Convenient enol equivalents for catalytic aldol-transfer reactions

Article abstract of DOI:10.1016/j.tetlet.2006.08.003

Solid crystalline and stable 1,1-diphenyl-1-hydroxy-3-butanone was shown to serve as an excellent precursor of the Al-enolate of acetone generated in situ for Al-BINOL catalyzed aldol-transfer reactions of aldehydes. The best yields were obtained with electron rich aromatic aldehydes and 2-pyridine carbaldehyde of which the latter gave 1-hydroxy-1-(2-pyridyl)-3-butanone in 79% yield.

Full text of DOI:10.1016/j.tetlet.2006.08.003

Tetrahedron Letters 47 (2006) 7133–7135
Convenient enol equivalents for catalytic aldol-transfer reactions
Bixia Xi and Vesa Nevalainen*
Department of Chemistry and Biochemistry, University of Massachusetts Dartmouth, 285 Old Westport Road,
North Dartmouth, MA 02474, USA
Received 18 July 2006; revised 1 August 2006; accepted 2 August 2006
Available online 22 August 2006
Abstract—Solid crystalline and stable 1,1-diphenyl-1-hydroxy-3-butanone was shown to serve as an excellent precursor of the
Al-enolate of acetone generated in situ for Al-BINOL catalyzed aldol-transfer reactions of aldehydes. The best yields were obtained
with electron rich aromatic aldehydes and 2-pyridine carbaldehyde of which the latter gave 1-hydroxy-1-(2-pyridyl)-3-butanone in
79% yield.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Nucleophile-transfer reactions offer great potential for
organic transformations.1–9 They are similar to MPV
type of reactions1 but the nucleophile transferred is
other than hydride. For example, Inoue and co-workers
described the use of Al- and Ti-based promotors2 and
La-alkoxide catalysts3 for cyanohydrin transfer reac-
tions. Maruoka and co-workers described alkynyl-trans-
fer reactions mediated by Al-4 and Zr-alkoxides.5 Allyl
and homopropargyl-transfer reactions have been
reported by Nokami and co-workers, Loh et al., and
Oshima and co-workers6 Aldol-transfer reactions of
aldehydes and diacetone alcohol 1 catalyzed by Al-BI-
NOL (Scheme 1) were described by Nevalainen et al.7
In this reaction 1 is converted via 2 and 3 to a diolmono-
ester 4 (R = alkyl) or aldol 5 (R = aryl, via 67d). Later
Schneider et al. reported8 the related Zr-BINOL pro-
cess. Finally, Chandrasekhar et al. reported the first L-
proline catalyzed enantioselective aldol-transfer reaction
for aldols 5.9
The most common enol equivalent for aldol-transfer
reactions is diacetone alcohol 1.7–9 Recently Schneider
et al. described Zr-BINOL catalyzed aldol-transfer reac-
tions using other enol equivalents.8a They reported that
1,1-diphenyl-1-hydroxy-3-butanone (7, Scheme 2) per-
forms poorly for the formation of Zr-analog of 4
(decomposition of 7 to acetone and benzophenone was
claimed to be the main reaction instead of the desired
O
Al
Al
Al
HO
O
O
O
R
O
O
O
O
BINOL (0.05 eq)
Me3Al (0.1 eq)
RCHO
RCHO
R
R
4 (60 - 80%)
1
2
3
HO
O
O
Al
O
HO
O
Me3Al (0.3 eq)
R
R
3
5
(20 - 84%)
6
Scheme 1. Catalytic aldol-transfer reactions of 1 and RCHO. In parentheses are given typical isolated yields of diols (from 4)7c and aldols (from 6)7d
obtained after acidic workup and flash chromatography.
*
Corresponding author. Tel.: +1 508 999 8276; fax: +1 508 999 9167; e-mail: vnevalainen@umassd.edu
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.08.003

7134
B. Xi, V. Nevalainen / Tetrahedron Letters 47 (2006) 7133–7135
1)
2)
4–6). Actually, with 7, the p-methoxyl derivative 5d was
obtained in 70% yield (the yield of 5d was 63% with 1).
Our new method7d was also checked with 1-naphthal-
dehyde and o-chlorobenzaldehyde to detect whether o-
substitution would have any effect. However, aldol 5g
was isolated in 48% yield (entry 7). This value is 28%
higher than that obtained earlier using 1. Unfortunately,
both 1 and 7, when reacted with o-chlorobenzaldehyde,
gave a bad mixture not worthy of purification.
BINOL (10 mol%)
Me3Al (40 mol%)
OH
O
OH O
Ph
Ph
R
3)
4)
RCHO (100 mol%), CH2Cl2, r.t., 43 h
HCl (1M)
7
5
Scheme 2. Aldol-transfer reactions of 1,1-diphenyl-1-hydroxy-3-buta-
none 7.
aldol-transfer pathway). In contrast to this, on the basis
of one early experiment, compound 7 has been sug-
gested7a to be a better enolate precursor than diacetone
alcohol 1. This poses a question: why do we care for the
utility of 7 as an enol equivalent for aldol-transfer reac-
tions? This is because 1 is a liquid, which slowly decom-
poses when stored. Therefore, compound 1 must always
be distilled before use (Lewis acid-catalyzed aldol-trans-
fer reactions require dry conditions). Compound 7, how-
ever, is a crystalline solid and can be easily dried under
vacuum. Furthermore, it can be stored for a longer time
without decomposition (the sample used for the early
experiment7a was a couple of decades old!). Therefore,
aldol-transfer reactions, which employ 7 instead of 1,
would be easier to conduct and would facilitate the fur-
ther development of aldol-transfer technology.
When 2-pyridine carbaldehyde was reacted with 7, aldol
5h was obtained in 79% yield (entry 8). That is 5% better
than the reference yield. On the other hand, the yields of
5i and 5j were only 24% and 30% and lower that the ref-
erence yields. Intensive polymerization, lowering the
yield of 5j, was observed for both reactions of 2-thio-
phene carbaldehyde (with 1 and 7).
In conclusion, easy to handle enol equivalent 7 used
according to our new alkoxide trapping method7d gives
aldols 5 in yields closely similar to those obtained earlier
with equivalent 1. Only with 4-nitrobenzaldehyde and
2-thiophene carbaldehyde were the yields clearly lower
(with 7). Slightly better yields were obtained with 7 when
it was reacted with p-methoxybenzaldehyde or 2-pyri-
dine carbaldehyde. Only in the case of 1-naphthyl carb-
aldehyde did the yield improve a lot when precursor 7
was used instead of 1. Finally, aldol 7 seems to be a
much better enol equivalent for Al-BINOL catalyzed
aldol-transfer reactions than for Zr-BINOL catalyzed
ones.8a This study confirms the utility of this stable
crystalline easy to dry and purify aldol 7 as an excellent
precursor of metal enolates of acetone (for in situ
generations) as well as the reactivity of the enolate
toward aldehydes leading to the formation of aldol
adducts. Further studies on structural modifications of
aldol 7 to optimize it for aldol-transfer reactions are in
progress.
In order to determine the performance of 7 as an enol
equivalent, we used our new method7d and reacted 10
(hetero)aromatic aldehydes with 7 in the presence of
40 mol % trimethylaluminum (Scheme 2) to obtain 5.
The results are summarized in Table 1. The results are
compared with those obtained earlier7d using 1 (the ref-
erence method).
The yield of 5a was only 26% (Table 1, entry 1). This
value is only 3% lower than that obtained earlier7d using
precursor 1 (entry 1, reference yield 29%). The same small
difference of yields of 5b was observed with 4-chlorobenz-
aldehyde (entry 2). Unfortunately, the main product with
both 1 and 7 was the corresponding enone isolated in 39%
and 33% yield, respectively. Interestingly, with electron-
poor and more reactive 4-nitrobenzaldehyde, the yield
of 5c (entry 3) was significantly lower than that observed
earlier using the reference method. With electron-rich
benzaldehydes, 7 worked almost as well as did 1 (entries
Typical procedure for the aldol-transfer reaction of
aromatic aldehydes is as follows: At room temperature
under argon, trimethylaluminum (0.08 mmol, 0.04 mL,
2 M in toluene or heptane) was added to a suspension
of 1,10-bi-2-naphthol (0.041 mmol, 11.8 mg) in dry
CH2Cl2 (0.5 mL) and stirred for 20 min. Then 2-pyridine
Table 1. Aldol-transfer reactions of aldehydes RCHO with 1,1-diphenyl-1-hydroxy-3-butanone 7a
Entry
R
Derivative
Yield of 5b (%)
Reference yieldc (%)
1
2
3
4
5
6
7
8
9
C6H5
p-Cl–C6H4
a
b
c
d
e
f
26
15d
22
70
77
78
48
79
24
30
29
18e
38
63
84
83
20
74
30
40
p-NO2–C6H4
p-CH3O–C6H4
3-CH3O, 4-C2H5O–C6H3
3,4,5-(CH3O)3C6H2
1-Naphthyl
Pyridine-2
Furan-2
Thiophene-2
g
h
i
10
j
a See Scheme 2. The products were characterized by spectral data.
b Isolated yields of 5 (relative to RCHO) after flash chromatography.
c The yield of 5 obtained when 1 was used instead of 7 (Ref. 7d).
d The corresponding enone was isolated in 39% yield.
e The corresponding enone was isolated in 33% yield.

B. Xi, V. Nevalainen / Tetrahedron Letters 47 (2006) 7133–7135
7135
6. Allyl-transfer: (a) Nokami, J.; Yoshizane, K.; Matsuura,
H.; Sumida, S. J. Am. Chem. Soc. 1998, 120, 6609; (b)
Sumida, S.; Ohga, M.; Mitani, J.; Nokami, J. J. Am.
Chem. Soc. 2000, 122, 1310; (c) Loh, T.-P.; Hu, Q.-Y.; Ma,
L.-T. Org. Lett. 2002, 4, 2389; (d) Hussain, I.; Komasaka,
T.; Ohga, M.; Nokami, J. Synlett 2002, 640; (e) Shafi, S.
M.; Chou, J.; Kataoka, K.; Nokami, J. Org. Lett. 2005, 7,
2957; (f) Hayashi, S.; Hirano, K.; Yorimitsu, H.; Oshima,
K. Org. Lett. 2005, 7, 3577; (g) Takada, Y.; Hayashi, S.;
Hirano, K.; Yorimitsu, H.; Oshima, K. Org. Lett. 2006, 8,
2515; Asymmetric allyl-transfer: (h) Nokami, J.; Anthony,
L.; Sumida, S.-I. Chem. Eur. J. 2000, 6, 2909; (i) Nokami,
J.; Ohga, M.; Nakamoto, H.; Matsubara, T.; Hussain, I.;
Kataoka, K. J. Am. Chem. Soc. 2001, 123, 9168; (j) Loh,
T.-P.; Hu, Q.-Y.; Chok, Y.-K.; Tan, K.-T. Tetrahedron
Lett. 2001, 42, 9277; (k) Loh, T.-P.; Lee, C.-L. K.; Tan,
K.-T. Org. Lett. 2002, 4, 2985; (l) Nokami, J.; Nomiyama,
K.; Matsuda, S.; Imai, N.; Kataoka, K. Angew. Chem.,
Int. Ed. 2003, 42, 1273; (m) Lee, C.-H. A.; Loh, T.-P.
Tetrahedron Lett. 2004, 45, 5819; (n) Nokami, J.; Nomi-
yama, K.; Shafi, S. M.; Kataoka, K. Org. Lett. 2004,
6, 1261; (o) Lee, C.-L. K.; Lee, C.-H. A.; Tan, K.-T.;
Loh, T.-P. Org. Lett. 2004, 6, 1281; (p) Lee, C.-H. A.; Loh,
T.-P. Tetrahedron Lett. 2006, 47, 809; Homopropargyl-
transfer: (q) Lee, K.-C. K.; Lin, M.-J.; Loh, T.-P. Chem.
Commun. 2004, 2456.
carbaldehyde (0.41 mmol, 44.0 mg) and 1,1-diphenyl-1-
hydroxy-3-butanone10 (0.41 mmol, 98.5 mg) were added
simultaneously in dry CH2Cl2 (0.5 mL). After stirring
for 1 h, trimethylaluminum (0.08 mmol, 0.04 mL) was
again added. After further stirring for 42 h, the mixture
was quenched with aqueous HCl (1 M, 10 mL). After
adding 10 mL EtOAc, the mixture was stirred until
homogeneous. The homogenized solution was neutral-
ized with 10% NaOH and saturated with NaCl. The
organic layer was separated and the aqueous layer was
extracted with EtOAc (2 · 10 mL). The combined ex-
tracts (about 30 mL) were dried over MgSO4 and fil-
tered. Evaporation of the filtrate gave 150.9 mg crude
product. Flash chromatographic purification of the crude
gave
1-hydroxy-1-(2-pyridyl)-3-butanone
(53.2 mg,
0.322 mmol, 79%) as white crystalline solid. Rf = 0.72
(CH2Cl2:MeOH 3:1); FTIR (neat, cmꢀ1): 3132, 1711,
1535; 1H NMR (300 MHz, CDCl3, 20 ꢁC, CHCl3,
7.26 ppm): d 8.53 (m, 1H), 7.68–7.74 (m, 1H), 7.46 (d,
J = 7.90 Hz, 1H), 7.19–7.23 (m, 1H), 5.18–5.22 (m,
1H), 4.18 (m, 1H), 3.00–3.07 (m, 1H), 2.98 (dd,
J = 8.31, J0 = 17.10 Hz, 1H), 2.24 (s, 3H); 13C NMR
(75 MHz, CDCl3, 77.0 ppm): d 208.54, 161.25, 148.19,
136.82, 122.30, 120.24, 69.68, 50.59, 30.67. These spec-
tral values match well with the literature data.11 All
compounds were characterized using 1H NMR, 13C
NMR, and IR spectroscopy. The spectral data of known
5a–j were well consistent with the literature values.7c,d,11
7. (a) Simpura, I.; Nevalainen, V. Angew. Chem., Int. Ed.
2000, 39, 3422; (b) Simpura, I.; Nevalainen, V. Tetra-
hedron Lett. 2001, 42, 3905; (c) Simpura, I.; Nevalainen, V.
Tetrahedron 2003, 59, 7435; (d) Xi, B.; Nevalainen, V.
Tetrahedron Lett. 2006, 47, 2561.
8. (a) Schneider, C.; Hansch, M.; Weide, T. Chem. Eur. J.
2005, 11, 3010; (b) Schneider, C.; Klapa, K.; Hansch, M.
Synlett 2005, 91; (c) Schneider, C.; Hansch, M. Synlett
2003, 837; (d) Schneider, C.; Hansch, M. Chem. Commun.
2001, 1218.
9. (a) Chandrasekhar, S.; Narsihmulu, C.; Ramakrishna
Reddy, N.; Shameen Sultana, S. Chem. Commun. 2004,
2450; (b) Chandrasekhar, S.; Ramakrishna Reddy, N.;
Shameem Sultana, S.; Narsihmulu, Ch.; Venkatram
Reddy, K. Tetrahedron 2006, 62, 338.
References and notes
1. (a) Meerwein, H.; Schmidt, R. Liebigs Ann. Chem. 1925,
444, 221; (b) Verley, A. Bull. Soc. Chim. Fr. 1925, 37, 537;
(c) Ponndorf, W. Angew. Chem. 1926, 39, 138.
2. Mori, A.; Kinoshita, K.; Osaka, M.; Inoue, S. Chem. Lett.
1990, 1171.
3. Mori, A.; Osaka, M.; Inoue, S. Chem. Lett. 1993, 375.
4. Ooi, T.; Miura, T.; Maruoka, K. J. Am. Chem. Soc. 1998,
120, 10790.
10. Synthesis of 1,1-diphenyl-1-hydroxy-3-butanone: (a) Paul-
son, D. R.; Hartwig, A. L.; Moran, G. F. J. Chem. Educ.
1973, 50, 216; (b) Rivett, D. E. A. J. Chem. Educ. 1980, 57,
751.
5. (a) Ooi, T.; Takaya, K.; Miura, T.; Maruoka, K. Synlett
2000, 69; (b) Ooi, T.; Miura, T.; Takaya, K.; Ichikawa, H.;
Maruoka, K. Tetrahedron 2001, 57, 867.
11. Chimni, S. S.; Mahajan, D. Tetrahedron 2005, 61, 5019.