Catalysis of Mukaiyama aldol reactions by a tricyclic aluminum alkoxide Lewis acid

Article abstract of DOI:10.1021/jo9009134

(Chemical Equation Presented) The Mukayiama aldol reaction of aldehydes is efficiently accomplished with a low concentration of the dimeric alumatrane catalyst 2 at mild or subambient temperatures. Our protocol tolerates a wide variety of electron-rich, neutral, and deficient aryl, alkyl, and heterocyclic aldehydes. A wide variety of enol silyl ethers are also tolerated. An intermediate that was isolated provides mechanistic information regarding the role of dimeric 2 in the Mukaiyama aldol reaction. Experimental evidence is presented for the stronger Lewis acidity of 5 compared with F₃B.

Full text of DOI:10.1021/jo9009134

pubs.acs.org/joc
Catalysis of Mukaiyama Aldol Reactions by a Tricyclic Aluminum
Alkoxide Lewis Acid
Steven M. Raders and John G. Verkade*
Department of Chemistry, Iowa State University, Ames, Iowa 50011
jverkade@iastate.edu
Received May 1, 2009
The Mukayiama aldol reaction of aldehydes is efficiently accomplished with a low concentration of
the dimeric alumatrane catalyst 2 at mild or subambient temperatures. Our protocol tolerates a wide
variety of electron-rich, neutral, and deficient aryl, alkyl, and heterocyclic aldehydes. A wide variety
of enol silyl ethers are also tolerated. An intermediate that was isolated provides mechanistic
information regarding the role of dimeric 2 in the Mukaiyama aldol reaction. Experimental evidence
is presented for the stronger Lewis acidity of 5 compared with F3B.
Introduction
Because of the utility of β-hydroxy carbonyl compounds,
many Lewis acid and Lewis base catalysts for their synthesis
have been investigated. Lewis acids that activate the carbonyl
moiety of an aldehyde or ketone in the Mukaiyama aldol
reaction include bismuth(III) triflate,2 lanthanum(III) bro-
Aldol reactions usually require electron deficient alde-
hydes and are often plagued by the formation of side
products such as R,β-unsaturated esters. Despite these defi-
ciencies, the Mukaiyama aldol reaction is one of the most
versatile carbon-carbon bond forming reactions allowing
access to synthetically challenging β-hydroxy carbonyl com-
pounds.1 Intensive efforts have been made to synthesize such
compounds owing to the pivotal nature of the Mukaiyama
aldol reaction in the synthesis of a variety of natural pro-
ducts.2 Utilization of this transformation for the synthesis of
β-hydroxy carbonyl compounds was a notable achievement
attained through the development of the addition of a silyl
enol ether to aldehydes and ketones. It may be noted that
very few methodologies for catalytic aldol reactions of
ketones have been developed compared with those for
aldehydes.3
mide,4 copper(I) fluoride,5 MgI2 (OEt2)n,5 iron(II) chloride,7
3
Me3SiNTf2,8 and Zr(IV) compounds.9 Common Lewis bases
that activate the silicon atom of silyl enol ethers utilized in the
Mukaiyama aldol reaction of aldehydes include N-heterocyclic
carbenes,10 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU),11 N-
methylimidazole,12 lithium benzylate,13 and amines.14 There
(4) Lannou, M.; Helion, F.; Namy, J. Tetrahedron 2003, 59, 10551–10565.
(5) Oisaki, K.; Suto, Y.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc.
2003, 125, 5644–5645.
(6) Li, W. Z.; Zhang, X. Org. Lett. 2002, 4, 3485–3488.
(7) Jankowska, J.; Paradowska, J.; Rakiel, B.; Mlynarski, J. J. Org.
Chem. 2007, 72, 2228–2231.
(8) Hiraiwa, Y.; Ishihara, K.; Yamamoto, H. Eur. J. Org. Chem. 2006,
1837–1844.
(9) Ishitani, H.; Ueno, M.; Kobayashi, S. J. Am. Chem. Soc. 1997, 119,
7153–7154.
(10) Song, J. J.; Tan, Z.; Reeves, J. T.; Yee, N. K.; Senanayake, C. H. Org.
Lett. 2007, 9, 1013–1016.
(11) Shen, Z.; Ji, S.; Loh, T. Tetrahedron Lett. 2005, 46, 507–508.
(12) Hagiwara, H.; Inoguchi, H.; Fukushima, M.; Hoshi, T.; Suzuki, T.
Tetrahedron Lett. 2006, 47, 5371–5373.
(13) Fujisawa, H.; Nakagawa, T.; Mukaiyama, T. Adv. Synth. Catal.
2004, 346, 1241–1246.
*To whom correspondence should be addressed. Phone: þ1 515 294 5023.
Fax: þ1 515 294 0105.
(1) For a referenced list of known Mukaiyama aldol products, see the
Supporting Information.
(2) Ollevier, T.; Bouchard, J.; Desyroy, V. J. Org. Chem. 2008, 73, 331–334.
(3) (a) Kobayashi, S.; Matsui, S.; Mukaiyama, T. Chem. Lett. 1988,
1491–1494. (b) Chen, J.; Sakamoto, K.; Orita, A.; Otera, J. J. Org. Chem.
1998, 63, 9739–9745. (c) Denmark, S. E.; Fan, Y. J. Am. Chem. Soc. 2002,
124, 4233–4235. (d) Oisaki, K.; Suto, Y.; Kanai, M.; Shibasaki, M. J. Am.
Chem. Soc. 2003, 125, 5644–5645. (e) Abe, M.; Shirodai, Y.; Nojima, M. J.
Chem. Soc., Perkin Trans I 1998, 3253–3260.
(14) (a) Zhuang, W.; Poulsen, T. B.; Jorgensen, K. A. Org. Biomol. Chem.
2005, 3, 3284–3289. (b) Mukaiyama, T.; Fujisawa, H.; Nakagawa, T. Helv.
Chim. Acta 2002, 85, 4518–4531.
DOI: 10.1021/jo9009134
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are also reports describing Lewis acids that have been grafted
onto polymer supports for recyclability in Mukaiyama aldol
reactions of aldehydes.15 Lewis basic ionic liquids have also
been shown to facilitate the synthesis of β-hydroxy carbonyl
products from aldehydes,16 and there are a few reports in
which photochemistry has been employed in the Mukaiyama
aldol reaction of aldehydes (although with the formation of
oxetene as a byproduct3d,17).
advantageous owing to their relatively low cost and toxicity.
Thus in view of the high concentrations required for
1 (R=Me), efforts to develop an aluminum Lewis acid able
to operate in catalytic amounts are worthwhile. In 2006, we
reported the synthesis of a novel tricyclic aluminum alkoxide
(alumatrane dimer 2) and showed that oxygen donor com-
pounds and amines can split this dimer to form monomeric
alumatranes.25 Of particular interest in the present context is
our observation that aldehydes rapidly split dimeric 2 to
Recent studies have centered on enolate substrates that
supply Mukaiyama aldol products similar to those provided
by the use of enol substrates. In 2006, Knochel and co-
workers developed an elegant route to β-hydroxy esters via a
Reformatsky reaction involving organozinc reagents instead
of silyl groups. Advantages of organozinc reagents include
their functional group tolerance, their stability in various
solvents, and the ease with which they are synthesized.18
β-Hydroxy esters are also obtainable by selectively opening
epoxides in the presence of a cobalt catalyst under an atmo-
sphere of carbon monoxide in methanol.19 Instead of tri-
methylsilyl enol ethers Nakajima and co-workers used
trichlorosilyl enol ethers in asymmetric aldol reactions car-
ried out in the presence of a chiral phosphine oxide
(S-BINAPO) to achieve high yields of the desired β-hydroxy
esters with high functional group tolerance.20 Scheeren and
co-workers developed a method for synthesizing β-hydroxy
esters from ketene acetals in the presence of 1 mol % of
readily available inexpensive zinc chloride.21 However, a
drawback of this procedure is that ketene acetals are not
commercially available and must be made from ortho esters
in the presence of a sterically hindered aluminum alkoxide.22
Reports of the use of aluminum Lewis acids in the
Mukaiyama aldol reaction are quite limited. Maruoka
et al. developed a bidentate organoaluminum Lewis acid 1
(R=Me) which, at the 1 equiv level, facilitated Mukaiyama
aldol reactions in methylene chloride at low temperatures to
produce high product yields.23 Maruoka et al. expanded
their methodology in 2007 by synthesizing several analo-
gues of the bidentate aluminum Lewis acid analogues of
1 (R=Me), namely, R=Ph, nOct, iPr, cHex, and H, in order
to evaluate the reactivity of different substituents in the
position ortho to the OAlMe2 groups.24 In that paper, it
was postulated that the use of the bidentate Lewis acid
1 (R=Me) doubly activates substrate carbonyls to augment
their reactivity and hence the selectivity of the carbonyl-
Lewis acid complexes for formation of the aldol product.
Again, however, one or more equivalents of 1 (R=Me) were
required to obtain high yields of the desired product.24
Aluminum compounds that function as efficient
promoters for the Mukaiyama aldol reaction would be
form monomeric alumatrane aldehyde adducts. It was
3
therefore speculated that 2 might serve as an advantageous
catalyst in various Lewis acid-catalyzed reactions, and herein
weexplore this application of this novel catalyst in Mukaiyama
aldol transformations.
Results and Discussion
Optimization Study of a Mukaiyama Aldol Reaction. The
coupling of o-anisaldehyde with methyl trimethylsilyl di-
methylketene acetal was conducted as a model screening
reaction and the results are summarized in Table 1. The
desired product was isolated after hydrolysis with 2 N aq
HCl after 24 h. By using 10 mol % of 2 in toluene at room
temperature, 40% of the desired product was obtained
(Table 1, entry 1). Interestingly, when the mole percentage
of alumatrane dimer 2 in toluene was decreased, the yield of
the desired products increased from 52% to 68% (Table 1,
entries 2-4). When the temperature was decreased from
room temperature to 0 °C, using 5 mol % of 2, the product
yield increased from 52% (entry 2) to 63% (entry 5).
Typically, Mukaiyama aldol reactions require a polar
solvent to obtain high yields. However, 2 in polar solvents
such as tetrahydrofuran or diethyl ether, form soluble ad-
ducts whose ligands are quite stable to further reactions such
as ether displacement by an aldehyde. On the other hand,
when dimer 2 is stirred in acetonitrile for 24 h, no adduct
1
formation is observed as shown by H NMR spectroscopy
and by visually observing that the alumatrane dimer 2
remains insoluble in this solvent as well as other solvents
that do not form adducts with 2.
When acetonitrile is used as the solvent for the screening
reaction in Table 1, a 5 mol % catalyst loading of 2 leads to a
nearly quantitative yield of product (entry 6). Upon lowering
the loading of dimeric 2 to 2.5 mol % and 0.5 mol %, 94%
and 84% yields of the desired product, respectively, were
obtained (Table 1, entries 7 and 8). Since we observed higher
product yields at lower loadings of 2 in toluene (entries 2-4),
the screening reaction was carried out with a 50/50 mixture of
acetonitrile/toluene containing 0.5 mol % of 2 in hopes of
substantially increasing the product yield over 84% in
(15) (a) Itsuno, S.; Arima, S.; Harauchi, N. Tetrahedron 2005, 61, 12074–
12080. (b) Takeuchi, M.; Akiyama, R.; Kobayashi, S. J. Am. Chem. Soc.
2005, 127, 13096–13097.
(16) (a) Chen, S.; Ji, S.; Loh, T. Tetrahedron Lett. 2004, 45, 375–377.
(17) Abe, M.; Ikeda, M.; Shirodai, Y.; Nojima, M. Tetrahedron Lett.
1996, 37, 5901–5904.
(18) Kloetzing, R. J.; Thaler, T.; Knochel, P. Org. Lett. 2006, 8, 1125–1128.
(19) Denmark, S. E.; Ahmad, M. J. Org. Chem. 2007, 72, 9630–9634.
(20) Kotani, S.; Hasimoto, S.; Nakajima, M. Tetrahedron 2007, 63, 3122–
3132.
(21) Aben, R. W.; Scheeren, J. W. Synthesis 1978, 400–402.
(22) McElvain, S. M.; Davie, W. R. J. Am. Chem. Soc. 1951, 73, 1400–1402.
(23) Ooi, T.; Tayama, E.; Takahasi, M.; Maruoka, K. Tetrahedron Lett.
1997, 38, 7403–7406.
(24) Ooi, T.; Takahashi, M.; Yamada, M.; Tayama, E.; Omoto, K.;
Maruoka, K. J. Am. Chem. Soc. 2004, 126, 1150–1160.
(25) Su, W.; Kim, Y.; Ellern, A.; Guzei, I. A.; Verkade, J. G. J. Am. Chem.
Soc. 2006, 128, 13727–13735.
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TABLE 1. Optimization of 2-Catalyzed Mukaiyama Aldol Reactions
TABLE 2. Reactions of Aryl Aldehydes with Methyl Trimethylsilyl
Dimethylketene Acetal
entry
alumatrance (mol %)
solvent
toluene
toluene
toluene
toluene
toluene
CH3CN
CH3CN
CH3CN
toluene/CH3CNd
CH3CN
yield (%)a,b
1
2
3
4
5
6
7
8
9
10
10
5
5
2.5
0.5
5
2.5
0.5
0.5
5
40
52
63c
60
68
99
94
84
86
74e
aReaction conditions: 1 mmol of o-anisaldehyde, 1.2 mmol of enol
silyl ether, 5 mL of solvent, rt, time: 24 h, then H3Oþ treatment. bAverage
c
d
of two runs. Reaction carried out at 0 °C for 3 days. 50/50 toluene/
CH3CN. eAlumatrane 326 was used for this reaction.
acetonitrile alone (entry 8) and 68% in toluene by itself (entry
4). However, the product yield rose to only 86%. The
sterically more congested alumatrane monomer 326 at
5 mol % loading was also screened, but the product yield
was only moderate (Table 1, entry 10). For the scoping
reactions discussed below, 2.5 mol % of 2 in acetonitrile
was employed unless noted otherwise.
Mukaiyama Aldol Reactions of Aryl Aldehydes with Met-
hyl Trimethylsilyl Dimethylketene Acetal. With use of the
optimized conditions in entry 7 of Table 1, the scope of our
methodology was explored with a variety of aryl aldehydes
(Table 2), including examples possessing activating or deac-
tivating functionalities. m-Anisaldehyde and p-anisaldehyde
when subjected to our protocol with methyl trimethylsilyl
dimethylketene acetal resulted in 92% and 90% yields of
the desired product (Table 2, entries 1 and 2, respectively) in
relatively short reaction times. A previous description of this
reaction with 5 mol % of MgI2 (OEt)n in CH2Cl2 for 30 min
3
resulted in only a 30% product yield.6 Deactivating groups
such as nitro, cyano, and ester functionalities were also
compatible with our protocol (entries 3-5, respectively).
Interestingly, dimer 2 prefers to cleave to form an adduct
with an aldehyde carbonyl rather than an ester carbonyl as
shown in entry 5, wherein a 92% isolated yield of the desired
β-hydroxy ester is recorded. Sterically hindered aldehydes
such as 1-naphthaldehyde and o-tolualdehyde provide the
corresponding products in 88% and 91% isolated yield,
respectively (Table 2, entries 7 and 8). Pleasingly, halogen-
substituted aryl aldehydes are stable to hydrodehalogena-
tion under our conditions (entry 11). p-Trifluorotolualde-
hyde reacted with methyl trimethylsilyl dimethylketene
acetal in the presence of 2, affording a 92% yield of the
desired β-hydroxy ester (entry 12). The highest yield of this
compound reported in the literature is 68%.3
aReaction conditions: 1 mmol of aldehyde, 1.2 mmol of enol silyl
ether, 2.5 mol % of dimeric 2, 5 mL of CH3CN, rt, 1-10 h, then H3Oþ
treatment. bAverage of two runs. Yields in parentheses are literature
yields (see the Supporting Information for references).
Mukaiyama Aldol Reaction of Heterocyclic and Alkyl
Aldehydes with Methyl Trimethylsilyl Dimethylketene Acetal.
With use of the optimized conditions in entry 7 of Table 1,
3-pyridinecarboxaldehyde was subjected to our protocol with
2.5 mol % of 2. With methyl trimethylsilyl dimethylketene
acetal in acetonitrile at room temperature, a 96% yield of the
desired β-hydroxy ester was achieved (Table 3, entry 1). This
yield is somewhat higher than the highest yield found in the
literature for this compound, which was synthesized by com-
bining 3-pyridinecarboxaldehyde and the appropriate enol
(26) Su, W.; Kobayashi, J.; Ellern, A.; Kawashima, T.; Verkade, J. G.
Inorg. Chem. 2007, 46, 7953–7959.
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TABLE 3. Hetero and Alkyl Aldehydes with Methyl Trimethylsilyl
Dimethylketene
product) decomposed to an intractable material upon
attempted purification by column chromatography. Column
chromatographic purification of the trimethylsilyl-protected
product failed, owing to desilylation and subsequent decom-
position.
The sulfur-containing heterocycles 2-thiophenecarboxal-
dehyde and thianaphthene-3-carboxaldehyde upon reaction
with methyl trimethylsilyl dimethylketene acetal produced
96% and 73%, respectively, of the desired products (entries
4 and 5 in Table 2). However, the latter reaction in the pre-
sence of 5 mol % of dimer 2 increased the product yield to
87% (entry 5). Alkyl aldehydes in our protocol gave good
product yields of 86% and 89% (entries 6 and 7, respec-
tively). The vinylic aldehyde in entry 8 can be used in our
procedure, but only a 52% yield of desired product was
realized owing to the Michael addition product that also
1
formed, as shown by the H NMR spectrum of the crude
reaction mixture. A higher loading of dimer 2 or a change of
solvent did not improve the yield of the desired product.
Mukaiyama Aldol Reaction of Various Aldehydes with
6-(tert-Butyldimethylsilyloxy)-3,4-dihydro-2H-pyran and 2-(Tri-
methylsiloxy)furan. 2-(Trimethylsiloxy)furan operates well in
our protocol, undergoing coupling with o-anisaldehyde with
use of the optimized conditions in Table 1, entry 7, to give
86% of the desired product (Table 4, entry 1). Although there
is an opportunity for 1,2 addition to the aldehyde with this
enol silyl ether, the only products obtained stemmed from the
desired 1,4 addition process. During the course of our study,
we discovered that for this reaction to occur, only aryl
aldehydes with ortho substituents or aryl aldehydes with
electron withdrawing substituents anywhere on the ring
functioned satisfactorily in our procedure. When m-anisal-
dehyde was employed, 5 mol % of 2 was required to obtain a
51% yield of the desired product (Table 4, entry 2). However,
when 4-cyanobenzaldehyde was used, 84% of the desired
product was obtained in a 1/2 syn/anti ratio (Table 4,
entry 3). 2-Fluorobenzaldehyde in our procedure gave a
93% product yield in a 1:1 syn:anti ratio (Table 4, entry 4)
but the use of o-tolualdehyde provided only a 61% yield.
However, when 5 mol % of dimeric 2 was used for the
reaction of the latter aldehyde, the yield increased to 72%
with a 1:4 syn:anti ratio (Table 4, entry 5).
The heterocyclic aldehyde 6-methylpyridinecarboxalde-
hyde is compatible with 2-(trimethylsiloxy)furan. However,
the desired product was isolated as the trimethysilyl-pro-
tected analogue because the hydrolyzed product decom-
posed on the chromatography column (Table 4, entry 6).
The isomeric selectivity of the reactions with 2-(trimethylsi-
loxy)furan was not appreciably changed upon increasing the
temperature from 0 to 70 °C.
Mukaiyama aldol reactions in which the β-hydroxy ester
product possesses acidic protons are plagued by dehydration
under basic conditions to produce the corresponding R,β
unsaturated esters.10,14 In an effort to expand the scope of
our methodology, a variety of aldehydes were coupled with
different silyl enol ethers to produce products with acidic
protons. To this end, 6-(tert-butyldimethylsilyloxy)-3,4-di-
hydro-2H-pyran was coupled with o-anisaldehyde by using
the optimized conditions in Table 1, entry 7. When the
reaction was carried out at room temperature, the major
product was the R,β unsaturated ester. Pleasingly, however,
lowering the temperature to 0 °C afforded the desired
aReaction conditions: 1 mmol of aldehyde, 1.2 mmol of enol silyl
ether, 2.5 mol % of dimeric 2, 5 mL of CH3CN, rt, 1-12 h, then H3Oþ
treatment. bAverage of two runs. Yields in parentheses refer to literature
yields (see the Supporting Information for references). c5 mol % of 2 was
used.
silyl ether in water after stirring for 24 h.27 A compound
containing two hetero atoms (Table 3, entry 2) provided a
95% yield of the desired product. This compound was pre-
viously synthesized only once according to the literature, in a
reaction using a PEG-supported ligand in the presence of 30
mol % of Cu(OTf)2,28 resulting in only a moderate yield (75%)
of the desired product.
Oxygenated heterocycles are also amenable to our proto-
col and are apparently not vulnerable to adduct formation
with 2 as is the case with THF.25 Thus when 2-benzofur-
ancarboxaldehyde was subjected to our protocol, 91% of the
desired (but previously unreported) β-hydroxy ester in entry
3 was realized. 2-Furaldehyde when subjected to our proto-
col underwent>95% conversion to the trimethylsilyl-pro-
tected product as revealed by 1H NMR spectroscopy.
However, after hydrolysis, the desired product (which was
shown to be present in the 1H NMR spectrum of the crude
(27) Loh, T.; Feng, L.; Wei, L. Tetrahedron 2000, 56, 7309–7312.
(28) Maurizio, B.; Cinquini, M.; Franco, C.; Giuseppe, C. Org. Biomol.
Chem. 2004, 2, 3401–3407.
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TABLE 4. Various Aldehydes with 6-(tert-Butyldimethylsilyloxy)-3,4-dihydro-2H-pyran and 2-(Trimethylsiloxy)furan
aAverage of two runs. bReaction conditions: 1 mmol of aldehyde, 1.2 mmol of enol silyl ether, 2.5 mol % of dimeric 2, 5 mL of CH3CN, rt, 1-3 h,
H3Oþ treatment. cReaction conditions: 1 mmol of aldehyde, 1.2 mmol of enol silyl ether, 2.5 mol % of dimeric 2, 5 mL of CH3CN, 0 °C, 6-15 h, then
treatment with TBAF. Yields in parentheses are literature yields (see the Supporting Information for references). dSyn/anti ratio determined by either
1H NMR spectroscopy or weight of separated isomer. e5 mol % of dimeric 2 was used.
β-hydroxy ester in 88% isolated yield after 7 h (Table 4,
spectroscopy. 1H NMR spectroscopy also revealed that the
final product was obtained in a 1:1 syn:anti ratio. This result
entry 7) with no dehydration product observed by 1H NMR
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demonstrates that our protocol not only tolerates trimethyl-
silyl-protected silyl enol ethers, but also tert-butyldimethyl-
silyl-protected silyl enol ethers which are more stable to
normal hydrolytic workup.
TABLE 5. Various Aldehydes with 1-(tert-Butydimethylsilyloxy)-1-
methoxyethene
Methyl 4-formylbenzoate, p-tolualdehyde, and 3-iodo-
benzaldehdye reacted with 6-(tert-butyldimethylsilyloxy)-
3,4-dihydro-2H-pyran affording 91%, 92%, and 83% yields,
respectively, of the desired products, each in a 1:1 syn:anti
ratio (Table 4, entries 8-11). However, when 4-formyl-
benzoate was used, the silyl-protected product was isolated
because on TBAF treatment, this product produced only the
R,β-unsaturated ester (Table 4, entries 8 and 9). Enolizable
hydrocinnamaldehyde gave an 87% isolated yield of product
in a 1:2 syn:anti ratio (Table 4, entry 12).
Mukaiyama Aldol Reaction of Various Aldehydes with
1-(tert-Butyldimethylsilyloxy)-1-methoxyethene. Since the
use of monosubstituted silyl enol ethers produced satisfying
results, we investigated a silyl enol ether lacking olefinic
substitution, namely, 1-(tert-butyldimethylsilyloxy)-1-meth-
oxyethene. At 0 °C, a variety of aldehydes reacted with this
silyl enol ether in the presence of 2.5 mol % of dimer 2, giving
the corresponding β-hydroxy ester products in high yields
with no dehydration products observable by 1H NMR
spectroscopy. Thus, o-anisaldehyde reacted with 1-(tert-
butyldimethylsilyloxy)-1-methoxyethene, leading to the de-
sired β-hydroxy ester in 90% yield (Table 5, entry 1). We
were able to find only one previous report of the synthesis of
this compound, and its low yield (33%) emanated from a
reaction with 10 mol % of DBU in THF at room temperature
for 24 h.11 3,5-Dimethoxybenzaldehyde is also a viable
substrate for our procedure, producing the expected (but
heretofore unreported) product in 96% isolated yield
(Table 5, entry 2).
Electron-deficient aryl aldehydes bearing a cyano or acetyl
group also function in our protocol (Table 5, entries 3 and 4,
respectively) producing the desired (but unreported) pro-
ducts in both cases. Although the product yield was only
57% in the latter case, 5 mol % of 2 raised this yield to 89%
(Table 5, entry 4). Electron-neutral aryl aldehydes also
provided high yields of the desired β-hydroxy ester (Table 5,
entries 5, 6, and 8).
Use of the sterically hindered aryl aldehyde 2-biphenyl-
carboxaldehyde facilitated a 94% product yield (Table 5,
entry 7) and heterocyclic 2-benzofurancarboxaldehyde also
led to an excellent product yield (95%, entry 9). The only
reported method we were able to find for synthesizing the
latter product was one in which the corresponding ketone
was presynthesized by reacting 2-acetylbenzofuran with
dimethyl carbonate in the presence of sodium hydride,
affording an 87% yield of the R-ketone, which upon sub-
sequent reduction with tartaric acid-modified Raney nickel
in the presence of hydrogen gave 100% of the β-hydroxy
ester.29 Reaction of 4-methyl-2-thiazolecarboxaldehyde with
1-(tert-butyldimethylsilyloxy)-1-methoxyethene gave the de-
sired (but unreported)product in81% isolated yield (Table5,
entry 10).
aReaction conditions: 1 mmol of aldehyde, 1.2 mmol of enol silyl
ether, 2.5 mol % of dimeric 2, 5 mL of CH3CN, 0 °C, 6-16 h, then
treatment with TBAF. bAverage of two runs. Yields in parenthesis refer
to literature yields (see the Supporting Information for references).
c5 mol % of 2 was used.
desired product (Table 5, entry 11). Literature methods for
synthesizing this product include alkylation of the dianion of
methylacetoacetate with benzyl bromide,30 and a seven-step
synthesis beginning with a sulfinate that was allowed to react
sequentially with carbon dioxide, benzyl bromide, and
diazomethane in the presence of aluminum amalgam to
The alkyl aldehyde hydrocinnamaldehyde when reacted
with 1-(tert-butyldimethylsilyloxy)-1-methoxyethene in the
presence of 2.5 mol % of dimer 2 afforded a 90% yield of the
(29) Haruna, N.; Acosta, D. E.; Nakagawa, S.; Yamaguchi, K.; Tai, A.;
Okuyama, T.; Sugimura, T. Heterocycles 2004, 62, 375–386.
(30) Kamal, A.; Krishnaji, T.; Khanna, G. B. R. Tetrahedron Lett. 2006,
47, 8657–8660.
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SCHEME 1. Suggested Pathway of the Mukaiyama Aldol Reaction of o-Anisaldehyde with Alumatrane Dimer 2
desulfinate the final product, resulting in an overall 80%
isolated yield.31 Product yields in the literature for this
compound ranged from 16% to 87%.
2,6-dimethylbenzaldehdye and 2,6-dimethoxybenzaldehdye
failed to produce detectable amounts of product (as shown
1
by H NMR spectroscopy) even though adduct formation
Structural and Mechanistic Considerations. Earlier we
reported that alumatrane dimer 2 is insoluble in acetonitrile,
but upon addition of benzaldehyde to the mixture, a light
yellow solution is formed. The same observation for the
various aldehydes employed in the present study is consistent
with splitting of dimeric 2 by the aldehydic oxygen to form
adducts such as 4 in Scheme 1. Adduct 4 was synthesized and
was indicated by the solubility of dimer 2 in acetonitrile when
either of these aldehydes was added. It would thus appear
that the bulk of the second ortho substituent in combination
with that of the alumatrane moiety increases the steric
shielding of the carbonyl carbon to the point where nucleo-
philic attack by the double bond of the silyl enol ether is
prevented, even though coordination of the aldehyde oxygen
to the aluminum might render the aldehyde carbon suffi-
ciently electrophilic.
If attack of 4 by an enol silyl ether is able to occur
(Scheme 1) it appears that the alumatrane monomer moiety
13 is then released from the adduct to immediately form an
adduct with another aldehyde before reforming dimer 2. This
assumption is based on our observation that no solids were
formed during the reaction until all of the aldehyde is con-
sumed. At the point in the reaction where insoluble dimer 2
began to form, a 2 M solution of aq HCl was added to the
reaction mixture to hydrolyze the silylated penultimate pro-
duct to the final aldol product. To demonstrate that the
precipitate was indeed 2, it was filtered under inert atmosphere
immediately after its formation (before hydrolytic workup)
and reused successfully in a duplicate reaction. Additional
evidence that the precipitate is 2 came from our observation of
similar recyclability of precipitated 2 in experiments involving
the addition of TMSCN to aldehydes.32
crystals suitable for X-ray analysis were grown from a 10:1
mixture of pentane:toluene (Figure 1). As shown in this
figure, the methoxy group appears to be quite free of steric
encumbrance by any of the three neighboring methyl groups
on the alumatrane moiety.
A comparison of some of the major X-ray crystallographic
structural parameters of 4 with the corresponding ones in
5-12 is of interest. Because such a comparison is not of
particular relevance to the thrust of the present work, however,
this discussion can be found in the Supporting Information.
Earlier in this paper it was noted that although 2-substi-
tuted aryl aldehydes functioned well in our protocol,
Lewis Acidity of 13. The existence of a N f Al dative bond
in monomeric 2 (as represented by 13) might be expected to
diminish its Lewis acidity sufficiently to preclude its useful-
ness in transformations such as the Mukaiyama aldol reac-
tion. In a previous publication we reported calculational
(31) Fujisawa, T.; Fujimura, A.; Sato, T. Bull. Chem. Soc. Jpn. 1988, 61,
1273–1279.
(32) Raders, S. M.; Verkade, J. G. Manuscript in progress.
J. Org. Chem. Vol. 74, No. 15, 2009 5423

Raders and Verkade
JOCArticle
results indicating that 13 is more Lewis acidic than BF3.26 In
the present work we provide experimental support for this
conclusion. Herein we measured the 31P NMR chemical
shifts of 13 OdPEt3 (61 ppm) and F3B OdPEt3 (78 ppm)
in C6D6, and we also characterized the former compound by
single-crystal X-ray crystallography (Figure 3). (Crystals of
13 OdPEt3 were grown from a concentrated solution of
toluene in a freezer for 2 days.) Both of the aforementioned
31P chemical shifts are downfield of the 55 ppm we measured
for OdPEt3 in the same solvent. However, the relative
magnitudes of these deshieldings cannot be taken to be
indicative of the relative Lewis acidities of 13 and BF3, owing
to differences in paramagnetic effects of the boron and
aluminum nuclei. We then added 1 equiv of triethyl phos-
3
3
3
phine oxide to a mixture of 1.1 equiv of BF3 OEt2 in toluene
to form the BF3 OdPEt3 adduct whose 31P NMR spectrum
was then taken (Scheme 2). The BF3 OdPEt3 adduct was
3
3
3
then dried under reduced pressure leaving a white solid to
which a 0.5 mol equiv of the alumatrane dimer 2 was added
to determine if the dimer was capable of removing OPEt3
from the BF3 OdPEt3 adduct. Consistent with the greater
Lewis acidity of 13, the 31P NMR spectrum of the reaction
3
mixture revealed only the 31P chemical shift of 13 OdPEt3
(Figure 2).
3
In a further effort to substantiate these results, the product
yields of the reaction of o-anisaldehyde and methyl tri-
methylsilyl dimethylketene acetal in the presence of dimer
2 and BF3 OEt2 were compared (Table 6). The reactions
were carried out in acetonitrile with 2.5 mol % of dimeric 2
3
and 5 mol % of BF3 OEt2, and after 1 h, the reactions were
quenched with 2 N aq HCl. As depicted in Table 6, the
3
alumatrane dimer 2 provided a 97% yield of the desired
product (entry 1), whereas BF3 OEt2 led to only a 35%
FIGURE 1. Computer drawing of the molecular structure of 4
3
at the 50% probability level. Hydrogen atoms are omitted for
˚
product yield (entry 2). This contrast in efficacy of 2 com-
pared with BF3 OEt2 is made the more striking because
clarity. Major bond distances: Al-N, 2.101(3) A; avg Al-Oeq
,
˚
˚
˚
1.751(3) A; Al-Oax, 1.986(3) A; CdO, 1.216(3) A. Major bond
angles: avg N-Al-Oeq, 92.76(13)°; avg Oeq-Al-Oeq, 119.77(12)°;
avg Oeq-Al-Oax, 87.26(13)°.
3
energy is required to split dimer 2 into 13, the Lewis acidic
species needed for carbonyl activation. These results are
FIGURE 2. (a) 31P NMR of OdPEt3 in C6D6. (b) 31P NMR of BF3 OdPEt3 in C6D6. (c) 31P NMR after addition of alumatrane dimer 2 to
BF3 OdPEt3.
3
3
5424 J. Org. Chem. Vol. 74, No. 15, 2009

Raders and Verkade
JOCArticle
TABLE 6. Comparison Reactions between Alumatrane Dimer 2 and
F3B OEt2
3
entry
Lewis acid
yield (%)a,b
1
2
3
4
2
BF3 OEt2
97
35
92
24
3
2c
BF3
d
aReaction conditions: 1 mmol of o-anisaldehyde, 1.2 mmol of methyl
trimethylsilyl dimethylketene acetal, 2.5 mol % alumatrane dimer 2, 5
mL of CH3CN, RT, 1 h, then H3Oþ treatment. bAverage of two runs. c5
mol % of diethyl ether added to the reaction mixture. d5 mol % as a 15%
solution in CH3CN.
TABLE 7. Comparison of Bond Lengths and Angles of Phosphine
Oxide Lewis Acid Adducts
entry
compd
PdO
LAa-O
LAa-O-P
FIGURE 3. Computer drawing of the molecular structure of
13 OdPEt3 at the 50% probability level. Hydrogen atoms are
omitted for clarity.
1
2
3
4
5
6
13 OdPEt3
1.499(6)
1.488(4)
1.497(17)
1.522(2)
1.519(4)
1.522(3)
1.850(6)
146.2(4)
3
14b
15c
16d
17c
18f
3
1.533(3)
1.925(2)
1.733(4)
1.526(6)
161.04(16)
142.5(1)
180
SCHEME 2. Reactions of Triethylphosphine Oxide with F3B
OEt2 and Alumatrane Dimer 2
134.5(2)
3
aLA=Lewis Acid. bSee ref 33. cSee ref 34. dSee ref 35. eSee ref 36. fSee
ref 37.
as do the three equatorial phenoxy oxygens. On the other
hand, the LA-O bond length in 13 OdPEt3 is shorter than
3
that in 16 wherein the lower electronegativity/electron-with-
drawing effect of Ge compared with Al and the higher
coordination number of 16 lengthens the LA-O bond
length. The longer LA-O bond length in 13 OdPEt3 than
in 15 and 18 can be attributed to the smaller size and greater
electronegativity of B relative to Al as well as the expanded
3
supportive of our earlier calculational results indicating that
13 is more Lewis acidic than BF3.26 Another experiment was
carried out with2.5mol % of alumatranedimer2 and 5 mol %
of diethyl ether in order to demonstrate that the presence of
diethyl ether does not materially affect the outcome of the
reaction. Pleasingly, 92% of the desired product was obtained
(entry 3). Since energy is also required to dissociate the
coordination number of Al in 13 OdPEt3. Unlike 17 (which
exhibits a 180° bond angle between the phosphorus
3
and the Lewis acid atom) 13 OdPEt3 displays a bond
angle of 146.2°. The origin of this difference is not readily
apparent.
3
ether moiety from BF3 OEt2, we carried out a reaction
3
using 5 mol % of BF3 obtained from a commercially avail-
able stock solution containing 15% BF3 in acetonitrile. Only
24% of the desired product was obtained in this reaction
(entry 4).
Since 13 OdPEt3 represents only the second example of
an Al OdPEt3 adduct and, more particularly, the first
3
3
Conclusions
example of an alumatrane OdPEt3 adduct whose molecular
structures have been determined by X-ray means, it is of
3
We have demonstrated the usefulness of alumatrane dimer
2 in the Mukaiyama aldol reaction. Our protocol tolerates a
wide variety of aryl, heterocyclic, and alkyl aldehydes and
interest to compare some structural parameters of 13
OdPEt3 with analogous metrics in phosphine oxide 14 and
in selected Lewis acid phosphine oxide complexes 15-18
3
(Table 7). The PdO bond in 13 OdPEt3 is within 3ꢀ the esds
3
ꢀ
(33) Novoa de Armas, H.; Perez, H.; Peeters, O. M.; Balton, N. M.;
de Ranter, C. J.; Lopez, J. M. Acta Cyrstallogr. Sect. C 2000, C56, e98–e99.
(34) Beckett, M. A.; Brassington, D. S.; Coles, S. J.; Hursthouse, M. B.
Inorg. Chem. Commun. 2000, 3, 530–533.
(35) Cheng, F.; Davis, M. F.; Hector, A. L.; Levason, W.; Reid, G.;
Webster, M.; Zheng, W. Eur. J. Inorg. Chem. 2007, 2488–2495.
(36) Burford, N.; Royan, B. W.; Spence, R.; Cameron, S.; Linden, A.;
Rogers, R. D. J. Chem. Soc., Dalton Trans. 1990, 1521–1528.
(37) Burford, N.; Spence, R.; Linden, A.; Cameron, S. Acta Crystallogr.
1990, C46, 92–95.
for this link in 14-18. Thus, there appears to be no sig-
nificant effect of the Lewis acids considered here on the PdO
bond distances in their phosphine oxide adducts 15-18. The
ꢀ
LA-O bond length in 13 OdPEt3 is longer than that in 17,
3
an observation that can be rationalized by the higher co-
ordination number of the aluminum in 13 OdPEt3 in which
the transannular N enriches the electron density on the metal
3
J. Org. Chem. Vol. 74, No. 15, 2009 5425

Raders and Verkade
JOCArticle
has high functional group tolerance. Ketone substrates failed
in our protocol, however. It should be noted that our
protocol requires the presence of an electron-donating OR
group on the olefin of the silyl enol ether. Other silyl
enol ethers [such as 1-phenyl-1-trimethylsiloxyethylene and
1-(trimethylsiloxy)cyclohexene] in the presence of o-anisal-
dehyde produced no desired products. But when 6-(tert-
butyldimethylsilyloxy)-3,4-dihydro-2H-pyran was employed
in this reaction, the desired product was obtained in high yield
(88%). It is reasonable to suggest that the presence of the
electron-inducting OR substituent on the olefinic moiety
provides the latter with sufficient nucleophilicity for attack
of the Lewis acid-activated carbonyl group. Our proposed
mechanism receives support from the isolation and structural
characterization of intermediate 4. Evidence supporting our
postulate that monomeric 2 (i.e., 13) is more Lewis acidic than
BF3 has also been presented. Comparisons of structural
parameters obtained from single-crystal X-ray experiments
δ 173.6, 173.2, 160.9, 160.8, 158.5, 158.4, 153.5, 153.0, 130.4 (d,
J=8.3 Hz), 130.1 (d, J=8.2 Hz), 128.6 (d, J=3.6 Hz), 128.1 (d,
J=3.8 Hz), 125.7 (d, J=13 Hz), 125.5 (d, J=13.2 Hz), 124.8,
123.5 (d, J = 5 Hz), 123.1 (d, J = 4.9 Hz), 115.7 (d, J=15.9 Hz),
115.4 (d, J = 15.7 Hz), 86.7, 85.6, 68.8, and 67.3 ppm; 19F NMR
(376 MHz, CDCl3) δ -118.07 and -118.41 ppm; HRMS m/z
calcd for C11H9FO3 (Mþ) 208.05357, found 208.05393.
Synthesis of 5-(Trimethylsiloxy(2-(6-methylpyridine))methyl)
furan-2(5H)-one (Table 4, entry 6). To a 10 mL vial equipped
with a stir bar was added 22.15 mg (2.5 mol %) of alumatrane
dimer 2 in a glovebox. Acetonitrile (5 mL) was added to the vial,
followed by 1 mmol of 6-methylpyridine-2-carboxaldehyde. The
reaction mixture was stirred for 30 min at room temperature to
form the aldehyde-alumatrane adduct and then 2-(trimethylsi-
loxy)furan (1.2 mmol) was added under inert atmosphere. The
reaction was allowed to proceed for 1 h at room temperature and
then the solid alumatrane dimer was filtered. The reaction
mixture was concentrated on a rotovap and the crude product
was purified by column chromatography (EtOAc:hexanes =
1:9). Clear, colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.61-
7.65 (t, 1H, J = 7.6 Hz), 7.25-7.27 (d, 1H, J = 8 Hz), 7.08-7.13
(m, 2H), 6.10-6.11 (d, 1H, J = 5.6 Hz), 5.58-5.59 (d, 1H,
J=1.2 Hz), 5.1-5.19 (d, 1H, J=2.8 Hz), 2.55 (s, 3H), and 0.11
(s, 9H) ppm; 13C NMR (100 MHz, CDCl3) δ 173.4, 158.7, 158.1,
152.8, 137.4, 123.2, 122.7, 117.7, 86.4, 74.7, 24.6, and 0.1 ppm;
HRMS m/z calcd for C14H19NO3Si (Mþ) 277.11341, found
277.11402.
for 4 and 13 OdPEt3 and for related compounds in the
3
literature are rationalized in terms of central atom electro-
negativity and coordination number expansion effects.
Further investigations illustrating the usefulness of dimer 2
in Lewis acid-catalyzed organic reactions are underway.
Experimental Section
General Procedure for Mukaiyama Aldol Reaction of 6-(tert-
Butyldimethylsilyloxy)-3,4-dihydro-2H-pyran and 1-(tert-Butyl-
dimethylsilyloxy)-1-methoxyethene. To a 10 mL vial equipped
with a stir bar was added 22.15 mg (2.5 mol %) of alumatrane
dimer 2 in a glovebox. Acetonitrile (5 mL) was added to the vial
followed by 1 mmol of the corresponding aldehyde, and then the
reaction mixture was stirred for 30 min at room temperature to
form the aldehyde-alumatrane adduct. The reaction mixture
was then cooled to 0 °C and 1.2 mmol of the corresponding silyl
enol ether was added under inert atmosphere. The reaction was
allowed to proceed for the allotted time as specified in the tables
and then a 0 °C solution of 3 mmol of a 1 M TBAF/THF
solution was added. The mixture was stirred at 0 °C for 1 h after
which 3 mL of water was added with stirring for an additional
hour at 0 °C. The reaction mixture was extracted with methylene
chloride (2 ꢀ 100 mL portions) and dried over Na2SO4. The
solution was filtered and dried on a rotovap followed by
purification of the crude product via column chromatography
(EtOAc:hexanes=1:9). Because the products synthesized from
6-(tert-butyldimethylsilyloxy)-3,4-dihydro-2H-pyran were new
compounds and attempts to separate them failed, we were
unable to determine which peaks in the 1H and 13C NMR
spectra corresponded to the syn and anti isomers.
3-(Hydroxy(2-methoxyphenyl)methyl)tetrahydro-2H-pyran-
2-one (Table 4, entry 7): white solid; 1H NMR (400 MHz,
CDCl3) δ 7.45-7.51 (dd, 2H, J=18 Hz, J=7.6 Hz), 7.23-7.29
(q, 2H, J=7.6 Hz), 6.96-7.01 (m, 2H), 6.84-6.88 (t, 2H,
J=8.4 Hz), 5.73 (s, 1H), 5.28-5.30 (d, 1H, J=8.4 Hz), 4.49-
4.50 (d, 1H, J=2 Hz), 4.26-4.31 (m, 4H), 3.82 (s, 6H), 3.12-
3.13 (d, 1H, J=3.6 Hz), 3.00-3.05 (dt, 1H, J=7.6 Hz, J=2.4 Hz),
2.79-2.84 (q, 1H, J=9.2 Hz), 1.75-1.88 (m, 5H), 1.53-1.58 (m,
2H), and 1.44-1.46 (m, 1H) ppm; 13C NMR (100 MHz, CDCl3)
δ 176.2, 174.9, 156.8, 155.5, 129.1, 129.1, 128.8, 128.3, 127.8,
127.3, 121.2, 120.6, 110.7, 110.0, 68.9, 68.6, 68.5, 67.1, 55.6, 55.4,
46.6, 44.2, 22.3, 21.9, 21.0, and 17.9 ppm; HRMS m/z calcd for
C13H16O4 (Mþ) 236.10486, found 236.10533.
General Procedure for Mukaiyama Aldol Reaction of Methyl
Trimethylsilyl Dimethylketene Acetal and 2-(Trimethylsiloxy)
furan. To a 10 mL vial equipped with a stir bar was added
22.15 mg (2.5 mol %) of alumatrane dimer 2 in a glovebox.
Acetonitrile (5 mL) followed by 1 mmol of the corresponding
aldehyde were added to the vial, and then the reaction mixture
was stirred for 30 min at room temperature to form the
aldehyde-alumatrane adduct. The corresponding silyl enol
ether (1.2 mmol) was added under inert atmosphere and then
the reaction was continued for the allotted time as recorded in
the tables. Then 3 mL of 2 N hydrochloric acid solution was
added and the reaction mixture was stirred 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 rotovap apparatus, and then the crude
product was purified by column chromatography (EtOAc:hex-
anes=1:9).
Methyl 3-hydroxy-2,2-dimethyl-3-(2-benzofuran)propionate
1
(Table 3, entry 3): white solid; H NMR (400 MHz, CDCl3) δ
7.55-7.57 (d, 1H), 7.45-7.47 (d, 1H), 7.22-7.30 (m, 2H), 6.67
(s, 1H), 4.96 (s, 1H), 3.77 (s, 3H), 3.73 (br, 1H), and 1.30-1.31
(d, 6H) ppm; 13C NMR (100 MHz, CDCl3) δ 177.8, 156.8, 154.7,
128.1, 124.3, 123.0, 121.2, 111.4, 104.9, 73.9, 52.5, 47.3, 23.0, and
20.4 ppm; HRMS m/z calcd for C14H16O4 (Mþ) 248.10485,
found 248.10512.
Methyl 3-hydroxy-2,2-dimethyl-3-(3-thianaphthene)propio-
nate (Table 3, entry 5): yellow oil; 1H NMR (400 MHz, CDCl3)
δ 7.84-7.90 (dd, 2H), 7.31-7.39 (m, 3H), 5.38 (s, 1H), 3.71 (s,
3H), 3.42 (br, 1H), 1.28 (s, 3H), and 1.16 (s, 3H) ppm; 13C NMR
(100 MHz, CDCl3) δ 178.3, 140.2, 138.7, 136.1, 124.7, 124.3,
124.1, 123.0, 122.8, 73.7, 52.4, 48.5, 23.5, and 19.6 ppm;
HRMS m/z calcd for C14H16O3S (Mþ) 264.08202, found
264.08256.
5-(Hydroxy(2-fluorophenyl)methyl)furan-2(5H)-one (Table 4,
entry 4): clear, colorless oil (syn/anti 1/1); 1H NMR (400 MHz,
CDCl3) δ 7.49-7.56 (m, 2H), 7.26-730 (m, 4H), 7.16-7.19
(t, 2H, J=7.6 Hz), 7.02-7.06 (t, 2H, J=8.4 Hz), 6.10-6.14
(t, 2H, J=7.6 Hz), 5.40-5.41 (d, 1H, J=4 Hz), 5.28-5.29 (d, 1H,
J=4 Hz), 5.19-5.20 (d, 1H, J=4 Hz), 5.07-5.08 (d, 1H,
J=4 Hz), and 3.82 (br, 2H) ppm; 13C NMR (100 MHz, CDCl3)
3-(tert-Butyldimethylsiloxy(methyl 4-benzoate)methyl)tetrahy-
dro-2H-pyran-2-one (Table 4, entry 8): clear, colorless oil; H
1
NMR (400 MHz, CDCl3) δ 7.93-7.98 (m, 4H), 7.38-7.43 (m,
4H), 5.63 (s, 1H), 5.53-5.54 (d, 1H, J = 4 Hz), 4.31-4.34
(m, 1H), 4.16-4.26 (m, 2H), 3.86 (s, 6H), 2.91-2.94 (m, 1H),
5426 J. Org. Chem. Vol. 74, No. 15, 2009

Raders and Verkade
JOCArticle
2.61-2.65 (t, 1H, J=9.2 Hz), 1.83-1.99 (m, 3H), 1.66-1.70
(m, 2H), 1.38-1.59 (m, 3H), 0.86-0.88 (d, 18H, J = 8 Hz),
0.03-0.06 (d, 6H, J = 7.6 Hz), -0.11 (s, 3H), and -0.18 (s, 3H)
ppm; 13C NMR (100 MHz, CDCl3) δ 171.6, 171.1, 167.0, 166.9,
147.8, 146.7, 129.6, 129.4, 127.1, 126.1, 74.0, 73.5, 70.0, 69.3,
52.2, 52.2, 49.5, 49.1, 26.0, 25.0, 22.8, 22.3, 19.8, 18.8, 18.3, 18.3,
-4.5, -4.8, -5.0, and -5.2 ppm; ESIþ m/z calcd for C20H30O5Si
(Mþ) 378.19, found 379.
Methyl 3-hydroxy-3-(2-fluorene)propionate (Table 5, entry 6):
white solid; 1H NMR (400 MHz, CDCl3) δ 7.74-7.79 (m, 2H),
7.54-7.58 (m, 2H), 7.30-7.41 (m, 3H), 5.20-5.24 (dd, 1H,
J=9.2 Hz, J=3.6 Hz), 3.88 (s, 2H), 3.75 (s, 3H), 3.38 (br, 1H),
and 2.74-2.88 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3) δ
173.0, 143.8, 143.6, 141.7, 141.5, 141.3, 127.0, 125.2, 124.6,
122.6, 120.1, 120.1, 70.8, 52.2, 43.7, and 37.1 ppm; HMRS m/z
calcd for C17H16O3 (Mþ) 268.10994, found 268.11063.
Methyl 3-Hydroxy-3-(2-biphenyl)propionate (Table 5, entry
7): clear, colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.69-7.70
(d, 1H, J = 7.6 Hz), 7.41-7.48 (m, 4H), 7.27-7.39 (m, 3H),
7.24-7.25 (d, 1H, J=1.2 Hz), 5.28-5.31 (d, 1H, J=9.6 Hz, J=
2.8 Hz), 3.65 (s, 3H), 3.48 (br, 1H), and 2.70-2.60 (m, 2H) ppm;
13C NMR (100 MHz, CDCl3) δ 172.8, 140.7, 140.6, 139.8, 130.2,
129.3, 128.5, 128.1, 127.7, 127.4, 126.0, 66.7, 51.9, and 42.5 ppm;
HRMS m/z calcd for C16H16O3 (Mþ) 256.10994, found
256.11029.
Methyl 3-hydroxy-3-(4-methyl-2-thiazole)propionate (Table 5,
entry 10): clear, colorless oil; 1H NMR (400 MHz, CDCl3) δ 6.83
(s, 1H), 5.32-5.35 (dd, 1H, J=8.4 Hz, J=3.2 Hz), 4.48 (br, 1H),
3.71 (s, 3H), 2.85-3.09 (m, 2H), and 2.39 (s, 3H) ppm; 13C NMR
(100 MHz, CDCl3) δ 172.7, 172.5, 152.8, 114.0, 68.6, 52.2, 41.6,
17.3 ppm; HRMS m/z calcd for C8H11NO3S (Mþ) 201.14596,
found 201.04619.
3-((Methyl 4-benzoate)2-methylene)trihydro-2H-pyran-2-one
1
(Table 4, entry 9): white solid; H NMR (400 MHz, CDCl3) δ
8.05-8.07 (d, 2H, J=8 Hz), 7.91 (s, 1H), 7.47-7.49 (d, 2H, J=8
Hz), 4.40-4.42 (t, 2H, J=5.2 Hz), 3.92 (s, 3H), 2.86-2.89 (t, 2H,
J=6.4 Hz), and 1.96-2.01 (sep, 2H, J=6 Hz) ppm; 13C NMR
(100 MHz, CDCl3) δ 166.7, 166.6, 140.4, 139.5, 130.5, 130.1,
129.9, 128.1, 69.0, 52.5, 26.2, and 23.2 ppm; HRMS m/z calcd
for C14H14O4 (Mþ) 246.0892, found 246.0892.
3-(Hydroxy(4-methylphenyl)methyl)tetrahydro-2H-pyran-2-
one (Table 4, entry 10): clear, colorless oil; 1H NMR (400 MHz,
CDCl3) δ 7.22-7.25 (m, 4H), 7.15-7.16 (m, 4H), 5.46 (s, 1H),
4.77-4.79 (d, 1H, J=8.8 Hz), 4.61 (br, 1H), 4.24-4.30 (m, 4H),
3.30 (br, 1H), 2.68-2.80 (m, 2H), 2.34 (s, 6H), 1.75-1.85 (m,
5H), 1.55-1.60 (m, 2H), and 1.49-1.53 (m, 1H) ppm; 13C NMR
(100 MHz, CDCl3) δ 175.9, 174.2, 138.1, 138.0, 137.2, 137.0,
129.3, 129.1, 127.0, 125.8, 75.0, 71.8, 69.2, 68.7, 47.4, 46.6, 22.3,
21.8, 21.7, 21.3, 21.2, and 18.1 ppm; HRMS m/z calcd for
C13H16O3 (Mþ) 220.10994, found 220.11016.
3-(Hydroxy(3-iodophenyl)methyl)tetrahydro-2H-pyran-2-
one (Table 4, entry 11): clear, colorless oil; 1H NMR (400 MHz,
CDCl3) δ 7.72 (d, 2H, J=1 Hz), 7.57-7.64 (dd, 2H, J=18 Hz,
J=8 Hz), 7.28-7.30 (d, 2H, J=7.2 Hz), 7.05-7.09 (dt, 2H,
J=7.6 Hz, J=2.4 Hz), 5.45 (s, 1H), 4.73-4.75 (d, 1H, J=8.8
Hz), 4.67 (br, 1H), 4.26-4.31 (m, 4H), 3.44 (br, 1H), 2.72-2.77
(m, 1H), 2.65-2.70 (m, 1H), 1.75-1.87 (m, 5H), 1.45-1.53 (m,
2H), and 1.34-1.43 (m, 1H) ppm; 13C NMR (100 MHz, CDCl3)
δ 175.5, 173.9, 143.6, 142.6, 137.4, 136.5, 136.0, 134.9, 130.4,
130.2, 126.6, 125.1, 94.7, 94.6, 74.3, 71.0, 69.3, 68.7, 47.3, 46.5,
22.3, 21.7, 21.6, and 17.8 ppm; HRMS m/z calcd for C12H13IO3
(Mþ) 331.99095, found 331.99164.
Methyl 3-hydroxy-3-(3,5-dimethoxyphenyl)propionate(Table5,
entry 2): yellow oil. 1H NMR (400 MHz, CDCl3) δ 6.51 (s, 2H),
6.35, (s, 1H), 5.02-5.06 (dd, 1H, J=9.2 Hz, J=4 Hz), 3.70-3.76
(d, 6H, J=72.8 Hz), 3.70 (s, 1H), 3.67 (br, 1H), and 2.64-2.76
(m, 2H) ppm; 13C NMR (100 MHz, CDCl3) δ 172.8, 161.0,
145.3, 103.6, 99.8, 70.4, 55.4, 52.0, and 43.4 ppm; HRMS m/z
calcd for C12H16O5 (Mþ) 240.09977, found 240.10006.
Synthesis of Alumatrane-Aldehyde Adduct 4. To a suspension
of dimer 2 (0.5 mmol) in 20 mL of toluene was added 2 mmol of
o-anisaldehyde. The reaction was stirred at room temperature
for 1 h to generate a yellowish solution that was concentrated
under reduced pressure to form a yellow solid. The yellow solid
was dissolved in 5 mL of toluene followed by the addition of 20
mL of pentane. The solution was placed in a freezer for 2 days to
1
form yellow crystals that were suitable for X-ray analysis. H
NMR (400 MHz, C6D6) δ 10.95 (s, 1H), 8.19-8.21 (d, 1H, J=
7.6 Hz), 7.00-7.16 (m, 4H), 6.56-6.58 (m, 4H), 6.11-6.13 (d,
1H, J=8.4 Hz), 4.45 (br, 3H), 3.00 (s, 3H), 2.60 (br, 3H), 2.42 (s,
9H), and 2.28 (s, 9H) ppm; 13C NMR (100 MHz, C6D6) δ 196.8,
164.5, 155.7, 139.6, 132.0, 131.9, 130.5, 128.2, 128.1, 127.7,
126.1, 121.6, 121.5, 112.3, 59.5, 55.5, 21.2, and 17.3 ppm.
Lewis Acidity Test of Alumatrane Dimer 2. To an argon-filled
100 mL flask was added 1 mmol (134.16 mg) of triethyl
phosphine oxide in 5 mL of toluene. To this solution was added
1.2 equiv of BF3 OEt2 (1.2 mmol, 170.32 mg) and then the
mixture was stirred for 2 h. Two layers (toluene and ether)
formed during this period. After drying under reduced pressure,
3
a
31P NMR spectrum of the solid residue in C6D6 revealed a
Methyl 3-hydroxy-3-(3-cyanophenyl)propionate (Table 5, en-
try 3): clear, colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.67 (s,
1H), 7.54-7.60 (m, 2H), 7.42-7.46 (m, 1H), 5.12-5.16 (t, 1H,
J=6.4 Hz), 3.78 (br, 1H), 3.70 (s, 3H), and 2.69-2.70 (d, 2H,
J=6.4 Hz) ppm; 13C NMR (100 MHz, CDCl3) δ 172.4, 144.3,
131.5, 130.4, 129.5, 129.5, 118.8, 112.6, 69.3, 52.3, and 43.1 ppm;
HRMS m/z calcd for C11H11NO3 (Mþ) 205.07389, found
205.07416.
Methyl 3-hydroxy-3-(4-acetylphenyl)propionate (Table 5, en-
try 4): white solid; 1H NMR (400 MHz, CDCl3) δ 7.88-7.90 (d,
2H, J=8.4 Hz), 7.43-7.45 (d, 2H, J=8 Hz), 5.15-5.18 (t, 1H,
J=5.2 Hz), 3.68 (s, 4H), 2.67-2.76 (m, 2H), and 2.55 (s, 3H)
ppm; 13C NMR (100 MHz, CDCl3) δ 198.1, 172.6, 148.1, 136.6,
128.8, 126.0, 70.0, 52.2, 43.2, and 26.8 ppm; HRMS m/z calcd
for C12H14O4 (Mþ) 222.08921, found 222.08954.
Methyl 3-hydroxy-3-(3-methylphenyl)propionate (Table 5, en-
try 5): clear, colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.23-
7.27 (m, 1H), 7.20 (s, 1H), 7.15-7.17 (d, 1H, J=7.2 Hz), 7.10-
7.12 (d, 1H, J=7.2 Hz), 5.08-5.12 (m, 1H, J=9.2 Hz, J=3.6 Hz),
3.72 (s, 3H), 3.40 (br, 1H), 2.67-2.80 (m, 2H), and 2.37 (s, 3H)
ppm; 13C NMR (110 MHz, CDCl3) δ 172.9, 142.6, 138.3, 128.6,
128.5, 126.4, 122.8, 70.4, 52.0, 43.4, and 21.6 ppm; HMRS m/z
calcd for C11H14O3 (Mþ) 194.09429, found 194.09467.
phosphorus shift at þ78 ppm corresponding to the BF3
3
OdPEt3. The solid was taken into a glovebox and weighed to
determine the yield of BF3 OdPEt3 (97% based on the triethyl
3
phosphine oxide). To this solid was added half an equivalent of
alumatrane dimer 2 (0.48 mmol, 430.20 mg). After addition of 5
mL of toluene to the reaction mixture, the suspension was stirred
for 2 h after which a 31P NMR spectrum revealed that all of the
F3B OdPEt3 compound disappeared. Thus only 13 OdPEt3
3
3
remained and no insoluble dimer 2 was observed in the solution.
Synthesis of the Boron Trifluoride Triethyl Phosphine Oxide
Adduct F3B OdPEt3. To a 50 mL round-bottomed flask in a
3
glovebox was charged 150 mg (1.12 mmol) of triethyl phosphine
oxide. The reaction flask was removed from the glovebox, 5 mL
of toluene was added, and then 190.2 mg (1.2 equiv, 1.34 mmol)
of boron trifluoride diethyl ether was added under inert atmo-
sphere. After 2 h of stirring, the solution was dried under
reduced pressure to produce analytically pure desired product
in 98% isolated yield. White solid; 1H NMR (400 MHz, C6D6) δ
1.52-1.60 (dq, 6H, J=12 Hz, J=7.6 Hz) and 0.81-0.89 (dt, 9H,
J=18 Hz, J=15.6 Hz) ppm; 13C NMR (100 MHz, C6D6) δ 17.2
(d, J=65 Hz) and 5.2 (d, J=5.1 Hz) ppm; 31P NMR (168 MHz,
C6D6) δ 78.855 ppm; 11B NMR (128 MHz, C6D6) δ -0.42 ppm;
19F NMR (376 MHz, C6D6) δ -146.43 ppm.
J. Org. Chem. Vol. 74, No. 15, 2009 5427

Raders and Verkade
JOCArticle
Synthesis of Triethylphosphine Oxide Alumatrane Adduct
13 OdPEt3. To a 100 mL round-bottomed flask in a glovebox
125.5, 124.9, 121.6, 59.2, 20.6, 18.6 (d, J=68.2 Hz), 17.4, and 5.9
(d, J=4.6 Hz) ppm; 31P NMR (168 MHz, CDCl3) δ 63.166 ppm;
APCIþ found 580 (calcd for C35H38AlNO5, 579.26).
3
was added 150 mg (1 equiv, 0.17 mmol) of alumatrane dimer 2
and 54.45 mg (2.4 equiv, 0.41 mmol) of triethyl phosphine oxide.
The reaction flask was removed from the glovebox and 10 mL of
toluene was added. After being stirred for 30 min, the solution
became clear and colorless. During stirring for an additional 4 h,
a white precipitate formed. The solids were filtered under inert
atmosphere providing 75 mg of the desired product in 78%
yield. Crystals suitable for X-ray analysis were obtained by
placing the toluene extract in a freezer for 2 days. White solid;
1H NMR (400 MHz, CDCl3) δ 6.95 (s, 3H), 6.67 (s, 3H), 4.32-
4.36 (d, 3H, J=13.6 Hz), 2.81-2.85 (d, 3H, J=13.6 Hz), 2.28 (s,
18H), 2.20-2.11 (dq, 6H, J=12 Hz, J=7.6 Hz), and 1.45-1.37
(dt, 9H, J=17.2 Hz, J=16.8 Hz) ppm; 13C NMR (100 MHz,
CDCl3) δ 155.5, 130.8, 130.7, 129.3, 128.4, 127.1, 127.0, 126.6,
Acknowledgment. We thank the National Science Foun-
dation for financial support in the form of grant 0750463,
and we thank Dr. Arkady Ellern of the Iowa State University
Molecular Structure Laboratory for the single-crystal X-ray
results.
Supporting Information Available: Tables of detailed struc-
tural and refinement data, CIF files, references to known
compounds, and H and 13C NMR spectra for coupled pro-
1
ducts. This material is available free of charge via the Internet at
http://pubs.acs.org.
5428 J. Org. Chem. Vol. 74, No. 15, 2009