Generally applicable organocatalytic tetrahydropyranylation of hydroxy functionalities with very low catalyst loading

Article abstract of DOI:10.1055/s-2007-965917

This paper presents the first acid-free, organocatalytic tetrahydropyran and 2-methoxypropene protection of alcohols, phenols, and other ROH derivatives utilizing privileged N,N′-bis[3,5-bis(trifluoromethyl)phenyl]thiourea and a polystyrene-bound analogue. The reactions are broadly applicably (also on preparative scale), in particular, to acid-sensitive substrates such as aldol products, hydroxy esters, acetals, silyl-protected alcohols, and cyanohydrins. The catalytic efficiency is truly remarkably with turnover numbers of 100,000 and turnover frequencies of up to 5700 h^-1 at catalyst loadings down to 0.001 mol%. The computationally supported mechanistic interpretation emphasizes the hydrogen bond assisted heterolysis of the alcohol and concomitant preferential stabilization of the oxyanion hole in the transition state. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-965917

FEATURE ARTICLE
779
Generally Applicable Organocatalytic Tetrahydropyranylation of Hydroxy
Functionalities with Very Low Catalyst Loading
O
rganocatalytic Tetrah
i
ydropy
k
r
anylation e Kotke, Peter R. Schreiner*
Institute of Organic Chemistry, Justus-Liebig University Gießen, Heinrich-Buff-Ring 58, 35392 Gießen, Germany
Fax +49(641)9934309; E-mail: prs@org.chemie.uni-giessen.de
Received 14 December 2006; revised 12 January 2007
bromide salts,6 but these generate HBr in situ;7 cerium(III)
chloride8 also catalyzes this reaction but is ineffective for
sterically hindered alcohols (e.g., adamantan-1-ol). There
is no single catalyst that can be applied to the entire spec-
Abstract: This paper presents the first acid-free, organocatalytic
tetrahydropyran and 2-methoxypropene protection of alcohols, phe-
nols, and other ROH derivatives utilizing privileged N,N¢-bis[3,5-
bis(trifluoromethyl)phenyl]thiourea and a polystyrene-bound ana-
logue. The reactions are broadly applicably (also on preparative trum of alcohols, in particular, to sterically hindered ter-
scale), in particular, to acid-sensitive substrates such as aldol prod-
tiary alcohols (elimination is a major side reaction) and
ucts, hydroxy esters, acetals, silyl-protected alcohols, and cyanohy-
deactivated phenols. We do not know of any general ap-
drins. The catalytic efficiency is truly remarkably with turnover
proach to the THP protection of highly acid-labile sub-
numbers of 100,000 and turnover frequencies of up to 5700 h–1 at
strates; such a method would, indeed, be highly desirable.
catalyst loadings down to 0.001 mol%. The computationally sup-
ported mechanistic interpretation emphasizes the hydrogen bond as-
Based on our excellent experience on the catalysis of ace-
talization reactions9 we contemplated that tetrahydropyr-
sisted heterolysis of the alcohol and concomitant preferential
stabilization of the oxyanion hole in the transition state.
anylations would also be feasible. The reasoning for this
is based on the observation that in the acetalization reac-
tions the thiourea catalyst (7, N,N¢-bis[3,5-bis(trifluoro-
Key words: acetals, alcohols, catalysis, protecting groups, support-
ed catalysis
methyl)phenyl]thiourea) assists the heterolysis of the ortho
ester 6 in the initial stages of the reaction by stabilizing the
incipient alcoholate (8, Scheme 2). This rationalization is
in line with well-established concepts in a multitude of en-
Introduction
zymatic reactions that are characterized through ‘oxy-
The acid-catalyzed reaction of alcohols and phenols 1
with 3,4-dihydro-2H-pyran (DHP, 2) to give tetrahydro-
pyranyl-substituted ethers 3 is a classic, and one of the
anion stabilization’ through explicit hydrogen bonds to
partially negatively charged oxygen atoms.10
most common, strategies for the protection of hydroxy
functions (tetrahydropyranylation, Scheme 1).1 The utili-
ty and popularity of this reaction lies in the ease of intro-
ducing and removing the tetrahydropyranyl (THP) group
and the fact that pyrans of type 3 are remarkably stable un-
der basic conditions.
OR
H
H
+
HC(OR)3
O
R
H
OR
6
8
9
CF3
CF3
S
catalyst
= (7)
+
R–OH
H
H
R
F3C
N
H
N
H
CF3
conditions
O
O
O
1
2 (DHP)
3–5
Scheme 2 Initiation step in thiourea-catalyzed acetalizations and
the structure of catalyst 7.
Scheme 1 General tetrahydropyran protection (tetrahydropyranyla-
tion). The product numbering refers to different types of THP-protec-
ted alcohols, as depicted in Tables 1–3.
A second clue was provided by the reactions of a,b-unsat-
urated carbonyl compounds 10 that underwent a domino
Michael addition followed by acetalization to give highly
oxygenated products 11 under the acetalization reactions
conditions (Scheme 3).9
There are many ways to catalyze this important reaction.
Various Brønsted acids, including acidic polymers and
ionic liquids,2 and also a large variety of Lewis acids, in-
cluding zeolites,3 acidic alumina,4 and clays,5 have been
utilized. There have been a few attempts to find ‘acid-
free’ variants of this reaction, e.g., with benzyltriphe-
nylphosphonium tribromide or tetrabutylammonium tri-
These mechanistic insights clearly mark the departure
from the often-implied concept of carbonyl11,12 (or
imino13,14) group activation through hydrogen bonding
with (thio)urea and other hydrogen-bonding catalysts.
Hence, this mechanistic alternative suggests either the hy-
drogen bond assisted generation of the free nucleophile
(e.g., RO–, CN–) or the stabilization of the active form of
SYNTHESIS 2007, No. 5, pp 0779–0790
x
x
.
x
x
.2
0
0
7
Advanced online publication: 08.02.2007
DOI: 10.1055/s-2007-965917; Art ID: E17006SS
© Georg Thieme Verlag Stuttgart · New York

780
M. Kotke, P. R. Schreiner
FEATURE ARTICLE
O
Results and Discussion
0.1–1 mol% of 7
R3O
R1
OR3
HC(OR3)3, R3OH, ~ 15 h, r.t.
R1
We used 3,4-dihydro-2H-pyran (DHP) as reactant and
solvent and conducted most of our reactions using two
equivalents of DHP; in cases where the alcohol was insol-
uble in DHP, a small amount of tetrahydrofuran was add-
ed as a co-solvent (see the experimental section for
details). We conducted control experiments in parallel and
found no conversion of the respective substrates in the
given time required for full conversion of the starting ma-
terials in the catalyzed reactions. The catalyst loadings of
7 were 1 mol% or less. Organocatalysts incorporating a
thiourea motif are generally highly effective and allow
practically low catalyst loadings.9 In combination with the
3,5-bis(trifluoromethyl)phenyl moiety, which was intro-
duced by us,11,15 these catalysts enjoy the status of being
‘privileged’16 because their success rate in a manifold of
reactions9,14,17,18 is exceptionally high. Our current results
are summarized in Tables 1– 4 and emphasize the broad
applicability of 7 in the THP protection of a very broad va-
riety of alcohols and other hydroxy-functionalized com-
pounds.
R1, R2 = H, Alk, –(CH2)2–, –(CH2)3–
R2
OR3
R2
10
11, 71–85% (isolated)
Scheme 3 Domino Michael addition of R3OH to a,b-unsaturated
carbonyl compounds followed by acetalization.
the nucleophile through hydrogen bonding and polar in-
teractions to the respective precursor [ROH, HC(OR)3,
HCN, TMSCN, etc.].
We envisioned that the intrinsic reactivity (not necessarily
acidity) of simple alcohols should be increased through
hydrogen bonding so that the polar reactions with, e.g.,
enol ethers such as 2 should be significantly accelerated.
As we will demonstrate in the following, this concept
works extremely well for the tetrahydropyranylation of a
wide variety of alcohols including phenols and sterically
hindered alcohols. Furthermore, the generality of this
method is demonstrated through the reactions of alcohols
with 2-methoxypropene (MOP), the protection of oximes
as well as aldols and several other highly acid-sensitive
substrates. The application of polystyrene-bound thiourea
catalysts and computations underscoring our mechanistic
hypothesis are also included.
Primary and secondary alcohols can be THP protected at
room temperature in excellent yields and reasonable reac-
tion times (Table 1). Benzyl alcohol stands out as being
Biographical Sketches
Mike Kotke was born in structor in the training de- versity in 2001 to prepare
Hanau, a city near Frank- partment of Degussa with his diploma thesis in organic
furt/Main, Germany, in responsibilities for the edu- chemistry in the group of
1969. He joined the Degus- cation of chemical laborato- Prof. R. Askani. Mike re-
sa company (Hanau-Wolf- ry workers. In October 1992 ceived his diploma degree
gang, Germany) in 1989 on he began his chemistry stud- on the ‘Synthesis of poten-
an apprenticeship as
a
ies at the Justus-Liebig Uni- tial precursors of a homoar-
chemical laboratory tech- versity, Gießen, Germany, omatic semibullvallene’ in
nicien. After two and a half and he completed his the spring of 2002 and then
years, Mike took his exami- coursework within eight se- began his Ph.D. studies on
nation early in 1992 and mesters. After a period of thiourea-based organocatal-
continued working for six working in various occupa- ysis under the supervision of
months as an assistant in- tions, he returned to the uni- Prof. Peter R. Schreiner.
Peter R. Schreiner is pro- at the University of Göttin- sors) in 1999, was a Liebig
fessor of organic chemistry gen (1999) in the group of Fellow (1997–1999) of the
at the Justus-Liebig-Univer- A. de Meijere. Before be- Fonds der Chemischen In-
sity Gießen. He studied coming head of the Organic dustrie, and held a Habil-
chemistry in his native city Institute in Gießen in 2002, itandenstipendium of the
at the University Erlangen- he was associate professor Deutsche
Forschungsge-
Nürnberg, Germany, where of chemistry at the Universi- meinschaft (1999). He cur-
he received his Dr. rer. nat. ty of Georgia (1999–2002). rently serves as the assistant
(1994) in organic chemistry P. R. Schreiner is the 2003 editor for the Journal of
with P. v. R. Schleyer. Si- recipient of the Dirac Medal Computational Chemistry
multaneously, he received a of the World Association of and as an international advi-
Ph.D. (1995) with Henry F. Theoretically
Oriented sory board member of the
Schaefer III in computation- Chemists. Amongst other European Journal of Organ-
al chemistry from the Uni- awards, he also received the ic Chemistry.
versity of Georgia. He ADUC Prize for Habil-
completed his Habilitation itanden (assistant profes-
Synthesis 2007, No. 5, 779–790 © Thieme Stuttgart · New York

FEATURE ARTICLE
Organocatalytic Tetrahydropyranylation
781
the most reactive in this group. Its effective THP protec-
tion at very low catalyst loadings down to 0.001 mol% to
give 3j emphasizes the catalytic power of 7. For the reac-
tion with the lowest catalyst loading we calculate maxi-
mum turnover numbers (TONs) close to 100,000 and
turnover frequencies (TOFs), a much more sensible mea-
sure of practicality, of around 2,000 h–1.
Table 1 THP Protection of Simple Primary and Secondary Sub-
stratesa
Product
Time (h) Yield (%)
THP–O–THP (from H2O)
EtOTHP
3ab
3b
3c
3d
3e
3f
19
94
98
98
96
96
98
97
24
PrOTHP
24.5
23
While ethylene glycol is diprotected to give 3m, the dif-
ference in the relative rates of reaction of primary vs. sec-
ondary hydroxy groups results in the formation of the di-
THP-substituted glycerol 3n. Our acid-free protocol also
allows the protection of tert-butyldimethylsilyl-substitut-
ed substrates leading to orthogonal hydroxy protection as
shown for 3k. For the same reason, tertiary alcohols,
which normally are difficult to protect as THP ethers ow-
ing to steric hindrance and elimination as a side reaction,
can also be THP protected under our conditions (Table 2).
Particularly striking is the tolerance of even the most ster-
ically hindered adamantan-1-ol (4k),8 diamantan-1-ol
(4l), and triphenylmethanol (4m) that can not be THP pro-
tected by established methods (see above).
BuOTHP
i-PrOTHP
24
CyOTHP
28.5
19
3g
OTHP
OTHP
3h
3i
16
15
96
98
OTHP
OTHP
9
9.5
10
48
98
98 (0.1 mol%)c
98 (0.01 mol%)c
98 (0.001 mol%)c
3j
Phenol derivatives are also readily converted into their
corresponding THP ethers (Table 2); only the reaction
temperature must be raised to 50 °C in order to maintain
comparable reaction times as for the substrates in Table 1.
As shown for phenol, THP protection to 4a can be
achieved with catalyst loadings down to 0.001 mol%, re-
sulting in a TOF of 5700 h–1! This is in the range of excel-
lent metal-catalyzed reactions and, to the best of our
knowledge, the most efficient organocatalytic reaction to
date.9,19 Indeed, although we mostly report reactions run
at 1 mol% catalyst loading used for our substrate screen-
ing, selected scale-up experiments show that a loadings of
only 0.01–0.1 mol% are sufficient and practical for pre-
parative THP protection; we routinely ran these reactions
on a 50 mmol scale.
OTHP
3k
15.5
31
91
93
TBDMSO
OTHP
3ld,e
3md 18
3nd
24
89
63
OTHP
OH
THPO
THPO
OTHP
a Preparative yields of products given from the respective alcohols (5
mmol scale). Catalyst loading = 1 mol%, unless noted otherwise; all
reactions were carried out at r.t. No reactions occurred for reference
experiments run in parallel even after one week.
The phenol derivatives also provide the important clue
that acidity is not a factor for the mechanistic interpreta- b Reaction run as emulsion.
c Reaction scale increased (see experimental section).
tion of these reactions because (a) phenols are more acidic
than alkanols and (b) electron-deficient phenols such as 4-
chlorophenol, 4-(trifluoromethyl)phenol, and 4-hydroxy-
benzonitrile react more slowly than electron-rich 4-meth-
ylphenol or 4-methoxyphenol (products 4c, 4e, and 4f vs.
4b and 4d, respectively).
d Run as emulsion with THF (0.1 mL) added as co-solvent.
e Reaction run at 50 °C, d.r. (GC) ~1:1.
tionalities,18,21,22 this opens up possibilities for organocat-
alytic domino reactions.
a-Hydroxy ketones can also be THP protected (Table 3,
products 5a and 5b) at 50 °C in good yields. More remark-
able is the possibility of protecting typical aldol products
(5c, TOF = 2000 h–1) as well as other highly acid-sensi-
tive substrates (at r.t.) such as b-hydroxy ester 5d, epoxide
5e, and acetonides 5f and 5g without side reactions in ex-
cellent yields. Although there are methods for the THP
protection of aldol products,20 the present method is by far
the most efficient and practical.
Oximes can also be THP protected at longer reaction
times in good preparative yields (5j and 5k). Protected
oximes are valuable building blocks in a variety of trans-
formations.23
To improve the practicality of this reaction further, we at-
tached the bis(trifluoromethyl)phenyl part of our catalytic
motif to simple amino-terminated polystyrene beads (P1
and P3, Scheme 4);21 the coupling of the isothiocyanate
12 is highly efficient and generates polymers that can be
handled easily. Commercially available, expensive com-
Cyanohydrins are also effectively THP protected at room
temperature (5h and 5i). As thiourea catalysts also affect
the addition of HCN to carbonyl as well as imino func-
Synthesis 2007, No. 5, 779–790 © Thieme Stuttgart · New York

782
M. Kotke, P. R. Schreiner
FEATURE ARTICLE
Table 2 THP Protection of Sterically Hindered and Phenolic
pound 12 can be prepared in a straightforward manner
(see experimental section). We selected a variety of sub-
strates for polymer-catalyzed THP protection and found
these transformations generally to be quite effective
(Table 4); this is in marked contrast to earlier attempts
with some other simple polystyrene-bound thiourea deriv-
atives.24
Substratesa
Product
Time (h) Yield (%)
10
10
11
17
97
97 (0.1 mol%)b
97 (0.01 mol%)b
97 (0.001 mol%)b
OTHP
4a
4b
4c
All reactions with polymer-bound catalysts were conduct-
ed on a 2 mmol scale with 50 mg of catalyst; the approxi-
mate thiourea concentration was 4 mmol per 1 g of
polymer. The catalyst loading on the polymer was deter-
mined through determining the residual amounts of 12.
The change in the polymer texture is visually apparent;
while the amino-terminated white polystyrene beads lump
together and are difficult to handle, the thiourea-function-
alized off-white beads are well defined and do not aggre-
gate (Figure 1). The polymer-bound catalyst are handled
and recovered easily (see below).
10
95
OTHP
Me
Cl
13
93
OTHP
4d
4e
4f
11
45
57
61
95
86
96
84
OTHP
MeO
F3C
NC
OTHP
OTHP
S
S
4gc
OTHP
OTHP
4h
4ic
48
46
83
89
OTHP
19
19
26
41
98
98 (0.1 mol%)b
98 (0.01 mol%)b
98 (0.001 mol%)b
Figure 1 Untreated amino-terminated polystyrene beads (left) and
polymer-bound thiourea P2 (cf. Scheme 4).
t-BuOTHP
4j
4kd
18.5
97
The catalyst loading is calculated to be ca. 10 mol% in the
reactions summarized in Table 4. Only P2 proved to be
effective in the THP protection of a selection of alcohols
and phenols because the N/NH moieties present in P4 ap-
parently suppress the catalytic process. This is consistent
with our finding that, in general, the presence of an NR2
moiety is incompatible with the catalytic process present-
ed here. As a consequence, amino alcohols cannot be THP
protected with the current protocol.
OTHP
4ld,e
40
83
OTHP
Ph3COTHP
4m
4nf
105
18
84
98
OTHP
The polymer-supported catalytic reactions essentially run
to completion at the expense of longer reaction times
(Table 4). It is encouraging to see that a large variety of
different substrates can be protected with this very conve-
nient method. The polymer catalyst can be readily sepa-
rated by simple filtration, washed with dichloromethane
and be reused several times without loss of activity; we
checked this for the repeated preparation of 3j (4 cycles).
OTHP
4o
4p
51
16
92
98
OTHP
a Scale: 5 mmol. Preparative yields of products given from the respec-
tive alcohols. Catalyst loading = 1 mol%, T = 50 °C. No reactions oc-
curred for control experiments run in parallel, even after one week.
b Reaction scales increased (see experimental section).
c d.r. (GC) ~1:1.
Protection with Alternative Enol Ethers
Other enol ethers such as benzofuran, dihydrofuran, and
2-methoxypropene (MOP)25 can also be used utilizing vir-
tually the same experimental protocol (see below). MOP
protection is particularly attractive because it does not
d Carried out on a 2 mmol scale.
e DHP (1 mL) and THF (2 mL) were added as co-solvent.
f Run at r.t.
Synthesis 2007, No. 5, 779–790 © Thieme Stuttgart · New York

FEATURE ARTICLE
Organocatalytic Tetrahydropyranylation
783
Table 3 THP Protection of Acid-Sensitive Substratesa
Table 4 THP Protection of Selected Substrates Utilizing Polymer-
Bound Thiourea P2a
Product
Temp Time Yield (%)
(°C)
(h)
Product
4i
Time (h)
53
Yield (%)
92
97
98
95
95
97
96
O
5ab,c 50
26
59
87
3j
21
OTHP
4j
29
O
5c
36
5b 50
5c r.t.
19
5d
38
OTHP
OTHP
18
34
35
49
98
3g
21
O
98 (0.1 mol%)d
98 (0.01 mol%)d
98 (0.001 mol%)d
4a
25
a Products given from the respective alcohols (suspension, 2 mmol
scale). Catalyst loading approximately 10 mol%, T = 50 °C. Refer-
ence reactions without P2 revealed no conversion under otherwise
identical conditions.
O
OTHP
5d 50
5e r.t.
5f r.t.
30
8
98
93
96
O
OTHP
O
O
20
Table 5 MOP Protection of Selected Substratesa
OTHP
O
Product
Time (h)
28
Yield (%)
95
THPO
O
13a
5gc r.t.
14
36
91
89
O
O
O
O
O
O
O
13b
13c
34
25
97
96
OTHP
CN
5hc r.t.
O
O
OTHP
CN
5ic r.t.
5j r.t.
34
30
88
68
O
O
13d
13e
20
15
95
94
O
N
OTHP
Cl
N
O
O
5k r.t.
31
94
OTHP
O
13f
13g
13h
22
29
42
95
94
92
a Preparative yields of products given from the respective alcohols
(5 mmol scale). Catalyst loading = 1 mol%. No reactions occurred for
reference experiments run in parallel even after one week.
b Reaction from suspension, THF (2 mL) and DHP (4.5 mL) added as
co-solvents.
O
O
c d.r. (GC) ~1:1.
O
O
d Reaction scales increased (see experimental section).
O
O
O
generate a stereogenic center that can sometimes unneces-
sarily clutter the NMR spectra of THP as well as other ad-
ducts. A second advantage is the low boiling point of
MOP (34–36 °C) easing its removal after the reaction. As
this normally limits the reaction temperature we were
pleased to see that the catalyzed reactions run smoothly at
room temperature for the examined subset of the sub-
strates presented above (products 13, Table 5). It must be
noted, however, that MOP is so reactive that the uncata-
lyzed reaction also proceeds, albeit at lower rates.
a Products given from the respective alcohols. Scale: 5 mmol; catalyst
loading = 1 mol%, r.t.
Mechanism
From a mechanistic viewpoint, the addition of an alcohol
1 to the double bond of an enol 14 is formally a forbidden
thermal [2+2] cycloaddition (Scheme 5). As a conse-
Synthesis 2007, No. 5, 779–790 © Thieme Stuttgart · New York

784
M. Kotke, P. R. Schreiner
FEATURE ARTICLE
CF3
S
NH2
N
H
N
H
CF3
F3C
F3C
NCS
12
P2
P1
CF3
H
H
N
or
r.t., THF, 12 h
NH2
NH2
N
N
S
S
N
CF3
CF3
N
N
NH
NH
H
P4
P3
H
CF3
Scheme 4 Simple preparation of polymer-bound thiourea derivatives.
R2
R2
O
δ+ δ–
H
O
R2
O
H
H
H
O
H
–26.4
–31.0
–30.6
–18.6
–20.7
–18.6
+
R
R
R3
O
O
O
O
R1
R3
O
R3
R1
O
δ– δ+
R1
19
3
+
= cat.
7 or 16
1
14
TS
15
H
H
Scheme 5 Generalized mechanism for the uncatalyzed formally
forbidden [2+2] cycloaddition of an alcohol to an enol ether, and im-
portance of strong polarization in the transition structure.
H
O
H
R
+ DHP
R
O
H
O
H
0.0
TS
+23.0
+25.6
+15.4
H
H
H
O
quence, the transition structure (TS) must be highly polar
and the overall addition highly asynchronous.
–15.3
–17.7
–18.9
H
+
–8.9
–9.0
–11.9
O
O
O
H
H
R
R
18
17
2
A reasonable mechanistic entry into this reaction may be-
gin with the complexation of the thiourea catalyst 7, or
thiourea 16 itself, with the alcohol to give 17 (Scheme 6).
This coordination increases the alcohol’s acidity as well
as polarizability and hence its ability to form a subsequent
complex 18 with 2; the catalyst remains attached during
the polar addition through transition structure TS and in
the product complex 19. Dissociation delivers the free
product 3 and returns the catalyst 7 or 16 for the next cy-
cle.
Scheme 6 Proposed thiourea-catalyzed tetrahydropyranylation cy-
cle. First entry: DH0 at B3LYP/6-31G(d,p) for MeOH and thiourea as
models; second entry: DH0 at CCSD(T)/cc-pVDZ//B3LYP/6-
31G(d,p)+ZPVE for MeOH and thiourea 16 as models; third entry:
DH0 at B3LYP/6-31G(d,p) for MeOH and our thiourea catalyst 7 (all
entries in kcal mol–1).
thereafter are dominated by polar interactions (which are
described well). The DFT approach is the only one feasi-
ble for our ‘real’ system utilizing 7 as the catalyst; these
results are given as the third entries in Scheme 6.
In order to elucidate this mechanistic proposal we under-
took density functional theory [DFT, B3LYP/6-31G(d,p)]
and high-level coupled cluster computations (CCSD(T)/
cc-pVDZ, see below for details); details are revealed in
Figures 2 and 3 with energies given in Scheme 6. To the
best of our knowledge, these are the first mechanistic
computations on an addition reaction of ROH to enol de-
rivatives and specifically for a tetrahydropyranylation.
The structural changes upon complexation of methanol
with thiourea and 7 (Figure 2) are quite remarkable and
much stronger for the latter. Generally, while the O–H
bond of methanol is lengthened only very slightly, the
C–O bond distance increases significantly (by 0.02 Å for
7). This is the result of increased polarization of the alco-
hol because the increased negative charge on oxygen re-
pels the C–H bonds of the methyl group. The interaction
can also be analyzed based on the changes in the thiourea
moiety in which the N–H and C=S bonds are significantly
lengthened. The complexation energies are remarkably
large (and would be significantly less in solution). Partic-
ularly striking is the fact that this complexation energy is
even larger than that of thiourea with simple diketones
(ca. 6.5 kcal mol–1).12
A comparison of the DFT relative energies with the high
level coupled cluster energy results (on the DFT opti-
mized structures) in Scheme 6 reveals that although DFT
methods do not include weak van der Waals interactions,
the results are qualitatively rather similar for a model re-
action of methanol with DHP catalyzed with thiourea 16.
In particular, the first complexation to give 17 is also
quantitatively reproduced at the DFT level, which pro-
vides further evidence that this association and the steps
Synthesis 2007, No. 5, 779–790 © Thieme Stuttgart · New York

FEATURE ARTICLE
Organocatalytic Tetrahydropyranylation
785
Figure 2 Computed structures [at B3LYP/6-31G(d,p) and CCSD(T)/-cc-pVDZ+ZPVE(B3LYP/6-31G(d,p)] and dissociation energies of the
complexes of methanol as a model alcohol with thiourea 16 and our actual catalyst 7.
The ternary complex 18 is stabilized relative to the com- alcohol. Hence, steric hindrance is not a critical factor, as
plex without the catalyst or 7 by about 70% (Figure 3, top found experimentally (Table 2).
structures from left to right). The association is tightened
A comparison of the differential stabilization energies of
upon complexation as evident from the geometrical fea-
starting materials, transition structure, and product
tures of the complexes. We also examined complexes to
(Scheme 6) reveals that while the starting materials and
the oxygen atom of DHP but they were all considerably
product receive about 2–3 kcal mol–1 differential stabili-
less favorably than those with the b-carbon atom that
zation, the transition structure benefits by about 5–6 kcal
eventually accepts the proton. Hence, the catalyst helps
mol–1 from complexation with the catalyst. Of course, this
pre-organize the reactants and the overall geometric
is a precondition in order to observe catalysis, but it is
changes in going from the complexes to the transition
comforting to see that it is shown by the computations as
well. Finally, the dissociation energies of the products as-
sociated with catalyst are in the same range (7.8, 10.3, and
structures (TSs, Figure 3 bottom row) are small and evi-
dently follow the least motion principle. The computed
absolute barrier for the addition of methanol to DHP is
12.0 kcal mol–1, respectively, at the levels of theory given
prohibitively high (45.2 kcal mol–1 at CCSD(T)) and no
in Scheme 6) as those of the catalyst with the alcohol re-
reaction occurs, in agreement with experimentation.
actant (8.9, 9.0, and 11.9 kcal mol–1). Within the expected
Complexation with thiourea 16 already lowers the abso-
level of accuracy of our qualitative computations, the
comparable complexation energies suppress product inhi-
bition and, as a consequence, this reaction displays very
lute barrier by a remarkable 20 kcal mol–1! Electron-defi-
cient 7 maximizes this stabilization to yield a barrier of
‘only’ 17.7 kcal mol–1. As a consequence, the catalytic ef-
high turnover.
fect is truly remarkable, as demonstrated by the experi-
mental results discussed.
The transition structures follow all the expected geometri-
cal parameters: the methanol O–H bond is lengthened
Conclusions and Outlook
(1.384 Å to 1.675 Å) and this is concomitant with H–C Thiourea organocatalyst 7 allows the highly efficient THP
bond lengthening of the newly formed bond (1.251 Å to protection of a large variety of hydroxy functionalities.
1.161 Å); the other structural parameters follow this trend While virtually all reported non-organocatalytic methods
very closely. The only bond that is lengthened in going can protect either primary and secondary alcohols or ter-
from the uncatalyzed to the reaction catalyzed with 7 is tiary as well as phenolic substrates, 7 operates effectively
the newly forming C–O bond (2.187 Å to 2.578 Å), which on all classes of hydroxy functionalities. This also in-
perfectly agrees with the oxyanion stabilization concept cludes acid-sensitive substrates such as a- and b-hydroxy
that is particularly effective for 7. A closer inspection of carbonyl compounds (including aldol products), cyanohy-
the transition structure with 7 reveals that the catalyst is drins, acetals, and oximes.
placed sideways and points away from the R group on the
Synthesis 2007, No. 5, 779–790 © Thieme Stuttgart · New York

786
M. Kotke, P. R. Schreiner
FEATURE ARTICLE
Figure 3 Optimized complexes (top) between methanol and DHP without and with thiourea 16 as well as catalyst 7; transition structures
(bottom) for the addition of methanol to DHP without and with thiourea as well as with 7 as catalyst. Level of theory for optimization: first
entry = B3LYP/6-31G(d,p), energy evaluations: second entry = CCSD(T)/cc-pVDZ, including ZPVE corrections at B3LYP/6-31G(d,p).
–18 °C until required. Except for (–)-menthol and (–)-terpinen-4-ol
all chiral substrates were used as racemates. Aminomethylated
polystyrene P1 (200–400 mesh, loading 2.00–3.00 mmol/g resin)
and tris-(2-aminoethyl)amine polystyrene P3 (200–400 mesh, load-
ing 2.20 mmol/g resin) were ordered from Merck Novabiochem
and were stored under an argon atmosphere at –18 °C. 4-tert-Bu-
tyldimethylsilyloxybenzyl alcohol was synthesized by reduction of
TBDMS protected 4-hydroxybenzaldehyde with NaBH4 following
a literature protocol.27 Hydroxy(phenyl)acetonitrile (technical
grade) was distilled once over a 10 cm Vigreux column prior to use;
all solvents used for extractions or filtrations were distilled once
with a rotary evaporator. Drying followed established literature pro-
cedures: THF and Et3N (both freshly distilled from Na/benzophe-
none ketyl); CH2Cl2 (P2O5, reflux, 3 h, then distilled once before
storage); EtOH (Na/diethyl phthalate, reflux); PrOH, i-PrOH,
BuOH, ethane-1,2-diol, and propane-1,3-diol (distilled once, 20 cm
Vigreux column). All dry chemicals were stored under an argon at-
mosphere and over activated 3 Å molecular sieve (MS) (alcohols)
and Na wire (Et3N, THF), respectively: t-BuOH, allyl alcohol,
BnOH, and propargyl alcohol were stored over MS 3 Å without pri-
or distillation; CDCl3 (99.8%, purchased from Deutero GmbH) was
stored over MS 4 Å. Filtrations for product purification were per-
formed on activated basic alumina (50–200 microns; Acros Organ-
ics). TLC was carried out on pre-coated Macherey-Nagel plastic
sheets Polygram ALOX N/UV254 (40–80 mm) using UV light or
molybdatophosphoric acid (5% in EtOH) for visualization. The
progress of reactions was monitored by GC-MS analyses with a
Quadrupol-MS HP MSD 5971(EI) and HP 5890A GC equipped
with a J & W Scientific fused silica GC column (30 m × 0.250 mm,
0.25 micron DB–5MS stationary phase: 5% phenyl and 95% methyl
silicone) using He (4.6 grade) as carrier gas; T-program standard
60–250 °C (15 °C/min heating rate), injector and transfer line
250 °C; 1H and 13C NMR spectra were recorded with Bruker spec-
trometer Avance II 200 MHz (AV 200) and Avance II 400 MHz
The catalyst is remarkably active for THP protection reac-
tions. Catalyst loadings can be as low as 0.001 mol%, giv-
ing a maximum turnover number of about 100,000 and
turnover frequencies of up to 5700 h–1. To the best of our
knowledge, this is the most efficient organocatalytic reac-
tion reported to date, and this emphasizes the power of
noncovalent catalysis and the remarkable role the thiourea
motif plays in organocatalysis.
From a mechanistic viewpoint, the reactions presented
here also mark the deviation from carbonyl (and related
functionalities) activation through double hydrogen bond-
ing.26 Instead, the catalyst preferentially stabilizes the de-
veloping oxyanion hole in the transition state through
double hydrogen bonding. This conclusion was reached
on the basis of a comparative computational analysis of
the uncatalyzed vs. catalyzed reactions. The stabilizing ef-
fect of 7 on the key transition structures amounts to ca. 23
kcal mol–1, which is in line with the experimentally found
efficacy of 7.
An analogue of 7 bound to polystyrene beads also effec-
tively catalyzes THP protection reactions although the
formal catalyst loading is significantly higher and the re-
action times are longer.
All chemicals were purchased from Aldrich, Acros Organics, Alfa
Aesar, Merck, and Lancaster in the highest purity available and
were used without further purification unless otherwise noted. 3,4-
Dihydro-2H-pyran (DHP) and 2-methoxypropene (MOP) (both
97% grade, Aldrich) were used as purchased; MOP was stored at
Synthesis 2007, No. 5, 779–790 © Thieme Stuttgart · New York

FEATURE ARTICLE
Organocatalytic Tetrahydropyranylation
787
WB (AV 400) using as the internal standard: TMS d(1H) = 0.00,
d(13C) = 0.0; CHCl3 [d(1H) = 7.26], CHCl3 [d(13C) = 77.0]; 13C sig-
nals were assigned with DEPT or APT (attached proton test) exper-
iments. IR spectra were measured with Bruker IFS25 and IFS48
spectrophotometers [for P2 and P4 using attenuated total reflection
(ATR)]; HRMS were recorded with a Sectorfield-MS: Finnigan
MAT 95, CHN analyses were obtained with a Carlo Erba 1106 (bal-
ance: Mettler Toledo UMX-2) analyzer. To keep reaction tempera-
tures constant a standard mercury contact thermometer controlled
by an IKAMAG RET-GS hot plate-stirrer was used.
–5 °C. Thiophosgene (7.85 mL, 100 mmol, 97% grade) was placed
in a second oven-dried three-necked flask serving as reaction ves-
sel, equipped with argon inlet, addition funnel with septum, ther-
mometer, and magnetic stirring bar; it was cooled (–5 to –10 °C)
with an ice/salt bath and vigorously stirred. The amine mixture was
slowly added to the cooled thiophosgene through an addition funnel
to initiate the exothermic reaction; to minimize warming of the
amine mixture only small portions (20–30 mL) were transferred
with a 50 mL plastic syringe into the addition funnel. The resulting
orange mixture was stirred at –10 °C for 15 min and the mixture was
allowed to warm to r.t. (~45 min) and stirred at r.t. for 12 h. The
brown mixture was poured into demineralized H2O (850 mL) in a
separation funnel and NaCl was added to facilitate separation of
layers. The aqueous layer was extracted with Et2O (3 × 250 mL)
and the organic layers were collected and dried (anhydrous Na2SO4/
Na2CO3). The drying agent was separated by filtration and washed
intensively with Et2O (~300 mL) to reduce loss of product. Evapo-
ration of the solvent from the combined organic layers afforded a
red-brown oily residue. Fractionated distillation (10 cm Vigreux
column) in vacuo gave analytically pure 12 as a yellowish transpar-
ent liquid that could be stored for several weeks under an argon at-
mosphere at 4 °C; yield: 8.03 g (74%); bp 103 °C/~20 mbar;
n20D +1.4336.
All analytical reaction mixtures were prepared in clean oven-dried
one-necked 10 mL (2 and 5 mmol scale experiments) and 25 mL (50
and 100 mmol scale experiments) standard glass flasks (Schott DU-
RAN) tightly sealed with a plastic plug. For experiments at 50 °C,
reaction flasks were sealed with a clamped glass plug and were
placed in a tempered oil bath (50 °C). For homogeneous catalysis
organocatalyst 7 and solid hydroxy substrate 3–5 were directly
weighed out into the reaction flasks, liquid substrates were added
via syringe and were dissolved in DHP (2 equiv, 0.91 mL/5 mmol
substrate, for larger scales the volume was adjusted proportionally)
or MOP (2 equiv, 0.96 mol/5 mmol substrate), respectively. The
quantity of catalyst refers to the substrate quantity that determines
the scale of the experiment. To reveal catalyst efficiency various
catalyst loadings (mol%) of 7 were employed: 1.0 [25 mg/5 mmol],
0.1 [12.5 mg/25 mmol], 0.01 [2.5 mg/50 mmol], and 0.001 mol%
[1 mg/200 mmol scale]. If not otherwise noted all experiments uti-
lizing 7 were run in homogeneous solns. In each experiment utiliz-
ing heterogeneous catalysis P2 or P4 (each 50 mg: ~10 mol% based
on ~4 mmol thiourea motif per gram polymer) were weighed into
the reaction flask, the respective hydroxy substrate 3–5 (2 mmol),
and DHP (0.36 mL) was added. In general, all volumes for the prep-
aration of analytical reactions were measured with new 1 mL plastic
syringes using dry cannulas. The reaction time measurements start-
ed with stirring of the freshly prepared reaction mixture after addi-
tion of DHP or MOP, respectively, serving as reagent as well as
solvent; in some cases THF was used as co-solvent (see Table foot-
notes). For stirring, standard Teflon-coated magnetic stirring bars (1
to 1.5 cm) were used. Reaction temperature (25 or 50 °C) for each
substrate is given in Tables 1– 5. To determine the catalytic effi-
ciency, all experiments were accompanied by a parallel control ex-
periment under same conditions, but without catalyst. In the case of
heterogeneous organocatalysis, reference experiments were per-
formed with aminomethylated polystyrene resin P1 or P3, respec-
tively. Sample volumes (~0.5 mL) were taken directly from the
stirred reaction mixture via 10 mL Hamilton syringe (in heteroge-
neous experiments given in Table 4 stirring was stopped prior to
sampling to allow the catalyst to precipitate) and were injected im-
mediately to record the GC-MS chromatogram. The course of each
hydroxy-protection reaction was monitored by integrating the start-
ing material and product signal; time-dependent conversion as a
percentage was determined from the integral ratio of starting mate-
rial and product signal. After completion of the reaction as con-
firmed by GC-MS, work-up followed according to the procedures
described below. More details concerning the various substrates and
potential exceptions to these general procedures are mentioned in
the footnotes to Tables 1– 5.
IR (film): 2034 (NCS), 1992, 1620, 1465, 1378, 1279, 1235, 1181
1137, 1107, 1004, 892, 849, 785, 712, 698, 683 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.65 (s, 2 H), 7.78 (s, 1 H).
13C NMR (100 MHz, CDCl3): d = 118.5, 120.5, 123.9 (1JCF = 273
Hz), 125.8, 133.3 (2JCF = 32 Hz), 141.1.
HRMS: m/z calcd for C9H3F6NS: 270.9890; found: 270.9891.
Anal. Calcd for C9H3F6NS: C, 39.86; H, 1.12; N, 5.17. Found: C,
39.50; H, 1.08; N, 5.16.
Polystyrene-Bound Thiourea Organocatalysts P2 and P4
In an oven-dried, two-necked, 10 mL flask equipped with argon-in-
let and septum, aminomethylated polystyrene P1 (0.8 g) was sus-
pended in anhydrous THF (5 mL) with low stirring with a magnetic
stirring bar. Pure 1,3-bis(trifluoromethyl)phenyl isothiocyanate (12,
1.95 g, 7.2 mmol) was added over 5 min. The resulting mixture was
stirred at r.t. under an argon atmosphere for 12 h, after which the
resin was separated by suction filtration through a round filter pa-
per. Excessive washing with anhydrous CH2Cl2 (5 × 10 mL) and
subsequent removal of CH2Cl2 in vacuo furnished yellowish thio-
urea functionalized P2; this was stored until use in a Schlenk tube
at –18 °C under argon. The unreacted excess of isothiocyanate 12
was recovered from the filtrate by evaporation of CH2Cl2. The cat-
alyst loading (thiourea moiety per gram P2) was determined via
consumption of isothiocyanate and amounted to about 4 mmol per
1 g polymer-bound organocatalyst.
P4 was synthesized analogously from tris(2-aminoethyl)amine
polystyrene P3 (0.8 g) suspended in anhydrous THF (5 mL) and
isothiocyanate 12 (2.86 g, 10.56 mmol, 3 equiv per NH2 group).
Catalyst loading was identical to P2. Thiourea functionalization of
P2 and P4, respectively, was analytically detected via IR measure-
ment revealing a strong thiocarbonyl band that is typical for thio-
urea derivatives; no residual isothiocyanate bands were detected.
All THP and MOP ethers were isolated and characterized by 1H and
13C NMR, IR, and MS; 3a–n, 4a–k, 4n–p, 5a–i, 13a–e, and 13h are
known compounds and their spectral data were consistent with lit-
erature data.
P2
Yellowish, crystalline, free-floating particles.
IR (ATR): 3257, 2923, 1582 (C=S), 1470, 1381, 1274 (CF3), 1170,
1125, 948, 883, 698, 680 cm–1.
1,3-Bis(trifluoromethyl)phenyl Isothiocyanate (12)
In an oven-dried, three-necked, 1 L flask equipped with argon-inlet,
thermometer, septum, and magnetic stirring bar, a homogeneous
mixture of 1,3-bis(trifluoromethyl)aniline (9.16 g, 40 mmol) and
anhydrous Et3N (16.9 mL) in anhydrous THF (400 mL) was pre-
pared and subsequently cooled with an ice/salt bath at approx.
P4
Yellow, crystalline, free-floating particles.
IR (ATR): 3267, 3025, 2922, 1668 (C=S), 1376, 1331, 1274 (CF3),
1170, 1126, 883, 846, 735, 697, 680 cm–1.
Synthesis 2007, No. 5, 779–790 © Thieme Stuttgart · New York

788
M. Kotke, P. R. Schreiner
FEATURE ARTICLE
2-(Benzyloxy)tetrahydro-2H-pyran (3j); Typical Procedure for
Homogeneous Organocatalysis Using Catalyst 7
13C NMR (100 MHz, CDCl3): d = 20.8, 25.3, 25.9, 30.2, 32.3, 32.5,
32.6, 32.7, 32.9, 37.1, 37.4, 37.5, 38.2, 39.8, 42.2, 42.7, 63.4, 68.8,
92.2.
Organocatalyst 7 (25 mg, 0.05 mmol, 1 mol% loading) was weighed
into an oven-dried, one-necked, 10 mL flask equipped with a mag-
netic stirring bar (1.5 cm). After addition of BnOH (0.52 mL, 5
mmol) and DHP (0.91 mL, 10 mmol) via a 1 mL syringe, the reac-
tion flask was sealed with a plastic plug and the mixture was vigor-
ously stirred at r.t. until the reaction was complete (9 h,
temperatures and times are given in Table 1). DHP was mostly
evaporated in vacuo, the resulting yellowish crude product was dis-
solved in n-pentane (~ 8 mL) and slowly passed through a short col-
umn of basic alumina (2.5 × 4.5 cm). Evaporation of n-pentane and
residual DHP with a rotary evaporator under reduced pressure (~30
mbar) at 50 °C bath temperature afforded analytically pure THP
ether 3j; yield: 0.94 g (98%); physical data were identical to those
reported in literature.
HRMS: m/z calcd for C19H28O2: 288.2089; found: 288.2083.
Anal. Calcd for C19H28O2: C, 79.12; H, 11.09. Found: C, 78.34; H,
10.10.
2-(Trityloxy)tetrahydro-2H-pyran (4m)
Yellowish crude product, purification: basic alumina column
(2.5 × 8 cm, n-pentane, ~ 10 mL, then Et2O ~15 mL); the solvent
was evaporated in vacuo at 50 °C bath temperature.
Colorless solid; yield: 84%.
IR (film): 3061, 3033, 2942, 2851, 1959, 1665, 1598, 1490, 1445,
1331, 1277, 1203, 1180, 1156, 1077, 1032, 1010, 970, 891, 759,
698, 639, 584, 510, 449 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.54–1.89 (m, 6 H), 3.52–3.59 (m,
1 H), 3.85–3.92 (m, 1 H), 4.96 (t, 3J = 3.3 Hz, 1 H), 7.19–7.78 (m,
15 H).
13C NMR (100 MHz, CDCl3): d = 20.4, 25.4, 31.5, 64.2, 82.1, 102.1,
126.4, 128.6, 130.1.
2-(Phenoxy)tetrahydro-2H-pyran (4a); Typical Procedure on a
Preparative Scale
In an oven-dried, one-necked, 25 mL flask, organocatalyst 7 (2.5
mg, 0.005 mmol, 0.01 mol% loading), phenol (4.71 g, 50 mmol),
and DHP (9.1 mL, 100 mmol) were added and the mixture was mag-
netically stirred for 11 h (Table 2) at 50 °C. The scaled-up workup
was performed according to the procedure for the 5 mmol experi-
ment (alumina column, 2.5 × 8 cm) to give 4a; yield: 8.64 g (97%);
physical data were consistent with those reported in literature.
HRMS: m/z calcd for C24H24O2: 344.1776; found: 344.1761.
Anal. Calcd for C24H24O2: C, 83.69; H, 7.02. Found: C, 84.01; H,
7.18.
3-(1-Methoxy-1-methylethoxy)prop-1-ene (13c); Typical Proce-
dure for Organocatalytic MOP Protection Using Catalyst 7
MOP protection of allyl alcohol (0.34 mL, 5 mmol) followed the
procedure described for THP protection of benzyl alcohol with the
modification that THP is replaced by MOP (0.96 mL, 10 mmol); ex-
cess MOP was evaporated without warming. Analytical grade MOP
ether 13c was obtained at r.t. in 25 h (Table 5); yield: 0.62 g (96%);
physical data were consistent with those reported in literature.
4-Chlorobenzaldehyde O-(Tetrahydro-2H-pyran-2-yl)oxime
(5j)
Yellowish crude product, purification: basic alumina column
(2.5 × 3 cm, n-pentane, ~ 6 mL, then Et2O, ~10 mL); the solvent
was evaporated in vacuo without warming.
Colorless oil, aromatic smell; yield: 68%.
IR (film): 2944, 2870, 1648, 1596, 1492, 1203, 1113, 1090, 1079,
1041, 1015, 981, 948, 825, 514 cm–1.
2-(Phenoxy)tetrahydro-2H-pyran (4a); Typical Procedure for
Heterogeneous Organocatalysis Using Polymer Catalyst P2
For heterogeneously catalyzed THP protection a suspension of phe-
nol (0.19 g, 2 mmol), polystyrene-bound thiourea P2 (50 mg, ~10
mol%), and DHP (0.36 mL, 4 mmol) was prepared in an oven-dried,
one-necked, 10 mL flask sealed with a plastic plug. Under gentle
stirring with a magnetic stirring bar (1 cm) at 50 °C the reaction was
complete within 25 h (Table 4). The catalyst was removed from
product by simple suction filtration, washed with CH2Cl2 (5 × 10
mL), and dried in vacuo to evaporate residual CH2Cl2. Recovered
P2 was directly reused for new THP protection reactions of phenol
(4 use/recovery cycles were examined) only with minor weight loss
(approx. 6% per recovery), but no detectable loss of catalytic activ-
ity. Evaporation of solvent with a rotary evaporator in vacuo (50 °C
bath temperature/~30 mbar) afforded a yellowish crude THP ether
that was diluted in n-pentane (5 mL) and slowly passed through a
basic alumina column (2.5 × 3 cm) to give analytically pure 4a;
yield: 0.34 g (96%); spectroscopic data were consistent with those
reported in literature.
1H NMR (400 MHz, CDCl3): d = 1.62–1.93 (m, 6 H), 3.66–3.70 (m,
1 H), 3.89–3.95 (m, 1 H), 5.38 (t, 3J = 3.3 Hz, 1 H), 7.42 (d, 3J = 8.8
Hz, 2 H), 7.56 (d, 3J = 8.8 Hz, 2 H), 8.16 (s, 1 H).
13C NMR (100 MHz, CDCl3): d = 22.3, 23.8, 30.2, 62.9, 101.2,
128.2, 128.8, 128.9, 141.4, 149.2.
HRMS: m/z calcd for C12H14ClNO2: 239.0713; found: 239.0705.
Anal. Calcd for C12H14ClNO2: C, 60.13; H, 5.89; N, 5.84. Found: C,
60.00; H, 6.18; N, 5.67.
Cyclooctanone O-(Tetrahydro-2H-pyran-2-yl)oxime (5k)
Yellowish crude product, purification: basic alumina layer (2.5
× 4.5 cm, n-pentane, ~8 mL, then Et2O, ~10 mL); the solvent was
evaporated in vacuo at 50 °C bath temperature.
Colorless semi-solid; yield: 94%.
IR (film): 3102, 2926, 2855, 2688, 1659, 1466, 1445, 1424, 1449,
1340, 1277, 1228, 1103, 1025, 954, 923, 904, 856, 825, 767, 748,
738, 614, 575, 514 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.40–2.50 (m, 20 H), 3.48–3.51
2-(Diamantan-1-yloxy)tetrahydro-2H-pyran (4l)
(m, 1 H), 3.93–3.96 (m, 1 H), 4.68 (t, 3J = 3.3 Hz, 1 H).
Yellowish crude product, purification: basic alumina column
(2.5 × 4.5 cm, n-pentane, ~6 mL, then Et2O, ~10 mL); the solvent
was evaporated in vacuo at 50 °C bath temperature.
13C NMR (100 MHz, CDCl3): d = 19.5, 22.8, 24.3, 24.5, 24.6, 25.5,
25.7, 26.6, 27.2, 27.3, 65.8, 100.8, 164.2.
Colorless oil, aromatic smell; yield: 83%.
HRMS: m/z calcd for C13H23NO2: 225.1728; found: 225.1782.
IR (film): 2905, 2849, 1460, 1439, 1379, 1127, 1112, 1091, 1076,
1023, 982, 869 cm–1.
Anal. Calcd for C13H23NO2: C, 69.29; H, 10.29; N, 6.22. Found: C,
69.09; H, 9.93, N, 6.38.
1H NMR (400 MHz, CDCl3): d = 1.3–2.37 (m, 25 H), 3.48 (m, 1 H),
(1-Methyl-1-methylethoxy)benzene (13f)
3.97 (m, 1 H), 4.82 (t, 3J = 3.3 Hz, 1 H).
Yellowish crude product, purification: basic alumina column
(2.5 × 5 cm, n-pentane, ~8 mL then Et2O, ~15 mL); the solvent was
evaporated in vacuo at 50 °C (bath temperature).
Synthesis 2007, No. 5, 779–790 © Thieme Stuttgart · New York

FEATURE ARTICLE
Organocatalytic Tetrahydropyranylation
789
Colorless oil, aromatic smell; yield: 95%.
(5) Hoyer, S.; Laszlo, P.; Orlovic, M.; Polla, E. Synthesis 1986,
655.
(6) Hajipour, A. R.; Pourmousavi, S. A.; Ruoho, A. E. Synth.
Commun. 2005, 35, 2889.
(7) Shirini, F.; Zolfigolb, M. A.; Paktinat, M. Synthesis 2006,
4252.
(8) Bartoli, G.; Giovannini, R.; Giuliani, A.; Marcantoni, E.;
Massaccesi, M.; Merchiorre, P.; Paoletti, M.; Sambri, L.
Eur. J. Org. Chem. 2006, 1476.
IR (film): 2994, 2942, 2831, 1596, 1586, 1493, 1382, 1372, 1278,
1257, 1231, 1209, 1181, 1131, 1066, 1026, 946, 875, 803, 766, 730,
694, 630, 511 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.47 (s, 6 H), 3.40 (s, 3 H), 7.05
(t, 1 H), 7.10 (d, 2 H), 7.27 (t, 2 H).
13C NMR (100 MHz, CDCl3): d = 25.1, 49.2, 103.5, 115.3, 120.81,
129.1, 155.2.
(9) Kotke, M.; Schreiner, P. R. Tetrahedron 2006, 62, 434.
(10) (a) Magnusson, A.; Hult, K.; Holmquist, M. J. Am. Chem.
Soc. 2001, 123, 4354. (b) Tantillo, D. J.; Houk, K. N. J.
Comput. Chem. 2002, 23, 84.
HRMS: m/z calcd for C10H14O2: 166.0993; found: 166.0979.
Anal. Calcd for C10H14O2: C, 72.26; H, 8.49. Found: C, 72.49; H,
8.73.
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2-(1-Methoxy-1-methylethoxy)-2-methylpropane (13g)
Yellowish crude product, purification: basic alumina column
(2.5 × 3 cm, n-pentane, ~8 mL, Et2O, ~10 mL); the solvent was
evaporated in vacuo (~200 mbar) and without warming.
Colorless oil, aromatic smell; yield: 94%.
IR (film): 2974, 1712, 1653, 1472, 1365, 1282, 1260, 1209, 1180,
1080, 1056, 994, 914, 827, 749 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.26 (s, 9 H), 1.38 (s, 6 H), 3.19
(s, 3 H).
13C NMR (100 MHz, CDCl3): d = 27.7, 30.6, 44.9, 54.6, 89.4.
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HRMS: m/z calcd for C8H18O2: 146.1306; found: 146.1328.
Anal. Calcd for C8H18O2: C, 65.71; H, 12.41. Found: C, 65.82; H,
12.19.
Computations. Becke’s gradient-corrected exchange functional28 in
conjunction with the Lee-Yang-Parr non-local correlation function-
al (B3LYP)29 and a 6-31G(d,p) basis set as implemented in
Gaussian03 were utilized for all optimizations.30 The energies of the
optimized structures were further refined at the coupled cluster level
of theory including single, double, and perturbatively determined
triple excitations [CCSD(T)]31 utilizing a cc-pVDZ basis set,32 uti-
lizing the frozen core (no deleted virtuals) approach. All optimized
structures were characterized as stationary points by means of de-
termining harmonic vibrational frequencies (with zero imaginary
frequencies for minima and one imaginary frequency for transition
structures). The xyz coordinates, structural drawings, and absolute
energies as well as ZPVEs are available upon request from the au-
thors.
Acknowledgment
This work was supported by the Deutsche Forschungsgemeinschaft
(SPP 1179). We thank Boryslav Tkachenko, Torsten Weil, and
Hartmut Schwertfeger for samples of some ROH substrates.
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