Mukaiyama aldol reactions catalyzed by a trimeric organo aluminum(III) alkoxide

Article abstract of DOI:10.1080/10426507.2014.906427

Mukaiyama aldol reactions of enol ethers with a variety of aldehydes and ketones are efficiently catalyzed at 0-25 °C by the sterically bulky trimeric organo aluminum(III) alkoxide 1 synthesized via the reaction of 3 equiv of AlMe₃ with tripodal tris(2-hydroxy-3-tert-butyl-5-methylphenyl) methane and the elimination of 3 equiv of methane. Comparisons of its catalytic properties with the less sterically hindered analogue 2, the more sterically hindered analogue 3, a monomeric aluminum near-analogue 4, and a dimeric alumatrane 5 revealed that 1 possesses superior activity.

Full text of DOI:10.1080/10426507.2014.906427

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Phosphorus, Sulfur, and Silicon and the
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Mukaiyama Aldol Reactions Catalyzed by
a Trimeric Organo Aluminum(III) Alkoxide
So Han Kima, Sungwoo Yoona, Youngjo Kima & John G. Verkadeb
a Department of Chemistry and BK21+ Program Research Team,
Chungbuk National University, Cheongju, 361-763, Chungbuk,
Republic of Korea
b Department of Chemistry, Iowa State University, Ames,
50011-3111, Iowa, USA
Published online: 04 Aug 2014.
To cite this article: So Han Kim, Sungwoo Yoon, Youngjo Kim & John G. Verkade (2014) Mukaiyama
Aldol Reactions Catalyzed by a Trimeric Organo Aluminum(III) Alkoxide, Phosphorus, Sulfur, and Silicon
and the Related Elements, 189:7-8, 1193-1206, DOI: 10.1080/10426507.2014.906427
To link to this article: http://dx.doi.org/10.1080/10426507.2014.906427
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Phosphorus, Sulfur, and Silicon, 189:1193–1206, 2014
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2014.906427
MUKAIYAMA ALDOL REACTIONS CATALYZED
BY A TRIMERIC ORGANO ALUMINUM(III) ALKOXIDE∗
∗
So Han Kim,1 † Sungwoo Yoon,1,† Youngjo Kim,1, ‡
∗
and John G. Verkade2,
1Department of Chemistry and BK21+ Program Research Team, Chungbuk
National University, Cheongju, Chungbuk 361-763, Republic of Korea
2Department of Chemistry, Iowa State University, Ames, Iowa 50011-3111, USA
GRAPHICAL ABSTRACT
Abstract Mukaiyama aldol reactions of enol ethers with a variety of aldehydes and ketones
are efficiently catalyzed at 0–25 ◦C by the sterically bulky trimeric organo aluminum(III)
alkoxide 1 synthesized via the reaction of 3 equiv of AlMe3 with tripodal tris(2-hydroxy-3-tert-
butyl-5-methylphenyl) methane and the elimination of 3 equiv of methane. Comparisons of its
catalytic properties with the less sterically hindered analogue 2, the more sterically hindered
analogue 3, a monomeric aluminum near-analogue 4, and a dimeric alumatrane 5 revealed
that 1 possesses superior activity.
Keywords Mukaiyama aldol reaction; trimeric; aluminum; tripodal ligand
INTRODUCTION
The Mukaiyama addition of a silyl enol ether to an aldehyde or ketone, leading to
β-hydroxy carbonyl compounds, is one of the most important carbon-carbon bond for-
mation reactions in classical organic synthesis.1 The commercial importance of a variety
of natural and synthetic products produced with this reaction has inspired considerable
efforts to develop more effective Mukaiyama aldol catalysts.2 In this regard, a variety
of Lewis acids and bases have been tested, including Bi(OTf)3,3 lanthanide iodides [e.g,
Received 6 February 2014; accepted 17 March 2014.
∗Dedicated to Professor Dr. Louis D. Quin on the occasion of his 86th birthday.
†
These authors contributed equally to this work.
‡
On Sabbatical Leave at Iowa State University.
Address correspondence to J. G. Verkade, Department of Chemistry, Iowa State University, Ames, Iowa,
USA, 50011-3111. E-mail: jverkade@iastate.edu
1193

1194
S. H. KIM ET AL.
SmI2(THF)2],4 CuF·3PPh3·2EtOH,5 MgI2·(OEt2)n,6 FeCl2,7 Me3SiOTf,8 Tf2CHCH2CHTf2
(a Bronsted acid precatalyst9), a Ti(IV) compound chelated by a chiral tridentate ligand
and 3,5-di-tert-butylsalicylate,10 Zr(IV) compounds with two modified chiral BINOL lig-
ands,11 N-heterocyclic carbenes,12 DBU,13 N-methylimidazole,14 lithium benzylate,15 and
proazaphosphatranes.16 Despite the numerous excellent catalysts for the Mukaiyama aldol
reaction that have been reported, the search for new catalysts remains of current interest.
The authors recognize that Al, the key element in the catalyst whose properties are
discussed in the present article, does not appear in the list of elements considered to be within
the Journal’s purview, namely, P, As, Sb, Bi; S, Se, Te; and Si, Ge, Sn. This list contains
elements usually classified as metalloids (Si, Ge, As, Sb, Te) nonmetals (P, S, Se) and metals
(Sn, Bi). Aluminum is usually classified as a metal because of its, metallic properties (e.g.,
high electrical and thermal conductivity, luster, malleability, and ductility).17 However,
because of several other properties which Al also possesses (e.g., directional bonding in
the solid state,18 covalent bonding in the majority of its compounds,19 formation of anionic
aluminates,20 amphoterism of its oxide21), Al has sometimes been classified as a metalloid.22
Based on the combination of metallic and metalloidal characteristics of this element, Al
could be eligible for inclusion in the list of elements whose chemistry is appropriate for
coverage in the Journal, particularly on the very special occasion of honoring Professor
Louis Quin in this issue.
Although Lewis acidic properties of aluminum compounds and their usefulness in
organic transformations are well-known, relatively few examples of such compounds [e.g.,
dimethylaluminum chloride,23 (2,6-dimethylphenoxy)dimethylaluminum,24 Me2AlNTf2,25
chiral tethered bis(8-quinolinolato) aluminum halide (TBOx),26 dimeric (2,7-disubsituted-
1,8-biphenylenedioxy)bis(dimethylaluminum),27 and monomeric/dimeric alumatrane com-
plexes ligated by tris(2-oxy-3,5-dialkylbenzyl)amine28,29] have been reported to function as
efficient promoters for the Mukaiyama aldol reaction. Interestingly, AlCl3 does not function
well as a catalyst for this reaction.30 All previous use of aluminum compounds as catalysts
for Mukayama reactions has focused on monomeric or dimeric aluminum systems;23–30
however, an example of a trimeric aluminum complex as a catalyst for this reaction has to
our knowledge not been reported.
Tripodal tris(2-hydroxy-3,5-dimethylphenyl)methane and its derivatives containing
various alkyl groups in the 3 and 5 positions of the phenyl rings are versatile ligands upon
deprotonation of their hydroxyl groups owing to coordination of their three phenoxide
oxygens to a variety of elements.25 Although many main group and transition metal com-
plexes containing such tripodal ligands31 have been reported, including an Al complex of
tris(2-oxy-3,5-di-tert-butylphenyl)methane,31c we found no reports describing their appli-
cation as catalysts for organic synthesis. Here we report for the first time the synthesis and
characterization of trimeric 1 and 2 and their efficacies as catalysts for the Mukaiyama
aldol reaction in comparison to 3–5 (Figure 1).
RESULTS AND DISCUSSION
The synthesis of 1 in 98% yield was accomplished by treating 3 equiv of AlMe3
◦
with tris(2-hydroxy-3-tert-butyl-5-methylphenyl)methane at 0 C in toluene. The axial
and equatorial trios of methyl groups bound to the Al centers are separated by 1.51 ppm
1
in the solution H NMR spectrum of 1 owing to differential shielding effects by the
aryl rings. In addition, despite a high quadrupolar relaxation rate for the 27Al nucleus

MUKAIYAMA ALDOL REACTIONS CATALYZED BY A TRIMERIC ORGANO
1195
Figure 1 Al complexes studied in this work.
(I = 5/2) and a broad background signal at about 60 ppm in the spectrum,32 a single broad
27Al NMR chemical shift was observed at 155.6 ppm, which is reasonably assigned to a
tetracoordinated aluminum atom in solution.33 Crystallographic studies that confirm the
structure shown for catalyst 1 will be published separately in due course.
The sterically less hindered analogue of 1, namely 2, was synthesized analogously in
99% yield using tris(2-hydroxy-3,5-dimethylphenyl)methane in the presence of trimethyl
aluminum. The sterically more hindered analogue 3 was synthesized via a literature proce-
dure31c in 95% yield using tris(2-hydroxy-3,5-di-tert-buthylphenyl)methane and trimethyl
aluminum. The monomeric near-analogue 4 was prepared in-situ in impure form [via the
reaction of trimethyl aluminum with 2-benzhydryl-6-(tert-butyl)-4-methylphenol] and was
used as such for catalytic screening. Evidence for the virtually quantitative conversion to 4
in its synthesis was the disappearance of the 1H NMR peak corresponding to the hydroxyl
proton of the ligand, and only small peaks assigned to impurities in its shifted and somewhat
more complicated spectrum. Alumatrane dimer 5 was prepared according to our previous
report.34
An evaluation of the relative efficacies of 1–5 in the room temperature aldol reaction of
Me2C C(OMe)OSiMe3 with o-anisaldehyde as a model reaction (Table 1) was carried out.
Good to excellent isolated yields of aldol products were obtained after room temperature
acid hydrolysis and purification by column chromatography. As shown in Table 1, 3.3 mol%
of 1 (10 mol% Al) in MeCN was the best catalyst system among those we tested (entries
1–2) while catalysts 2–5 gave lower yields of reaction products (entries 3–10). Surprisingly,
sterically crowded 1 facilitated higher yields (entries 1 and 2) than the sterically less
encumbered analogue 2 (entries 3 and 4) while the lower yields observed with the sterically
more hindered analogue 3 were expected (entries 5 and 6). In situ-generated monomeric
4 (which reasonably resembles one-third of a trimeric 1 molecule) and also the dimeric
alumatrane 5 led to relatively poor product yields (entries 5–8). Catalysts 1–5 displayed

1196
S. H. KIM ET AL.
Table 1 Survey of aluminum complexes in a Mukaiyama aldol reaction catalyzed by 1–5.a
Entry
Catalyst
Catalyst (mol%)
Al (mol%)
Yield (%)c
1
2
3
4
5
6
7
8
9
1a
2a
3a
4b
5a
3.3
1.7
3.3
1.7
3.3
1.7
10
5.0
5.0
2.5
10
5.0
10
5.0
10
5.0
10
5.0
10
92
89
84
78
82
81
64
42
70
66
10
5.0
aReaction conditions: 1 mmol o-anisaldehyde, 1.2 mmol Me2C C(OMe)OSiMe3, 5 mL acetonitrile, room
temperature, 1 h.
bReaction conditions: in situ-generated 4, 1 mmol o-anisaldehyde, 1.2 mmol Me2C C(OMe)OSiMe3, 1 mL
toluene + 4 mL acetonitrile, room temperature, 1 h.
cYields are averages of three runs.
greater catalytic activity for our model reaction in acetonitrile than in toluene. Because 5
required more than 30 min to dissolve in acetonitrile, even with vigorous stirring, the 1-h
reaction solution in Table 1 was created after 5 had dissolved. Because 4 is not soluble in
acetonitrile but is soluble in toluene, the reactions in entries 7 and 8 of Table 1 were carried
out in the solution that persisted after 3 had been dissolved in 1 mL of toluene followed by
the addition of 4 mL of acetonitrile.
We next examined a variety of aldehydes using the best catalyst (1) in the Mukaiyama
aldol reaction of Me2C C(OMe)OSiMe3. As observed in Table 1, better yields and/or
shortened reaction times for catalyst 1 than those for 5 were also observed in Tables 2–4.
Both electron-neutral and electron-donating aldehydes reacted with a slight excess of
Me2C C(OMe)OSiMe3 to afford the desired aldol products in good to excellent yields
within 30–180 min at room temperature (Table 2). Reaction times required for good product
yields varied, depending on the aldehyde employed. Electron-neutral aryl aldehydes, such
as benzaldehyde (entry 1), 1-naphthaldehyde (entry 2), and 2-naphthaldehyde (entry 3)
underwent clean addition reactions with Me2C C(OMe)OSiMe3 to give the expected aldol
products in excellent yields. However, the reaction time for 2-naphthaldehyde was longer
than for 1-naphthaldehyde to achieve a comparable yield of the corresponding aldol product.
Aldehydes with electron-donating substituents, such as those in entries 4–12, provided
good to excellent isolated yields of the corresponding aldol products. p-Tolualdehyde was
more reactive than o-tolualdehyde (entries 4–5), while o-anisaldehyde and p-anisaldehyde
showed similar reactivities (entries 6 and 8). Among the aldehydes in entries 6–8, m-
anisaldehyde provided the highest yield under the same reaction conditions. All the di-
substituted benzaldehydes investigated featured one methoxy group meta to the CHO
functionality, and as the second methoxy group moved closer to the CHO position, better
reactivity was observed (entries 9–11). Regardless of the acyclic or cyclic structures (entries

MUKAIYAMA ALDOL REACTIONS CATALYZED BY A TRIMERIC ORGANO
1197
Table 2 Scope of the Mukaiyama aldol reaction of electron-neutral and electron-donating aryl aldehydes with
Me2C C(OMe)OSiMe3 catalyzed by 1a
Entry
1
Aldehydes
Product
Time (min)
Yield (%)b
30
60
91
95
(Lit: 60)
(Lit: 95)
2
3
90
(Lit: 120)
88
(Lit: 88)
120
90
(Lit: 120)
(Lit: 92)
4
5
60
180
(Lit: 180)
82
97
(Lit: 91)
60
89
(Lit: 180)
(Lit: 85)
6
7
8
30
81
30
(Lit: 120)
90
(Lit: 92)
30
60
83
99
(Lit: 60)
(Lit: 90)
9
30
98
10
60
60
91
86
11
12
60
120
85
99
(Lit: 120)
(Lit: 98)
aReaction conditions: 1 mmol aldehyde, 1.2 mmol Me2C C(OMe)OSiMe3, 3.3 mol% 1, 5 mL CH3CN, room
temperature.
bIsolated yields after silica gel column chromatography. Times and yields in parentheses are literature values
associated with 5.22

1198
S. H. KIM ET AL.
Table 3 Scope of the Mukaiyama aldol reaction of electron-withdrawing aryl aldehydes with
Me2C C(OMe)OSiMe3 catalyzed by 1a
Entry
1
Aldehydes
Product
Time (min)
180
Yield (%)b
62
2
3
4
5
120
87
60 (Lit: 240)
96 (Lit: 93)
180
180
87
85
6
7
180 (Lit: 420)
180 (Lit: 360)
92 (Lit: 95)
91 (Lit: 92)
aReaction conditions: 1 mmol aldehyde, 1.2 mmol Me2C C(OMe)OSiMe3, 3.3 mol% 1, 5 mL CH3CN, room
temperature.
bIsolated yields after silica gel column chromatography. Times and yields in parentheses are literature values
associated with 5.28
11 and 12) product yields were similar. Interestingly, the best isolated product yield (98%)
was realized in only 30 min for 2,5-dimethoxybenzaldehyde (entry 9). Enolizable aldehydes
are apparently not favorable candidates under our conditions. Thus cinnamaldehyde did not
provide the desired product under the reaction conditions given in Table 1.
A variety of aldehydes bearing electron-withdrawing groups were also screened with
Me2C C(OMe)OSiMe3 using 1 as the catalyst, and the results are summarized in Table 3.
Except for 1-fluorobenzaldehyde (entry 1), all the other benzaldehydes in Table 3 provided
good to excellent isolated yields of aldol products within 60–180 min. Interestingly, 2-
chlorobenzaldehyde led to a better yield than 2-fluorobenzaldehyde despite the presence of a
more electronegative fluoro group in the latter (entries 1–2), whereas 4-chlorobenzaldehyde
gave a better yield than the less electronegative 4-bromobenzaldehyde (entries 3–4). The

MUKAIYAMA ALDOL REACTIONS CATALYZED BY A TRIMERIC ORGANO
1199
Table 4 Scope of the Mukaiyama aldol reaction of heterocyclic aldehydes with Me2C C(OMe)OSiMe3 cat-
alyzed by 1a
Entry
1
Aldehydes
Product
Time (min)
Yield (%)b
98 (Lit: 96)
180 (Lit: 360)
2
3
180
91
180 (Lit: 300)
98 (Lit: 91)
aReaction conditions: 1 mmol aldehyde, 1.2 mmol Me2C C(OMe)OSiMe3, 3.3 mol% 1, 5 mL CH3CN, room
temperature.
bIsolated yields after silica gel column chromatography. Times and yields in parentheses are literature values
associated with 5.28
three electron-deficient benzaldehydes (entries 5–7) and ester-functionalized methyl 4-
formylbenzoate underwent clean reactions giving good yields of products within 180 min
(entries 5–7).
We then turned our attention to screening several heterocyclic aldehydes with
Me2C C(OMe)OSiMe3 using catalyst 1, and the results are summarized in Table 4. The 5-
membered ring aldehydes bearing O or S heteroatoms afforded the expected aldol products
in excellent isolated yields (91–98%) within 180 min.
We then screened aldehydes with C6H5C( CH2)OSiMe3, C6H9OSiMe3, and (2-
C4H3O)OSiMe3 in the presence of 1 as shown in Table 5. A benzaldehyde containing
an electron-donating or electron-withdrawing substituent generally gave a good yield of
product as did a sterically bulky aliphatic aldehyde. Although there is an opportunity for 1,2
addition to the aldehyde with 2-(trimethylsiloxy)furan, the only products obtained stemmed
from the desired 1,4 addition process (entries 9–12).
It is interesting that aluminum catalysts for Mukaiyama reactions involving ke-
tone substrates have not been reported.23–30 We now disclose that Mukaiyama aldol
additions of the enol ether Me2C C(OMe)OSiMe3 to acetone, acetophenone, 2,2,2-
trifluoroacetophenone, and benzophenone are very efficient in the presence of 1 as catalyst,
◦
although a longer reaction time (72 h), lower reaction temperature (0–5 C) and a higher
catalyst loading (10 mol%) are required than for aldehydes (Table 6). It is interesting that the
reaction of Me2C C(OMe)OSiMe3 with ketones afforded the corresponding hydrolyzed
products after work up rather than TMS-protected species.

1200
S. H. KIM ET AL.
Table 5 Scope of the Mukaiyama aldol reaction of aldehydes with C6H5C( = CH2)OSiMe3,C6H9OSiMe3, and
(2-C4H3O)OSiMe3 catalyzed by 1a
Entry
1
Aldehydes
TMS-enolate
Product
Yield (%)b
91
2
97
94
3
4
91
94
5
6
97
7
96
90
90
8
9
10
96
98
11
12
91
aReaction conditions: 1 mmol aldehyde, 1.2 mmol TMS ether, 3.3 mol% 1, 5 mL CH3CN, room temperature,
180 min.
bIsolated yields after silica gel column chromatography.
Acetone, acetophenone, 2,2,2-trifluoroacetophenone, and benzophenone were also
screened with other silyl ethers such as TBDMSC( CH2)OMe, (tert-Bu)C( CH2)OTMS,
(2-C4H3O)OSiMe3, and PhC( CH2)OTMS using 1 as the catalyst, and the results are
summarized in Table 7. All the ketones in Table 7 provided excellent isolated yields of

MUKAIYAMA ALDOL REACTIONS CATALYZED BY A TRIMERIC ORGANO
1201
Table 6 Scope of the Mukaiyama aldol reaction of ketones with Me2C C(OMe)OSiMe3 catalyzed by 1a
Entry
1
Ketones
Product
Yield (%)b
92
2
3
95
93
90
4
aReaction conditions: 1 mmol ketone, 1.2 mmol Me2C C(OMe)OSiMe3, 10 mol% 1, 5 mL CH3CN, 0–5◦C,
72 h.
bIsolated yields after silica gel column chromatography.
◦
aldol products within 72 h at a reaction temperature of 0–5 C. Except for entries 8, 11,
12, and 15, the reactions of ketones with silyl ethers provided the corresponding α,β-
unsaturated ketones in excellent yield. It is not clear why elimination was not observed for
at least some of the ketones investigated.
Earlier we reported that dimeric alumatrane 5 is insoluble in acetonitrile, but upon
addition of benzaldehyde29 or 2-methoxybenzaldehyde28 to the mixture, a light yellow
solution formed and an isolable monomeric alumatrane adduct containing benzaldehyde
coordinated to the aluminum atom was obtained after workup. Similarly, an acetonitrile-d3
solution of trimeric 2 became reddish orange upon benzaldehyde addition. In carrying out
a similar experiment in an NMR tube, increasing the mole ratio of 2 beyond 1:1 induced
broadening of the PhC( O)H proton in its 1H NMR spectrum, which supports formation
of a 1:1 benzaldehyde adduct of 2.
EXPERIMENTAL SECTION
Synthesis of 1. A 2.0 M solution of AlMe3 in toluene (1.5 mL, 3.0 mmol) was added
dropwise to a solution of tris(2-hyd◦roxy-3-tert-butyl-5-methylphenyl)methane (0.50 g,
1.0 mmol) in toluene (30 mL) at 0 C. The reaction mixture was allowed to warm to
room temperature over 1 h and then was stirred overnight. All volatiles were evaporated
under reduced pressure, leaving a colorless solid, to which 10 mL of toluene were added.
The solution was then filtered and stored at –20 ◦C in a refrigerator. Yield, 98% (0.66 g). 1H

1202
S. H. KIM ET AL.
Table 7 Scope of the Mukaiyama aldol reaction of ketones with various enol ethers catalyzed by 1a
Entry
1
Ketones
TMS-enolate
Product
Yield (%)b
90
2
91
92
3
4
96
5
95
98
94
6
7
8
97
91
90
9
10
11
93
99
12
13
92
(Continued on next page)

MUKAIYAMA ALDOL REACTIONS CATALYZED BY A TRIMERIC ORGANO
1203
Table 7 Scope of the Mukaiyama aldol reaction of ketones with various enol ethers catalyzed by 1a (Continued)
Entry
14
Ketones
TMS-enolate
Product
Yield (%)b
91
95
15
aReaction conditions: 1 mmol ketone, 1.2 mmol Me2C C(OMe)OSiMe3, 10 mol% 1, 5 mL CH3CN, 0–5◦C,
72 h.
bIsolated yields after silica gel column chromatography.
NMR (400.15 MHz, C6D6, ppm): δ 8.84 (s, 1H, CH), 7.74 (s, 3H, PhH) 7.00 (s, 3H, PhH),
2.05 (s, 9H, CH3), 1.39 (s, 27H, C(CH3)3), 0.33 (s, 9H, Al-CH3), −1.17 (s, 9H, Al-CH3).
1
13C{ H} NMR (100.6 MHz, C6D6, ppm): δ 151.26, 139.81, 135.16, 128.85, 128.32, 127.29
(Ph), 35.70 (C(CH3)3), 32.27 (C(CH3)3), 27.83 (CH), 21.35 (CH3), −5.72 (Al-CH3), −7.96
(Al-CH3). 27Al NMR (104.2 MHz, C6D6, ppm): δ 155.6 (ꢀν1/2 = 2082.9 Hz). Anal. Calcd
for C40H61Al3O3: C, 71.61; H, 9.17. Found: C, 71.92; H, 9.56.
Synthesis of 2. This compound was prepared in 99% (0.54 g) yield by reacting AlMe3
(1.5 mL, 3.0 mmol) with tris(2-hydroxy-3,5-dimethylphenyl)methane (0.376 g, 1.0 mmol)
◦
1
in toluene (30 mL) at 0 C in a manner analogous to the procedure for 1. H NMR
(400.15 MHz, C6D6, ppm): δ 8.84 (s, 1H, CH), 7.52 (s, 3H, PhH), 6.54 (s, 3H, PhH), 2.06
(s, 9H, CH3), 1.99 (s, 9H, CH3), 0.21 (s, 9H, Al-CH3), –1.33 (s, 9H, Al-CH3). 13C{ H}
1
NMR (100.63 MHz, C6D6, ppm): δ 151.54, 135.31, 134.36, 130.85, 129.61, 126.47 (Ph),
29.23 (CH), 21.02 (CH3), 17.12 (CH3), −6.90 (Al-CH3), −11.60 (Al-CH3). 27Al NMR
(104.15 MHz, C6D6, ppm): δ 154.6 (ꢀν1/2 = 1978.8 Hz). Anal. Calcd for C31H43Al3O3:
C, 68.37; H, 7.96. Found: C, 68.26; H, 8.13.
Synthesis of 4. Sulfuric acid (1.66 mL, 30 mmol) was added dropwise to a solution of
2-tert-butyl-4-methylphenol (1.64 g, 10 mmol) and diphenylmethanol (1.84 g, 10 mmol) in
glacial acetic acid (40 mL) at room temperature. The reaction mixture was stirred overnight
and then 50 mL of distilled water was added. The aqueous layer was extracted twice
with diethyl ether (30 mL), and the combined organic portions were dried over MgSO4,
filtered, and evaporated to dryness. After washing with 20 mL of n-hexane and drying,
2-benzhydryl-6-tert-butyl-4-methylphenol was obtained as a colorless powder. Yield, 94%
(3.17 g). 1H NMR (400.15 MHz, C6D6, ppm): δ 7.32–7.12 (m, 9H, CH(C6H5)2), 7.00 (s,
1H, PhH), 6.39 (s, 1H, PhH), 5.57 (s, 1H, CH(C6H5)2), 4.49 (s, 1H, OH), 2.15 (s, 3H, CH3),
1
1.34 (s, 9H, C(CH3)3). 13C{ H} NMR (100.6 MHz, C6D6, ppm): δ 150.14, 142.06, 136.95,
130.62, 129.39, 128.84, 128.71, 128.50, 128.46, 126.93, 126.27, 126.24 (Ph, CH(C6H5)2),
51.79 (CH(C6H5)2), 34.54 (C(CH3)3), 29.87 (C(CH3)3), 21.11 (CH3). HRMS m/z calcd
for C24H26O (M+) 330.1984. Found 330.1980.
The 2-benzhydryl-6-tert-butyl-4-methylphenol obtained was used for the in-situ syn-
thesis of 4. A 2.0 M solution of AlMe3 in toluene (1.5 mL, 3.0 mmol) was added dropwise
to a solution of tris(2-hydroxy-3,5-dimethylphenyl)methane (0.376 g, 1.0 mmol) in toluene

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S. H. KIM ET AL.
(6 mL) at 0 ◦C. The reaction mixture was allowed to warm to room temperature over 1 h
and then stirred overnight. The solution was used directly as a stock solution of 4. The 1H
NMR spectrum of 4 is consistent with its proposed constitution.
RepresentativeProcedureforMukaiyamaAldolReactions ofMe2C C(OMe)OSiMe3
with Aryl Aldehydes Catalyzed by 1–5. To an oven-dried 10-mL vial equipped with a
magnetic stirring bar and a septum was added acetonitrile (5 mL), 1 (0.03 mmol), and
aldehyde (1.0 mmol). The mixture was stirred for 30 min at room temperature, followed
by addition of Me2C C(OMe)OSiMe3 (1.2 mmol). When the reaction was judged to be
complete by TLC, the reaction was quenched by adding 2 N HCl (3 mL) solution followed
by stirring the reaction mixture for an additional 3 h at room temperature. The reaction
mixture was extracted with methylene chloride and dried over Na2SO4, the solution was
filtered and dried on a rotavap apparatus, and then the crude product was purified by silica
gel column chromatography (EtOAc:hexanes = 1:9).
Methyl 3-hydroxy-2,2-dimethyl-3-(2,5-dimethoxybenzene)propionate. (Table 2, en-
1
try 9): yellow oil. H NMR (400.15 MHz, CDCl3, ppm): δ 6.86 (s, 1H, PhH), 6.76 (s,
2H, PhH), 5.21 (s, 1H, CHOH), 3.73 (s, 6H, OCH3), 3.69 (s, 3H, C( O)COCH3), 3.60
1
(br, 1H, OH), 1.13 (d, J = 17.6 Hz, 6H, C(CH3)2). 13C{ H} NMR (100.6 MHz, CDCl3,
ppm): δ 178.10, 153.23, 151.20, 129.03, 114.96, 113.17, 111.45 (Ph), 73.94 (CHOH),
55.67 (OCH3), 55.65 (OCH3), 51.97 (C( O)COCH3), 48.49 (C(CH3)2), 22.86 (C(CH3)2),
19.16 (C(CH3)2). HRMS m/z calcd for C14H20O5 (M+) 268.1311. Found 268.1306.
Methyl 3-hydroxy-2,2-dimethyl-3-(3,5-dimethoxybenzene)propionate. (Table 2, en-
1
try 10): yellow oil. H NMR (400.15 MHz, CDCl3, ppm): δ 6.43 (s, 2H, PhH), 6.35 (s,
1H, PhH), 4.79 (s, 1H, CHOH), 3.75 (s, 6H, OCH3), 3.69 (s, 3H, C( O)COCH3), 3.08
1
(br, 1H, OH), 1.10 (d, J = 14.4 Hz, 6H, C(CH3)2). 13C{ H} NMR (100.63 MHz, CDCl3,
ppm): δ 178.06, 160.15, 142.42, 105.78, 99.52 (Ph), 78.73 (CHOH), 55.28 (OCH3), 52.09
(C( O)COCH3), 47.63 (C(CH3)2), 23.07 (C(CH3)2), 19.32 (C(CH3)2). HRMS m/z calcd
for C14H20O5 (M+) 268.1311. Found 268.1305.
CONCLUSIONS
In summary, we have synthesized the novel bulky trimeric complex 1 in which an
(Me2Al)3O3 six-membered cyclohexanoid ring is axially bonded via the bridging phenoxide
oxygens of a tris(2-oxy-3-tert-butyl-5-dimethylphenyl)methane ligand. Complex 1 is a po-
tent catalyst at room temperature for Mukaiyama aldol reactions of Me2C C(OMe)OSiMe3
with a diverse range of aryl aldehydes. As Table 1 reveals, the catalytic activity of 1 is
superior to that of a less hindered trimeric analogue (2), a more hindered trimeric analogue
(3), a monomeric near-analogue (4), and a dimeric alumatrane (5). The superior nature of 1
over 5 in the reactions reported here is accentuated by our reaction times and yields realized
with 1 compared with those we reported earlier with 528 for 13 of the reactions reported
in Tables 2–4. Of those 13 reactions, 3 facilitated shorter times but greater yields, 5 facili-
tated shorter times and approximately the same yields, 2 facilitated equal times and greater
yields and 3 facilitated ca equal times and yields. Under the same conditions (Table 5) 1 also
showed excellent catalytic activity for the reactions of other enol ethers with aryl aldehydes
and bulky trimethylacetaldehyde. As shown in Tables 6 and 7, the catalytic activity of 1 for
the Mukaiyama addition of enol ethers to ketones was advantageously strong. However,
compared with aldehydes, a longer reaction time, a lower reaction temperature, and a higher
catalyst loading were required.

MUKAIYAMA ALDOL REACTIONS CATALYZED BY A TRIMERIC ORGANO
1205
FUNDING
The authors thank the National Science Foundation for financial support to JGV in the
form of grant 0750436. YK gratefully acknowledges the LG YONAM Foundation for its
financial support of his sabbatical stay at Iowa State University and the National Research
Foundation grant funded by the Korean Government (MOE) (2013R1A1A2006317).
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