2-Pyridyldimethylsilyl Group as a Removable Hydrophilic Group in Aqueous Organic Reactions: Formation of Molecular Aggregates and Dramatic Rate Enhancement in Diels-Alder Reactions

Article abstract of DOI:10.1002/1615-4169(200206)344:3/4<441::AID-ADSC441>3.0.CO;2-7

A novel methodology for aqueous organic reactions utilizing a 2-pyridyldimethylsilyl (2-PyMe₂Si) group as a removable hydrophilic group has been developed. It was found that 1,3-dienes bearing the 2-PyMe₂Si group form molecular aggregates in water when 1.0 equivalent of HCl was added, as evidenced by dynamic light-scattering experiments. The Diels-Alder reaction of 2-PyMe₂Si-substituted 1,3-dienes with various dienophiles took place in water at room temperature. The Diels-Alder reaction in organic solvents (Et₂O/toluene) under the same reaction temperature and time gave the cycloadduct in much lower yield, indicating the dramatic rate acceleration in water. The removal of the 2-PyMe₂Si group was accomplished by desilylation, oxidation, and electrophilic substitution.

Full text of DOI:10.1002/1615-4169(200206)344:3/4<441::AID-ADSC441>3.0.CO;2-7

FULL PAPERS
2-Pyridyldimethylsilyl Group as a Removable Hydrophilic Group
in Aqueous Organic Reactions: Formation of Molecular
Aggregates and Dramatic Rate Enhancement in Diels Alder
Reactions
Kenichiro Itami, Toshiki Nokami, Jun-ichi Yoshida*
Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Yoshida,
Kyoto 606-8501, Japan
Fax: ( ‡ 81)-75-753-5911, e-mail: yoshida@sbchem.kyoto-u.ac.jp
Received: November 20, 2001; Accepted December 12, 2001
Supportinginformation for this article is available on the WWW under http://asc.wiley-vch.de/home/
solvents (Et2O/toluene) under the same reaction
temperature and time gave the cycloadduct in much
lower yield, indicatingthe dramatic rate acceleration
in water. The removal of the 2-PyMe2Si group was
accomplished by desilylation, oxidation, and electro-
philic substitution.
Abstract: A novel methodology for aqueous organic
reactions utilizinga 2-pyridyldimethylsilyl (2-PyMe Si)
2
group as a removable hydrophilic group has been
developed. It was found that 1,3-dienes bearingthe
2-PyMe2Si group form molecular aggregates in water
when 1.0 equivalent of HCl was added, as evidenced
by dynamic light-scattering experiments. The Diels
Alder reaction of 2-PyMe2Si-substituted 1,3-dienes
with various dienophiles took place in water at room Keywords: Diels Alder reaction; removable hydro-
temperature. The Diels Alder reaction in organic philic group; water
Introduction
involved in their dissolution so as to minimize the
energetically unfavorable contact between water mol-
ecules and non-polar carbon chains. Indeed, dynamic
The continuingevolution of organic synthesis is heavily
based on the discovery of reactions and strategies that light-scattering experiments on an aqueous solution
allows the production of complex molecules in a safe, (containing1.0 equivalent of HCl) of dimethyl( n-oc-
cheap, and environmentally acceptable fashion. Al- tyl)(2-pyridyl)silane revealed the presence of molecular
though the use of water as a solvent is most desirable in aggregates with average hydrodynamic radii of 61 nm.
every sense, it is only recently that organic reactions in Moreover, we have already established that the 2-PyMe2
water have received much attention in synthetic organic Si group can be easily removed from the organic
chemistry.[1,2] This is mainly due to the solubility and molecule by several methods such as oxidation,[5c]
stability problems of the reaction components in water. protodesilylation,[5m] electrophilic substitution,[5h] and
Therefore, many of the reported aqueous organic cross-couplingreaction. [5i] These facts led us to explore
reactions have to rely on the use of organic co-solvents the concept of a removable hydrophilic group, which
at the expense of the many inherent advantages and enables the induction of molecular aggregations in
unique properties of water, such as hydrophobic effects, water and the removal from the molecules when needed.
hydrogen-bonding effects, and polarity effects. More-
We envisioned that, if the 2-PyMe2Si group works as a
over, in today×s economic and environmentally con- removable hydrophilic group and induces molecular
scious climate, new strategies for the organic reactions in aggregation in water, organic reactions in aqueous
water, the only true environmentally benign solvent, are molecular aggregates should be possible when the
highly called for.[3]
reaction site is located on a hydrophobic side chain of
Recently, we have developed the 2-pyridyldimethyl- the 2-PyMe2Si-substituted molecule (Figure 2).[6] The
silyl (2-PyMe2Si) group as a multifunctional phase tag advantage of using the 2-PyMe2Si group is apparent, as it
for solution-phase synthesis, which relies on the mis- can be readily removed from the molecule when
cibility of 2-PyMe2Si-substituted molecules in acidic required by utilizingthe several methods described
water (Figure 1).[4,5] Molecular aggregation seems to be above. Moreover, easy separation and purification
Adv. Synth. Catal. 2002, 344, No. 3+4
¹ VCH Verlagsgesellschaft mbH, 69451 Weinheim, Germany, 2002 1615-4150/02/3443+4-441 451 $ 17.50+.50/0
441

Kenichiro Itami et al.
FULL PAPERS
philic groups such as sodium salts of carboxylic or
phosphoric acids, and ammonium salts undergo the DA
reaction in water with enhanced rates and stereoselec-
tivities.[9] Several other related approaches are also
known.[11] In these aqueous DA reactions, the formation
of molecular aggregates such as micelles by the water-
soluble reactants has been suggested.[9a,9c,11] Rate accel-
eration by the formation of molecular aggregates stands
in sharp contrast to the Breslow×s observation that the
addition of an external ×salting in× agent such as
guanidinium chloride to dissolve the non-polar reactant
in water, most likely in a monomeric form, greatly
H+
Me2Si
N
Me2Si
N
H
molecule
molecule
organic phase
aqueous phase
X
removal
molecular aggregation
molecule
Figure 1.
processes (isolation of the product from the aqueous decreases the rate of the reaction.[8] The only disadvant-
phase) are expected by takingadvantage of the simple
age of using water-soluble reactants might be that it is
acid-base ™phase switching∫ technique (Figure 1).[4] not easy to remove or convert those hydrophilic groups
Recently, we reported the ™proof-of-principle∫ of our to other functional groups. This drawback profoundly
strategy of using removable hydrophilic group in diminishes the synthetic utility of the otherwise attrac-
aqueous organic reactions by utilizing an intermolecular tive methodology for organic reactions in water. There-
Diels Alder reaction as a showcase.[7] In this paper, we fore, we thought that the use of a removable hydrophilic
report on the full details of this study.
group should greatly expand the scope and limitation of
this extremely interesting strategy for aqueous organic
reactions.[15]
Background on Aqueous Diels Alder
Reactions
Results and Discussion
The Diels Alder reaction (DA reaction) is currently
one of the most active areas of research where the use of
water gives rise to exceptional rate enhancement and Synthesis of 2-PyMe2Si-Substituted 1,3-Dienes
appreciable high stereoselectivity.[8 12] In 1980, half a
century after the first discovery by Diels and Alder, The 2-PyMe2Si-substituted 1,3-dienes 1, 2, and 3 were
Breslow made the first observation of dramatic rate prepared usingour recently developed methods. Dienes
acceleration of the DA reaction in water.[8] This rate 1 and 2 were prepared in one-pot by the Peterson-type
enhancement is most likely attributed to the poor reactions of (2-PyMe2Si)2CHLi with acrolein and meth-
solubility of the reaction components in water, which acrolein, respectively.[5h] In both cases, complete stereo-
causes an increase of hydrophobic interactions.[13] En- selectivities (>99% E) were observed. Diene 3 was
forced hydrophobic interactions and hydrogen-bonding prepared by the reaction of 2-PyMe2SiCH2Li[5g] with
effects have also been suggested as explanations for the (E,E)-1-bromo-2,4-hexadiene.[16] For comparison, we
enhanced rate of the DA reaction in water.[10,14]
also prepared the PhMe2Si-substituted 1,3-diene 4
An alternative approach toward the aqueous DA (Figure 3).
reaction is the use of a water-soluble diene and/or
dienophile. Grieco reported that dienes bearinghydro-
Figure 2.
442
Adv. Synth. Catal. 2002, 344, 441 451

2-Pyridyldimethylsilyl Group as a Removable Hydrophilic Group in Aqueous Organic Reactions
FULL PAPERS
O
R
H2O
X
Si
Me2
N
Si
Me2
+
HCl (1.0 equiv.)
rt, 38 h
N
Si
Me2
1: X = N, R = H
2: X = N, R = CH3
4: X = C, R = H
3
O
1
(3.0 equiv.)
SiPy
O
O
O
Figure 3.
desilylation
oxidation
5 (quant.)
Solution Behavior of 2-PyMe2Si-Substituted 1,3-
Dienes in Water
O
PySi = 2-PyMe2Si
Scheme 1.
Before embarkingon the aqueous DA reactions using
1,3-dienes bearingthe 2-PyMe Si group (1 3), we
2
SiPy
O
SiPy
O
O
examined if they form unambiguous molecular aggre-
gates in water (containing 1.0 equivalent of HCl) as
expected since there are no precedents for such
surfactants. First, dynamic light-scattering experiments
on aqueous solutions (containing1.0 equivalent of HCl)
of dienes 1, 2, and 3 were conducted at the concentration
of 0.05 M. These experiments undoubtedly revealed the
presence of molecular aggregates with average hydro-
dynamic radii of 197, 138, and 307 nm, respectively.
However, the determination of the exact structure of the
molecular aggregates must await further investigations.
The large radii observed can probably be attributed to
non-ordered structures of the molecular aggregates in
aqueous solution. Short hydrophobic carbon chains
desilylation
p-BQ
O
+
O
O
O
-H+
oxidation
5
p-BQ
H
O
Scheme 2.
(four and seven) may be the reason for the non-ordered none and a subsequent desilylation and deprotonation
structures of the molecular aggregates. Nevertheless, sequence (Scheme 2).[18]
the detection of molecular aggregates led us to explore
Several control experiments were conducted to assess
the aqueous reactions of 1 3, irrespective of the the effects of the 2-PyMe2Si group. When the DA
structures of their molecular aggregations.
reaction of 1 and p-benzoquinone was performed at
elevated temperature (50 8C), the reaction rate did
increase as expected. However, presumably because of
the thermal instability of 1 in acidic aqueous media, the
product 5 was obtained in lower yield (85% after 22 h).
Therefore, all the control experiments were performed
Aqueous Diels Alder Reaction of 1 with p-
Benzoquinone
Havingsubstantiated the potential of the 2-PyMe Si at room temperature (Table 1). Decreasingthe amount
2
group as a hydrophilic group, we investigated the of HCl added slowed down the reaction enormously and
intermolecular DA reactions. Throughout this work, only a trace amount of 5 was formed with starting
the aqueous DA reactions were conducted at the material 1 recovered (entries 2 and 3). On the other
concentration of 0.5 M of diene, which is greatly above hand, the addition of 2.0 equivalents of HCl did not
the concentration we detected in molecular aggregates affect the rate and yield. We believe that at least
by dynamic light-scattering experiments. The DA reac- 1.0 equivalent of HCl is required for the diene 1 to form
tion of 1 and p-benzoquinone occurred at room temper- molecular aggregates and that the reaction probably
ature in water (containing1.0 equivalent of HCl) with
occurs in the interior of aggregates with enhanced
simultaneous desilylation and oxidation to afford naph- hydrophobic interactions,[13] and not in the aqueous bulk
thoquinone 5 quantitatively (Scheme 1). In this case, an phase.[8] The use of H2SO4 also gave rise to a rate
additional chemical operation was unnecessary for the enhancement, but not as dramatic as that with HCl
removal of the 2-PyMe2Si group. Interestingly, we found (entry 4). In the reaction, the added HCl should play a
that this desilylation is not the ordinary protodesilyla- major role as water-solubilizingagent for 2-PyMe 2Si-
tion under HCl/H2O conditions.[17] Since there was no substituted diene by complexingwith pyridyl group, but
deuterium incorporation under DCl/D2O conditions, not as dienophile activator. In accord with this assump-
desilylation most likely occurred by the electron transfer tion, the reaction in Et2O/toluene with HCl gave 5 in
from an allylic silane intermediate to the p-benzoqui- 22% yield after 38 h (entry 5). The reaction in Et2O/
Adv. Synth. Catal. 2002, 344, 441 451
443

Kenichiro Itami et al.
Yield [%][b]
FULL PAPERS
Table 1. Aqueous Diels Alder reactions under various conditions.[a]
Entry
Diene
Solvent
Additive [equiv.]
Time [h]
1
2
3
4
5
6
7
8
1
1
1
1
1
1
4
H2O
H2O
H2O
H2O
Et2O/toluene
Et2O/toluene
H2O
HCl (1.0)[c]
HCl (0.2)
ÀÀ
38
47
89
38
38
38
38
38
quant.
2
4
73
22
6
H2SO4 (1.0)
HCl (1.0)
À
HCl (1.0)
7 (1.0) ‡ HCl (1.0)
0
0
1,3-pentadiene
H2O
[a]
All reactions were performed at room temperature using1,3-diene (1.0 equivalent, 0.5 M concentration) and p-
benzoquinone (3.0 equivalents).
Isolated yields.
The addition of 2.0 equivalents of HCl did not affect the rate and yield.
[b]
[c]
toluene without HCl also resulted in much lower yield of usual endo selectivity. The relative stereochemistry
the product (6%) with 88% recovery of diene 1 was unambiguously confirmed by X-ray crystal struc-
(entry 6), indicatingthe huge rate acceleration in water.
Fleminghas reported that the related DA reaction of 1-
ture analysis.
The aqueous DA reaction of 3 with p-benzoquinone
trimethylsilyl-1,3-butadiene with substituted benzoqui- was complete within 1 h to give the cycloadduct 10 (82%
none requires extremely harsh conditions (32% yield yield) after silica gel chromatography (entry 3). In this
after 24 h at 140 8C).[19] The most strikingcontrast was
case, a catalytic amount of HCl (0.2 equivalents) was
seen in the reaction with the PhMe2Si-substituted 1,3- enough to promote the reaction. Interestingly, the
diene 4 giving no cycloadduct at all in water (entry 7). formation of molecular aggregates (average hydrody-
Next, we examined the aqueous reaction of 1,3- namic radii: 65 nm) was observed even at the end of the
pentadiene with p-benzoquinone in the presence of reaction. Moreover, the rate acceleration in water was
protonated dimethyl(n-octyl)(2-pyridyl)silane (7) as a again observed. Changing the solvent to Et2O/toluene
surfactant. The hard-to-dissolve 1,3-pentadiene dis- (containing1.0 equivalent of HCl) resulted in 12% yield
solved in water when 7 and HCl were added. Thereafter, of 10 under otherwise identical conditions.
p-benzoquinone was added to the solution. However, in
The formation of 10 may be worth a comment. Since
sharp contrast with the reaction of 1, no cycloadduct was we observed only the non-oxidized cycloadduct in the
observed at room temperature (entry 8). These results crude reaction mixture, the oxidation presumably took
are in line with the previous reports by other groups that place on silica gel with p-benzoquinone which was
the rate accelerations induced by external surfactants employed in an excess amount (3.0 equivalents). In line
are generally modest and even retardations are observ- with this assumption, the oxidized product 10 was not
ed.[8b,10g,10j,20] It is apparent that the use of a reacting formed when the excess amount (2.0 equivalents) of 3
surfactanthasanadvantageintermsofreactivityover the was employed (entry 4). In this case, initial adduct was
combined use of an external surfactant.
isomerized to hydroquinone 11 duringthe silica gel
chromatography.
The diene 3 also underwent aqueous DA reactions
with naphthoquinone and N-ethylmaleimide giving the
cycloadducts 12 and 13 in 90 and 88% isolated yield,
respectively (entries 5 and 6). In these cases, the initial
Aqueous Diels Alder Reactions of 2-PyMe2Si-
Substituted 1,3-Dienes
Havingestablished the viability of aqueous DA reac-
adducts were not oxidized. Again, the reaction proved
1
tions, other 2-PyMe2Si-substituted 1,3-dienes and dien- to be endo selective. The H NMR analysis and NOE
ophiles were subjected to the aqueous DA reaction experiments supported the proposed relative stereo-
(Table 2). The diene 2 also underwent DA reaction with chemistry.
p-benzoquinone to afford the substituted naphthoqui-
none 8 in quantitative yield (entry 1). The DA reaction
of 1 with N-ethylmaleimide proceeded smoothly giving Removal of 2-PyMe2Si Group
the cycloadduct 9 in 91% yield after 1 h. Unlike the
reaction with p-benzoquinone, the initial adduct did not In our strategy, the 2-PyMe2Si group must be removed
undergo the subsequent desilylation/oxidation se- after the aqueous reaction. First, we examined the direct
quence. Moreover, the reaction proceeded in a virtually removal of the 2-PyMe2Si group from the DA cyclo-
completely diastereoselective fashion, followingthe
adducts. For example, we subjected 13 to the typical 2-
444
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2-Pyridyldimethylsilyl Group as a Removable Hydrophilic Group in Aqueous Organic Reactions
FULL PAPERS
Table 2. Aqueous Diels Alder reactions of 2-PyMe2Si-substituted 1,3-dienes.
Entry
Diene
Dienophile
Product
Time [h]
Yield [%][c]
quant.
O
O
O
Me
1[a]
2
8
9
38
O
O
H
H
O
NEt
O
2[b]
1
3
1
91
NEt
O
N
N
N
N
SiMe2
Me
O
O
3[a]
10
11
12
13
1
1
8
82 (81)[d]
Me2
Si
O
O
O
Me
Me
Me
OH
4[b]
3
3
3
91
90
88
Me2
Si
OH
O
O
O
H
H
5[b]
Me2
Si
O
O
O
H
H
O
NEt
O
6[b]
0.5
NEt
O
Me2
Si
N
[a]
The reactions were performed at room temperature using1,3-diene (1.0 equivalent, 0.5 M concentration), dienophile
(3.0 equivalents), and HCl (1.0 equivalent) in water.
The reactions were performed at room temperature using1,3-diene (2.0 equivalents, 0.5 M concentration), dienophile
(1.0 equivalent), and HCl (2.0 equivalents) in water.
Isolated yields.
0.2 equivalents of HCl were employed.
[b]
[c]
[d]
PyMe2Si group oxidation conditions (H2O2/KF/KHCO3 the slightly basic nature of the reaction media, but not
in MeOH/THF at 40 8C);[5c,21] this produced the corre- via the retro-DA reaction. In practice, the cycloadduct
spondingalcohol 14, together with the exo isomer 15 13 did not undergo either a retro-DA reaction or
(14:15 ˆ 69:31; Scheme 3). Under the prolonged reac- isomerization under thermal conditions (40 8C in
tion time, the selective production of 15 is possible THF/MeOH).
(14:15 ˆ 13:87). We assume that the isomerization to the
By takingadvantage of the allylic silane nature of the
exo isomer most likely occurred via enolization under cycloadduct 9, electrophilic substitution can also be
Adv. Synth. Catal. 2002, 344, 441 451
445

Kenichiro Itami et al.
FULL PAPERS
Me
O
O
Me
OH
Me
Me
O
O
H
H
H
H
NaBH4
CeCl3·7H2O
30% H2O2
KF, KHCO3
NEt
O
NEt
O
13
+
MeOH
rt
MeOH, THF
40 oC
Me2
Si
Me2
Si
N
N
OH
HO
HO
14
15
10
11 (73%)
8 h: 14 (55%), 15 (25%)
36 h: 14 (9%), 15 (59%)
BnBr
Me
OBn
NaOH
Bu4NBr
Scheme 3.
CH2Cl2, H2O
rt
O
Me2
Si
O
O
H
H
CH3COCl (5 equiv.)
AlCl3 (5 equiv.)
N
OBn
NEt
O
NEt
O
17 (59%; 78% NMR)
CH2Cl2
–78 oC to rt
Me
OBn
H
H
N
SiMe2
30% H2O2
KF, KHCO3
16 (55%)
9
MeOH, THF
40 o
C
Scheme 4.
HO
OBn
18 (89%)
Scheme 5.
utilized as a protocol for the removal of the 2-PyMe2Si
group. For example, treatment of 9 with CH3COCl in the
presence of AlCl3 afforded the methyl ketone 16 in 55%
yield (Scheme 4). The reaction proved to be highly
Conclusions
stereoselective followingthe usual anti attack of the A novel methodology for aqueous organic reactions
electrophile.[22] The relative stereochemistry was con- utilizinga removable hydrophilic rgoup has been
firmed by the 1H NMR analysis and NOE experiments. developed. The 2-PyMe2Si group was successfully
Quite interestingly, however, the allylic silane 9 exhibits exploited as such a removable hydrophilic group. It
remarkably high stability toward protic acids. The was found that organic compounds having a 2-PyMe2Si
treatment of 9 with TsOH (3 equivalents) under reflux group do form molecular aggregates in water when
in benzene or with HCl (10 equivalents) under reflux in 1.0 equivalent of HCl is added, as evidenced by dynamic
water did not cause any protodesilylation (9 was light-scattering experiments. Dramatic rate accelera-
recovered in over 80% yield in both cases). These tions were observed in the aqueous DA reactions of 2-
results were in sharp contrast with those of Fleming, PyMe2Si-substituted 1,3-dienes with dienophiles. The
where the similar allylic silane underwent facile proto- removal of the 2-PyMe2Si group from the products was
desilylation with TsOH under reflux in benzene.[19]
easily accomplished by desilylation, H2O2 oxidation, or
Since the 2-PyMe2Si group is quite stable under electrophilic substitution. Importantly, the strategy
various reaction conditions,[5] the intervention of several described herein should not be limited to the aqueous
synthetic manipulations between the aqueous reaction Diels Alder reaction and can in principle be applied to
and the final removal step is also feasible (Scheme 5). the other aqueous organic reactions as well. The
For example, the reduction of 10 in NaBH4/CeCl3 system extensions to the other aqueous organic reactions as
afforded the substituted hydroquinone 11 in 73% yield. well as the development of other removable hydrophilic
The protection of the phenolic hydroxy groups with groups are currently underway.
benzyl groups afforded 17 in 59% yield (78% by NMR
spectroscopy). Importantly, the 2-PyMe2Si group was
unaffected throughout these transformations, which
indicates the reasonable chemical stability of this group.
Experimental Section
Finally, the oxidation of 17 with H2O2 afforded 18 in 89%
À
isolated yield without affectingthe C C double bond
and benzyl protectingrgoup or erodingthe stereo-
chemistry at the allylic carbon atoms. This specific 2-
PyMe2Si group removing protocol substantially aug-
ments the value of our methodology.
General Methods
NMR spectra were recorded on Varian GEMINI-2000 (1H
300 MHz, 13C 75 MHz), JEOL A-400 (1H 400 MHz, 13C
100 MHz), and JEOL A-500 (1H 500 MHz, 13C 125 MHz)
spectrometers in CDCl3 with internal standards (7.26 ppm 1H,
77.0 ppm 13C). Mass spectra (EI) were recorded on a JMS-
SX102A spectrometer. Infrared spectra were recorded on a
Shimadzu FTIR-8100 spectrophotometer. Gel permeation
446
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2-Pyridyldimethylsilyl Group as a Removable Hydrophilic Group in Aqueous Organic Reactions
FULL PAPERS
chromatography was carried out with Japan Analytical Indus-
try LC-918. Unless otherwise noted, all materials were
obtained from commercial suppliers and used without further
purification. 3-Phenyldimethylsilylpropenal,[23] 2-PyMe2Si-
mixture at room temperature for 38 h, NaHCO3 was added to
the mixture until the aqueous phase became neutral. Extrac-
tive work-up and subsequent silica gel chromatography
afforded naphthoquinone; yield: 79 mg(quantitative).
substituted 1,3-dienes 1 and 2,[5h] (E,E)-1-bromo-2,4-hexa-
diene,[16] and dimethyl(n-octyl)(2-pyridyl)silane (7)
were
[5c]
prepared accordingto the published procedures.
Cycloadduct 9
1H NMR (300 MHz): d ˆ 0.47 (s, 3H), 0.56 (s, 3H), 1.06 (t, J ˆ
7.2 Hz, 3H), 2.12 2.22 (m, 2H), 2.63 (ddd, J ˆ 15.0, 6.0, 1.8 Hz,
1H), 3.09 (ddd, J ˆ 8.7, 7.8, 1.8 Hz, 1H), 3.27 (dd, J ˆ 8.7, 6.0Hz,
1H), 3.44 (q, J ˆ 7.2 Hz, 2H), 5.86 5.99 (m, 2H), 7.21 7.25 (m,
1H), 7.61 7.66 (m, 2H), 8.76 (dm, J ˆ 4.8 Hz, 1H); 13C NMR
(75 MHz): d ˆÀ 3.9, À 3.4, 13.3, 23.1, 24.4, 33.9, 41.0, 41.7,
123.0, 129.3, 129.7, 129.9, 134.4, 150.1, 167.4, 179.6, 180.2; IR
(KBr): n ˆ 1692, 1410, 1347, 1246, 1229 cmÀ1. HRMS: m/z
calcd. for C17H22N2O2Si: 314.1451; found: 314.1451.
2-PyMe2Si-Substituted Diene 3
To a solution of 2-pyridyltrimethylsilane (201 mg, 1.33 mmol)
in dry Et2O (2 mL) was added dropwise a solution of t-BuLi
(1.58 mmol, 1.37 M solution in pentane) at À 78 8C. The
mixture was stirred for additional 30 min. To the resultant
solution of [(2-pyridyldimethylsilyl)methyl]lithium was ad-
ded (E,E)-1-bromo-hexa-2,4-diene (256 mg, 1.59 mmol) at
À 78 8C and the mixture was stirred for 1 h. After stirringthe
mixture at room temperature for 11 h, the reaction was
quenched with water. Extractive work-up and subsequent
silica gel chromatography (hexane/EtOAc ˆ 10/1 as eluents)
afforded 3 as a colorless oil; yield: 147 mg(48%); 1H NMR
(300 MHz): d ˆ 0.32 (s, 6H), 0.90 0.96 (m, 2H), 1.70 (d, J ˆ
6.3 Hz, 3H), 2.06 2.14 (m, 2H), 5.47 5.60 (m, 2H), 5.90 6.02
(m, 2H), 7.18 (ddd, J ˆ 7.5, 4.5, 1.5 Hz, 1H), 7.47 (dt, J ˆ 7.5,
1.5 Hz, 1H), 7.57 (td, J ˆ 7.5, 1.5 Hz, 1H), 8.77 (dt, J ˆ 4.5,
1.5 Hz, 1H); 13C NMR (125 MHz): d ˆÀ 3.6, 14.5, 18.0, 26.7,
122.7, 126.6, 129.06, 120.07, 131.6, 133.9, 134.3, 150.1, 167.5. IR
(neat): n ˆ 3015, 2957, 1576, 1418, 1248 cmÀ1; anal. calcd. for
C14H21NSi: C 72.66, H 9.15, N 6.05; found: C 72.68, H 9.25, N
6.00; HRMS: m/z calcd. for C14H21NSi: 231.1443; found:
231.1444.
The relative stereochemistry of 9 was determined by an X-
ray crystal structure analysis (Figure 4). Crystal data: C17H22N2
O2Si, M ˆ 314.46, orthorhombic, space group Pbca (No. 61),
a ˆ 8.4169(3) ä, b ˆ 18.1734(5) ä, c ˆ 22.1037(8) ä, Vˆ
3381.1(2) ä3, Z ˆ 8, Dc ˆ 1.235 g/cm3. Intensity data were
measured on a Rigaku RAXIS imaging plate area detector
with graphite-monochromated Mo-Ka radiation (l ˆ
0.71069 ä). The data were collected at 23 Æ 1 8C to a maximum
2q value of 55.0 . Of the 28282 reflections that were collected,
4311 were unique (Rint ˆ 0.038); equivalent reflections were
merged. The structure was solved by direct methods and
expanded usingFourier techniques. The non-hydrogen atoms
were refined anisotropically. Hydrogen atoms were refined
isotropically. The final cycle of full-matrix least-squares refine-
ment on F was based on 2614 observed reflections (I > 3.00s
(I)) and 222 variable parameters and converged (largest
parameter shift was 0.00 times its esd) with unweighted and
weighted agreement factors of R ˆ 0.056 (Rw ˆ 0.059). The
standard deviation of an observation of unit weight was 1.74.
All calculations were performed usingthe CrystalStructure
crystallographic software package. Tables of atomic coordi-
nates, anisotropic displacement parameters, bond lengths,
bond angles, and torsion angles are listed in the Supporting
Information. Crystallographic data (excluding structure fac-
tors) for the structure reported in this paper have been
deposited withthe CambridgeCrystallographic Data Centre as
supplementary publication no. CCDC-176393. Copies of the
data can be obtained free of charge on application to CCDC, 12
Union Road, Cambridge CB21EZ, UK [fax.: (‡44)1223-336-
033; e-mail: deposit@ccdc.cam.ac.uk].
PhMe2Si-Substituted Diene 4
To a suspension of methyltriphenylphosphonium bromide
(1.43 g, 4.0 mmol) in Et2O (4 mL) was added BuLi (4.0 mmol,
1.50 M in hexane) at room temperature. After stirringthe
mixture for 1 h, 3-phenyldimethylsilylpropenal (745 mg,
4.0 mmol) was added and the mixture was refluxed for 15 h.
Filtration, extractive work-up, and subsequent silica gel
chromatography (hexane as eluent) afforded 4 as a colorless
1
oil; yield: 319 mg(42%); H NMR (300 MHz): d ˆ 0.37 (s, 6H),
5.15 (dd, J ˆ 9.9, 1.8 Hz, 1H), 5.25 (dd, J ˆ 16.8, 1.8 Hz, 1H),
6.00 (dd, J ˆ 18.0, 0.6 Hz, 1H), 6.39 (dtd, J ˆ 16.8, 9.9, 0.6 Hz,
1H), 6.59 (dd, J ˆ 18.0, 9.9 Hz, 1H), 7.34 7.39 (m, 3H), 7.51
7.55 (m, 2H); 13C NMR (75 MHz): d ˆÀ 2.8, 118.3, 127.9, 129.1,
132.4, 133.9, 138.6, 139.8, 146.3. IR (neat): n ˆ 2954, 1572, 1428,
1248 cmÀ1; anal. calcd. for C12H16Si: C 76.53, H 8.56; found: C
76.34, H 8.70; HRMS: m/z calcd. for C12H16Si: 188.1021; found:
188.1024.
Typical Procedure for the Diels Alder Reaction of 2-
PyMe2Si-Substituted 1,3-Diene with Dienophile
(Scheme 1)
To a solution of HCl (0.5 mmol) in water (1 mL) was added 1
(95 mg, 0.5 mmol) and the mixture was stirred at room
temperature for 10 min. To this mixture was added p-benzo-
quinone (162 mg, 1.5 mmol) in one portion. After stirring the
Figure 4.
Adv. Synth. Catal. 2002, 344, 441 451
447

Kenichiro Itami et al.
FULL PAPERS
Cycloadduct 10
Coupling Constant
8.4 Hz
NOE
1H NMR (400 MHz): d ˆ 0.26 (s, 3H), 0.28 (s, 3H), 0.83 0.89
(m, 2H), 1.14 (d, J ˆ 7.0 Hz, 3H), 1.35 1.46 (m, 1H), 1.66 1.77
(m, 1H), 3.31 3.40 (m, 2H), 5.76 5.83 (m, 2H), 6.64 (d, J ˆ
10.1 Hz, 1H), 6.67 (d, J ˆ 10.1 Hz, 1H), 7.15 (ddd, J ˆ 7.5, 5.1,
1.8 Hz, 1H), 7.43 (dt, J ˆ 7.5, 1.2 Hz, 1H), 7.54 (td, J ˆ 7.5,
1.8 Hz, 1H), 8.71 (ddd, J ˆ 5.1, 1.8, 1.2 Hz, 1H); 13C NMR
(100 MHz): d ˆÀ 3.9, À 3.8, 11.6, 22.5, 29.7, 30.8, 36.6, 122.8,
126.8, 129.1, 130.0, 133.9, 136.36, 136.37, 143.2, 144.8, 150.1,
167.1, 186.8, 186.9; IR (neat): n ˆ 2961, 1651, 1453, 1294, 1248,
841, 750 cmÀ1; HRMS: m/z calcd. for C20H23NO2Si: 337.1498;
found: 337.1512.
12%
12%
6.0 Hz
6.9 Hz
7% 11% 12%
H
H
H
H
H
H
H
H
6% 10% 9%
Me
O
Me
PySi
PySi
O
O
O
N
N
Et
Et
Figure 6.
The relative stereochemistry of 13 was determined on the
basis of the couplingconstants and the NOE experiments
described below (Figure 6).
Cycloadduct 12
1H NMR (500 MHz): d ˆ 0.30 (s, 3H), 0.32 (s, 3H), 0.70 (d, J ˆ
7.6 Hz, 3H), 0.76 (td, J ˆ 12.8, 4.6 Hz, 1H), 0.96 (td, J ˆ 12.9,
4.6 Hz, 1H), 1.74 1.82 (m, 1H), 1.88 1.95 (m, 1H), 2.25 2.30
(m, 1H), 2.70 2.75 (m, 1H), 3.38 (dd, J ˆ 7.4, 5.2 Hz, 1H), 3.50
(dd, J ˆ 5.2, 5.2 Hz, 1H), 5.57 (dt, J ˆ 10.4, 3.4 Hz, 1H), 5.74 (d,
J ˆ 10.4 Hz, 1H), 7.22 7.24 (m, 1H), 7.49 (d, J ˆ 7.4 Hz, 1H),
7.62 (t, J ˆ 7.4 Hz, 1H), 7.68 7.72 (m, 2H), 7.87 7.90 (m, 1H),
Procedure for the Direct Oxidative Removal of 2-
PyMe2Si Group from the Diels Alder Cycloadduct
To amixture of KF (24.6 mg, 0.41 mmol) and KHCO3 (41.3 mg,
0.41 mmol) in MeOH (1 mL) and THF (1 mL) were added 13
(71.6 mg, 0.20 mmol) and then 30% aqueous H2O2 (0.68 g,
6.00 mmol). The mixture was stirred at 40 8C for 8 h. After
beingcooled at room temperature, the reaction mixture was
treated with water (3 mL). The mixture was extracted with
EtOAc and the combined organic phase was washed succes-
8.03
8.06 (m, 1H), 8.74 (d, J ˆ 4.9 Hz, 1H); 13C NMR
(75 MHz): d ˆÀ 3.9, À 3.8, 12.9, 18.4, 26.4, 32.0, 40.1, 48.4,
52.4, 122.7, 125.8, 126.4, 128.8, 129.0, 129.9, 133.5, 134.0, 134.1,
135.3, 137.6, 149.9, 167.2, 198.5, 199.2; IR (KBr): n ˆ 1690,
1248 cmÀ1; HRMS: m/z calcd. for C24H27NO2Si: 389.1811;
found: 389.1809.
The relative stereochemistry of 12 was determined on the
basis of the couplingconstants and the NOE experiments
described below (Figure 5).
sively with 15% aqueous Na2S2O3 (3 mL). Dryingover MgSO
and subsequent gel permeation chromatography afforded 14
4
(yield: 26.4 mg, 55%) and 15 (yield: 11.8 mg, 25%).
1
Alcohol 14: H NMR (300 MHz): d ˆ 1.07 (t, J ˆ 7.2 Hz,
3H), 1.46 (d, J ˆ 7.5 Hz, 3H), 1.83 (s, 1H), 2.00 2.10 (m, 1H),
2.20 2.32 (m, 1H), 2.43 2.49 (m, 2H), 2.99 (dd, J ˆ 8.4, 6.6 Hz,
1H), 3.27 (dd, J ˆ 8.4, 6.6 Hz, 1H), 3.45 (q, J ˆ 7.2 Hz, 2H), 3.75
3.83 (m, 1H), 3.91 3.98 (m, 1H), 5.61 5.70 (m, 2H);
13C NMR (125 MHz): d ˆ 13.1, 16.6, 31.1, 33.4, 33.6, 33.8, 43.7,
45.3, 61.4, 132.4, 134.6, 177.3, 178.2. IR (neat): n ˆ 3440, 1684,
1406, 1352, 1231 cmÀ1. HRMS: m/z calcd. for C13H19NO3:
237.1365; found: 237.1368.
Cycloadduct 13
1H NMR (300 MHz): d ˆ 0.36 (s, 6H), 1.03 (tm, J ˆ 7.2 Hz, 5H),
1.40 (d, J ˆ 7.2 Hz, 3H), 1.77 1.89 (m, 1H), 1.93 2.06 (m, 1H),
2.11 2.14 (m, 1H), 2.31 2.36 (m, 1H), 2.89 (dd, J ˆ 8.4, 6.9 Hz,
1H), 3.08 (dd, J ˆ 8.4, 6.0 Hz, 1H), 3.41 (q, J ˆ 7.2 Hz, 2H), 5.60
(dt, J ˆ 9.0, 2.7 Hz, 1H), 5.67 (dt, J ˆ 9.0, 2.7 Hz, 1H), 7.19 (dd,
J ˆ 4.8, 2.4 Hz, 1H), 7.53 (dm, J ˆ 7.2 Hz, 1H), 7.59 (tm, J ˆ
7.2 Hz, 1H), 8.76 (dm, J ˆ 4.8 Hz, 1H); 13C NMR (125 MHz):
d ˆÀ 3.8, À 3.6, 13.0, 13.4, 16.6, 25.1, 31.1, 33.2, 39.8, 43.4, 45.3,
122.7, 129.1, 133.0, 133.9, 134.0, 150.0, 167.4, 177.3 (two
carbons); IR (neat): n ˆ 1698, 1404, 1352, 1246, 1231 cmÀ1;
HRMS: m/z calcd. for C20H28N2O2Si: 356.1919; found:
356.1920.
The relative stereochemistry of 14 was determined on the
basis of the couplingconstants and the NOE experiments
described below (Figure 7).
1
Alcohol 15: H NMR (500 MHz): d ˆ 1.16 (t, J ˆ 7.3 Hz,
3H), 1.34 (d, J ˆ 7.1 Hz, 3H), 1.83 1.87 (m, 1H), 1.88 1.96 (m,
1H), 2.19 (tm, J ˆ 7.1 Hz, 2H), 2.45 2.48 (m, 2H), 2.79 (dd, J ˆ
8.8, 6.4 Hz, 1H), 3.55 (q, J ˆ 7.1 Hz, 2H), 3.79 3.85 (m, 2H),
5.66 5.71 (m, 2H); 13C NMR (125 MHz): d ˆ 13.0, 20.9, 30.2,
30.7, 33.6, 39.0, 43.7, 45.9, 59.9, 130.9, 132.9, 178.7, 180.4; IR
(neat): n ˆ 3447, 1698, 1404, 1350, 1227 cmÀ1; HRMS: m/z
calcd. for C13H19NO3: 237.1365; found: 237.1366.
NOE
3% 2%
7%
6%
4%
2%
4%
H
H
H
H
31%
Me
HO
O
O
N
Et
Figure 5.
Figure 7.
448
Adv. Synth. Catal. 2002, 344, 441 451

2-Pyridyldimethylsilyl Group as a Removable Hydrophilic Group in Aqueous Organic Reactions
FULL PAPERS
The relative stereochemistry of 15 was determined on the
basis of the couplingconstants and the NOE experiments
described below (Figure 8).
1.2 Hz, 1H), 7.64 (td, J ˆ 7.5, 1.5 Hz, 1H), 8.87 (ddd, J ˆ 4.8, 1.5,
1.2 Hz, 1H); 13C NMR (75 MHz): d ˆÀ 3.5, À 2.9, 12.2, 22.7,
30.1, 32.4, 36.7, 113.2, 113.8, 123.3, 127.8, 128.2, 128.3, 129.7,
131.6, 134.9, 146.5, 147.9, 149.8, 167.3; IR (neat): n ˆ 2442, 1487,
1250 cmÀ1. HRMS: m/z calcd. for C20H25NO2Si: 339.1655;
found: 339.1671.
NOE
Et
N
Protection of 11: To a solution of 11 (87 mg, 0.25 mmol) in
CH2Cl2 (0.5 mL) was added 1 N aqueous solution of NaOH
(0.5 mL, 0.5 mmol). To this solution were added tetrabutylam-
moniumbromide(8.9 mg, 0.028 mmol) in CH2Cl2 (0.5 mL) and
H2O (0.5 mL), and then benzyl bromide (219 mg, 1.28 mmol).
The reaction mixture was further stirred at room temperature
for 40 min. Extractive work-up and subsequent silica gel
chromatography (hexane/EtOAc ˆ 10/1 as eluents) afforded
17; yield: 78 mg(59%); 1H NMR (300 MHz): d ˆ 0.26 (s, 6H),
0.86 1.08 (m, 2H), 1.30 (d, J ˆ 6.9 Hz, 3H), 1.41 1.54 (m, 1H),
1.97 2.08 (m, 1H), 3.62 3.75 (m, 2H), 4.99 (s, 2H), 5.01 (d, J ˆ
12.0 Hz, 1H), 5.06 (d, J ˆ 12.0 Hz, 1H), 5.96 (dd, J ˆ 9.9, 4.5 Hz,
1H), 6.03 (dd, J ˆ 9.9, 4.8 Hz, 1H), 6.70 (s, 2H), 7.15 (ddd, J ˆ
7.5, 4.8, 1.5 Hz, 1H), 7.29 7.46 (m, 11H), 7.50 (td, J ˆ 7.5,
1.5 Hz, 1H), 8.74 (dt, J ˆ 4.8, 1.2 Hz, 1H); 13C NMR
(100 MHz): d ˆÀ 3.9, À 3.7, 12.4, 23.0, 30.2, 32.2, 37.6, 70.0,
70.1, 108.75, 108.77, 122.6, 126.9, 127.0, 127.55, 127.59, 128.2,
128.45, 128.46, 129.1, 130.1, 131.2, 131.5, 134.0, 137.78, 137.79,
149.9, 150.00, 150.04, 167.6; IR (neat): n ˆ 2957, 1599, 1480,
1453, 1256, 1107 cmÀ1; HRMS (EI): m/z calcd. for C34H37NO2
Si: 519.2594; found: 519.2588.
H2O2 Oxidation of 18: To a mixture of KF (15 mg,
0.26 mmol) and KHCO3 (27 mg, 0.27 mmol) in MeOH
(1 mL) and THF (1 mL) were added 17 (71 mg, 0.14 mmol)
and then 30% aqueous H2O2 (0.47 g, 4.12 mmol). The mixture
was stirred at 40 8C for 14 h. After beingcooled at room
temperature, the reaction mixture was treated with water
(2 mL). The mixture was extracted with EtOAc (5 Â 5 mL),
and the combined organic phase was washed successively with
15% aqueous Na2S2O3 (5 mL). Dryingover Na 2SO4 and
removal of the solvents under reduced pressure afforded the
crude product. Silica gel chromatography (hexane/EtOAc ˆ 5/
1 as eluents) of the crude product afforded 18; yield: 49 mg
(89%); 1H NMR (300 MHz): d ˆ 1.35 (d, J ˆ 6.6 Hz, 3H), 1.50
1.80 (br, 1 H) 1.85 1.93 (m, 2H), 3.66 (t, J ˆ 6.0 Hz, 2H), 3.72
3.86 (m, 2H), 4.98 5.11 (m, 4H), 5.96 6.04 (m, 2H), 6.75 (d,
J ˆ 9.0 Hz, 1H), 6.79 (d, J ˆ 9.0 Hz, 1H), 7.33 7.47 (m, 10 H);
13C NMR (75 MHz): d ˆ 22.6, 30.2, 31.4, 41.7, 60.9, 70.1, 70.9,
109.0, 109.2, 127.0, 127.5, 127.7, 128.1, 128.5, 128.6, 128.7, 129.4,
131.4, 131.6, 137.1, 137.6, 150.0, 150.4; IR (neat): n ˆ 3029, 1599,
1482, 1453, 1258, 793, 737, 696 cmÀ1. HRMS: m/z calcd. for C27
H28O3: 400.2038; found: 400.2037.
O
O
H
H
11%
HO
C
CH2
5%
Me
8%
H2
3%
10%
H
H
Figure 8.
Procedure for the Acylation of Allylic Silane 9
To a mixture of CH3COCl (40.8 mg, 0.52 mmol) and AlCl3
(68.2 mg, 0.51 mmol) in CH2Cl2 (0.5 mL) was added slowly
a solution of 9 (32.0 mg, 0.10 mmol) in CH2Cl2 (1.5 mL) at
À 78 8C. After stirringthe mixture for 24 h at room temper-
ature, the reaction mixture was washed with saturated aqueous
NaHCO3. Dryingover Na 2SO4 and subsequent gel permeation
chromatography afforded 16 (319 mg, 42%) as a colorless oil;
yield: 319 mg(42%); 1H NMR (500 MHz): d ˆ 1.14 (t, J ˆ
7.3 Hz, 3H), 1.98 (ddd, J ˆ 13.7, 8.6, 5.8 Hz, 1H), 2.18 2.25
(m, 1H), 2.23 (s, 3H), 3.05 3.09 (m, 1H), 3.23 (dt, J ˆ 8.3,
5.8 Hz, 1H), 3.39 3.43 (m, 1H), 3.53 (q, J ˆ 7.3 Hz, 2H), 6.01
(ddd, J ˆ 10.1, 4.0, 2.5 Hz, 1H), 6.12 (dm, J ˆ 10.1 Hz, 1H);
13C NMR (125 MHz): d ˆ 13.0, 23.1, 28.4, 33.8, 37.5, 40.9, 45.4,
123.8, 127.6, 176.3, 178.4, 206.8; IR (neat): n ˆ 1698, 1404, 1352,
1225 cmÀ1; HRMS: m/z calcd. for C12H15NO3: 221.1052; found:
221.1052.
The relative stereochemistry of 16 was determined on the
basis of the NOE experiments described below (Figure 9).
Synthetic Transformation/2-PyMe2Si Group Removal
Sequence from the Diels Alder Cycloadduct
Reduction of 10: To a solution of 10 (2.27 g, 6.73 mmol) in
MeOH (20 mL) were added CeCl3 ¥ 7H2O (8.78 g, 23.6 mmol)
and NaBH4 (872 mg, 23.1 mmol) at 0 8C. After stirringthe
mixture at 08 for 30 min, the reaction was quenched with 1 N
aqueous HCl (10 mL). Extractive work-up and subsequent
silica gel chromatography (hexane/EtOAc ˆ 5/1 to 1/1 as
eluents) afforded 11; yield: 1.67 g(73%);
1H NMR
(300 MHz): d ˆ 0.34 (s, 3H), 0.38 (s, 3H), 0.90 1.11 (m, 2H),
1.29 (d, J ˆ 6.9 Hz, 3H), 1.50 1.62 (m, 1H), 2.07 2.18 (m, 1H),
3.53 3.59 (m, 2H), 5.96 (dd, J ˆ 9.9, 4.8 Hz, 1H), 6.03 (dd, J ˆ
9.9, 4.8 Hz, 1H), 6.53 (d, J ˆ 8.9 Hz, 1H), 6.64 (d, J ˆ 8.9 Hz,
1H) 7.25 (ddd, J ˆ 7.5, 4.8, 1.5 Hz, 1H), 7.54 (ddd, J ˆ 7.5, 1.5,
Acknowledgements
9%
8%
5%
H
This work was supported by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Science, Sports, and
Culture, Japan, and in part by the Mitsubishi Foundation. We
thank Professor Kazunari Akiyoshi (Kyoto University) for the
assistance with dynamic light-scattering experiments and fruit-
ful discussions. Professor Susumu Yoshikawa and Professor
Masahiro Kinoshita (Kyoto University) are gratefully acknowl-
edged for critical discussions.
2%
H
0%H
H
3%
Me
H
Me
O
O
3%
H
H
H
H
11%
O
O
6%
8%
10%
NEt
NEt
H
O
O
Figure 9.
Adv. Synth. Catal. 2002, 344, 441 451
449

Kenichiro Itami et al.
FULL PAPERS
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¬
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