (3b). 110 mg 3b (9.8%) as a colourless oil (procedure
A); IR (neat) nmax 3117, 3028, 2971, 2804, 1726, 1398,
1106, 1069 cm21; 1H NMR d¼7.40–7.10 (10H, m, CHPh),
4.83 (1H, d, J¼2.3 Hz, H2), 4.55 (1H, dd, J¼3.0, 12.1 Hz,
H6), 1.88 (1H, dq, J¼2.3, 7.2 Hz, H3), 1.84 (1H, dd,
J¼12.1, 13.6 Hz, H5), 1.71 (1H, dd, J¼3.0, 13.6 Hz, H5),
1.60 (3H, s, –CH3), 0.72 (3H, d, J¼7.2 Hz, –CH3); 13C
NMR d¼142.5, 141.4, 128.3, 128.0, 127.4, 126.6, 125.7,
125.3, (CHPh), 78.7, 77.6, (C2, C4, C6), 45.5, 42.8, (C3,
C5), 27.2, 7.5, (2£–CH3); HRMS: calcd for C19H22O2
282.1620. Found: 282.1620.
Procedure B. Alcohols (Ha–Hi): The same procedure as
described for titanium(IV)-alkoxides was used with 4 mmol
of the corresponding alcohol.
3.3.1. 4e-Methyl-2e,6e-diphenyl-tetrahydropyran-4a-ol
(1a). 93 mg 1a (8.7%) as a colourless oil (procedure A);
IR (neat) nmax 3498, 2908, 1454, 1379, 1211, 1137, 1050,
1
1012 cm21; H NMR d¼7.41–7.12 (10H, m, CHPh), 4.88
(2H, dd, J¼1.9, 11.7 Hz, H2, H6), 1.78 (2H, dd, J¼1.9,
13.5 Hz, H3, H5), 1.70 (2H, dd, J¼11.7, 13.5 Hz, H3, H5),
1.21 (3H, s, –CH3); 13C NMR d¼143.0, 128.3, 127.3,
125.9, (CPh), 75.3, 69.0, (C2, 4, 6), 46.6, (C3, 5), 31.6,
(–CH3); HRMS: m/z calcd for C18H20O2 268.1463. Found:
268.1463.
3.3.7. 3a,4e-Dimethyl-2e,6e-diphenyl-tetrahydropyran-
4a-ol (4b). 100 mg 4b (8.8%) as a colourless oil (procedure
A); IR (neat) nmax 3416, 2975, 1702, 1603, 1495, 1450,
1
3.3.2. 4a-Methyl-2e,6e-diphenyl-tetrahydropyran-4e-ol
(2a).3 225 mg 2a (20.1%) as a colourless solid (procedure
A); IR (neat) nmax 3483, 2914, 1495, 1455, 1382, 1212,
1379, 1142, 1096, 1056, 1018 cm21; H NMR d¼7.50–
7.20 (10H, m, CHPh), 5.37 (1H, d, J¼2.3 Hz, H2), 4.96 (1H,
dd, J¼3.0, 11.3 Hz, H6), 1.90 (1H, dq, J¼2.3, 7.2 Hz, H3),
1.80 (1H, dd, J¼11.3, 13.9 Hz, H5), 1.70 (1H, dd, J¼3.0,
13.9 Hz, H5), 1.40 (3H, s, –CH3), 0.86 (3H, d, J¼7.2 Hz,
–CH3); 13C NMR d¼143.2, 142.0, 128.1, 127.8, 127.0,
126.2, 125.6, 125.4, (CHPh), 76.4, 75.3, 72.0, (C2, C4, C6),
44.9, 41.9, (C3, C5), 29.4, 9.7, (2£–CH3); HRMS: calcd for
C19H22O2 282.1620. Found: 282.1620.
1
1115, 1056, 986 cm21; H NMR d¼7.41–7.18 (10H, m,
CHPh), 4.53 (2H, dd, J¼1.9, 11.6 Hz, H2, H6), 1.96 (2H, dd,
J¼1.9, 10.5 Hz, H3, H5), 1.70 (2H, dd, J¼10.5, 11.6 Hz,
H3, H5), 1.51 (3H, s, –CH3); 13C NMR d¼142.2, 128.4,
127.5, 125.9, (CPh), 77.5, 69.8, (C2, C4, C6), 48.2, (C3, C5),
25.8, (–CH3); HRMS: m/z calcd for C18H20O2 268.1463.
Found: 268.1463.
3.3.8. anti-2,3-Dimethyl-1-phenyl-butan-1,3-diol (5b).5
80 mg 5b (10.3%) as a colourless oil (procedure A);
1H NMR d¼7.30–7.10 (5H, m, CHPh), 4.47 (1H, d,
J¼10.2 Hz, H1), 1.86 (1H, dq, J¼6.8, 10.2 Hz, H2), 1.18
(6H, s, 2£–CH3), 0.42 (3H, d, J¼6.8 Hz, –CH3); 13C NMR
d¼143.8, 128.3, 127.6, 125.6, (CHPh), 78.9, 75.0, (C1, C3)
48.7, (C2), 30.3, 14.2, (2£–CH3); HRMS: calcd
for C12H16O (M2H2O) 176.1201. Found: 176.1201
(M2H2O).
3.3.3. 3-Methyl-1-phenyl-butan-1,3-diol (5a).4 125 mg 5a
(17.3%) as a colourless oil (procedure A); 1H NMR
d¼7.50–7.23 (5H, m, CHPh), 5.09 (1H, dd, J¼2.3,
11.3 Hz, H1), 1.99 (1H, dd, J¼11.3, 14.7 Hz, H2), 1.70
(1H, dd, J¼2.3, 14.7 Hz, H2), 1.47 (3H, s, –CH3), 1.32
(3H, s, –CH3); 13C NMR d¼144.7, 128.5, 127.5, 125.7,
(CPh), 72.3, 71.7, (C2, C4, C6), 50.4, (C3, C5), 31.9, 27.6
(2£–CH3).

M. Markert et al. / Tetrahedron 60 (2004) 993–999
997
3.3.9. 3e,4a,5e-Trimethyl-2e,6e-diphenyl-tetrahydro-
pyran-4e-ol (2c). 300 mg 2c (25.3%) colourless solid
(procedure A); mp 160–162 8C (hexane/ethylacetate); IR
(neat) nmax 3478, 2974, 2882, 1495, 1453, 1381, 1312, 1208,
(neat) nmax 2917, 1712, 1602, 1494, 1452, 1103, 1067,
1
1028 cm21; H NMR d¼7.40–7.10 (10H, m, CHPh), 4.88
(1H, dd, J¼3.0, 10.9 Hz, H1), 2.72 (2H, d, J¼13.7 Hz, H4),
1.75 (1H, dd, J¼3.0, 13.2 Hz, H2), 1.69 (1H, dd, J¼10.9,
13.2 Hz, H2), 1.18 (3H, s, –CH3); 13C NMR d¼142.9, 137.7,
130.6, 128.7, 128.5, 128.2, 127.3, 126.9, (CHPh), 75.1, 70.5,
(C1, C3), 50.1, 45.1, (C2, C4), 29.1(–CH3); HRMS: calcd for
C17H16 (M-2H2O) 220.1252. Found: 220.1252 (M22H2O).
1
1069, 1026, 984 cm21; H NMR d¼7.36–7.12 (10H, m,
CHPh), 4.18 (2H, d, J¼10.6 Hz, H2, H6), 1.88 (2H, dq,
J¼7.2, 10.6 Hz, H3, H5), 1.18 (3H, s, –CH3), 0.64 (6H, d,
J¼7.2 Hz, –CH3); 13C NMR d¼141.0, 128.3, 127.8, 127.3,
(CHPh), 83.4, 73.9, (C2, C4, C6), 49.2, (C3, C5), 14.7, 10.4,
(3£–CH3); HRMS: calcd for C20H24O2 296.17763. Found:
296.17763.
3.3.14. 3e-Isopropyl-4a-methyl-2e,6e-diphenyl-tetra-
1
hydropyran-4e-ol (2f). H NMR d¼7.50–7.10 (10H, m,
CHPh), 4.54 (1H, dd, J¼2.6, 11.3 Hz, H6), 4.45 (1H, d,
J¼10.9 Hz, H2), 2.17 (1H, dqq, J¼7.2, 7.2, 9.4 Hz,
–CHMe2), 1.91 (1H, dd, J¼2.6, 12.8 Hz, H5), 1.88 (1H,
dd, J¼11.3, 12.8 Hz, H5), 1.81 (1H, dd, J¼9.4, 10.9 Hz,
H3), 1.51 (3H, s, –Me), 0.88 (3H, d, J¼7.2 Hz, –Me), 0.41
(3H, d, J¼7.2 Hz, –Me); 13C NMR d¼142.3, 141.4, 128.8,
128.3, 128.2, 128.1, 127.4, 125.9, 80.6, 77.2, 73.1 (C2, C4,
C6), 56.4, 51.6 (C3, C5), 24.5, 24.4, 22.7, 18.7.
The isomers 1c, 3c and 4c could not be separated by
chromatography. The ratio of these isomers was determined
by integration of important signals in the 1H and 13C NMR
spectra.
3.3.10. 3e,30a,4e-Trimethyl-2e,6e-diphenyl-tetrahydro-
pyran-4a-ol (1d). 755 g 1d (63.7%) as colourless crystals
(procedure A); mp 129–130 8C (hexane/ethylacetate); IR
(neat) nmax 3505, 2976, 1686, 1454, 1363, 1287, 1201, 1144,
3.3.15. 9a-Methyl-2e,4e-diphenyl-3-oxa-bicyclo[3.3.1]-
nonan-9e-ol (3g). 283 mg 3g (23%) as a colourless oil
(procedure A); IR (neat) nmax 3454, 2960, 1738, 1372, 1215,
1141, 1050 cm21; 1H NMR d¼7.50–7.10 (10H, m, CHPh),
5.09 (1H, m, H2, H4), 2.10–1.00 (11H, m, H1, H5, H6, H7,
H8, 2CH3); 13C NMR d¼141.8, 128.1, 126.7, 125.2,
(CHPh), 79.0, 71.8, (C2, C4, C6), 45.4, (C3, C5), 26.6, 20.4,
(3£–CH2), 19.0 (–CH2); HRMS: calcd for C21H24O2
308.1776. Found: 308.1776.
1
1119, 1091, 1058, 1039, 1007 cm21; H NMR d¼7.39–
7.11 (10H, m, CHPh), 4.91 (1H, dd, J¼2.6, 12.1 Hz, H6),
4.89 (1H, s, H2), 1.95 (1H, dd, J¼12.1, 13.9 Hz, H5), 1.64
(1H, dd, J¼2.6, 13.9 Hz, H5), 1.14 (3H, s, –CH3), 0.85 (3H,
s, –CH3), 0.75 (3H, s, –CH3); 13C NMR d¼143.2, 139.6,
128.3, 128.2, 127.2, 127.1, 126.9, 125.6, (CHPh), 82.0, 75.4,
73.7, (C2, C4, C6), 44.4, 40.8, (C3, C5), 25.6, 18.6, 17.9, (3£–
CH3);HRMS:calcdforC20H24O2 296.1776.Found:296.1776.
3.3.11. 3e,30a,4a-Trimethyl-2e,6e-diphenyl-tetrahydro-
pyran-4e-ol (3d). 150 mg 3d (12.7%) as a colourless oil
(procedure A); IR (neat) nmax 3484, 2975, 1720, 1495, 1453,
3.3.16. 9e-Methyl-2e,4e-diphenyl-3-oxa-bicyclo[3.3.1]-
nonan-9a-ol (4g). 230 mg 4g (18.7%) as colourless crystals
(procedure A); mp 132–133 8C (hexane/ethylacetate); IR
(neat) nmax 3251, 2925, 1738, 1496, 1449, 1380, 1207, 1139,
1
1385, 1102, 1081, 1066, 1036 cm21; H NMR d¼7.43–
1
7.14 (10H, m, CHPh), 4.65 (1H, dd, J¼2.6, 12.1 Hz, H6),
4.50 (1H, s, H2), 2.05 (1H, dd, J¼12.1, 13.6 Hz, H5), 1.74
(1H, dd, J¼2.6, 13.6 Hz, H5), 1.52 (3H, s, –CH3), 0.93 (3H,
s, –CH3), 0.78 (3H, s, –CH3); 13C NMR d¼142.5, 139.1,
128.3, 128.1, 127.4, 127.3, 127.2, 125.7, (CHPh), 84.1, 77.2,
73.5, (C2, C4, C6), 45.9, 41.8, (C3, C5), 23.3, 19.6, 16.0,
(3£–CH3); HRMS: calcd for C20H24O2 296.1776. Found:
296.1776.
1064 cm21; H NMR d¼7.42–7.11 (10H, m, CHPh), 5.50
(2H, m, H2, H4), 2.09–1.13 (11H, m, H1, H5, H6, H7, H8,
–CH3); 13C NMR d¼142.5, 127.9, 126.3, 125.2, (CHPh),
76.5, 72.4, (C2, C4, C9), 45.4, (C1, C5), 27.9, 23.0, (C6, C7,
C8), 19.3, (–CH3); HRMS: calcd for C21H24O2 308.1776.
Found: 308.1776.
3.3.17. anti-2-Hydroxybenzyl-1-methyl-cyclohexan-1-ol
(5g).6 147 mg 5g (16.7% yield) as a colourless oil
(procedure A); 1H NMR d¼7.30–7.10 (5H, m, CHPh),
4.46 (1H, d, J¼10.2 Hz, CHOH), 1.72–0.68 (12H, m, H2,
H3, H4, H5, H6, –CH3); 13C NMR d¼142.4, 128.3, 127.8,
127.3, (CHPh), 78.7, 74.5, (C1, CHOH), 52.1, 42.2, (C2,
C6), 27.0, 25.5, 23.6, 21.0, (C3, C4, C5, –CH3).
3.3.12. 4e-Methyl-2e-3e,6e-triphenyl-tetrahydropyran-
4a-ol (4e). 250 mg 4e (18.2%) as a colourless oil (procedure
A); IR (neat) nmax 3479, 3032, 1719, 1492, 1453, 1116,
1059, 1022 cm21; 1H NMR d¼7.43–7.01 (15H, m, CHPh),
5.17 (1H, d, J¼10.6 Hz, H2), 5.12 (1H, dd, J¼2.3, 11.3 Hz,
H6), 2.88 (1H, d, J¼10.6 Hz, H3), 2.05 (1H, dd, J¼2.3,
13.6 Hz, H5), 1.88 (1H, dd, J¼11.3, 13.6 Hz, H5), 1.03 (3H,
s, –CH3); 13C NMR d¼142.8, 141.0, 137.5, 130.6, 130.5,
128.6, 128.3, 128.2, 127.3, 127.0, 126.5, 125.9, (CHPh),
79.6, 75.1, 70.4, (C2, C4, C6), 58.5, 47.3, (C3, C5), 29.9,
(–CH3); HRMS: calcd for C24H24O2 344.1776. Found:
344.1776.
3.3.18. 3e-Chlor-4a-methyl-2e,6e-diphenyl-tetrahydro-
pyran-4e-ol (2h). 470 mg 2h (38.8%) as a colourless oil
(procedure B); IR (neat) nmax 3279, 1690, 1602, 1495, 1449,
1300, 1094, 1065, 1028 cm21
;
1H NMR d¼7.45–7.12
(10H, m, CHPh), 4.65 (1H, dd, J¼2.3, 11.7 Hz, H6), 4.42
(1H, d, J¼10.6 Hz, H2), 3.99 (1H, d, J¼10.6 Hz, H3), 2.13
(1H, dd, J¼2.3, 13.6 Hz, H5), 2.06 (1H, dd, J¼11.7,
13.6 Hz, H5), 1.58 (3H, s, CH3); 13C NMR d¼140.7, 138.6,
128.6, 128.4, 128.3, 127.9, 127.7, 125.9, (CHPh), 81.7, 71.9,
71.1, (C2, C3, C4, C6), 47.7, (C5), 21.9 (–CH3); HRMS:
calcd for C18H19ClO2 302.1074. Found: 302.1072.
The isomer 2e could not be separated by column
chromatography. The ratio of the isomers 2e and 4e was
determined by integration of important signals in the 1H and
13C NMR spectra.
3.3.13. syn-3-Methyl-1,4-diphenyl-butan-1,3-diol (5e).
350 mg 5e (34.2%) as a colourless oil (procedure A); IR
3.3.19. 8a-Methyl-2e,4e-diphenyl-3-oxa-bicyclo[3.2.1]-
octan-8e-ol (3i). 550 mg 3i (46.7%) as a colourless oil

998
M. Markert et al. / Tetrahedron 60 (2004) 993–999
(procedure B); IR (neat) nmax 3304, 2873, 1495, 1330, 1292,
1
3.3.25. 2e,6e-Di-isopropyl-4a-methyl-tetrahydro-pyran-
4e-ol (8d). 290 mg 8d (36.2%) as a colourless oil (procedure
B); IR (neat) nmax 2959, 2929, 1733, 1469, 1369, 1154,
1120, 1108, 1002 cm21; H NMR d¼7.40–7.13 (10H, m,
CHPh), 5.00–4.96 (2H, m, H2, H4), 2.02–1.95 (2H, m, H1,
H5), 1.73 (3H, s, –CH3), 1.52–1.49 (4H, m, H6, H7); 13C
NMR d¼141.7, 128.0, 126.8, 125.7, (CHPh), 79.9, 77.9,
(C2, C4, C8), 51.1, (C1, C5), 21.0, 20.3, (C6, C7, –CH3);
HRMS: calcd for C20H22O2 294.1619. Found: 294.1620.
1
1127, 1084, 1015; H NMR d¼2.86 (2H, ddd, J¼2.3, 6.8,
11.7 Hz; H2, H6), 1.85–1.76 (4H, m; 2£H3C–CH2–CHR),
0.95 (6H, t, J¼7.3 Hz; 2£H3C–CH2R); 13C NMR d¼79.9
(C2, C4), 43.4 (C3, C5), 33.3 (2£CH), 26.3 (CH3), 18.7,
18.6 (2£CH3); HRMS: calcd for C12H23O2 199.1698.
Found: 199.1700.
3.3.20. 5e-(2-Hydroxy-isopropyl)-3e-isopropenyl-2e-
phenyl-tetrahydropyran (6). 860 mg 6 (82.6%) were
isolated as a colourless oil by the reaction of 1-hydroxy-3-
methyl-2-buten (procedure B); IR (neat) nmax 3412, 2970,
1453, 1371, 1191, 1073 cm21; 1H NMR d¼7.33–7.12 (5H,
m, CHPh), 4.56 (2H, m, CH2), 4.17 (1H, ddd, J¼2.7, 3.8,
10.9 Hz, H6), 4.03 (1H, d, J¼10.2 Hz, H2), 3.38 (1H, dd,
J¼10.9, 11.3 Hz, H6), 2.29 (1H, ddd, J¼3.4, 10.2, 10.2 Hz,
H3), 1.91 (1H, ddd, J¼3.4, 3.5, 12.6 Hz, H4), 1.78 (1H,
dddd, J¼3.4, 3.8, 11.3, 12.1 Hz, H5), 1.52 (1H, ddd,
J¼10.2, 12.1, 12.6 Hz, H4), 1.43 (3H, s, –CH3), 1.22 (6H,
s, –CH3); 13C NMR d¼146.0, 140.8, 128.1, 127.8,
127.3,112.3, (CHPh, Cq, CH2), 84.2, (C2), 71.3, (–COH),
69.8, (–CH2O), 50.6, 46.8, 31.6, (C3, C4, C5), 27.8, 27.3,
21.5, (3£CH3); HRMS: calcd for C17H24O2 260.1776.
Found: 260.1776.
3.3.26. 2a,4a,8a-Trimethyl-3-oxa-bicyclo-[3.2.1]-octan-
8e-ol (9a). 160 mg 9a (28.5%) as a colourless oil (procedure
B); IR (neat) nmax 3317, 2971, 2917, 1738, 1464, 1371,
1348, 1297, 1130, 1089, 1069 cm21; 1H NMR: d¼3.78 (2H,
q, J¼6.4 Hz, H2, H4), 1.55–1.71 (4H, m, H6, H7), 1.45
(3H, s, CH3), 1.43 (2H, m, H1, H5), 1.03 (6H, d, J¼6.4 Hz,
2£CH3); 13C NMR 80.1 (C8), 72.5 (C2, C4l), 49.8 (C1, C5),
21.0 (C6, C7), 20.0 (CH3), 19.5 (2£CH3); HRMS: calcd for
C10H18O2 170.1307. Found: 170.1306.
3.3.27. 2e,4e-Diethyl-8a-methyl-3-oxa-bicyclo[3.2.1]-
octan-8e-ol (9b). 280 mg 9b (35.3%) as a colourless oil
(procedure B); IR (neat) nmax 3307, 2970, 2919, 1738, 1365,
1217, 1127, 1070, 989 cm21
;
1H NMR d¼3.42 (2H, t,
J¼6.78 Hz; H2, H4), 1.69–1.14 (13H, m, H1, H5, H6, H7,
2£–CH2, –CH3), 0.83 (6H, t, J¼7.0 Hz; 2£–CH3); 13C
NMR d¼80.4, (C8), 76.9 (2£C2, C4), 49.0, (C1, C5), 26.3,
21.5 (2£CH2, C6, C7), 20.1 (CH3), 10.3 (2£CH3); HMRS:
calcd for C12H22O2 198.1620. Found: 198.1624.
3.3.21. 4e-Methyl-2e,6e-di-npropyl-tetrahydro-pyran-
4a-ol (7c). 160 mg 7c (20%) as a colourless oil (procedure
B); IR (neat) nmax 3117, 2959, 2806, 1735, 1381, 1147,
1124, 1077 cm21; 1H NMR d¼3.21 (2H, m, H2, H6), 1.20–
1.59 (12H, m, H3, H5, 4£CH2), 1.24 (3H, s, CH3), 0.85 (6H,
dd, J¼6.8, 7.2 Hz, 2£CH3); 13C NMR d¼74.7 (C2, C4),
69.5 (C4), 46.5 (C3, C5), 38.4 (2£CH2), 26.2 (–CH3), 19.0
(–CH2), 14.0 (2£CH3); HRMS: calcd for C12H24O2
200.1776. Found: 200.1743.
3.3.28. 8a-Methyl-2e,4e-di-npropyl-3-oxa-bicyclo[3.2.1]-
octan-8e-ol (9c). 350 mg 9c (38.7%) as a colourless oil
(procedure B); IR (neat) nmax 3321, 2954, 2867, 1738, 1464,
1374, 1323, 1217, 1131, 1093 cm21; 1H NMR d¼3.52 (2H,
t, J¼7.16 Hz; H2, H4), 1.69–1.14 (17H, m, H1, H5, H6, H7,
4£CH2, CH3), 0.82 (6H, t, J¼7.2 Hz; 2£–CH3); 13C NMR
d¼80.4 (C8), 78.6 (2£C2, C8), 48.3 (C1, C5), 26.3, 21.5
(2£CH2, C6, C7), 20.1 (CH3), 10.3 (2£CH3); HMRS: calcd
for C14H26O2 226.1933 Found: 226.1933.
3.3.22. 2e,4a,6e-Trimethyl-tetrahydro-pyran-4e-ol
(8a).12 210 mg 8a (36.4%) as a colourless oil (procedure
1
B); H NMR d¼3.43 (2H, ddq, J¼1.5, 6.2, 10.7 Hz, H2,
H6), 1.58 (2H, dd, J¼2.3, 10.7 Hz, H3, H5), 1.33 (2H, dd,
J¼1.5, 2.3 Hz, H3, H5), 1.25 (3H, s, CH3), 1.15 (6H, d,
J¼6.2 Hz, 2£CH3); 13C NMR d¼77.2 (C2, C5), 70.9 (C4),
47.6 (C3, C5), 26.0, 22.0 (3£CH3).
Acknowledgements
3.3.23. 2e,6e-Diethyl-4a-methyl-tetrahydro-pyran-4e-ol
(8b). 180 mg 8b (26.1%) as a colourless oil (procedure
B); IR (neat) nmax 3388, 2965, 2936, 1731, 1460, 1371,
This research was supported by the Deutsche Forschungs-
gemeinschaft. The authors thank B. Ziemer and P. Neubauer
for performing out the X-ray analysis.
1
1175, 1141, 1125, 1080, 1023 cm21; H NMR d¼3.18–
3.09 (2H, m; H2, H6), 1.64–1.14 (11H, m, H3, H5, 2£CH2,
CH3), 0.88 (6H, t, J¼7.3 Hz; 2£–CH3); 13C NMR d¼76.3,
(C2, C6), 69.5 (C4), 46.2, (C3, C5), 29.2 (2£CH2), 26.2
(–CH3), 10.1 (2£–CH3); HRMS: calcd for C9H17O2
(M2CH3) 157.122855. Found: 157.12288.
References and notes
1. (a) Mahrwald, R. Angew. Chem. 2002, 114, 1423–1425,
Angew. Chem., Int. Ed. Engl. 2002, 41, 1361–1363, see also
(b) Mahrwald, R. Angew. Chem. 2003, 115, 2547; Angew.
Chem., Int. Ed. Engl. 2003, 42.
3.3.24. 4a-Methyl-2e,6e-di-npropyl-tetrahydro-pyran-
4e-ol (8c). 120 mg 8c (15%) as a colourless oil (procedure
B); IR (neat) nmax 3407, 2958, 2930, 1736, 1459, 1376,
1217, 1142, 1125, 1082 cm21; 1H NMR d¼3.54 (2H, dddd,
J¼1.9, 2.3, 4.5, 15.8 Hz, H2, H6), 1.18–1.48 (12H, m, H3,
H5, 4£CH2), 1.17 (3H, s, CH3), 0.85 (6H, dd, J¼6.8, 7.2 Hz,
2£CH3); 13C NMR d¼72.6 (C2, C6), 68.8 (C4), 44.7 (C3,
C5), 38.3 (2£CH2), 31.8 (CH3), 16.9 (2£CH2), 14.1
(2£CH3); HRMS: calcd for C12H24O2: 200.1776. Found:
200.1774.
2. The crystal structures have been deposited at the Cambridge
Crystallographic Data Centre and been allocated the depo-
sition numbers CCDC 206864 for 1d, CCDC 206865 for 2b
and CCDC 206866 for 4g.
3. Faller, J. W.; Linebarrier, D. L. Organometallics 1990, 9,
3182–3184.
4. Behnke, D.; Henning, L.; Findeisen, M.; Welzel, P.; Mu¨ller,

M. Markert et al. / Tetrahedron 60 (2004) 993–999
999
D.; Thormann, M.; Hoffmann, H.-J. Tetrahedron 2000, 56,
1081–1095.
LaRochelle, L. K.; Walsh, P. J. J. Am. Chem. Soc. 2002, 124,
10970–10971. (c) Dosa, P. I.; Fu, G. C. J. Am. Chem. Soc.
1998, 120, 445–446. Stereoselective allylation of ketones:
(d) Casolari, S.; D’Addario, D.; Tagliavini, E. Org. Lett. 1999,
1, 1061–1063.
5. Bartoli, G.; Bellucci, M. C.; Bosco, M.; Dalpozzo, R.;
Marcantoni, E.; Sambri, L. Chem. Eur. J. 2000, 6, 2590–2598.
6. Ghera, E.; Shoua, S. J. Org. Chem. 1972, 37, 1292–1298.
7. Snider, B. B. The Prins and Carbonyl Ene Reactions. In
Comprehensive Organic Synthesis; Heathcock, C. H., Ed.;
Vol. 2, (Trost, B. M. Ed.), 1991, Chapter 2.1, pp 527–561.
8. Corey, E. J.; Guzman-Perez, A. Angew. Chem. 1998, 110,
402–415; Angew. Chem., Int. Ed. Engl. 1998, 37, 388–401.
9. Stereoselective alkylation of ketones: (a) Ramon, D. J.; Yus,
M. Tetrahedron Lett. 1998, 39, 1239–1242. (b) Garcfa, C.;
10. Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923.
11. Mahrwald, R.; Ziemer, B.; Ramm, M. J. Prakt. Chem. 1996,
338, 583–585.
12. (a) Ballard, S. A.; Holm, R. T.; Williams, P. H. J. Am. Chem.
Soc. 1950, 72, 5734–5737. (b) Williams, P. H.; Ecke, G. G.;
Ballard, S. A. J. Am. Chem. Soc. 1950, 72, 5738–5741.