Reductive cross-aldol reaction using bromoaldehyde and an aldehyde mediated by germanium(II): One-pot, large-scale protocol

Article abstract of DOI:10.1021/ol050533i

(Chemical Equation Presented) The reaction of α-bromoaldehyde with aldehyde in the presence of GeCl₂-dioxane gave the syn-selective cross-aldol equivalent. A catalytic amount of Bu₄NBr improved the yield and selectivity. The initially formed aldol adduct (β- germoxyaldehyde) did not suffer from over-reaction. This system enabled an intramolecular aldol reaction to give cyclic compounds effectively. One-pot synthetic methodology including bromination of aldehyde followed by cross-aldol reaction with the second aldehyde was successful on a large-scale.

Full text of DOI:10.1021/ol050533i

ORGANIC
LETTERS
2005
Vol. 7, No. 9
1845-1848
Reductive Cross-Aldol Reaction Using
Bromoaldehyde and an Aldehyde
Mediated by Germanium(II): One-Pot,
Large-Scale Protocol
Makoto Yasuda, Shin-ya Tanaka, and Akio Baba*
Department of Molecular Chemistry and Handai Frontier Research Center,
Graduate School of Engineering, Osaka UniVersity, 2-1 Yamadaoka, Suita,
Osaka 565-0871, Japan
yasuda@chem.eng.osaka-u.ac.jp
Received March 11, 2005
ABSTRACT
The reaction of
r-bromoaldehyde with aldehyde in the presence of GeCl2−dioxane gave the syn-selective cross-aldol equivalent. A catalytic
amount of Bu4NBr improved the yield and selectivity. The initially formed aldol adduct (
â
-germoxyaldehyde) did not suffer from over-reaction.
This system enabled an intramolecular aldol reaction to give cyclic compounds effectively. One-pot synthetic methodology including bromination
of aldehyde followed by cross-aldol reaction with the second aldehyde was successful on a large-scale.
Numerous cross-aldol reactions have been reported for
stereoselective carbon-carbon bond formation to give func-
tionalized compounds in organic synthesis.1 Most of them
deal with the reactions of enolates derived from ketones or
esters with aldehydes. However, cross-aldol reaction between
enolates from aldehydes with aldehydes has rarely been
reported probably because the aldol product (â-hydroxyal-
dehyde) would suffer from undesired further reactions. To
avoid this problem, hydroformylation of allylic alcohols can
provide an approach to anti-â-hydroxyaldehyde derivatives.2
A few examples of the stereoselective cross-aldol reactions
between aldehydes have recently appeared from some groups
and can be classified into two types. One is a direct aldol
system that was reported in 1997 as the first stereoselective
cross-aldol reaction between aldehydes using a combination
of a base and a Lewis acid to give a syn-adduct.3 This system
has been developed for asymmetric synthesis by chiral
organocatalysis.4 These direct reactions may be a simple and
ideal methodology, but a self-aldol reaction could be a
problem. Therefore, the amount of substrates and the period
of their loading should be optimized. The second type is the
reaction of aldehyde-enolates with aldehydes. Titanium
enolates enabled anti-selective reactions.5 An excellent
system using trichlorosilyl enolates to give either syn- or anti-
products was developed in asymmetric synthesis.6
We now report a third type that is a reductive cross-aldol
reaction using R-bromoaldehyde, aldehyde, and Ge(II) as a
(3) Mahrwald, R.; Costisella, B.; Gu¨ndogan, B. Tetrahedron Lett. 1997,
38, 4543-4544.
(4) Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124,
6798-6799.
(5) (a) Yachi, K.; Shinokubo, H.; Oshima, K. J. Am. Chem. Soc. 1999,
121, 9465-9466. (b) Han, Z.; Yorimitsu, H.; Shinokubo, H.; Oshima, K.
Tetrahedron Lett. 2000, 41, 4415-4518.
(1) (a) ComprehensiVe Organic Syntheses; Trost, B. M., Ed.; Pergamon
Press: Oxford, U.K., 1991; Vol. 2, pp 99-319. (b) Mahwald, R. Chem.
ReV. 1999, 99, 1095-1120.
(6) Denmark, S. E.; Ghosh, S. K. Angew. Chem., Int. Ed. 2001, 40, 4759-
4762.
(2) Breit, B.; Demel, P.; Gebert, A. Chem. Commun. 2004, 114-115.
10.1021/ol050533i CCC: $30.25
© 2005 American Chemical Society
Published on Web 03/25/2005

reductant.7 This system is operationally simple and requires
no preparation of metal enolates to give the syn-cross-aldol
equivalents in high yields.
Table 2. Optimization of Reaction Conditionsa
We examined several low-valent metals as reducing agents
for the reaction of 2-bromoheptanal 1a with benzaldehyde
2a (Table 1). The typical metal species for reductants such
entry
solvent
additive
yield/%
syn/anti
1
2b
3
4
5
6
7
8
9
THF
Et2O
DMF
hexane
CH2Cl2
THF
Et2O
DMF
57
11
0
70:30
57:43
Table 1. Investigation of Reductants for Reductive
Cross-Aldol Reaction
0
18
52
86
0
56
63
47:53
68:32
83:17
Bu4NBr
Bu4NBr
Bu4NBr
Bu4NBr
Bu4NBr
hexane
CH2Cl2
82:18
79:21
entry
reductant
conditions
yield/%
syn/anti
10
1
2
3
4
5
Zn
SmI2
CrCl2
SnCl2
68 °C, 2 h
-78 °C, 2 h
rt, 14 h
rt, 2 h
rt, 2 h
0
0
0
0
60
a All reactions were performed using bromoaldehyde 1a (0.6 mmol),
benzaldehyde 2a (0.6 mmol), and GeCl2-dioxane (0.6 mmol) in solvent
(2 mL) at rt for 2 h. b 4 h.
GeCl2-dioxane
64:36
further nucleophilic addition to the initially formed aldol
adduct (stannoxide) occurs in the reaction course. On the
contrary, the GeCl2 system provided a clean reaction to
synthesis of 4aa without over-reactions. The addition order
is also important: The bromoaldehyde should be the last
reagent to be added because premixing of the bromoaldehyde
and GeCl2 caused lower yields.
as Zn, SmI2, or CrCl2 gave a complex mixture that probably
involves over-reaction products and others (entries 1-3).
Gratifyingly, GeCl2-dioxane8 gave the aldol product 3 in
60% yield without any side products (entry 5), while SnCl2
failed to form 3 with recovery of the starting materials (entry
4).
We explored several sets of representative bromoaldehydes
1 and aldehydes 2 (Table 3). In all cases, the syn-cross-aldol
products 4 were predominantly obtained in moderate to high
yields. The aromatic, primary, and secondary aldehydes were
applicable to this system. In the reaction of 1a with 2b, an
increased amount of Bu4NBr improved the diastereoselec-
tivity (entries 2 and 3). The secondary aldehyde 2c gave the
product 4ac (entry 4) but the tertiary one (pivalaldehyde)
gave no desired product. The â-branched bromoaldehyde 1b
also gave the product 4ba in high yield (entry 5). The
reaction with benzaldehydes bearing either an electron-
donating or -withdrawing group took place effectively
(entries 7-9). In the reaction with aliphatic aldehydes 2b
and 2c bearing R-hydrogens, this reductive system certainly
gave a reliable result to synthesize only the cross-aldol
adducts (entries 2-4, 10-12) without any homoaldol spe-
cies.
As isolation of the aldol 3 was difficult because of its
instability, and MeOH quenching6 was performed to afford
the â-hydroxyl dimethyl acetal 4aa which can be isolated
as an aldol equivalent (Table 2, entry 1). On using this
workup, reaction conditions were reinvestigated. The results
in entries 1-5 suggest that an appropriate coordination is
effective. We previously reported a remarkable effect of Bu4-
NBr on activation of stannyl enolate.10 Therefore, Bu4NBr
was added to the reaction mixture and thus strikingly raised
the yields of the product 4aa in the reactions using some
solvents. When Et2O was used with Bu4NBr (1 mol %), the
best yield and selectivity were obtained (entry 7).11 Using
SnCl2 with Bu4NBr (10 mol %) instead of GeCl2-dioxane,
the reaction proceeded to give a complex mixture without
4aa, and some amounts of the starting materials (2a, 62%,
and 1a, 18%) were recovered.12 This result indicates that
The brominated bis-aldehyde 5 effectively provided the
cyclic aldol derivative 6 (Scheme 1). This type of intramo-
lecular reaction (bromoaldehyde + CHO) has not been
reported as far as we know. Instead of GeCl2-dioxane, we
tried using SmI2, which mediates intramolecular Reformatsky
reactions (bromoester + CHO),13 but obtained only a
complicated mixture.
(7) The reductive cross-aldol reactions between aldehydes not concerned
with stereoselectivity or giving moderate selectivity have been reported.
(a) Kato, J.; Mukaiyama, T. Chem. Lett. 1983, 1727-1728. (b) Maeda, K.;
Shinokubo, H.; Oshima, K. J. Org. Chem. 1998, 63, 4558-4560.
(8) We prepare the reductant GeCl2-dixoane in large-scale by the known
method (ref 9). It is noted that the price of prepared GeCl2-dioxane (price/
mol) is not as high as those of SmI2 or CrCl2 that are widely used in synthetic
chemistry as useful reductants.
(9) Roskamp, C. A.; Roskamp, E. J. In Encyclopedia of Reagents for
Organic Synthesis; Paquette, L. A., Ed.; John Wiley & Sons: New York,
1995; Vol. 4, p 2606.
(10) (a) Yasuda, M.; Chiba, K.; Ohigashi, N.; Katoh, Y.; Baba, A. J.
Am. Chem. Soc. 2003, 125, 7291-7300. (b) Yasuda, M.; Chiba, K.; Baba,
A. J. Am. Chem. Soc. 2000, 122, 7549-7555. (c) Yasuda, M.; Hayashi,
K.; Katoh, Y.; Shibata, I.; Baba, A. J. Am. Chem. Soc. 1998, 120, 715-
721.
One-pot synthesis including bromination14 of the first
aldehyde 7 followed by the reductive cross-aldol reaction
(12) This procedure was performed without MeOH quenching. The use
of SnCl2 with Bu4NBr (1 mol %) resulted in almost no reaction.
(13) Molander, G. A.; Etter, J. B.; Harring, L. S.; Thorel, P.-J. J. Am.
Chem. Soc. 1991, 113, 8036-8045.
(14) Bellesia, F.; Ghelfi, F.; Grandi, R.; Pagnoni, U. M. J. Chem. Res.,
Synop. 1986, 428-429.
(11) The use of GeBr2-dioxane and GeI2 instead of GeCl2-dioxane
under the same conditions as in entry 7 gave lower yields of 72% (80:20)
and 27% (88:12), respectively.
1846
Org. Lett., Vol. 7, No. 9, 2005

Table 3. Reductive Cross-Aldol Reactiona
Scheme 3. Plausible Reaction Course and Undesired Side
Paths (Dashed Arrow)
proceeds through an acyclic transition state to give syn-
product predominantly. This reaction could suffer from
undesired side reactions as shown by dashed arrows in
Scheme 3: (a) formation of homo-coupling product of 1
through 8, (b) tautomerization of 8 into R-germylaldehyde
10 which is less nucleophilic than 8,15 (c) further transforma-
tion of the adduct 9 into an over-reaction product. In fact,
the mixture of 1a and GeCl2-dioxane with Bu4NBr (1 mol
%) in the absence of aldehyde 2 gave a complicated mixture
probably because of paths a and b. However, fast generation
of 8 and its carbonyl addition to 2 predominate over these
side paths. The most important point is that the formed
germoxide 9 does not suffer from further nucleophilic
additions (path c), while the SnCl2 system resulted in over-
reaction. The germanium(IV) in 9 seems to have much lower
Lewis acidity than the stannyl analogues.
a All reactions were performed using bromoaldehyde 1 (0.6 mmol),
benzaldehyde 2 (0.6 mmol), GeCl2-dioxane (0.6 mmol), and Bu4NBr (1
mol %) in Et2O (2 mL) at rt for 2 h and quenched by methanol. b Bu4NBr
(5 mol %). c Bu4NBr (0.5 mol %). d 0 °C, 4 h. e EtOAc was used as a
solvent. f Slow addition of bromoaldehyde for 5 min.
To get preliminary information for Lewis acidity of Ge-
(IV), the acidity of GeCl4 is estimated as compared with other
typical Lewis acids (TiCl4 and SnCl4) by measurement of
δ(13C) or ν/cm-1 of the carbonyl group in heptanal (Table
4).16 As expected, significant downfield shift in 13C NMR
with another aldehyde 2a succeeded to give 4aa (Scheme
2). It is also interesting that our procedure can be performed
on a large-scale. In fact, 100 mmol scale synthesis gave 4aa
in 65% yield (17.3 g) in pure form after column chroma-
tography.
Table 4. Effect of Metal Halides on δ(13C)a or ν/cm-1 b of
Carbonyl Group in Heptanal
Scheme 1. Intramolecular Cross-Aldol Reaction
entry metal halide δ(13C)/ppm ∆δ(13C)/ppm ν/cm-1 ∆ν/cm-1
1
2
3
4
none
202.61
219.13
216.89
201.70
0
1728
1674
1668
1728
0
-46
-40
0
TiCl4
SnCl4
GeCl4
+16.52
+14.28
-0.91
a NMR: heptanal and metal halide (2.4 equiv) in CDCl3. b IR: heptanal
and metal halide (1.0 equiv) in CCl4.
A plausible reaction course is shown in Scheme 3. GeCl2-
dioxane gives the germyl enolate 8 which adds to aldehyde
2 to afford the cross-aldol germoxide 9. The loaded Bu4-
NBr acts as a ligand to the germanium center and increases
the nucleophilicity of the enolate 8. The carbonyl addition
and a marked decrease in the carbonyl stretching frequency
in the IR spectrum for the carbonyl group were observed
with TiCl4, which is a typical Lewis acid. SnCl4 also showed
a similar change with TiCl4. Surprisingly, neither the
chemical shift nor carbonyl stretching was affected by GeCl4.
This result shows the low Lewis acidity of GeCl4 as
compared with SnCl4. It also indicates the germanium center
Scheme 2. One-Pot and Large-Scale Synthesis
(15) Kagoshima, H.; Hashimoto, Y.; Oguro, D.; Saigo, K. J. Org. Chem.
1998, 63, 691-697.
(16) (a) Power, M. B.; Bott, S. G.; Atwood, J. L.; Barron, A. R. J. Am.
Chem. Soc. 1990, 112, 3446-3451. (b) Power, M. B.; Bott, S. G.; Clark,
D. L.; Atwood, J. L.; Barron, A. R. Organometallics 1990, 9, 3086-3097.
Org. Lett., Vol. 7, No. 9, 2005
1847

does not activate the carbonyl group in 9 but might even
retard further addition owing to its steric factor.17
of germanium(IV) accomplished a clean reaction pathway
without side reactions.
In conclusion, a novel type of the cross-aldol reaction
between different aldehydes effectively proceeded in the
reaction of R-bromoaldehyde with aldehyde mediated by
GeCl2-dioxane. A catalytic amount of Bu4NBr improved
the yield and selectivity. The germanium species is reputed
to be of low toxicity,9 easy to handle for conventional
operation under nitrogen, and not more expensive than some
typical reductants used in organic synthesis. The appropriate
reducing ability of germanium(II) and the low Lewis acidity
Acknowledgment. This work was supported by a Grant-
in-Aid for Scientific Research from the Ministry of Educa-
tion, Culture, Sports, Science and Technology of the Japanese
Government. We also acknowledge financial support from
the Sumitomo Foundation. Thanks are due to Mr. H.
Moriguchi, Faculty of Engineering, Osaka University, for
assistance in obtaining MS spectra.
Supporting Information Available: Experimental pro-
cedures, spectroscopic details of new compounds, and data
of single-crystal X-ray analysis of 6 (CIF). This material is
available free of charge via the Internet at http://pubs.acs.org.
(17) In NMR study of the Bu4NBr-catalyzed reaction between 1a and
2a mediated by GeCl2-dioxane in CD2Cl2, the adduct 9 and free dioxane
were observed. Therefore, the dioxane has no important role for decreasing
of Lewis acidity of germanium(IV) in 9.
OL050533I
1848
Org. Lett., Vol. 7, No. 9, 2005