Enolate Formation from α-Iodoaldehydes and α-Iodoketones by Means of Allylsilane-Titanium Tetrachloride and Its Application to an Aldol Reaction

Full text of DOI:10.1021/jo980456n

4558
J . Org. Chem. 1998, 63, 4558-4560
Sch em e 1
Sch em e 2
En ola te F or m a tion fr om r-Iod oa ld eh yd es
a n d r-Iod ok eton es by Mea n s of
Allylsila n e-Tita n iu m Tetr a ch lor id e a n d Its
Ap p lica tion to a n Ald ol Rea ction
Katsuya Maeda, Hiroshi Shinokubo, and
Koichiro Oshima*
Department of Material Chemistry, Graduate School of
Engineering, Kyoto University, Sakyo-ku, Yoshida,
Kyoto 606-8501, J apan
bonyl compounds with an allylsilane-titanium tetra-
chloride system would provide an expeditious route to
titanium enolates.6 We have indeed found that sequen-
tial treatment of a solution of R-iodoaldehydes and
allyltrimethylsilane with titanium tetrachloride and ac-
etaldehyde provided â-hydroxy aldehydes7 in good yields
(Scheme 2).
Received March 10, 1998
The renaissance that has occurred in the study of the
aldol-type reaction in the last two decades has been
mainly due to the development of methods for the
formation and use of preformed enolates.1 Despite
extensive work on the aldol-type reaction between the
various metal enolates, derived from ketones, esters, or
amides, and aldehydes, only a few reports have been
published on the cross-aldol reaction between enolates
generated from an aldehyde (R1CH2CHO) and another
aldehyde (R2CHO).2 Mixed aldol reactions between two
different aldehydes generally give mixtures when each
aldehyde can function both as an enolate precursor and
electrophilic component.3 Another problem encountered
in mixed aldol reactions is a formation of a complex
mixture derived from further reaction of the aldol adduct
(R2CH(OH)CHR1CHO) with the enolate (R1CHdC(H)O-).
To solve these problems, it is desirable to have a facile
route to enolates from aldehydes under mild reaction
conditions.
Recently, we have reported that treatment of vicinal
methoxyiodoalkanes or acetoxyiodoalkanes with an al-
lylsilane-titanium tetrachloride system provided alkenes
stereospecifically (Scheme 1).4 The elimination of iodide
and the methoxy or acetoxy groups proceeded in anti
fashion. The coordination of oxygen of the methoxy or
acetoxy group to titanium tetrachloride would facilitate
the attack of allyltrimethylsilane on the iodine atom. It
then occurred to us that, if R-iodoaldehyde5 should behave
as vicinal methoxyiodoalkanes, treatment of R-iodocar-
We examined the reaction of 1-iodocyclohexanecarbal-
dehyde (1) with acetaldehyde with several Lewis acids
such as TiCl4, Cp2TiCl2, (i-PrO)2TiCl2, TiCl3, ZrCl4, SnCl4,
AlCl3, BCl3, and La(OTf)3 in combination with allyltri-
methylsilane. Among them, only titanium tetrachloride
gave an aldol adduct, 1-(1-hydroxyethyl)cyclohexanecar-
baldehyde (3) in good yield via titanium enolate 2. The
representative results are summarized in Table 1.
It was expected that allylation of the aldehyde moiety
would compete with trichlorotitanium enolate formation
upon treatment of a less hindered R-iodoaldehyde such
as 2-iododecanal (6) with allyltrimethylsilane-TiCl4. In
fact, treatment of 6 with allyltrimethylsilane-TiCl4
followed by quenching with methanol provided a mixture
of decanal (7) and 4-hydroxy-5-iodo-1-tridecene (8) (Scheme
3). To optimize the conditions for enolate formation, the
reaction was performed under several reaction conditions
in which the solvent and temperature were varied. For
example, an addition of TiCl4 (1.0 mmol) to a solution of
6 (1.0 mmol) and allyltrimethylsilane (2.0 mmol) in
toluene at -78 °C provided a mixture of decanal (7, 44%)
and 8 (17%). In contrast, use of dichloromethane as a
solvent at -78 °C has proved to be the best condition to
give decanal in 80% yield along with a trace amount of
8.
(1) Mukaiyama, T. Org. React. 1982, 28, 203. Mekelburger, H. B.;
Wilcox, C. S. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: New York, 1991; Vol. 2, Chapter
1.4, pp 99-131. Heathcock, C. H. In Comprehensive Organic Synthesis;
Trost, B. M., Fleming, I., Eds.; Pergamon Press: New York, 1991; Vol.
2, Chapter 1.6, pp 181-238. Kim, B. M.; Williams, S. F.; Masamune,
S. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon Press: New York, 1991; Vol. 2, Chapter 1.7, pp 239-275.
Rathke, M. W.; Weipert, P. In Comprehensive Organic Synthesis; Trost,
B. M., Fleming, I., Eds.; Pergamon Press: New York, 1991; Vol. 2,
Chapter 1.8 pp 277-299. Paterson, I. In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: New York,
1991; Vol. 2, Chapter 1.9, pp 301-319.
(2) Heathcock, C. H. In Comprehensive Organic Synthesis; Trost,
B. M., Fleming, I., Eds.; Pergamon Press: New York, 1991; Vol. 2,
Chapter 1.5, pp 133-179. Heathcock, C. H. Modern Synthetic Methods;
Sheffold, R., Ed.; Springer-Verlag: Berlin, 1992; p 1; Heathcock, C.
H. Aldrichmica Acta 1990, 23, 99. Very recently, aldol reaction between
two different aldehydes in the presence of TiCl4 and a base has been
reported. Mahrwald, R.; Costisella, B.; Gru¨ ndogan, B. Tetrahedron
Lett. 1997, 38, 4543. This method, however, could be applied only to
the synthesis of 3-hydroxyaldehydes following Lieben’s rule.3
(3) Lieben, A. Monatsh. Chem. 1901, 22, 289.
The allylation of the aldol adduct also could compete
with enolate formation and cause a problem in that the
(5) R-Iodoaldehydes were prepared from silyl enolates of the corre-
sponding aldehydes with I2 and aqueous NaHCO3 in ether. Details are
available in the Supporting Information section.
(6) (a) Nakamura, E.; Shimada, J .; Horiguchi, Y.; Kuwajima, I.
Tetrahedron Lett. 1983, 24, 3341. (b) Nakamura, E.; Kuwajima, I.
Tetrahedron Lett. 1983, 24, 3343. (c) Harrison, C. R. Tetrahedron Lett.
1987, 28, 4134. (d) Siegel, C.; Thornton, E. R. J . Am. Chem. Soc. 1989,
111, 5722. Brocchini, S. J .; Eberle, M.; Lawton, R. G. J . Am. Chem.
Soc. 1988, 110, 5211. (e) Morris, J .; Wishka, D. G.; Luke, G. P.; J udge,
T. M.; Gammill, R. B. Tetrahedron 1997, 53, 11211. (f) Crimmins, M.
T.; King, B. W.; Tabet, E. A. J . Am. Chem. Soc. 1997, 119, 7883. (g)
Toshida, Y.; Hayashi, R.; Sumihara, H.; Tanabe, Y. Tetrahedron Lett.
1997, 38, 8727. (h) Baker, R. K.; Rupprecht, K. M.; Armistead, D. M.;
Boger, J .; Frankshun, R. A.; Hodges, P. J .; Hoogsteen, K.; Pisano, J .
M.; Witzel, B. E. Tetrahedron Lett. 1998, 39, 229. (i) Mahrwald, R.;
Gu¨ndogan, B. J . Am. Chem. Soc. 1998, 120, 413. (j) Reetz, M. T.
Organotitanium Reagents in Organic Synthesis; Springer-Verlag:
Berlin, 1986.
(7) For synthesis of â-hydroxyaldehyde by other methods, see (a)
Reduction of â-hydroxyamide: Mukaiyama, T.; Iwasawa, N. Chem.
Lett. 1982, 1903. (b) Enzymatic method: Bianchi, D.; Cesti, P.; Golini,
P. Tetrahedron 1982, 45, 869.
(4) Yachi, K.; Maeda, K.; Shinokubo, H.; Oshima, K. Tetrahedron
Lett. 1997, 38, 5161. Maeda, K.; Shinokubo, H.; Oshima, K. J . Org.
Chem. 1997, 62, 6429.
S0022-3263(98)00456-3 CCC: $15.00 © 1998 American Chemical Society
Published on Web 05/20/1998

Notes
J . Org. Chem., Vol. 63, No. 13, 1998 4559
Ta ble 1. Ald ol Rea ction of Tr ich lor otita n iu m En ola tes Der ived fr om r-Iod oa ld eh yd es
R-iodoaldehyde
R1
reaction
temp. time
adduct
yield(%)
entry
R2
aldehyde R3
additive
1
2
3
4
5
6
7
8
9
-(CH2)5-
1
1
1
4
5
6
6
6
6
Et
i-Pr
Ph
i-Pr
i-Pr
i-Pr
i-Pr
Et
-
-78 °C 1 h
0 °C 1 h
85
87
75
75
-
-
0 °C 1 h
0 °C 1 h
0 °C 1 h
Et
Et
Me
H
-
n-C9H19
n-C8H17
-
79a
50b
68c
55d
44e
-
-78 °C 1 h
-78 °C 1 h
-78 °C 1 h
-78 °C 1 h
Ti(O-n-Bu)4
Ti(O-n-Bu)4
Ti(O-n-Bu)4
n-C3H7CHdCH
Isomeric ratio ) 75/25. syn/anti ) 50/50. c syn/anti ) 64/36. syn/anti ) 80/20. e syn/anti ) 90/10.
a
b
d
Ta ble 2. Ald ol Rea ction of Tr ich lor otita n iu m En ola tes
Sch em e 3
Der ived fr om r-Iod ok eton es
carbonyl
adduct
entry
R-iodoketone
compounds yield (%) anti/syn
1
2
3
4
5
6
CH3CHO
PhCHO
98
96
86
92
66
87
19/81
20/80
30/70
Sch em e 4
i-PrCHO
CH3COCH3
CH3CHO
n-C5H11COCH2I
n-C4H9CH(I)COCH3 CH3CHO
20/80
39/61
69
7
CH3CHO
aldol adduct is not obtained as a single product. Thus,
treatment of 2-iododecanal 6 with allylsilane-TiCl4 in
dichloromethane followed by an addition of 2-methylpro-
panal afforded 3,5-dihydroxy-2-methyl-4-octyl-7-octene
(10) in 20% yield along with the desired aldol adduct (9,
50%, Scheme 4). The formation of 10 could be suppressed
by an addition of titanium tetrabutoxide8 (equimolar
amount for TiCl4) prior to an addition of 2-methylpropa-
nal to provide 9 (syn/anti ) 64/36) in 68% yield without
contamination by 10 (Table 1, entry 7). The addition of
Ti(O-n-Bu)4 was also effective in the case of other
aldehydes (Table 1, entries 8 and 9). In contrast, in the
case of R,R-dialkyl substituted R-iodoacetaldehydes (1, 4,
and 5, entries 1-5), the addition of titanium tetrabutox-
ide was not required since aldol adducts were obtained
in good yields without contamination by further allylated
products.
2.61H), 0.97 (t, J ) 7.1 Hz, 0.39H), 1.04 (t, J ) 7.5 Hz,
3H), 1.27 (tq, J ) 7.2, 7.5 Hz, 2H), 2.04 (dq, J ) 7.8, 7.1
Hz, 0.26H), 2.27-2.41 (m, 3.74H), 4.85 (t, J ) 7.4 Hz,
0.87H), 5.57 (t, J ) 7.8 Hz, 0.13H)). The spectrum data
was almost identical with the reported data6a for
CH3CH2C(OTiCl3)dCHCH3.
Exp er im en ta l Section
Gen er a l P r oced u r e for En ola te F or m a tion fr om r-Io-
d oa ld eh yd es. To a solution of titanium tetrachloride (1.0
mmol) in dichloromethane (7 mL) at -78 °C was added a mixture
of R-iodocyclohexanecarbaldehyde (1, 238 mg, 1.0 mmol) and
allyltrimethylsilane (0.24 mL, 1.5 mmol) in dichloromethane (2
mL), and the mixture was stirred for 10 min at -78 °C.
Propanal (0.14 mL, 2.0 mmol) was added to the resulting red
solution at -78 °C, and the reaction mixture was stirred for 1 h
at -78 °C. Extractive workup followed by silica gel column
purification afforded 1-(1-hydroxypropyl)cyclohexanecarbaldehyde
Then we applied our new method to the aldol-type
reaction between an enolate from R-iodoketone and
carbonyl compounds.9,10 The use of R-iodoketones instead
of R-iodoaldehydes gave the corresponding â-hydroxy
ketones in good yields. The results are shown in Table
2.
(145 mg, 0.85 mmol) in 85% yield: IR (neat) 3380, 1722 cm-1
;
1H NMR (CDCl3) δ 0.96 (t, J ) 7.2 Hz, 3H), 1.08-1.47 (m, 6H),
1.47-1.82 (m, 5H), 1.94-2.03 (m, 1H), 2.03-2.12 (m, 1H), 3.40
(dd, J ) 10.7, 2.3 Hz, 1H), 9.64 (s, 1H); 13C NMR (CDCl3) δ 11.01,
22.31, 22.43, 24.61, 25.53, 27.73, 28.33, 54.02, 78.35, 208.85.
The formation of trichlorotitanium enolate was ascer-
tained by the examination of the H NMR spectrum of a
CDCl3 solution of 3-iodo-4-heptanone, allyltrimethylsi-
lane, and TiCl4. ((E/ Z ) 13/87), δ 0.96 (t, J ) 7.4 Hz,
1
(9) For a reductive formation of enolate from R-iodoketone with
various organometallic compounds, see: Aoki, Y.; Oshima, K.; Utimoto,
K. Chem. Lett. 1995, 463.
(10) The use of ethyl iodoacetate, 3-bromo-4-heptanone, and 2,2-
dibromo-3-heptanone in this system would not give any aldol adducts,
and the starting halocarbonyl compounds were recovered quantita-
tively. The reaction of 1,1-dibromo-3,3-dimethyl-2-butanone (11) pro-
vided 4-bromo-5-hydroxy-2,2-dimethyl-3-hexanone (12) in 41% yield
along with the recovered starting material 11 (50%) upon treatment
with allylsilane-TiCl4 followed by an addition of acetaldehyde.
(8) Titanium tetraisopropoxide and titanium tetraphenoxide were
not so effective as titanium tetrabutoxide. Although the role of titanium
tetrabutoxide is not clear at this stage, we are tempted to assume that
the bulky butoxy group on titanium in the aldol adduct â-titanoxyal-
dehyde would inhibit the attack of allylsilane on the aldehyde moiety.
The protection of the aldehyde group by a bulky aluminum complex
from an attack of a nucleophile has been reported, see: Maruoka, K.;
Imoto, H.; Saito, S.; Yamamoto, H. J . Am. Chem. Soc. 1994, 116, 4131.
Maruoka, K.; Ito, M.; Yamamoto, H. J . Am. Chem. Soc. 1995, 117, 9091.
Saito, S.; Yamamoto, H. J . Org. Chem. 1996, 61, 2928. Ooi, T.; Miura,
T.; Kondo, Y.; Maruoka, K. Tetrahedron Lett. 1997, 38, 3947.

4560 J . Org. Chem., Vol. 63, No. 13, 1998
Additions and Corrections
Anal. Found: C, 70.33; H, 10.73%. Calcd for C10H18O2: C,
70.55; H, 10.66%.
22.52, 23.74, 26.58, 26.94, 27.74, 29.13, 29.23, 29.28, 29.63, 29.82,
30.91, 31.18, 31.74, 54.58, 54.84, 75.83, 76.47, 205.80, 206.27.
Anal. Found: C, 73.56; H, 12.43%. Calcd for C14H28O2: C,
73.63; H, 12.36%.
Ald ol Rea ction in th e P r esen ce of Tita n iu m Tetr a bu -
toxid e. To a solution of titanium tetrachloride (1.0 mmol) in
CH2Cl2 (7 mL) at -78 °C was added a mixture of 2-iododecanal
(6, 282 mg, 1.0 mmol) and allyltrimethylsilane (0.24 mL, 1.5
mmol) in CH2Cl2 (2 mL), and the mixture was stirred for 10 min.
Titanium tetrabutoxide (1.0 mL, 1.0 M CH2Cl2 solution, 1.0
mmol) was added, and the mixture was stirred for 10 min at
-78 °C. Then, 2-methylpropanal (0.18 mL, 2.0 mmol) was
added, and the whole was stirred for 1 h. Extractive workup
followed by silica gel column purification afforded 2-(1-hydroxy-
2-methylpropyl)decanal (syn/anti ) 6/4, 146 mg, 0.64 mmol) in
Ack n ow led gm en t. Financial support by Grant-in
Aid for Encouragement of Young Scientists (No. 3302)
from the Ministry of Education, Science, Sports, and
Culture, J apan is acknowledged.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and compound characterization data (7 pages). This
material is contained in libraries on microfiche, immediately
follows this article in the microfilm version of the journal, and
can be ordered from the ACS; see any current masthead page
for ordering information.
1
64% yield: IR (neat) 3400, 1721 cm-1; H NMR (CDCl3) δ 0.85
(t, J ) 6.6 Hz, 3H), 0.89 (d, J ) 6.6 Hz, 1.8H), 0.91 (d, J ) 6.9
Hz, 1.2H), 0.94 (d, J ) 6.9 Hz, 1.2H), 0.96 (d, J ) 6.6 Hz, 1.8H),
1.14-1.46 (m, 12H), 1.49-1.86 (m, 3.6H), 1.95-2.07 (m, 0.4H),
2.38-2.48 (m, 1H), 3.54 (dd, J ) 6.0, 5.7 Hz, 0.4H), 3.65 (dd, J
) 7.1, 4.7 Hz, 0.6H), 9.72 (d, J ) 2.4 Hz, 0.6H), 9.73 (d, J ) 2.7
Hz, 0.4H); 13C NMR (CDCl3) δ 13.95, 16.62, 17.72, 19.28, 19.48,
J O980456N
Additions and Corrections
Vol. 60, 1995
J osep h J . P . Zh ou , Boyu Zh on g, a n d Rich a r d B.
Silver m a n *. An Improved Procedure for the Synthesis of
Substituted â-Hydroxynitriles.
Page 2262. All of the analytical data for compound 4e
and those for 4f should be switched. Also, a 1H NMR
1
peak at δ 1.11 (s, 9 H) should be added to the H NMR
data for 4f. The diastereomeric ratio for compound 4d
was found to be 4:1 anti:syn (not one pure compound as
implied); the data for the major compound was reported.
Also, a 13C NMR peak at δ 126.3 should be added to the
13C NMR data for 4d . We thank Professor Paul Carlier
(Hong Kong University of Science and Technology) for
notifying us of these oversights.
J O984005E
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Vol. 62, 1997
M. A. Ca r r , P . E. Cr eviston , D. R. Hu tch ison , J . H.
Ken n ed y, V. V. Kh a u , T. J . Kr ess,* M. R. Lea n n a , J . D.
Ma r sh a ll, Mich a el J . Ma r tin elli,* B. C. P eter son , D. L.
Va r ie,* a n d J . P . Wep siec. Synthetic Studies Towards the
Partial Ergot Alkaloid LY228729, a Potent 5HT1a Receptor
Agonist.
Page 8640, column 2, ref 4 should read as follows:
Nichols, D. E.; Robinson, J . M.; Li, G. S.; Cassady, J . M.;
Floss, H. G. Org. Prep. Proc. Int. 1977, 9, 277-280.
J O9840022
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Vol. 63, 1998
Ma r k . A. Bla sk ovich , Gh ota s Evin d a r , Nich ola s G. W.
Rose, Scott Wilk in son , Yu e Lu o, a n d Gilles A.
La joie*. Stereoselective Synthesis of Threo and Erythro â-Hy-
droxy and â-Disubstituted-â-Hydroxy R-Amino Acids.
Page 3635, Table 4. The heading “ketone substrate”
should be moved to column 3 and placed above R1.
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