Tetranuclear BINOL-titanium complex in selective direct aldol additions

Article abstract of DOI:10.1021/jo7014054

(Chemical Equation Presented) The extremely robust and water-stable tetranuclear complex Ti₄(μ-BINOLato)₆(μ₃- OH)₄ (1) catalyzes the direct aldol addition with high degrees of regioselectivity at the sterically more encumbered α-side of unsymmetrical ketones. The formation of quaternary stereocenters is described. Oxygen-containing ene components can also be used as starting material in these reactions. When used with aliphatic aldehydes, acetals 18 or acetals of aldol adducts 20 were observed. As few as 0.2 mol % loadings with this catalyst 1 were enough to complete the reactions. Mechanistical aspects of the reactions are discussed.

Full text of DOI:10.1021/jo7014054

Tetranuclear BINOL-Titanium Complex in Selective Direct Aldol
Additions
Bernd Schetter,† Burkhard Ziemer,† Gregor Schnakenburg,‡ and Rainer Mahrwald*,†
Institut fu¨r Chemie der Humboldt-UniVersita¨t zu Berlin, Brook-Taylor-Strasse 2, 12489 Berlin, Germany,
and Institut fu¨r Anorganische Chemie der UniVersita¨t Bonn, Gerhard-Domagk-Straâe 1,
D-53121 Bonn, Germany
rainer.mahrwald@rz.hu-berlin.de
ReceiVed July 20, 2007
The extremely robust and water-stable tetranuclear complex Ti4(µ-BINOLato)6(µ3-OH)4 (1) catalyzes
the direct aldol addition with high degrees of regioselectivity at the sterically more encumbered R-side
of unsymmetrical ketones. The formation of quaternary stereocenters is described. Oxygen-containing
ene components can also be used as starting material in these reactions. When used with aliphatic aldehydes,
acetals 18 or acetals of aldol adducts 20 were observed. As few as 0.2 mol % loadings with this catalyst
1 were enough to complete the reactions. Mechanistical aspects of the reactions are discussed.
Introduction
purification of the reaction products more difficult. The recovery
of the catalyst also proves impossible in these cases. Other
catalysts are produced in situ, preventing reproduceable reaction
conditions as well as making mechanistic studies difficult.4 Last
but not least, many catalysts are only accessible by complicated
multistep reaction sequences or need rare and expensive metals
as reactive reagents.5 Recent research has focused on the
development of stable and storable catalysts, and first remarkable
results have been presented by Kobayashi et al.,6 who presented
air- and water-stable rare earth and zirconium catalysts for
Mannich, aza Diels-Alder, and Mukaiyama aldol reactions. Bull
et al. described the deployment of a moisture-stable titanium
triflate in aza-Diels-Alder reactions.7 Recently, we published
preliminary results of the catalytical use of Mikamis tetranuclear
titanium cluster 1 in aldol chemistry and presented the first air-
stable catalyst for highly regioselective and direct aldol additions
in a preliminary note.8 This catalyst 1 is crystalline and stable
An abundance of titanium catalysts for carbon-carbon bond-
formation processes have been the area of an intensive research
over the past 2 decades.1 In particular the aldol addition excels
as one of the most powerful methods in this field.2 The direct
aldol addition in the presence of metal catalysts represents a
biomimetic aldol process. Since the mid-1990s, various methods
for direct aldol additions have been developed.3 However, most
of the Lewis acid catalysts that have been employed are sensitive
to air and/or moisture, causing extended expenditure in handling.
On the other hand, quenching the reactions with water often
causes the decomposition of the moisture-sensitive catalysts.
The decomposition products, such as BINOL, render the
† Institut fu¨r Chemie der Humboldt-Universita¨t zu Berlin.
‡ Institut fu¨r Anorganische Chemie der Universita¨t Bonn.
(1) For an overview see the following. (a) Acid catalysis: Yamamoto,
H.; Futatsugi, K. Angew. Chem. 2005, 117, 1958. (b) Mikami, K.; Terada,
M. In Lewis Acids in Organic Synthesis; Hisashi, Y., Ed.: Wiley-VCH:
Weinheim, 2000. (c) Titanium complexes: Mikami, K.; Matsumoto, Y.;
Shiono, T. In Science of Synthesis; Bellus, D., Jacobsen, N. E., Ley, S. V.,
Noyori, R., Regitz, M., Reider, P. J., Schaumann, E., Shinkai, I., Thomas,
E. J., Trost, B. M., Eds.: Thieme: Stuttgart, 2003; Product class 10:
Organometallic Complexes of Titanium. (d) Applications to organic
synthesis: Titanium and Zirconium in Organic Synthesis; Marek, I., Ed.:
Wiley-VCH: Weinheim 2002. (e) Transition Metals For Organic Chem-
istry: Building Blocks and Fine Chemicals, 2nd ed.; Beller, M., Bolm, C.,
Eds.; Wiley-VCH: Weinheim, 2004. (f) Ramon, D. J.; Yus, M. Chem. ReV.
2006, 106, 2126. (g) Skato, F.; Urabe, H.; Okamoto, S. Chem. ReV. 2000,
100, 2835.
(2) (a) Heathcock, C. H., Chapter 1.6; Kim, B. M., Williams, S. F.,
Masamune, S., Chapter 1.7; Rathke, M. W., Weipert, P., Chapter 1.8;
Paterson, I., Chapter 1.9; Gennari, C., Chapter 2.4 In ComprehensiVe
Organic Synthesis; Trost, B. M., Fleming, I., Heathcock, C. H., Eds.:
Pergamon: Oxford, 1993, Vol. 2. (b) Braun, M. In Houben-Weyl, Methoden
der Organischen Chemie; Helmchen, G., Hoffmann, R. W., Mulzer, J.,
Schaumann, E., Eds.; Thieme: Stuttgart, 1996; Vol. E21b, p 160. (c)
Machajewski, T. D.; Wong, C. H. Angew. Chem., Int. Ed. 2000, 39, 1352.
(d) Mahrwald, R. Modern Aldol Reactions; Wiley-VCH: Weinheim, 2004.
(e) Schetter, B.; Mahrwald, R. In Quaternary Stereo Centers-Challenges
for Organic Synthesis; Christoffers, J., Baro, A., Eds.: Wiley-VCH:
Weinheim, 2005; p 51.
10.1021/jo7014054 CCC: $40.75 © 2008 American Chemical Society
Published on Web 01/08/2008
J. Org. Chem. 2008, 73, 813-819
813

Schetter et al.
was able to catalyze the direct aldol addition between aromatic
aldehydes 2a-f and unsymmetric ketones 3 in a remarkably
clean way. Even very low catalysts loadings11 (0.2 mol %)
yielded aldol adducts 4a-m (Table 1).12
This reaction was found to be highly regioselective. Aldol
addition is strongly preferred at the sterically more encumbered
R-carbon atom of the ketone. In many cases only one regioi-
somer could be detected. Methyl groups of alkan-2-ones were
found to be unaffected under these reaction conditions. The
determination of structure of aldol adducts 4a-m and regioi-
somers 4a-m was achieved by analysis and comparison of 1H
and 13C NMR spectra with data reported in the literature.13
Initially, the mechanistical aspects of this high regioselectivity
were tried to explain by electronical effects, which render the
intermediate formation of enolates at the methyl group unfavor-
able.14 Subsequent competition experiments of reaction mixtures
containing 1 equiv of acetone and 1 equiv of methyl ethyl ketone
with 1 equiv of benzaldeyde yielded a ratio of 48:15:3 for 4b:
4n:4o (4b: R1 ) Ph, R2 ) Me, R3 ) R4 ) H; 4n: R1 ) Ph,
R2 ) R3 ) R4 ) H; 4o: R1- ) Ph, R2 ) R3 ) H, R4 ) Me,
Table 1). First, these results demonstrate the high regioselectivity
described for aldol adducts 4b:4o (48:3). Also, these results
indicate that the methyl group of acetone reacts five times faster
than the methyl group of methyl ethyl ketone (4n:4o ) 15:3).
Moreover, the ratio observed is time-independent. Same ratio
is detected in the very first 3-4 h or after 10 days. No
thermodynamic equilibration is observed. These observations
make electronic effects a sole explanation for the high regiose-
lectivities obtained untenable.
FIGURE 1. Crystal structure of the tetranuclear titanium complex rac-
Ti4(µ-BINOLato)6(µ3-OH)4 1; hydrogen atoms are omitted for clarity.
even against boiling 1 N HCl and 1 N LiOH in dioxane and
easy to synthesize from Ti(OiPr)4, R-BINOL or S-BINOL, and
water.9 We have synthesized this catalyst 1 with rac-BINOL10
and found that all the six BINOL molecules that are incorporated
in each cluster have the same configuration. No clusters
appeared in crystalline form with mixed configuration of the
incorporated BINOLs (Figure 1).
Results and Discussion
Only a very limited number of applications of catalyst 1 in
organic reactions are known (cycloadditions,9a asymmetric ene
reactions,9b,c and enantioselective sulfoxidation9d).
This unusual regioselective outcome of the reaction with
methyl ketones can be explained by steric aspects at best (Figure
To test the applicability of this titanium complex 1 in aldol
additions, we reacted several aromatic and aliphatic aldehydes
with symmetric and unsymmetric ketones 3. In fact, the complex
(6) (a) Ishikawa, S.; Hamada, T.; Manabe, K.; Kobayashi, S. J. Am.
Chem. Soc. 2004, 126, 12236. (b) Kobayashi, S.; Ueno, M.; Mizuki, Y.;
Ishitani, H.; Yamashita, Y. Proc. Nat. Acad. Sci. U.S.A. 2004, 101, 5476.
(7) Bull, S. D.; Davidson, M. G.; Johnson, A. L.; Robinson, D. E. J. E.
Mahon, M. F. Chem. Commun. 2003, 1750.
(3) (a) Mahrwald, R. Chem. Ber. 1995, 128, 919. (b) Yamada, Y. M.
A.; Yoshikawa, N.; Sasai, H.; Shibasaki, M. Angew. Chem. 1997, 109, 1942;
Angew. Chem., Int. Ed. Engl. 1997 36, 1871. (c) Fujii, K.; Maki, K.; Kanai,
M.; Shibasaki, M. Org. Lett. 2003, 5, 733. (d) Yoshikawa, N.; Yamada, Y.
M. A.; Das, J.; Sasai, H.; Shibasaki, M. J. Am. Chem. Soc. 1999, 121, 4168.
(e) Yoshikawa, N.; Kumagai, N.; Matsunaga, S.; Moll, G.; Oshima, T.;
Suzuki, T.; Shibasaki, M. J. Am. Chem. Soc. 2001, 123, 2466. (f) Yoshikawa,
N.; Shibasaki, M. Tetrahedron 2001, 57, 2569. (g) Yoshikawa, N.; Suzuki,
T.; Shibasaki, M. J. Org. Chem. 2002, 67, 2556. (h) Kumagai, N.;
Matsunaga, S.; Kinoshita, T.; Harada, S.; Okada, S.; Sakamoto, S.;
Yamaguchi, K.; Shibasaki, M. J. Am. Chem. Soc. 2003, 125, 2169. (i) Trost,
B. M.; Ito, H. J. Am. Chem. Soc. 2000, 122, 12003. (j) Trost, B. M.; Silcoff,
E. R.; Ito, H. Org. Lett. 2001, 3, 2497. (k) Trost, B. M.; Frederiksen, M.
U.; Papillon, J. P. N.; Harrington, P. E.; Shin, S.; Shireman, B. T. J. Am.
Chem. Soc. 2005, 127, 3666. (l) Trost, B. M.; Yeh, Y. S. C. Org. Lett.
2002, 4, 3513. (m) Suzuki, T.; Yamagiwa, N.; Matsuo, Y.; Sakamoto, S.;
Yamaguchi, K.; Shibasaki, M.; Noyori R. Tetrahedron Lett. 2001, 42, 4669.
(n) Mahrwald, R. Org. Lett. 2000, 2, 4011.
(4) (a) Keck, G. E.; Krishnamurthy, D. J. Am. Chem. Soc. 1995, 117,
2363. (b) Kitamoto, D.; Imma, H.; Nakai, T. Tetrahedron Lett. 1995, 36,
1861. (c) Terada, M.; Matsumoto, Y.; Nakamura, Y.; Mikami, K. Inorg.
Chim. Acta 1999, 267. (d) Delas, C.; Szymoniak, J.; Lefranc, H.; Mo¨ıse,
C. Tetrahedron Lett. 1999, 40, 1121. (e) De Rosa, M.; Soriente, A.; Scettri,
A. Tetrahedron: Asymmetry 2000, 11, 3187. (f) Davis, J. T.; Balsells, J.;
Caroll, P. J.; Walsh, P. J. Org. Lett. 2001, 3, 699. (g) Zimmer, R.; Peritz,
A.; Czerwonka, R.; Schefzig, L.; Reissig, H.-U. Eur. J. Org. Chem. 2002,
3419. (h) Villano, R.; De Rosa, M.; Salerno, C.; Soriente, A.; Scettri, A.
Tetrahedron: Asymmetry 2002, 13, 1949. (i) Villano, R.; Acocella, M.;
De Rosa, M.; Soriente, A.; Scettri, A. Tetrahedron: Asymmetry, 2004, 15,
2422.
(8) Mahrwald, R.; Schetter, B. Org. Lett. 2006, 8, 281.
(9) (a) Mikami, K.; Ueki, M.; Matsumoto, Y.; Terada, M. Chirality 2001,
13, 541. (b) Terada, M.; Matsumoto, Y.; Nakamura, Y.; Mikami, K. Inorg.
Chim. Acta 1999, 296, 267. (c) Pandiaraju, S.; Chen, G.; Lough, A.; Yudin,
A. K. J. Am. Chem. Soc. 2001, 123, 3850. (d) Pescitelli, G.; diBari, L.;
Salvatori, P. J. Organomet. Chem. 2006, 691, 2311.
(10) The experimental procedure was the same as that given by Mikami
et al. The catalyst was obtained as dark red rectangular crystals. A single
crystal structure analysis was made of a suitable crystal. The complex was
found to crystallize in the cubic space group F43c. a ) b ) c ) 32.348 Å;
R1 ) 0.049, wR2 ) 0.118. Crystallographic data have been deposited at
the Cambridge Crystal Data Centre (CCDC 279234). This material can be
obtained upon request to CCDC, 12 Union Road, Cambridge 1EZ, U.K.
(http://www.ccdc.cam.ac.uk; email: deposit@ccdc.cam.ac.uk). The structure
was refined with SHELX97 (Sheldrick, G.M. SHELX97. Program for the
Refinement of Crystal Structures; Universita¨t Go¨ttingen: Go¨ttingen, 1997.)
(11) So far, the catalysts loadings for similar reactions range usually
between 2 and 20 mol %; recently, Ding et al. presented an enantioselective
carbonyl-ene reaction with comparable low catalyst loadings: Yuan, Y.;
Zhang, X.; Ding, K. Angew. Chem. Int. Ed. 2003, 42, 5478.
(12) Typical Experimental Procedure. One equivqlent of aldehyde and
1.5 equiv of ketone were mixed at room temperature. If problems with the
solubility occured, small amounts of CH2Cl2 were used as solvent, then
0.2 mol % of the catalyst was added. The progress of the reaction was
monitored by TLC, and when the turnover was complete, the reaction
mixture was diluted with diethyl ether and the reaction was quenched with
aqueous NH4Cl. The organic layer was separated, dried (MgSO4), and
filtered, and the ether was removed in vacuo. Column chromatography
(hexane/ethyl acetate) afforded the pure aldols. Yields have not been
optimized. Large amounts of recovered aldehyde indicate the necessity to
use longer reacion times or higher reaction temperatures in some cases.
(13) See Supporting Information.
(5) (a) Sawamura, M.; Ito, Y. Catalytic Asymmetric Synthesis, 2nd ed.;
Ojima, I., Ed.; Wiley-VCH: New York, 2000. (b) Ito, Y.; Sawamura, M.;
Hayashi, T. J. Am. Chem. Soc. 1986, 108, 6405. (c) Ito, Y.; Sawamura,
M.; Hayashi, T. Terahedron Lett. 1987, 28, 6215. (d) Sawamura, M.; Ito,
Y. Catal. Asymmetric Synth. 1993, 367.
(14) Roy, R. K.; Tajima, N.; Hirao, K. J. Phys. Chem. A 2001, 105,
2117.
814 J. Org. Chem., Vol. 73, No. 3, 2008

Tetranuclear BINOL-Titanium Complex
TABLE 1. Direct and Regioselective Aldol Additions of Aromatic Aldehydes to Unsymmetrical Ketones
regioselectivitya
(4a-m:regioisomers 4a-m)
entry
R1
R2
R3
R4
product
yield (%) of 4a-m
syn/anti ratio of 4a-m
1
2
3
4
5
6
7
8
9
10
11
12
13
Ph
Ph
Ph
Ph
Ph
Ph
n-Bu
Me
Me
Ph
Me
Me
Me
Me
Me
n-Bu
Me
Me
Me
H
H
H
H
Me
Cl
H
Me
H
H
H
H
H
H
H
Me
H
Me
H
H
Me
H
4a
4b
4c
4d
97:3
95:5
68
74
85
78
22d
18:82
53:47
50:50
<5:95
>95:5b
51:49
4e
no reaction
PhCtC
PhCtC
4f
4g
4h
4i
4k
4l
>95:5b
60:40
95:5
88
56e
55
71
54
64
24c
67:33
4-EtO-C6H4
4-EtO-C6H4
4-Cl-C6H4
3-MeO-C6H4
R-thiophenyl
50:50
10:90
57:43
50:50
38:62
H
>95:5b
Me
Me
H
4m
>95:5b
a Ratio was detected by NMR experiments. b Regioselectivity was generally below the detection limit of 300 MHz 1H NMR (>95:5). c 70% of the
thiophenecarbaldehyde was recovered. d 75% of the benzaldehyde was recovered. e 40% of the phenylpropargyl aldehyde was recovered.
SCHEME 1. Formation of Bicyclic Diketone 6 Is Strongly
Preferred over Formation of Wieland-Miescher Ketone 7
FIGURE 2. Working model for the explanation of the high regiose-
lectivities. Blocked side of the ketone is shown in red; acessible side
of the ketone is shown in green.
quaternary stereocenters with defined relative configuration
(endo-CH3, exo-OH, Figure 3).16
2). It is assumed that in a first coordination step the less sterically
Other quaternary carbon atoms were also synthesized by
encumbered side of the ketone (red) is turned toward to the
reacting aromatic aldehydes 2a-e with 2-methylcyclopentanone
8 (Table 2) and 2-methylcyclohexanone 11 (Table 3). The
catalyst. At this stage the more encumbered side (green) is
accessible for the attack by an aldehyde. This assumption allows
regioselectivities in these reactions depend upon the nature of
the minimization of steric interactions between catalyst and
the cyclic ketone. Aldol adducts of 2-methylcyclopentanone 8
are formed with higher degrees of regioselectivity than aldol
methyl ketones. Also, this working model explains the fact that
the methyl groups of alkan-2-ones are almost inert (structure
adducts of the 2-methylcyclohexanone series. The configurations
B, Figure 2), whereas the methyl group of acetone is more
of aldol adducts 9a-e and 10a-e were established by compar-
reactive (structure A, Figure 2). Even in the extremely unfavored
ing chemical shifts and coupling constants of signals in the 1H
case with 2-methyl diethylketone the reaction still proceeds at
NMR spectra with those of syn-configured aldol adduct 9d. The
configuration of aldol adduct syn-9d was established unambi-
gously by a X-ray crystal structure analysis (Figure 4).
The configurations of aldol adducts 12a-e and 13a-e were
the more encumbered R-position of the ketone, though with
lower selectivities (entries 5 and 8, Table 1). In contrast to that,
electronic reasons are supposed to be responsible for the striking
behavior of 3-chlorobutan-2-one to act as an ene component in
established by comparing chemical shifts and coupling constants
these reactions (entry 6, Table 1).
of signals in the 1H NMR spectra with spectral data of 12a and
This reaction behavior was also observed in intramolecular
13a reported in the literature.17
aldol additions. The Wieland-Miescher ketone 5 avoids the
typically aldol cyclization to the CD-bicyclic steroidal inter-
(16) The relative stereochemistry was unambigously determined by single
mediate 7 (Scheme 1).15 Instead of the expected formation of
crystal structure analysis. Substance 6 crystallizes in the orthorhombic space
the bicyclic dione 7, only dione 6 could be detected with a high
degree of diastereoselectivity (>95:5). Dione 6 possesses two
group Pna21. a ) 12.024 Å, b ) 10.6931 Å, c ) 7.1249 Å; R1 ) 0.025,
wR2 ) 0.061. Crystallographic data have been deposited at the Cambridge
Crystal Data Centre (CCDC 279235). This material can be obtained upon
request to CCDC, 12 Union Road, Cambridge 1EZ, U.K. (http://www.c-
cdc.cam.ac.uk; email: deposit@ccdc.cam.ac.uk).
(15) Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1615.
J. Org. Chem, Vol. 73, No. 3, 2008 815

Schetter et al.
FIGURE 3. Crystal structure of the bicyclic diketone 6.
FIGURE 4. Crystal structure of aldol syn-9d.
TABLE 2. Direct and Regioselective Aldol Additions to
2-Methylcyclopentanone
that the aldol process (step 1) is the rate-determining step of
the reaction sequence, followed by the much faster acetalization
(step 2).
Longer reaction times and higher temperatures favored the
formation of thermodynamically preferred ketals 16a-i. For-
mally, these products were produced by an aldol/ketalization
process with hydroxyacteone 14. The ketals 16a-i are stable;
no retroketalization is observed. In summary, under kinetic
reaction control acetalization of aldol adduct 17 is obtained,
whereas under thermodynamic reaction control ketals 16a-i
of aldol adduct 17 were observed. Ketalization of isolated aldol
adduct 17 with hydroxyacetone 14 did not proceed under the
described reaction conditions. Therefore we assume the exist-
ence of further intermediates, which yield the ketals 16a-i via
reaction step 4. These intermediates could be formed from the
educts (step 3) as well as from the intermediately formed free
aldol adducts 17 (step 5). Generally it was found that a 5-fold
excess of aldehyde 2a-i and prolonged reaction times was the
best way to obtain aldol adducts 16a-i and to supress the
selfaldol reaction of hydroxyacetone 14 (see below). The
configurations of products syn-16a and anti-16a were confirmed
by a X-ray crystal structure analysis. (Figures 5 and 6). The
structure of syn-16b-h and anti-16b-h were established by
comparison of chemical shifts and coupling constants with those
of syn-16a and anti-16a.
regio-
overall
entry
R1
selectivity 9:10 syn-9:anti-9 yield (%)
1
2
3
4
5
a: Ph
>95:5a
94:6
52:48
51:49
65:35
55c:45
67:33
85
81
61b
68
68
b: PhCtC
c: 4-EtO-C6H4
d: 4-Cl-C6H4
e: 3-MeO-C6H4
>95:5a
96:4
96:4
a Regioselectivity was generally below the detection limit of 300 MHz
1H NMR (>95:5). b 28% of the aldehyde were recovered. c Relative
configuration was determined by X-ray structure analysis.
Next, we focused our attention on direct aldol additions with
oxygen-containing ene components. In contrast to the regiose-
lective TiCl4-mediated direct aldol addition,18 this reaction is
applicable even to hydroxylated ene components, but great
differences in the outcome of reactions were observed depending
on conditions and substrates. Hydroxyacetone 14 reacts with
aromatic aldehydes 2a-i to yield the protected syn- and anti-
configured aldol adducts 16a-i. (Table 4). This reaction also
proceeds highly regioselectively; only one regioisomer could
be detected. The attack of aldehydes 2a-i was observed
exclusively at the oxygen-containing R-position of hydroxyac-
teone 14. The outcome of this reaction was found to be time-
dependent. Shorter reaction times yield the kinetically favored
products 15 (acetals of aldol adduct 17, Scheme 2). These
products can be isolated, but they are not stable at room
temperature. Retro-acetalization takes place, and the unprotected
aldol adducts 17 as well as free aldehydes 2a-i and hydroxy-
acetone 14 can be detected. The acetalization process (step 2)
proceeds quickly and smoothly. Even isolated and unprotected
aldol adducts 17 react with aldehydes under the same reaction
conditions to give acetals 15. This observations make it likely
In contrast to the aromatic series enolizable aldehydes react
in a different way. When non-oxygen-containing ene compo-
nents 3, 8, and 11 were used as starting material, trimerization
of the starting aldehydes 2a-e was observed at room temper-
ature. The corresponding trioxanes 18a-e were isolated with
high yields (Table 5). The structure of trioxanes 18a-e was
determined by comparison of spectral data with those reported
in the literature.
TABLE 3. Direct and Regioselective Aldol Additions to 2-Methylcyclohexanone
entry
R1
regioselectivitya 12:13
syn-12: anti-12
syn-13: anti-13
overall yield (%)
1
2
3
4
5
a: Ph
b: PhCtC
c: 4-EtO-C6H4
d: 4-Cl-C6H4
e: 3-MeO-C6H4
66:34
78:22
no reaction
81:19
75:25
55:45
52:48
72:28
70:30
53b
72
65:35
63:37
67:33
65:35
34
12c
a Ratio was detected by NMR experiments. b 38% of the aldehyde was recovered. c 78% of the aldehyde were recovered.
816 J. Org. Chem., Vol. 73, No. 3, 2008

Tetranuclear BINOL-Titanium Complex
TABLE 4. Direct and Regioselective Aldol Additions to
Hydroxyacetone
entry
R
yield 16 (%)
syn-16: anti-16
1
2
4
5
6
7
8
9
10
16a: Ph
16b: PhCtC
67
63
41
70
66
12
35
16:84
20:80
15:85
32:68
19:81
24:76
17:83
27:73
16c: 4-EtO-C6H4
16d: 4-Cl-C6H4
16e: 3-MeO-C6H4
16f: R-thiophenyl
16g: 2,4-Me2-C6H4
16h: 4-MeO-C6H4
16i: 4-NO2-C6H4
FIGURE 5. Crystal structure of protected aldol adduct anti-16a.
33
no reaction
SCHEME 2. Direct Aldol Additions of Hydroxyacetone
with Nonenolizable Aldehydes
FIGURE 6. Crystal structure of protected aldol adduct syn-16a.
TABLE 5. Formation of Trioxanes in in the Presence of
Complex 1
In contrast to these results, aliphatic aldehydes 2a-h reacted
immediately with oxygen-containing ene components such as
hydroxyacetone 14 to the corresponding ketalacetals 19a-h
(Table 6). The ketalacetals 19a-h were found to be moisture-
sensitive and were obtained in moderate to good yields. The
degree of syn-diastereoselectivity observed in this reaction
depends on the nature of the starting aldehyde 2a-h. When
using aldehydes with bulky residues higher syn-diastereoselec-
tivities were detected (entries 4,6, and 7, Table 6). In reactions
with R-chiral racemic aldehydes 2f and 2g, four diastereo-
isomeres were isolated (entries 6 and 7, Table 6). No 1,2-
asymmetric induction could be detected during these experi-
ments. Both syn-configured 19f and 19g as well as anti-19f and
19g were isolated as diastereomeric mixtures of 1:1. The
structure of trioxanes 19a-e was determined by comparison
of spectral data with those of compound 19d. The configuration
of compound 19d was determined by NOE experiments. These
experiments were carried out especially with acetal 19d, since
intensive NOE effects occurred in this case due to the bulky
tert-butyl group.19
entry
R
yield (%)
1
2
3
4
5
a: Et
b: iPr
c: Cy
51
70
90
45
77
d: Ph-(CH2)2-
e: rac-Ph-CHMe-
In addition, hydroxyacetone 14 reacts in the absence of
aldehydes to the hydroxyketone protected self-aldol adduct 22
(Scheme 3). Formally 22 stems from ketalization of intermediate
aldol adduct 21. The unprotected selfaldol adduct could not be
detected under these reaction conditions. Notably, only one
regio- as well as diastereoisomer of the protected aldol adduct
22 was observed and isolated with 55% yield. The relative
configuration of 22 was determined by NOE experiments. The
following calculations resulted in the geometry-optimized
structure presented in ref 21.
It has to be pointed out that the one-step-synthesis to these
acetals represents a great improvement, since currently acetal
20a has to be synthesized by a more complicated multistep
reaction sequence.20
(19) Stereochemical investigation of the ketalacetal 19d and determination
of the relative stereochemistry. NOE effects are visualized with green arrows.
See Supporting Informations.
When this reaction was carried out over longer periods and
at higher temperatures, again products derived from an aldol
addition were observed (Table 7). Acetalprotected aldol adducts
20a-d of hydroxyacetone 14 were isolated in good yields.
(17) Ward, D. E.; Sales, M.; Sasmal, P. K. J. Org. Chem. 2004, 69,
4808.
(18) Mahrwald, R.; Gu¨ndogan, B. J. Am. Chem. Soc. 1998, 120, 413.
J. Org. Chem, Vol. 73, No. 3, 2008 817

Schetter et al.
TABLE 6. Kinetically Controlled Formation of Ketalacetals of
Hydroxyacetone and Aliphatic Aldehydes
chiral R- and S-configured BINOL complexes were employed
in these reactions. No enantioselectivities were detected in these
tranformations. Recently, other multinuclear chiral titanium
clusters (e.g., a hexanuclear cluster with a chiral reactive cave)
have been synthesized in our laboratories, and the catalytical
properties will be explored.23
entry
R
yield (%)
syn-19:anti-19
Conclusion
1
2
3
4
5
6
7
8
a: Me
b: Et
c: iPr
d: tBu
e: Cy
32
62
70
49
53
46
34
20
62:38
65:35
67:33
84:16
69:31
69:31a
70:30a
65:35
In summary, we have expanded our results concerning direct
aldol additions. These reactions were promoted by extreme low
loadings of air- and water-stable titanium catalyst 1. The method
in hand represents a valuable addition to kinetically controlled
regioselectivities as they were observed in several other direct
aldol additions to unsymmetrical methyl ketones.
f: rac-Et-CHMe-
g: rac-nPr-CHMe-
h: Ph-(CH2)2-
24-31
For
a Internal diastereoselectivity 50:50.
control of regioselectivity in aldol additions of trimethylsilyl
enol ethers of unsymmetrical ketones depending on counterac-
TABLE 7. Thermodynamically Controlled Formation of
Ketalacetals 20 of Hydroxyacetone and Aliphatic Aldehydes
(21) Calculated structure of the protected aldol 22 (geometric optimiza-
tion/SymApps). NOE effects are visualized with green arrows. See
Supporting Information.
entry
R
yield (%)
1
2
3
4
a: Ph-(CH2)2-
b: iPr
c: Cy
25
25
34
32
d: tBu
SCHEME 3. Trimerization of Hydroxyacetone; New C-C
Bond Is Indicated in Red
(22) (a) Keck, G. E.; Tabert, K. H. J. Am. Chem. Soc. 1993, 115, 8467.
(b) Faller, J. W.; Sams, D. W. I.; Liu, X. J. Am. Chem. Soc. 1996, 118,
1217.
(23) Schetter, B.; Stosiek, C.; Ziemer, B.; Mahrwald, R. Appl. Organomet.
Chem. 2007, 21, 139.
(24) Proline-catalyzed direct aldol additions: (a) Liu, H.; Peng, L.; Zhang,
T.; Li, Y. New J. Chem. 2003, 27, 1159. (b) Tang, Z.; Yang, Z.-H.; Cun,
L.-F.; Gong, L.-Z.; Mi, A.-Q.; Jiang, Y.-Z. Org. Lett. 2004, 6, 2285. (c)
Kano, T.; Tokuda, O.; Takai, J.; Maruoka, K. Chem. Asian J. 2006, 1, 210.
(d) Samanta, S.; Zhao, C.-G. Tetrahedron Lett. 2006, 47, 3383. (e) Mase,
N.; Nakai, Y.; Ohara, N.; Yoda, H.; Takabe, K.; Tanaka, F.; Barbas, C. F.,
III. J. Am. Chem. Soc. 2006, 128, 734. (f) Guizzetti, S.; Benaglia, M.;
Raimondi, L.; Celentano, G. Org. Lett. 2007, 9, 1247. (g) Samanta, S.;
Zhao, C.-G. Tetrahedron Lett. 2006, 47, 3383. (h) Sakthivel, K.; Notz, W.;
Bui, T.; Barbas, C. F., III. J. Am. Chem. Soc. 2001, 123, 5260.
(25) Antibody-catalyzed direct aldol additions: (a) Baker-Glenn, C.;
Ancliff, R.; Gouverneur, V. Tetrahedron 2004, 60, 7607. (b) Maggiotti,
V.; Bahmanyar, S.; Reiter, M.; Resmini, M.; Houk, K. N.; Gouverneur, V.
Tetrahedron 2004, 60, 619. (c) Maggiotti, V.; Wong, J.-B.; Razet, R.;
Cowley, A. R.; Gouverneur, V. Tetrahedron: Asymmetry 2002, 13, 1789.
(d) Maggiotti, V.; Resmini, M.; Gouverneur, V. Angew. Chem., Int. Ed.
2002, 41, 1012. (f) Tanaka, F.; Barbas, C. F., III. In Modern Aldol Reactions;
Mahrwald, R., Ed.: Wiley-VCH: Weinheim 2004; Vol. 1, p 273.
(26) MgI2-amine-promoted direct aldol addition: Wei, H.-X.; Jasoni, R.
L.; Shao, H.; Hu, J. Pare´, P. W. Tetrahedron 2004, 60, 11829.
(27) Bis(amido)magnesium-mediated aldol additions: Allan, J. F., Hend-
erson, K. W., Kennedy, A. R. Chem. Commun. 1999, 1325.
(28) Organoaluminium-promoted direct aldol condensations: (a) Tsuji,
J.; Yamada, T.; Kaito, M.; Mandai, T. Tetrahedron Lett. 1979, 24, 2257.
(b) Tsuji, J.; Yamada, T.; Kaito, M.; Mandai, T. Bull Chem. Soc. Jpn. 1980,
53, 417.
Because tetranuclear titanium catalyst 1 is extremely resistant
to air, moisture, and acids, neither drying of the reagents and
the solvents nor the application of protection gas techniques
were necessary. Although the reaction stopped after adding 1
equiv of water, the aldol reaction proceeded after removing
water (3 Å molecular sieves after separation of the aqueous
layer), indicating that the catalyst remained stable and active.
It was even possible to recover unchanged catalyst from the
reaction mixture. Higher reaction temperatures and higher
catalysts loadings accelerated the reaction rates in many cases,
but it has to be pointed out that this advantage is generally
associated with greater amounts of byproducts, lower selectivi-
ties, and lower yields. Further experiments concerning the
concept of chiral amplification and chiral poisoning22 of the
racemic catalyst are ongoing, but only low to moderate
enantioselectivities were detected in initially experiments. Also,
(29) Aluminium oxide promoted aldol condensation: Nondek, L.; Malek,
J. Collect. Czech. Chem. Commun. 1980, 45, 1812.
(30) Lithium enolates: Gaudemar, M. C. R. Seances Acad. Sci., Ser. C
1974, 279, 961.
(31) Similar results of kinetically controlled regioselectivities in orga-
nocatalyzed direct aldol additions depending on the bulkiness of unsym-
metrical ketones used were reported by Kano, T.; Tokuda, O.; Takai, J.;
Maruoka, K. Chem. Asian J. 2006, 1, 210.
(20) Calinoud, P.; Veyssieres-Rambaud, S. Bull. Soc. Chim. Fr. 1973,
2769.
818 J. Org. Chem., Vol. 73, No. 3, 2008

Tetranuclear BINOL-Titanium Complex
1076, 1045, 1012, 915, 903, 848, 797, 755, 702. Anal. Calcd for
C13H16O4: C, 66.09; H, 6.83. Found: C, 66.04; H, 6.82. MS (EI,
relative intensity, %): 205.1 (0.5), 163.1 (3), 145.1 (10), 121.1 (42),
91.1 (100), 77.0 (18). HRMS (ESI) [C13H16O4; M]+: calcd
236.1049, found 236.1049.
tions (lithium or potassium). see ref 32. The synthetical power
of this reaction significantly exceeds that of the TiCl4-mediated,
since interesting results were obtained with oxygen-containing
ene components. Further investigations aiming at an enantiose-
lective execution are underway.
1-(2,4-Dimethyl-[1,3]dioxolan-4-yloxy)-propan-2-one (19a).20
Hydroxyacetone (148 mg, 2 mmol;1 equiv) and acetaldehyde (352
mg, 8 mmol; 4 equiv) were mixed at room temperature, 0.2 mol %
of the calalyst was added, and the mixture cooled to avoid
evaporation of acetaldehyde. The procedure of the reaction was
monitored by TLC, and when the turnover was complete, the
reaction mixture was diluted with diethyl ether and quenched with
aqueous NH4Cl. The organic layer was separated, dried (MgSO4),
and filtered, and the ether was removed in vacuo. Column
chromatography (hexane/ethylacetate) afforded 50 mg (32%) pure
acetals.
Experimental Section
3-Butyl-4-hydroxy-4-phenyl-butan-2-one (4a).33 Benzaldehyde
(636 mg, 6 mmol; 3 equiv) and heptan-2-one (228 mg, 2 mmol; 1
equiv) were mixed at room temperature, and 0.2 mol % of the
calalyst was added. The procedure of the reaction was monitored
by TLC, and when the turnover was complete, the reaction mixture
was diluted with diethyl ether and quenched with aqueous NH4Cl.
The organic layer was separated, dried (MgSO4), and filtered, and
the ether was removed in vacuo. Column chromatography (hexane/
ethylacetate) afforded 299 mg (68%) pure aldols.
Major. 1H NMR: δ 1.30 (d, J ) 4.91, 3 H, CH3), 1.45 (s, 3 H,
CH3), 2.13 (s, 3 H, CH3), 3.81 (d, J ) 8.5 Hz, 1 H, CH), 3.91 (d,
J ) 8.7 Hz, 1 H, CH), 4.04 (d, J ) 16.8 Hz, 1 H, CH), 4.14 (d, J
) 17.0 Hz, 1 H, CH), 5.19 (q, J ) 4.91 Hz, 1 H, CH). 13C NMR:
δ 19.4, 21.3, 26.5, 68.1, 76.3, 101.3, 105.4, 206.4.
1
syn-4a. Colorless oil. H NMR: δ 0.69 (t, 7.2 Hz, 3 H, CH3),
0.90-1.65 m, 6 H, CH2CH2CH2), 1.83 (s, 3H, CH3), 2.73 (dt, J1
) 4.9 Hz, J2 ) 6.0 Hz, 1 H, CH), 4.69 (d, 6.0 Hz, 1 H, CHOH),
7.10-7.25 (m, 5 H, ar). 13C NMR: δ 13.8, 22.8, 27.1, 29.9, 31.8,
59.6, 74.1, 126.1, 127.6, 128.4, 142.0, 213.2.
Minor. 1H NMR: δ 1.37 (d, J ) 4.91, 3 H, CH3), 1.46 (s, 3 H,
CH3), 2.11 (s, 3 H, CH3), 3.58 (d, J ) 9.44 Hz, 1 H, CH), 4.01 (d,
J ) 17.0 Hz, 1 H, CH), 4.06 (d, J ) 7.4 Hz, 1 H, CH), 4.11 (d, J
) 16.4 Hz, 1 H, CH), 5.05 (q, J ) 4.91 Hz, 1 H, CH). 13C NMR:
δ 19.5, 22.7, 26.7, 68.3, 74.9, 102.6, 105.1, 207.4. IR (KBr): 2991,
2937, 2892, 1733, 1717, 1446, 1411, 1381, 1356, 1230, 1175, 1144,
1112, 1097, 895. MS (EI, relative intensity, %). 157.1 (5), 133.1
(9), 115.1 (16), 101.1 (84), 57.0 (54), 43.0 (100). Anal. Calcd for
C8H14O4: C, 55.16; H, 8.10. Found: C, 55.12; H, 8.04. HRMS
(ESI) [C8H14O4Na; M + Na]+: calcd 197.0784, found 197.0785.
1,4,7-Trimethyl-3,5,9,10-tetraoxa-tricyclo[5.2.1.04,8]decane (22).
Hydroxyacetone (148 mg, 2 mmol) was mixed with 0.2 mol % of
the catalyst at room temperature. The progress of the reaction was
monitored by TLC, and when the turnover was complete, the
reaction mixture was diluted with diethyl ether and quenched with
aqueous NH4Cl. The organic layer was separated, dried (MgSO4),
and filtered, and the ether was removed in vacuo. Column
chromatography (hexane/ethylacetate) afforded 67 mg (54%) pure
1
anti-4a. Colorless oil. H NMR: δ 0.74 (t, J ) 7.2 Hz, 3 H,
CH3), 0.90-1.65 m, 6 H, CH2CH2CH2), 1.83 (s, 3 H, CH3), 2.33
(dt, J1 ) J2 ) 7.5 Hz, 1 H, CH), 4.99 (dd, J1 ) 4.2 Hz, J2 ) 8.7
Hz, 1 H, CHOH), 7.10-7.25 (m, 5 H, ar). 13C NMR: δ 13.9, 22.4,
23.4, 29.9, 31.3, 43.7, 69.9, 125.6, 127.6, 128.4, 142.8, 211.7.
Large amounts of recovered ketone indicate the necessity to use
longer reacion times or higher reaction temperatures in some cases,
especially when the reactivity of the employed aldehydes or ketones
was lower.
1,5-Dimethyl-3-phenyl-2,6,8-trioxa-bicyclo[3.2.1]octan-4-ol
(16a). Hydroxyacetone (148 mg, 2 mmol; 1 equiv) and benzalde-
hyde (1060 mg, 10 mmol; 5 equiv) were mixed at room temperature,
and 0.2 mol % of the calalyst was added. The procedure of the
reaction was monitored by TLC, and when the turnover was
complete, the reaction mixture was diluted with diethyl ether and
quenched with aqueous NH4Cl. The organic layer was separated,
dried (MgSO4), and filtered, and the ether was removed in vacuo.
Column chromatography (hexane/ethylacetate) afforded 158 mg
(67%) pure aldols.
1
aldol. Colorless solid, mp 40-41 °C. H NMR: δ 1.29 (s, 3 H,
CH3), 1.41 (s, 3 H, CH3), 1.42 (s, 3 H, CH3), 3.57 (d, J ) 10.9 Hz,
1 H, CH2), 3.62 (d, J ) 10.2 Hz, 1 H, CH2), 3.63 (d, J ) 11.3 Hz,
syn-16a. Colorless solid. Mp ) 70-71 °C. 1H NMR: δ 1.56 (s,
3 H, CH3), 1.62 (s, 3 H, CH3), 1.85 (d, J ) 9.0 Hz, 1 H, OH), 3.40
(dd, J1 ) 2.25 Hz, J2 ) 9.0 Hz, 1 H, CH), 3.76 (d, J ) 8.3 Hz, 1
H, CH), 4.20 (d, J ) 8.7 Hz, 1 H, CH), 5.16 (d, J ) 2.6 Hz, 1 H,
CH), 7.25-7.40 (m, 5 H, ar). 13C NMR: δ 20.4, 20.7, 70.6, 72.0,
75.3, 104.4, 108.7, 126.1, 127.8, 128.4, 137.4. IR (KBr): 3478,
3058, 3034, 2905, 2357, 1244, 1226, 1187, 1088, 1075, 1037, 868.
Anal. Calcd for C13H16O4: C, 66.09; H, 6.83. Found: C, 65.82; H,
6.99. MS (EI, relative intensity, %): 235.1 (0.5), 205.1 (1), 163.1
(6), 145.1 (9), 121.1 (26), 91.1 (100), 77.0 (20). HRMS (ESI)
[C13H16O4; M]+: calcd 236.1049, found 236.1049.
1 H, CH2), 4.05 (d, J ) 10.2 Hz, 1 H, CH2), 4.06 (s, 1 H, CH). 13
C
NMR: δ 20.6, 22.1, 24.8, 69.4, 74.8, 85.1, 86.2, 102.9, 105.5. IR
(KBr): 2985, 2935, 2876, 1449, 1382, 1293, 1253, 1172, 1126,
1096, 1079, 1039, 903, 885, 836. MS (EI, relative intensity, %):
186.1 (0.5) 156.1 (8), 141.1 (2), 114.1 (4), 97.1 (100), 85.0 (7),
43.0 (49). Anal. Calcd for C9H14O4: C, 58.05; H, 7.58. Found: C,
58.49; H, 7.33. HRMS (ESI) [C9H14O4; M]+: calcd 186.0892, found
186.0892.
Acknowledgment. This work was supported by the Deutsche
Forschungsgemeinschaft, Konrad-Adenauer-Stiftung and Bayer
Schering Pharma AG, Bayer Services GmbH, BASF AG and
Sasol GmbH. Enantiopure BINOL was a gift of Merck KGaA,
Darmstadt, Germany. Petra Neubauer is grateful acknowledged
for technical support.
anti-16a. Colorless solid. Mp ) 128-129 °C. 1H NMR: δ 1.55
(s, 3 H, CH3), 1.61 (s, 3 H, CH3), 1.76 (d, J ) 9.0 Hz, 1 H, OH),
3.25 (dd, J1 ) J2 ) 9.9 Hz, 1 H, CH), 3.81 (d, J ) 8.3 Hz, 1 H,
CH), 4.25 (d, J ) 8.3 Hz, 1 H, CH), 4.54 (d, J ) 8.3 Hz, 1 H,
CH), 7.25-7.40 (m, 5 H, ar). 13C NMR: δ 19.8, 20.4, 72.8, 74.1,
79.0, 104.4, 108.7, 127.2, 128.5, 138.4 (one aryl signal is hidden
under the 127.2 or 128.5 signal). IR (KBr): 3486, 3446, 3064, 3034,
2944, 2905, 2894, 1452, 1383, 1248, 1228, 1206, 1186, 1144, 1098,
Supporting Information Available: General experimental
procedures, characterization data, and NMR spectra for all new
compounds and X-ray crystal data in CIF format for compounds
1, 6, syn-9d, syn-16a, and anti-16a are available. This material is
available free of charge via the Internet at http://pubs.acs.org.
(32) Duhamel, P.; Cahard, D.; Quesnel, Y.; Poirier, J.-M. J. Org. Chem.
1996, 61, 2232.
(33) Masamune, S.; Mori, S.; Van Horn, D.; Brooks, D. W. Tetrahedron
Lett. 1979, 19, 1665.
JO7014054
J. Org. Chem, Vol. 73, No. 3, 2008 819