Methodology for in situ protection of aldehydes and ketones using trimethylsilyl trifluoromethanesulfonate and phosphines: Selective alkylation and reduction of ketones, esters, amides, and nitriles

Article abstract of DOI:10.1248/cpb.c13-00666

A methodology for selective transformations of ketones, esters, Weinreb amides, and nitriles in the presence of aldehydes has been developed. The use of a combination of PPh₃-trimethylsilyl trifluoromethanesulfonate (TMSOTf) promotes selective transformation of aldehydes to their corresponding, temporarily protected, O,P-acetal type phosphonium salts. Because, hydrolytic work-up following ensuing reactions of other carbonyl moieties in the substrates liberates the aldehyde moiety, a sequence involving aldehyde protection, transformation of other carbonyl groups, and deprotection can be accomplished in a one-pot manner. Furthermore, the use of PEt₃ instead of PPh ₃ enables ketones to be converted in situ to their corresponding O,P-ketal type phosphonium salts and, consequently, selective transformations of esters, Weinreb amides, and nitriles in the presence of ketones can be performed. This methodology is applicable to various dicarbonyl compounds, including substrates that possess heteroaromatic skeletons and hydroxyl protecting groups.

Full text of DOI:10.1248/cpb.c13-00666

1298
Regular Article
Chem. Pharm. Bull. 61(12) 1298–1307 (2013)
Vol. 61, No. 12
Methodology for in Situ Protection of Aldehydes and Ketones Using
Trimethylsilyl Trifluoromethanesulfonate and Phosphines: Selective
Alkylation and Reduction of Ketones, Esters, Amides, and Nitriles
Kenzo Yahata, Masaki Minami, Yuki Yoshikawa, Kei Watanabe, and Hiromichi Fujioka*
Graduate School of Pharmaceutical Sciences, Osaka University; 1–6 Yamada-oka, Suita 565–0871, Japan.
Received August 21, 2013; accepted September 16, 2013; advance publication released online September 21, 2013
A methodology for selective transformations of ketones, esters, Weinreb amides, and nitriles in the
presence of aldehydes has been developed. The use of a combination of PPh3-trimethylsilyl trifluoromethane-
sulfonate (TMSOTf) promotes selective transformation of aldehydes to their corresponding, temporarily pro-
tected, O,P-acetal type phosphonium salts. Because, hydrolytic work-up following ensuing reactions of other
carbonyl moieties in the substrates liberates the aldehyde moiety, a sequence involving aldehyde protection,
transformation of other carbonyl groups, and deprotection can be accomplished in a one-pot manner. Fur-
thermore, the use of PEt3 instead of PPh3 enables ketones to be converted in situ to their corresponding O,P-
ketal type phosphonium salts and, consequently, selective transformations of esters, Weinreb amides, and
nitriles in the presence of ketones can be performed. This methodology is applicable to various dicarbonyl
compounds, including substrates that possess heteroaromatic skeletons and hydroxyl protecting groups.
Key words carbonyl group; selectivity; one-pot; reversing reactivity; in situ protection
From a synthetic perspective, carbonyl groups are among
the most important functional groups in organic substances
because they participate in simultaneous C–C bond and hy-
droxyl forming reactions. So they are frequently utilized in
organic synthesis and their reactivity is well investigated. It
is well known that the reactivity of different types of car-
bonyl groups towards nucleophiles falls in the following order:
aldehydes>ketones>esters>amides and nitriles. By using
this reactivity profile, numerous selective transformations of
more reactive carbonyl groups in the presence of less reactive
counterparts have been developed.1) In contrast, multiple-step
sequences, which include often complicated protection and
Chart 1. Selective One-Pot Transformation of a Ketone in the Presence
of Aldehyde Group
deprotection steps, are required for selective conversion of less
reactive carbonyl groups in substrates that also contain more
reactive carbonyl moieties. Moreover, the few methods that ketones, esters, Weinreb amides and nitriles in the presence of
have been devised to reverse the reactivity order of carbonyl aldehydes, and of esters, Weinreb amides, and nitriles in the
groups2–19) have drawbacks that include low substrate scope presence of ketones.
and reactions that require strict stoichiometry control and use
of expensive reagents. Thus, in spite of their ability to sim-
plify preparative sequences, these methods have rarely been
used in synthetic organic chemistry.
Results and Discussion
Our initial studies were focused on the reduction of keto-
aldehyde 1a with borane (Table 1). In previous work, we
Previously, we have developed a concise and practical observed that acetal-selective deprotection of substrates
method, which utilizes a combination of trimethylsilyl tri- containing both an acetal and ketal group can be carried out
fluoromethanesulfonate (TMSOTf) and PPh3 or PEt3, for using a combination of 2,4,6-collidine and triethylsilyl trifluo-
selective transformation of ketones and esters in the presence romethansulfonate (TESOTf).21,22) In this effort, we found that
of aldehydes and ketones20) (Chart 1). Unique advantages of excess amounts of reagents (3eq of 2,4,6-collidine and 2eq of
this method, which involves in situ generation of O,P-acetal TESOTf) are required in order to promote complete reaction.
or -ketal type phosphonium salts, are that commercially avail- We also observed that acetals can be deprotected using a com-
able reagents can be utilized and that PPh3 can be employed to bination of TESOTf and a phosphine.23) In the earlier study,
form salts with aldehydes rather than ketones even when it is we attempted formation of a collidinium salt of the aldehyde
used in excess. Consequently, the method is simple to execute group in keto-aldehyde 1a selectively by using TESOTf and
and no need exists to rigorously control the stoichiometry of 2,4,6-collidine. However, a complex mixture was generated
reagents even in reactions of substrates that contain both al- perhaps as a consequence of the basicity of 2,4,6-collidine. In
dehyde and ketone moieties. Below we describe the results of a continuation of these studies, our attention turned to using
an effort that has expanded the utility of this method by dem- a phosphine in place of 2,4,6-collidine for the acetal form-
onstrating that it can be applied to selective transformations of ing process. Indeed, reaction of 1a with the bulky Lewis acid
tert-butyldimethylsilyl trifluoromethanesulfonate (TBSOTf)
and PPh3 followed by treatment with borane–tetrahydro-
The authors declare no conflict of interest.
© 2013 The Pharmaceutical Society of Japan
*To whom correspondence should be addressed. e-mail: fujioka@phs.osaka-u.ac.jp

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Table 1. Conditions for Selective Reactions of Keto-Aldehyde 1a
Table 2. Selective Transformation of Ketone or Ester in the Presence of
Aldehyde
Run
1
Substrate
Reagent (eq)
Product
Yield
96%
Run
Lewis acid
PPh3
Reagent
Yielda)
1b)
2b)
3
TBSOTf (2.0eq)
TESOTf (2.0eq)
TMSOTf (2.0eq)
BF3·OEt2 (2.0eq)
TMSOTf (1.2eq)
TMSOTf (1.2eq)
—
3.0eq
3.0eq
3.0eq
3.0eq
1.2eq
1.2eq
—
BH3·THF (4.0eq)
BH3·THF (4.0eq)
BH3·THF (4.0eq)
BH3·THF (4.0eq)
BH3·THF (1.5eq)
BH3·THF (1.5eq)
BH3·THF (1.2eq)
PhMgBr (3.0eq)
94%
86%
90%
Trace
88%
96%
0%
BH3·THF (1.5)
2
3
4
PhMgBr (3.0)
EtMgCl (1.5)
allylMgBr (1.5)
93%
87%
75%
4
5c)
6c,d)
7e)
8f)
TMSOTf (1.2eq)
1.2eq
93%
a) Isolated yield of 2a and 2b. b) 3.0eq of TBAF was used for work-up. c) PPh3
and TMSOTf were at rt. d) Reduction was performed at −40°C. e) The reaction was
performed in the absence of Lewis acid and PPh3. f) Alkylation was performed at
room temperature.
5
BH3·THF (1.5)
BH3·THF (1.5)
MgBr (3.0)
87%
furan (THF) complex and then tetrabutylammonium fluoride
(TBAF) led to formation of 2a, arising be selective reduction
of the ketone moiety (run 1). The selective reduction could be
promoted by using either less bulky TESOTf or TMSOTf in
place of TBSOTf (runs 2, 3). Moreover, when TMSOTf was
used as the Lewis acid, final treatment of the reaction mixture
with TBAF was not required because the O,P-acetal could
be cleaved by using saturated aqueous NaHCO3. In addition,
we observed that BF3·Et2O could not be employed as a Lewis
acid (run 4), that reducing the amount of reagents used did not
affect the efficiency of the process (run 5), and that the reac-
tion performed at −40°C takes place in highest yield (run 6).
Furthermore, the desired product was not formed when the re-
action was conducted in the absence of either PPh3 or a Lewis
acid, but rather the corresponding diol and ketol are produced
in respective 20% and 74% yields. Finally, this selective al-
dehyde protection methodology was also applied to Grignard
reaction of 1a at room temperature, which forms the tertiary
phenyl-carbinol 2b in high yield (run 8).
Selective Transformation of Carbonyl Groups in the
Presence of Aldehydes The scope of the selective protection
methodology described above was explored by using reduc-
tion and Grignard addition reactions of a variety of dicarbonyl
substrates containing aldehyde group (Table 2). The results
show that the in situ protection methodology enabled ketone-
selective reduction and alkylation reactions of keto-aldehyde
substrates (runs 1–13). In addition, transformations of the
5-oxoaldehyde derivative 1c to 2f and 2g in high yields (runs
6, 7) demonstrated that the method can be utilized in efficient
routes for the construction of synthetically useful lactols.
Aromatic aldehydes also participated in the selective in situ
phosphonium salts protection process (runs 8–13). Moreover,
the use of Corey–Bakshi–Shibata (CBS) reagent enabled
asymmetric reduction of a ketone in the presence of an alde-
hyde with good selectivity (run 9). It is notable that the ketone
group in the readily enolizable ketone 1e could be selectively
reduced in high yield, demonstrating that the protection/de-
protection conditions employed in this method are very mild
(run 11). Moreover, 1f, which possesses a bulky ketone group,
was also selectively converted into the corresponding alcohol
2l when 2eq of the reductant BH3–THF were used (run 12).
In the case of benzophenone-type ketone 1g, reduction took
6
7
89%
93%
8
9
BH3·THF (1.5)
96%
(S)-CBS (2.0)
BH3·THF (2.0)
77%
(90% ee)
10
11
12
PhMgBr (3.0)
BH3·THF (1.5)
BH3·THF (2.0)
84%
87%
74%
13
BH3·THF (2.0)
50%
14
15
16
DIBAL-H (3.0)
DIBAL-H (3.0)
MeMgBr (3.0)
69%
71%
69%
17
18
DIBAL-H (2.2)
EtMgCl (3.0)
80%
76%

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Vol. 61, No. 12
Table 3. Selective Transformation of Weinreb Amide or Nitrile in the
Presence of Aldehyde
place to generate the desired product 2m in only moderate
yield owing to over reduction of the product that produced
4-benzylbenzaldehyde in 17% yield (run 13). Ester groups in
substrates that also contain aldehyde moieties could also be
selectively transformed to primary alcohols by diisobutylalu-
minum hydride (DIBAL-H) reduction and tertiary alcohols
by Grignard additions using the in situ protection method
(runs 14–18). Finally, DIBAL-H reaction of ester-aldehyde 1h
at −78°C, under in situ protection conditions, produced the
semi-reduced dialdehyde 2o in good yield (run 15).
Run
1
Substrate
Reagent (eq)
Product
Yield
76%
DIBAL-H (3.0)
As can be seen by viewing the results given in Table 3, the
in situ protection method enabled selective transformations
of amide and nitrile groups in substrates that also contain
aldehyde moieties. Reduction and Grignard addition reactions
of Weinreb amides took place smoothly to yield the respec-
tive dialdehydes and keto-aldehydes (runs 1–5). In addition,
the results showed that tert-butyldimethylsilyl (TBS) and
methoxymethyl (MOM) groups were shown to tolerate the in
situ protection/deperotection conditions (runs 6–9). However,
simple, less reactive N,N-dialkyl substituted amides, such as
1n and 1o derived from pyrrolidine and N-butylaniline, were
not suitable for this methodology because complicated product
mixtures were formed (runs 10, 11). In these cases, long reac-
tion times were required to consume the starting materials
and this may enable competitive decomposition of phospho-
nium protective groups. Although the nitrile groups in nitrile-
aldehydes underwent selective reduction using DIBAL-H
(runs 12, 14), the yield for formation of the corresponding
ketone product was low (run 13).
2
3
PhMgBr (3.0)
MeMgBr (3.0)
71%
77%
4
DIBAL-H (3.0)
MeMgBr (3.0)
62%
62%
5
66%
74%
66%
6
7
DIBAL-H (2.0)
MeMgBr (3.0)
NMR analysis was used to demonstrate that phosphonium
salt intermediates are selectively formed by treatment of keto-
aldehydes under the in situ protection conditions. Inspection
1
of H-NMR spectra (Chart 2) shows that the resonance for
the aldehyde proton at 10.1ppm disappears when a CDCl3
solution of 1d is treated with PPh3 (1.2eq) and TMSOTf
(1.2eq) despite the retention of the signal at 2.7ppm associated
with from acetyl methyl protons. Also, the aromatic proton
resonances of 1d are shifted to higher fields owing to the fact
that O,P-acetal formation removes the electron-withdrawing
aldehyde carbonyl group. Furthermore, the signal derived
from O,P-acetal proton is newly observed at 7.14 (1H, d,
JCH-P=5.0Hz). These results indicated the selective formation
of the phosphonium salt intermediates at the aldehyde in the
presence of the ketone.
Selective Transformation of the Carbonyl Groups in
the Presence of Ketone Moieties Treatment of ketone-
containing substrates with even excess amounts of TMSOTf
and PPh3 did not lead to formation of O,P-ketal containing
phosphonium salts. We hypothesized that this lack of reactiv-
ity is caused by the steric bulkiness and low nucleophilicity
of PPh3. Studies with less bulky phosphines revealed that a
combination of PEt3 and TMSOTf could be employed to form
the desired ketone O,P-ketals.
8
DIBAL-H (1.5)
9
10
11
12
MeMgBr (3.0)
DIBAL-H (3.0)
DIBAL-H (3.0)
DIBAL-H (3.0)
68%
N.D.
N.D.
65%
Use of the PEt3 based in situ ketone protection methodology
in ester selective reactions of keto-esters was demonstrated by
the results displayed in Table 4. Various keto-esters, includ-
ing 3c which contains a cyclohexanone moiety, reacted with
DIBAL-H and Grignard reagents to furnish the corresponding
primary and tertiary alcohols, involving initial formation of
ketone protected phosphonium ketals. While the highly eno-
lizable β-keto ester 3e did not participate in this process (run
13a)
14a)
PhMgBr (4.0)
50%
DIBAL-H (3.0)
72%
a) 2eq of PPh3 and TMSOTf were used.

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1301
Chart 2. 1H-NMR Monitoring of the Reaction of 1d with PPh3 and TMSOTf
6), keto-ester substrates containing TBS and MOM protecting
groups and pyridine heterocyclic ring underwent selective re-
actions at their ester centers (runs 7–10).
This methodology was employed to carry out selective reac-
tions of substances that contain ketone moieties along with ei-
ther Weinreb amide or nitrile groups. The results showed that
while Weinreb amide groups generally participated in efficient
reduction and alkylation reactions of these substrates, some-
times the reduction processes were attended by low yields
(runs 2, 7). In addition, the desired products were not formed
at all in the case of the substrates with heteroaromatic ring
(runs 6, 9).24) These results may be referred from the reaction
of electron deficient aldehydes with highly nucleophilic phos-
phines.25) The nitrile 3n was also not effective in this reaction
and only 32% of desired product was obtained (run 11).
Chart 3. Reversing the Selectivity of Transformations of Carbonyl
Groups by Using the in Situ Protection Methods
Experimental
All reagents were purchased from commercial sources and
used without further purification, unless otherwise noted.
Reactions were performed under a nitrogen atmosphere using
Conclusion
In the study described above, we developed a new, in purchased anhydrous solvent. All reactions were monitored
situ protection methodology that enables selective reduction by thin-layer chromatography using Merck silica gel 60 F254.
and alkylation reactions of less reactive carbonyl groups The products were purified by column chromatography over
in substrates that also contain more reactive aldehyde and silica gel Kieselgel 60 (70–230 mesh ASTM) purchased
ketone moieties (Chart 3). By using a combination of PPh3 from Merck or Silica Gel 60N (40–50µm, spherical neutral)
1
and TMSOTf, aldehyde groups in substrates of this type are purchased from Kanto Chemical. H- and 13C-NMR spectra
selectively protected in the form of O,P-acetals and, as a re- were recorded at 25°C on a JEOL JNM-AL300 (at 300MHz
sult, ketone, ester, Weinreb amide, and nitrile groups undergo and 75MHz, respectively), a JEOL JNM-ECS 400 (at 400,
selective reactions with a variety of reagents, including BH3, 100MHz, respectively) or a JEOL JNM-LA 500 (at 500,
DIBAL-H, and Grignard reagents as well as CBS reagent. In 125MHz, respectively), and the chemical shifts are reported
addition, selective transformations of ester, Weinreb amide relative to internal tetramethylsilane (TMS) (1H, δ=0.00) or
and nitrile groups in substrates that also contain ketone moi- CD2HCN (1H, δ=1.93) and CDCl3 (13C, δ=77.0) or CD3CN
1
eties can be accomplished by performing preliminary in situ (13C, δ=118.2). Data for H-NMR spectra are reported as fol-
ketone protection using PEt3 and TMSOTf. These methodolo- lows: chemical shift (δ ppm) (multiplicity, coupling constant
gies can be applied to various dicarbonyl substrates including (Hz), integration). Multiplicity and qualifier abbreviations are
heteroaromatic substrates and substrates having protective as follows: s=singlet, d=doublet, t=triplet, q=quartet, quin=
groups. The fact that the reagents employed in the processes quintet, sex=sextet, m=multiplet, br=broad. IR spectra (KBr)
are commercially available and that no need exists to control were recorded by a SHIMADZU FTIR-8400 or SHIMADZU
reagent stoichiometries, makes the in situ ketone and aldehyde IRAffinity-1, and are reported in frequency of absorption
protection methods simple and highly applicable in synthetic (cm−1). High-resolution mass spectra (matrix assisted laser
organic chemistry.
desorption/ionization (MALDI)-MS, FAB-MS and electron
ionization (EI)-MS) were performed by the Elemental Analy-
sis Section of Graduate School of Pharmaceutical Science in

1302
Vol. 61, No. 12
Table 4. Selective Transformation of Ester in the Presence of Ketone
Table 5. Selective Transformation of Weinreb Amide or Nitrile in the
Presence of Ketone
Run
1
Substrate
Reagent (eq)
Product
Yield
82%
Run
1
Substrate
Reagent (eq)
Product
Yield
93%
DIBAL-H (3.0)
MeMgBr (3.0)
2
3
PhMgBr (4.0)
76%
76%
2
DIBAL-H (3.0)
58%
DIBAL-H (3.0)
3
4
MeMgBr (3.0)
DIBAL-H (3.0)
75%
4
DIBAL-H (3.0)
93%
79%
5
MeMgBr (3.0)
PhMgBr (3.0)
EtMgCl (3.0)
83%
N.D.
74%
5
MeMgBr (3.0)
DIBAL-H (3.0)
84%
N.D.
6
6
7a)
7
8
DIBAL-H (3.0)
47%
82%
8a)
EtMgCl (3.0)
80%
MeMgBr (1.5)
9
DIBAL-H (3.0)
MeMgBr (3.0)
62%
76%
9
DIBAL-H (3.0)
MeMgBr (3.0)
N.D.
98%
10
10
a) Salt was formed at 0°C.
11
EtMgCl (3.0)
32%
Osaka University. Melting points were determined using a
YANAGIMOTO MICRO MELTING POINT APPARATUS
and all melting points were uncorrected. Optical rotations
were measured on a JASCO P-1020. Enantiomeric excess
(ee) was measured by chiral HPLC analysis: Daicel chiralpak
AD-H column (4.6mm×25cm) using a multiwavelength de- mixture was then cooled to −40°C, and BH3·THF (0.28mL
tector JASCO MD-2010. of 1.08M in THF, 0.302mmol, 1.5eq) was added slowly via
General Procedure for the Selective Reduction of Ke- syringe. Stirring was continued at −40°C until the starting
tones in the Presence of Aldehydes (Table 2, Runs 1, 5, material was consumed (TLC analysis was conducted after
8, and 11–13) To a solution of keto-aldehyde (0.200mmol, quenching a small amount of the reaction mixture with a drop
1.0eq) and PPh3 (63.0mg, 0.240mmol, 1.2eq) in CH2Cl2 of TBAF (1.0M in THF)). To the mixture were added satu-
(2.0mL, 0.1M) was added TMSOTf (43µL, 0.238mmol, 1.2eq) rated aqueous NaHCO3 solution (2.0mL) and MeOH (1.0mL),
dropwise at rt. After being stirred for 1h at rt, the reaction and the resulting solution was then stirred for 2h at 40°C.

December 2013
1303
After being cooled to rt, the mixture was extracted several ald ester) (0.200mmol, 1.0eq) and PPh3 (63.0mg, 0.240mmol,
times with EtOAc (50mL). The organic layer was dried over 1.2eq) in CH2Cl2 (2.0mL, 0.1M) was added TMSOTf (43µL,
Na2SO4, filtered, and concentrated under reduced pressure to 0.238mmol, 1.2eq) dropwise at rt. After being stirred for
give a residue. Purification was accomplished by flash column 1h at rt, the reaction mixture was added slowly to a solution
chromatography to afford the desired product.
of Grignard reagent (0.600mmol, 3.0eq) in THF (or Et2O)
1
12-Hydroxytetradecanal20) (2a): H-NMR (400MHz, CDCl3) via cannula. Stirring was continued at rt until the starting
δ: 9.76 (1H, t, J=1.9Hz), 3.53–3.50 (1H, m), 2.42 (2H, dt, material was consumed (TLC analysis was conducted after
J=1.9, 7.2Hz), 1.63 (2H, tt, J=7.2, 7.2Hz), 1.55–1.28 (18H, m), quenching a small amount of the reaction mixture with a drop
0.94 (3H, t, J=7.6 Hz).
of TBAF (1.0M in THF)). To the mixture were added saturated
4-Hydroxycyclohexylacetaldehyde20) (2e): 1H-NMR (400 aqueous NaHCO3 solution (2.0mL) and MeOH (1.0mL), and
MHz, CDCl3) δ: 9.76 (1H, t, J=2.2Hz), 3.57 (1H, tt, J=10.8, then the resulting solution was stirred for 2h at 40°C. After
4.4Hz), 2.01–1.97 (2H, m), 1.91–1.79 (3H, m), 1.51 (1H, brs), being cooled to rt, the aqueous layer was extracted several
1.37–1.27 (2H, m), 1.13–1.03 (2H, m).
times with EtOAc (50mL). The organic layer was dried over
6-Phenyl-δ-valerolactol26) (2f): 1:1 mixture of diastereoiso- Na2SO4, filtered and concentrated under reduced pressure to
1
mers; H-NMR (500MHz, CDCl3) δ: 7.38–7.25 (5H, m), 5.43 give a residue. Purification was accomplished by flash column
(0.5H, s), 5.01 (0.5H, dd, J=11.5, 2.5Hz), 4.85–4.82 (0.5H, m), chromatography to afford the desired product.
4.46 (0.5H, dd, J=12.0, 2.0Hz), 3.46 (0.5H, d, J=6.0Hz), 2.99
12-Hydroxy-12-phenyltetradecanal20)
(2b):
1H-NMR
(0.5H, s), 2.08–1.37 (6H, m).
(500MHz, CD3CN) δ: 9.66 (1H, t, J=1.9Hz), 7.36 (2H, d,
1
4-(1-Hydroxyethyl)benzaldehyde27) (2h): H-NMR (400MHz, J=7.5Hz), 7.30 (2H, t, J=7.5Hz), 7.18 (1H, t, J=7.5Hz),
CDCl3) δ: 9.97 (1H, s), 7.85 (2H, d, J=8.4Hz), 7.53 (2H, d, 2.71–2.70 (1H, m), 2.36 (2H, dt, J=1.9, 7.2Hz), 1.83–1.66 (4H,
J=8.4Hz), 4.98 (1H, q, J=6.5Hz), 2.50 (1H, brs), 1.51 (3H, d, m), 1.54 (2H, tt, J=7.2, 7.2Hz), 1.24–1.18 (13H, m), 0.94–0.88
J=6.5 Hz).
(1H, m), 0.67 (3H, t, J=7.3 Hz).
4-(2-Hydroxypropyl)benzaldehyde20) (2k): 1H-NMR (400
12-Ethyl-12-hydroxytetradecanal20) (2c): 1H-NMR (400MHz,
MHz, CDCl3) δ: 9.96 (1H, s), 7.82 (2H, d, J=8.2Hz), 7.39 (2H, CDCl3) δ: 9.76 (1H, t, J=1.9Hz), 2.42 (2H, dt, J=1.9, 7.3Hz),
d, J=8.2Hz), 4.08 (1H, tq, J=6.3, 6.3Hz), 2.88–2.78 (2H, m), 1.63 (2H, quin, J=7.3Hz), 1.46 (4H, q, J=7.5Hz), 1.42–1.38
1.82 (1H, brs), 1.26 (3H, d, J=6.3 Hz).
(2H, m), 1.28 (14H, m), 1.13 (1H, brs), 0.86 (6H, t, J=7.5 Hz).
4-(1-Hydroxy-2,2-dimethylpropyl)benzaldehyde20) (2l): 1H-
12-Ethyl-12-hydroxypentadec-14-enal20) (2d): 1H-NMR
NMR (400MHz, CDCl3) δ: 9.98 (1H, s), 7.82 (2H, d, (500MHz, CDCl3) δ: 9.76 (1H, t, J=1.8Hz), 5.88–5.80 (1H,
J=8.2Hz), 7.48 (2H, d, J=8.2Hz), 4.47 (1H, s), 2.12 (1H, br s), m), 5.13–5.09 (2H, m), 2.42 (2H, dt, J=1.8, 7.3Hz), 2.21 (2H,
0.93 (9H, s).
4-(Hydroxyphenylmethyl)benzaldehyde29) (2m): 1H-NMR 1.42–1.40 (3H, m), 1.30–1.28 (14H, m), 0.88 (3H, t, J=7.4 Hz).
(400MHz, CDCl3) δ: 9.96 (1H, s), 7.83 (2H, d, J=8.4Hz), 7.56
6-Phenyl-6-(prop-1-ynyl)-δ-valerolactol20) (2g): 1H-NMR
(2H, d, J=8.4Hz), 7.35–7.17 (5H, m), 5.88 (1H, s), 2.30 (1H, (400MHz, CDCl3) δ: 7.65 (2H, d, J=7.2Hz), 7.35 (2H, t,
br s). J=7.2Hz), 7.27 (1H, t, J=7.2Hz), 5.41 (1H, dd, J=9.8, 1.8Hz),
d, J=7.5Hz), 1.63 (2H, tt, J=7.3, 7.3Hz), 1.50–1.45 (2H, m),
Selective Asymmetric Reduction of Ketone in the Pres- 2.12–1.94 (2H, m), 1.93 (3H, s), 1.88–1.76 (2H, m), 1.68–1.60
ence of Aldehyde (Table 2, Run 9) (+)-4-(1-Hydroxyethyl)- (1H, m), 1.44–1.33 (1H, m).
benzaldehyde (2i): To a solution of 1d (45.3mg, 0.306mmol)
4-(1-Hydroxy-1-phenylethyl)benzaldehyde20) (2j): 1H-NMR
and PPh3 (78.6mg, 0.300mmol, 1.2eq) in CH2Cl2 (1.0mL) (400MHz, CDCl3) δ: 9.95 (1H, s), 7.82–7.79 (2H, m), 7.60–7.57
was added TMSOTf (54µL, 0.299mmol) dropwise at rt. After (2H, m), 7.40 (2H, dt, J=7.3, 1.8Hz), 7.32 (2H, tt, J=7.3,
being stirred for 1h at rt, the reaction mixture was then cooled 1.8Hz), 7.26 (1H, tt, J=7.3, 1.8Hz), 1.97 (3H, s).
to −30°C, and the resulted solution was added to a solution of
10-Hydroxy-10-methylundecanal (2p): Collerless oil. TLC
BH3·THF (0.56mL of 1.08M in THF, 0.605mmol) and (S)- (SiO2): Rf=0.41 (hexanes–EtOAc 2:1). IR (KBr) 3394.7,
(−)-2-methyl-CBS-oxazaborolidine (160mg, 0.577mmol) at 2929.9, 1854.7, 1722.4, 1465.9, 1375.3, 1149.6, 906.5cm−1.
−30°C via cannula. Stirring was continued at −30°C until the 1H-NMR (400MHz, CDCl3) δ: 9.77 (1H, t, J=1.9Hz), 2.43
starting material was consumed (TLC analysis was conducted (2H, td, J=7.4, 1.9Hz), 1.65–1.61 (2H, m), 1.48–1.44 (2H, m),
after quenching a small amount of the reaction mixture with 1.36–1.31 (10H, m), 1.21 (6H, s). 13C-NMR (MHz, CDCl3) δ:
a drop of TBAF (1.0M in THF)). To the mixture were added 202.9, 70.9, 43.9, 43.8, 30.0, 29.3, 29.2 (2×C), 29.1, 24.2, 22.0.
saturated aqueous NaHCO3 solution (1.0mL) and MeOH HR-MS (FAB) Calcd for C12H24O2Na [M+Na]+: 223.1674,
(0.5mL), and the resulting solution was then stirred for 2h Found 223.1683.
at 40°C. After being cooled to rt, the mixture was extracted
4-(1-Ethyl-1-hydroxypropyl)benzaldehyde (2r)20) 1H-NMR
:
several times with EtOAc (50mL). The organic layer was (400MHz, CDCl3) δ: 10.0 (1H, s), 7.88–7.85 (2H, m), 7.58–7.56
dried over Na2SO4, filtered, and concentrated under reduced (2H, m), 1.96–1.80 (5H, m), 0.76 (6H, t, J=7.6 Hz).
pressure to give a residue. Purification was accomplished by
Selective Reduction of Ester to Alcohol in the Presence
flash column chromatography (hexanes–AcOEt, 2:1) to afford of Aldehyde (Table 2, Run 14): 10-Hydroxydecanal30) (2n)
2i (35.3mg, 0.235mmol, 77%, 90% ee). The ee value was de- To a solution of 1h (40.1mg, 0.200mmol) and PPh3 (63.0mg,
termined with chiral HPLC analysis (AD-H, 1.0mL/min, 10% 0.240mmol) in CH2Cl2 (2.0mL) was added TMSOTf (43µL,
IPA in hexanes) [α]D26 +34.8 (c=0.979, CHCl3), (lit.28) [α]D26 0.238mmol) dropwise at rt. After being stirred for 1h at rt,
−36.5 (c=1.25, CHCl3) for (S)-2i).
the reaction mixture was then cooled to 0°C, and DIBAL-H
General Procedure for the Selective Alkylation of Ke- (0.59mL of 1.02M in hexane, 0.602mmol, 3.0eq) was added
tone and Ester in the Presence of Aldehyde (Table 2, Runs slowly via syringe. Stirring was continued at 0°C until the
2–4, 7, 10, 16, and 18) To a solution of keto-aldehyde (or starting material was consumed (TLC analysis was conducted

1304
Vol. 61, No. 12
after quenching a small amount of the reaction mixture with 0°C until the starting material was consumed (TLC analysis
a drop of TBAF (1.0M in THF)). To the mixture were added was conducted after quenching a small amount of the reaction
saturated aqueous NaHCO3 solution (2.0mL) and MeOH mixture with a drop of TBAF (1.0M in THF)). To the mixture
(1.0mL), and the resulting solution was then stirred for 2h at were added saturated aqueous NaHCO3 solution (2.0mL) and
40°C. After being cooled to rt, the mixture was extracted sev- MeOH (1.0mL), and then the resulting solution was stirred
eral times with EtOAc (50mL). The organic layer was dried for 2h at 40°C. After being cooled to rt, the aqueous layer
over Na2SO4, filtered, and concentrated under reduced pres- was extracted several times with EtOAc (50mL). The organic
sure to give a residue. Purification was accomplished by flash layer was dried over Na2SO4, filtered and concentrated under
column chromatography to afford 2n (23.8mg, 0.138mmol, reduced pressure to give a residue. Purification was accom-
1
69%). H-NMR (400MHz, CDCl3) δ: 9.77 (1H, t, J=1.8Hz), plished by flash column chromatography to afford the desired
3.64 (2H, t, J=6.6Hz), 2.42 (2H, td, J=7.3, 1.8Hz), 1.65–1.56 product.
1
(4H, m), 1.31–1.25 (10H, m).
4-Benzoylbenzaldehyde34) (1g): H-NMR (400MHz, CDCl3)
General Procedure for the Selective Reduction of Ester δ: 10.14 (1H, s), 8.02–8.00 (2H, m), 7.94–7.92 (2H, m),
and Weinreb Amide in the Presence of Aldehyde (Table 2, 7.83–7.80 (2H, m), 7.66–7.62 (1H, m), 7.54–7.50 (2H, m).
1
Runs 15 and 17; Table 3, Runs 1, 4, 6, and 8) To a solu-
4-Acetylbenzaldehyde20) (1d): H-NMR (400MHz, CDCl3)
tion of ald ester (or ald amide) (0.200mmol, 1.0eq) and PPh3 δ: 10.12 (1H, s), 8.11 (2H, d, J=8.2Hz), 7.99 (2H, d, J=8.2Hz),
(63.0mg, 0.240mmol, 1.2eq) in CH2Cl2 (2.0mL, 0.1M) was 2.68 (3H, s).
added TMSOTf (43µL, 0.238mmol, 1.2eq) dropwise at rt.
10-Oxoundecanal35) (2t): 1H-NMR (300MHz, CDCl3)
After being stirred for 1h at rt, the reaction mixture was then δ: 9.77 (1H, t, J=2.4Hz), 2.46–2.40 (4H, m), 2.14 (3H, s),
cooled to −78°C, and DIBAL-H (0.59mL of 1.02M in hexane, 1.65–1.54 (4H, m), 1.30–1.25 (8H, m).
0.602mmol, 3.0eq) was added slowly via syringe. Stirring
3-Acetyl-5-(tert-butyldimethylsilyloxy)benzaldehyde
(2v):
was continued at −78°C until the starting material was con- Colorless oil. TLC (SiO2): Rf=0.37 (EtOAc). IR (KBr) 3369.6,
sumed (TLC analysis was conducted after quenching a small 2955.0, 2731.2, 2254.8, 1693.5, 1591.3, 1454.3, 1311.6, 1255.7,
1
amount of the reaction mixture with a drop of TBAF (1.0M in 1217.1, 1147.7, 1024.2, 912.3, 742.6cm−1. H-NMR (400MHz,
THF)). To the mixture were added saturated aqueous NaHCO3 CDCl3) δ: 10.02 (1H, s), 8.04 (1H, dd, J=1.3, 1.4Hz), 7.67
solution (2.0mL) and MeOH (1.0mL), and the resulting solu- (1H, dd, J=1.3, 2.7Hz), 7.52 (1H, dd, J=1.4, 2.7Hz), 2.65 (3H,
tion was then stirred for 2h at 40°C. After being cooled to rt, s), 1.01 (9H, s), 0.26 (6H, s). 13C-NMR (100MHz, CDCl3) δ:
the mixture was extracted several times with EtOAc (50mL). 196.7, 191.2, 156.8, 139.2, 138.0, 125.2, 124.1, 123.0, 26.8,
The organic layer was dried over Na2SO4, filtered, and con- 25.5, 18.2, −4.5. HR-MS (MALDI) Calcd for C15H23O3Si [M+
centrated under reduced pressure to give a residue. Purifica- H]+: 279.1416, Found 279.1405.
tion was accomplished by flash column chromatography to
3-Acetyl-5-(methoxymethoxy)benzaldehyde (2x): Colorless
oil. TLC (SiO2): Rf=0.56 (hexanes–EtOAc, 1:1). IR (KBr)
afford the desired product.
1
Decanedial31) (2o): H-NMR (400MHz, CDCl3) δ: 9.77 (2H, 3363.9, 2927.9, 2254.8, 1697.4, 1593.2, 1296.2, 1155.4, 1028.1,
t, J=1.7Hz), 2.43 (4H, td, J=7.4, 1.7Hz), 1.65–1.59 (4H, m), 912.3, 742.6cm−1. H-NMR (400MHz, CDCl3) δ: 10.04 (1H,
1
1.41–1.23 (8H, m).
s), 8.08 (1H, dd, J=1.3, 1.4Hz), 7.87 (1H, dd, J=1.4, 2.5Hz),
4-Hydroxymethylbenzaldehyde (2q)20): Reduction was con- 7.74 (1H, dd, J=1.3, 2.5Hz), 5.29 (2H, s), 3.50 (3H, s), 2.66
1
ducted with 2.2eq of DIBAL-H. H-NMR (300MHz, CDCl3) (3H, s). 13C-NMR (100MHz, CDCl3) δ: 196.6, 191.1, 158.0,
δ: 9.99 (1H, s), 7.86 (2H, d, J=8.0Hz), 7.53 (2H, d, J=8.0Hz), 139.1, 137.9, 123.2, 121.6, 120.3, 94.4, 56.3, 26.7. HR-MS
4.80 (2H, s), 2.34 (1H, brs).
(FAB) Calcd for C11H13O4 [M+H]+: 209.0814, Found 209.0823.
Selective Reduction of Nitrile of 1p (Table 3, Run 12):
Benzene-1,4-dicarboxaldehyde32) (2s) To a solution of 1p
Benzene-1,4-dicarboxaldehyde32) (2s): 1H-NMR (400MHz,
CDCl3) δ: 10.15 (2H, s), 8.07 (4H, s).
5-(tert-Butyldimethylsilyloxy)isophthalaldehyde33) (2u): 1H- (26.2mg, 0.200mmol) and PPh3 (63.0mg, 0.240mmol) in
NMR (400MHz, CDCl3) δ: 10.04 (2H, s), 7.99–7.98 (1H, m), CH2Cl2 (2.0mL) was added TMSOTf (43µL, 0.238mmol)
7.59–7.58 (2H, m), 1.01 (9H, s), 0.27 (6H, s).
dropwise at rt. After being stirred for 1h at rt, the reaction
5-(Methoxymethoxy)isophthalaldehyde (2w): Colorless oil. mixture was then cooled to 0°C, and DIBAL-H (0.58mL of
TLC (SiO2): Rf=0.71 (hexanes–EtOAc, 1:1). IR (KBr) 3388.9, 1.03 M in hexane, 0.597mmol) was added slowly via syringe.
2931.8, 2733.1, 2254.8, 1693.5, 1593.2, 1454.3, 1288.5, 1151.5, Stirring was continued at 0°C until the starting material was
1
912.3, 742.6cm−1. H-NMR (400MHz, CDCl3) δ: 10.07 (2H, consumed (TLC analysis was conducted after quenching a
s), 8.03 (1H, t, J=1.6Hz), 7.80 (2H, d, J=1.6Hz), 5.30 (2H, small amount of the reaction mixture with a drop of TBAF
s), 3.51 (3H, s). 13C-NMR (100MHz, CDCl3) δ: 190.7, 158.4, (1.0 M in THF)). To the mixture were added saturated aque-
138.3, 124.7, 121.7, 94.4, 56.4. HR-MS (FAB) Calcd for ous NaHCO3 solution (2.0mL) and MeOH (1.0mL), and the
C10H11O4N [M+H]+: 194.0657, Found 194.0666.
resulting solution was then stirred for 2h at 40°C. After being
General Procedure for the Selective Alkylation of Wein- cooled to rt, the mixture was extracted several times with
reb Amide in the Presence of Aldehyde (Table 3, Runs 2, 3, EtOAc (50mL). The organic layer was dried over Na2SO4,
5, 7, and 9) To a solution of ald amide (0.200mmol, 1.0eq) filtered, and concentrated under reduced pressure to give
and PPh3 (63.0mg, 0.240mmol, 1.2eq) in CH2Cl2 (2.0mL, a residue. Purification was accomplished by flash column
0.1 M) was added TMSOTf (43µL, 0.238mmol, 1.2eq) drop- chromatography (hexanes–AcOEt, 3:1) to afford 2s (17.4mg,
wise at rt. After being stirred for 1h at rt, the reaction mixture 0.130mmol, 65%).
was then cooled to 0°C, and a solution of Grignard reagent
Selective Reduction of Nitrile of 1q (Table 3, Run 14):
(0.600mmol, 3.0eq) in THF (or Et2O) was added slowly to Decanedial31) (2o) To a solution of 1q (45.3mg, 0.271mmol)
the reaction mixture via syringe. Stirring was continued at and PPh3 (143mg, 0.545mmol) in CH2Cl2 (2.7mL), was

December 2013
1305
added TMSOTf (98µL, 0.542mmol) dropwise at rt. After (400MHz, CDCl3) δ: 3.75 (2H, t, J=6.6Hz), 2.41–2.31 (4H,
being stirred for 1h at rt, the reaction mixture was then m), 2.13–2.07 (2H, m), 2.00–1.90 (1H, m), 1.69–1.58 (3H, m),
cooled to −78°C, and DIBAL-H (0.79mL of 1.03M in hex- 1.49–1.39 (2H, m).
1
ane, 0.814mmol) was added slowly via syringe. Stirring was
4-Hydroxymethylacetophenone20) (4d): H-NMR (400MHz,
continued at −78°C until the starting material was consumed CDCl3) δ: 7.93 (2H, d, J=8.4Hz), 7.45 (2H, d, J=8.4Hz), 4.77
(TLC analysis was conducted after quenching a small amount (2H, s), 2.59 (3H, s), 2.39 (1H, brs).
of the reaction mixture with a drop of TBAF (1.0M in THF)).
1
1-(6-(Hydroxymethyl)pyridin-2-yl)ethanone36) (4i): H-NMR
To the mixture were added saturated aqueous NaHCO3 solu- (400MHz, CDCl3) δ: 7.97 (1H, d, J=7.7Hz), 7.85 (1H, t,
tion (2.0mL) and MeOH (1.0mL), and the resulting solution J=7.7Hz), 7.45 (1H, d, J=7.7Hz), 4.85 (2H, d, J=4.4Hz), 3.74
was then stirred for 2h at 40°C. After being cooled to rt, the (1H, t, J=4.4Hz), 2.75 (3H, s).
resulted solution was evaporated and the residue was dissolved
General Procedure for Selective Alkylation of Ester in
with THF (2.0mL). The solution was acidified with 1N HCl the Presence of Ketone (Table 4, Runs 2, 5–8, and 10) To
and stirred for 10min. The mixture was extracted several a solution of keto ester (0.200mmol, 1.0eq) and PEt3 (0.18mL
times with EtOAc (50mL). The organic layer was dried over of 20% in toluene, 0.244mmol, 1.2eq) in CH2Cl2 (0.50mL,
Na2SO4, filtered, and concentrated under reduced pressure to 0.4M) was added TMSOTf (43µL, 0.238mmol, 1.2eq) drop-
give a residue. Purification was accomplished by flash column wise at rt. After being stirred for 1h at rt, Grignard reagent
chromatography (hexanes–AcOEt, 5:1) to afford 2o (33.2mg, (0.600mmol, 3.0eq) was added slowly via syringe. Stirring
0.195mmol, 72%).
was continued at rt until the starting material was consumed
Selective Alkylation of Nitrile of 1p (Table 3, Run 13) (TLC analysis was conducted after quenching a small amount
4-Benzoylbenzaldehyde34) (1g): To a solution of 1p (65.6mg, of the reaction mixture with a drop of TBAF (1.0M in THF)).
0.500mmol) and PPh3 (262.3mg, 0.100mmol) in CH2Cl2 To the mixture were added saturated aqueous NaHCO3 solu-
(5.0mL) was added TMSOTf (0.18mL, 0.996mmol) dropwise tion (2.0mL) and MeOH (1.0mL), and the resulting solution
at rt. After being stirred for 1h at rt, the resulted solution was then stirred for 2h at 40°C. After being cooled to rt, the
was added to a solution of PhMgBr (1.8mL of 1.10M in THF, mixture was extracted several times with EtOAc (50mL). The
1.98mmol) slowly via cannula. Stirring was continued at rt organic layer was dried over Na2SO4, filtered, and concen-
for 3h (TLC analysis was conducted after quenching a small trated under reduced pressure to give a residue. Purification
amount of the reaction mixture with a drop of TBAF (1.0M in was accomplished by flash column chromatography to afford
THF)). To the mixture were added saturated aqueous NaHCO3 the desired product.
solution (5.0mL) and MeOH (2.0mL), and the resulting solu-
Equilibrium Mixture of 5-Hydroxy-5,5-diphenylpentan-
tion was then stirred for 2h at 40°C. After being cooled to rt, 2-one and 2-Methyl-5,5-diphenyltetrahydrofuran-2-ol20) (4b):
the resulted solution was evaporated and the residue was dis- 1H-NMR (400MHz, CDCl3) δ: 7.45–7.40 (4H, m), 7.32–7.17
solved with THF (2.0mL). The solution was acidified with 1N (6H, m), 2.87 (0.5H, ddd, J=12.2, 11.9, 7.0Hz), 2.77 (0.5H, s),
HCl and stirred for 15min. The mixture was extracted several 2.66 (0.5H, ddd, J=12.2, 7.2, 3.0Hz), 2.59 (1H, t, J=6.9Hz),
times with EtOAc (50mL). The organic layer was dried over 2.47 (1H, t, J=6.9Hz), 2.41 (0.5H, brs), 2.11–2.06 (2H, m),
Na2SO4, filtered, and concentrated under reduced pressure to 1.89 (0.5H, ddd, 11.9, 11.9, 7.2Hz), 1.64 (1.5H, s).
give a residue. Purification was accomplished by flash column
chromatography (hexanes–AcOEt, 7:1) to afford 1g (56.4mg, (400MHz, CDCl3) δ: 7.95–7.91 (2H, m), 7.60–7.57 (2H, m),
4-(2-Hydroxypropan-2-yl)acetophenone20) (4e): 1H-NMR
0.252mmol, 50%).
2.60 (3H, s), 1.60 (6H, s).
General Procedure for Selective Reduction of Ester in
3-(tert-Butyldimethylsilyl)oxy-5-(3-hydroxypentan-3-
the Presence of Ketone (Table 4, Runs 1, 3, 4, and 9) To a yl)acetophenone20) (4g): 1H-NMR (400MHz, CDCl3) δ:
solution of keto ester (0.200mmol, 1.0eq) and PEt3 (0.18mL of 7.59–7.58 (1H, m), 7.280–7.276 (1H, m), 7.10–7.09 (1H, m),
20% in toluene, 0.244mmol, 1.2eq) in CH2Cl2 (0.50mL, 0.4M) 2.59 (3H, s), 1.92–1.77 (5H, m), 1.00 (9H, s), 0.76 (6H, t,
was added TMSOTf (43µL, 0.238mmol, 1.2eq) dropwise at J=7.6Hz), 0.22 (6H, s).
rt. After being stirred for 1h at rt, the reaction mixture was
3-(Methoxy methoxy)-5-(3-hyd roxy pentan-3-yl)-
then cooled to 0°C, and DIBAL-H (0.58mL of 1.03M in hex- acetophenone20) (4h): 1H-NMR (400MHz, CDCl3) δ:
ane, 0.597mmol, 3.0eq) was added slowly via syringe. Stir- 7.632–7.626 (1H, m), 7.494–7.488 (1H, m), 7.294–7.285 (1H,
ring was continued at 0°C until the starting material was con- m), 5.23 (2H, s), 3.50 (3H, s), 2.61 (3H, s), 1.93–1.78 (4H, m),
sumed (TLC analysis was conducted after quenching a small 0.77 (6H, t, J=7.2 Hz).
amount of the reaction mixture with a drop of TBAF (1.0M in
1-(6-(2-Hydroxypropan-2-yl)pyridin-2-yl)ethanone (4j): Col-
THF)). To the mixture were added saturated aqueous NaHCO3 orless oil. TLC (SiO2): Rf=0.45 (hexanes–EtOAc 2:1). IR
solution (2.0mL) and MeOH (1.0mL), and the resulting solu- (KBr) 3441.0, 2974.2, 2929.9, 1681.9, 1585.5, 1359.8, 1300.0,
1
tion was then stirred for 2h at 40°C. After being cooled to rt, 1180.4, 964.4, 819.8, 597.9cm−1. H-NMR (300MHz, CDCl3)
the mixture was extracted several times with EtOAc (50mL). δ: 7.96 (1H, dd, J=10.4, 1.8Hz), 7.88 (1H, t, J=10.4Hz), 7.61
The organic layer was dried over Na2SO4, filtered, and con- (1H, dd, J=10.4, 1.8Hz), 4.78 (1H, s), 2.75 (3H, s), 1.60 (6H, s).
centrated under reduced pressure to give a residue. Purifica- 13C-NMR (75MHz, CDCl3) δ: 199.5, 165.6, 151.3, 138.0, 122.4,
tion was accomplished by flash column chromatography to 119.8, 71.9, 30.6, 25.8. HR-MS (FAB) Calcd for C10H14NO2
afford the desired product.
[M+H]+: 180.1025, Found 180.1020.
General Procedure for Selective Reduction of Weinreb
14-Hydroxytetradecan-3-one20) (4a): 1H-NMR (400MHz,
CDCl3) δ: 3.64 (2H, t, J=6.8Hz), 2.44–2.38 (4H, m), 1.59–1.53 Amide in the Presence of Ketone (Table 5, Runs 2, 4, 6,
(5H, m), 1.36–1.27 (14H, m), 1.05 (3H, t, J=7.3 Hz).
7, and 9) To a solution of keto amide (0.200mmol, 1.0eq)
4-(2-Hydroxyethyl)cyclohexanone20)
(4c):
1H-NMR and PEt3 (0.18mL of 20% in toluene, 0.244mmol, 1.2eq)

1306
Vol. 61, No. 12
in CH2Cl2 (0.50mL, 0.4M) was added TMSOTf (43µL, 0.996mmol) dropwise at rt. After being stirred for 1h at rt, the
0.238mmol, 1.2eq) dropwise at rt. After being stirred for resulted solution was added to a solution of PhMgBr (1.4mL
1h at rt, the reaction mixture was then cooled to −78°C, of 1.10M in THF, 1.54mmol) slowly via cannula. Stirring was
and DIBAL-H (0.58mL of 1.03M in hexane, 0.597mmol, continued at rt for 30min (TLC analysis was conducted after
3.0eq) was added slowly via syringe. Stirring was continued quenching a small amount of the reaction mixture with a drop
at −78°C until the starting material was consumed (TLC of TBAF (1.0M in THF)). To the mixture were added saturated
analysis was conducted after quenching a small amount of aqueous NaHCO3 solution (5.0mL) and MeOH (2.0mL), and
the reaction mixture with a drop of TBAF (1.0M in THF)). the resulting solution was then stirred for 2h at 40°C. After
To the mixture were added saturated aqueous NaHCO3 solu- being cooled to rt, the resulted solution was evaporated and
tion (2.0mL) and MeOH (1.0mL), and the resulting solution the residue was dissolved with THF (2.0mL). The solution
was then stirred for 2h at 40°C. After being cooled to rt, the was acidified with 1N HCl and stirred for 15min. The mixture
mixture was extracted several times with EtOAc (50mL). The was extracted several times with EtOAc (50mL). The organic
organic layer was dried over Na2SO4, filtered, and concen- layer was dried over Na2SO4, filtered, and concentrated under
trated under reduced pressure to give a residue. Purification reduced pressure to give a residue. Purification was accom-
was accomplished by flash column chromatography to afford plished by flash column chromatography (hexanes–AcOEt,
the desired product.
5:1) to afford 4t (40.4mg, 0.181mmol, 36%). 1H-NMR
9-Benzoylnonanal37) (4m): 1H-NMR (400MHz, CDCl3) δ: (400MHz, CDCl3) δ: 8.04 (4H, s), 3.05 (2H, q, J=7.2Hz), 2.65
9.76 (1H, t, J=1.9Hz), 7.97–7.95 (2H, m), 7.56 (1H, tt, J=7.4, (3H, s), 1.25 (3H, t, J=7.2 Hz).
1.5Hz), 7.48–7.44 (2H, m), 2.97 (2H, t, J=7.4Hz), 2.42 (2H, td,
J=7.3, 1.9Hz), 1.77–1.70 (2H, m), 1.64–1.59 (2H, m), 1.40–1.25
Acknowledgments This work was financially supported
by the Hoansha Foundation, the Uehara Memorial Foundation,
(8H, m).
10-Oxoundecanal38) (4p): 1H-NMR (300MHz, CDCl3) Takeda Science Foundation, and a Grant-in-Aid for Scientific
δ: 9.77 (1H, t, J=2.4Hz), 2.46–2.40 (4H, m), 2.14 (3H, s), Research from the Ministry of Education, Culture, Sports,
1.65–1.54 (4H, m), 1.30–1.25 (8H, m).
Science and Technology of Japan. Kenzo Yahata is grateful
General Procedure for Selective Alkylation of Wein- for financial support from the Japan Society for the Promotion
reb Amide in the Presence of Ketone (Table 5, Runs 1, of Science Research Fellowship for Young Scientists.
3, 5, 8, and 10) To a solution of keto amide (0.200mmol,
1.0eq) and PEt3 (0.18mL of 20% in toluene, 0.244mmol,
1.2eq) in CH2Cl2 (0.50mL, 0.4M) was added TMSOTf (43µL,
0.238mmol, 1.2eq) dropwise at rt. After being stirred for 1h
at rt, the reaction mixture was then cooled to 0°C, and Gri-
gnard reagent (0.600mmol, 3.0eq) was added slowly via sy-
ringe. Stirring was continued at 0°C until the starting material
was consumed (TLC analysis was conducted after quenching
a small amount of the reaction mixture with a drop of TBAF
(1.0 M in THF)). To the mixture were added saturated aque-
ous NaHCO3 solution (2.0mL) and MeOH (1.0mL), and the
resulting solution was then stirred for 2h at 40°C. After being
cooled to rt, the mixture was extracted several times with
EtOAc (50mL). The organic layer was dried over Na2SO4,
filtered, and concentrated under reduced pressure to give a
residue. Purification was accomplished by flash column chro-
matography to afford the desired product.
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