Powerful stereoselective aldol-type additions of phenyl and phenylthio esters with aldehydes or ketones mediated by TiCl4/amine reagent

Article abstract of DOI:10.1055/s-2001-18780

An efficient TiCl₄/amine-promoted aldol-type addition of phenyl and phenylthio esters with aldehydes or ketones has been performed. The present method includes a practical merit from the green chemical viewpoint with regard to yields, variations of substrates, availability of reagents, and simple operations.

Full text of DOI:10.1055/s-2001-18780

LETTER
1959
Powerful Stereoselective Aldol-type Additions of Phenyl and Phenylthio Esters
with Aldehydes or Ketones Mediated by TiCl4/Amine Reagent
Stereoselective
A
ld
o
ol-Type
A
d
o
ditions of Phenyl an
T
d
P
henylthio E
a
sters nabe,* Noriaki Matsumoto, Syunsuke Funakoshi, Naoki Manta
School of Science, Kwansei Gakuin University, 2-1 Gakuen, Sanda, Hyogo 669-1337, Japan
Fax +81(795)659077; E-mail: tanabe@kwansei.ac.jp
Received 1 October 2001
hydes lacking -protons, that is, an undesirable side self-
Abstract: An efficient TiCl4/amine-promoted aldol-type addition
of phenyl and phenylthio esters with aldehydes or ketones has been
performed. The present method includes a practical merit from the
green chemical viewpoint with regard to yields, variations of sub-
strates, availability of reagents, and simple operations.
aldol addition predominately occurred between the two
acceptors possessing -protons. To overcome the prob-
lem, we chose slightly acidic phenyl esters 1 because of
the higher acidity of 1 than that of alkyl esters.5d Phenyl
esters are readily prepared by several methods and are
easily hydrolyzed under milder conditions compared with
alkyl esters.6
Key words: aldol reactions, titanium, stereoselectivity, esters,
amines
Table 1 lists these results.7 The salient features are as fol-
lows. (1) The present method is very powerful due to the
specific character of titanium enolates,5,8 so that not only
aldehydes, but also less reactive ketones act as good ac-
ceptors to afford desired -hydroxyl esters 2. (2) Et3N is
slightly superior to Bu3N with regard to yield (entries 1–
4) in contrast to the Ti-aldol addition of ketones.5b,c (3)
The employed substrates covered , -disubstituted phe-
nyl esters (entries 10–15) including basic labile -chloro
and -mesyloxy esters (entries 16–19), which generally
undergo further Darzens-type reactions to form , -ep-
oxyesters by means of basic media.9 (4) The reactions of
, -disubstituted phenyl esters were performed at 0–5 °C
rather than –78 °C, because in contrast to the Zr-Claisen
condensation5d the competitive side Ti-Claisen condensa-
tion could be adequately suppressed even at such higher
temperature. (5) The syn-stereoselectivity with aldehydes
was moderate to good. (6) TMSCl co-catalyst, which
works as an effective promoter in the related Ti-aldol ad-
ditions,5c did not affect the present reaction. (7) The key
intermediate for the synthesis of an useful perfume, a fura-
none analog of dehydrojasmone, was more easily pre-
pared than in the previously reported method (entry
20).10,11
The aldol-type addition of esters with carbonyl acceptors
(aldehydes or ketones) has been extensively investigated
due to its wide utility in organic syntheses, particularly the
straightforward access to useful -hydroxyl esters.1 Two
methods are representative for this objective: (1) ester
metal enolates, which are generated by strong basic re-
agents such as LDA and Li(K)HMDSO (metal exchanged
enolates are also employable), react with the carbonyl ac-
ceptors, and (2) esters are converted to reactive ketene si-
lyl acetals, which react with carbonyl acceptors that are
promoted by a variety of catalysts (the Mukaiyama proto-
col).
Direct aldol-type addition of esters with carbonyl accep-
tors using Lewis acids combined with amines has several
advantages: simple procedure, high regio- and stereose-
lectivity, and tolerance to basic labile functionalities. Due
to a lower enolization ability than that of ketones or alde-
hydes, however, there have been a few successes to this
end, namely, the protocols using diazabromoborane (Co-
rey’s group),2 dicyclohexyliodoborane (Brown’s group)3
and boron triflate (Masamune and Abiko’s group).4 These
leading achievements prompted us to investigate a direct
aldol-type addition of simple esters using a more power-
ful, accessible and economic agent from the recent green
chemical point of view. Consistent with our continuous
interests in Ti- or Zr-Claisen and aldol reactions,5 we re-
port direct, powerful, and stereoselective aldol-type addi-
tions of phenyl and phenylthio esters 1, 3 with aldehydes
and ketones promoted by a cheap and available TiCl4/
amine reagent.
The use of phenylthio or 4-nitrophenylthio esters 3 instead
of phenyl esters 1 has a notable advantage. Table 2 lists
these results and the salient features are as follows.12 (1)
These reactions proceeded in excellent yields in every
case examined except for a few cases to afford the desired
-hydroxyl thioesters 4, whose fact suggests a complete
Ti-enolate formation. (2) In contrast to the case using phe-
nyl esters 1, Bu3N is slightly superior to Et3N with regard
to yield (entries 1 and 2). (3) , -Disubstituted phenylthio
esters also underwent the additions at 0–5 °C (entries 9–
12). (4) After screening several arylthio propanoates,13 the
reaction using the 4-nitrothiophenyl analog to benzalde-
hyde proceeded with high syn-stereoselectivity (entry 13).
First, we examined the reaction of methyl propanoate with
benzaldehyde and the desired -hydroxyl ester was ob-
tained in 51% yield. Unfortunately, the carbonyl acceptor
against methyl propanoate seemed to be limited to alde-
Synlett 2001, No. 12, 30 11 2001. Article Identifier:
1437-2096,E;2001,0,12,1959,1961,ftx,en;Y19301ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214
In conclusion, the present protocol includes practical ad-
vantages from the viewpoint of green chemistry, for ex-

1960
Y. Tanabe et al.
LETTER
Table 1 Aldol-type Addition of Phenyl Esters 1 with Aldehydes or
Table 2 Aldol-type Addition of Phenylthio Esters 3 with Alde-
Ketones using TiCl4/Et3Na
hydes or Ketones using TiCl4/Bu3Na
O
O
OH
OH
R3
R4
R2
R3
R4
R2
R3
R4
R3
R4
CO2Ph
R2 R1
COSAr
R2 R1
R1
CO2Ph
R1
COSAr
TiCl4 - Et3N
TiCl4 - Bu3N
1
3
2
4
Entry R1
R2
H
R3
Ph
R4
Yield syn/antib
Entry
R1
R2
H
R3
Ph
R4
Yield
syn/antib
(%)
(%)
1
2
Me
H
H
80
82:18
<Ar=Ph>
(75)c
84
(85:15)
1
2
Me
H
99
86:14
(94)c (86:14)
3
Me
H
n-Pr
84:16
4
(76)c
79
(84:16)
3
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
Ph
H
H
H
H
Et
Et
H
H
H
H
94
98
96
99
77
98
80
76
97
86
86:14
82:18
81:19
83:17
–
5
Me
Me
Me
Me
Bu
H
i-Pr
Ph
Et
H
89:11
4
H
n-Pr
i-Pr
6
H
Et
Et
83
64:36
5
H
7
H
77
–
6
H
CH2CH2PH
8
H
Ph
Ph
Ph
n-Pr
i-Pr
Ph
Et
CH2Cl 77
68:32
7
H
Et
9
H
H
H
H
H
Et
Et
76
87
80
80
81
73
81:12
8
H
Ph
77:23
–
10
11
12
13
14
15
16
17
18
19
20
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
n-Pr
Me
Me
Me
Me
Me
Me
Cl
–
9
Me
Me
Cl
Cl
Ph
–
10
11
12
n-Pr
Ph
–
(70:30)d
(80:20)d
–
–
n-Pr
–
<Ar=4-NO2-Ph>
Ph
Ph
Et
CH2Cl 79
–
13
14
15
16
Me
Me
Me
Me
H
H
H
H
Ph
H
H
H
Et
99
97
98
87
94:6
84:16
80:20
–
H
88
69
86
71
(70:30)d
n-Pr
i-Pr
Et
Cl
Et
H
–
OMs
OMs
H
Ph
Et
(82:18)d
a These reactions were carried out in CH2Cl2 at –78 °C (entries 1–8
and 13–16) and at 0–5 °C (entries 9–12). Molar ratio/3:ketone or al-
dehyde:TiCl4:Bu3N = 1:1.2:1.2:1.4.
Et
–
Me
CH2OAc 60
n.d.
b These ratios were determined by 1H NMR (300 MHz) of the crude
product.
a These reactions were carried out in CH2Cl2 at –78 °C (entries 1–9
and 20) and at 0–5 °C (entries 10–19). Molar ratio/1:ketone or alde-
hyde:TiCl4:Et3N = 1:1.2:1.2:1.4.
c Use of Et3N in the place of Bu3N.
d Syn/anti was not assigned.
b These ratios were determined by 1H NMR (300 MHz) of the crude
product.
c Use of Bu3N in the place of Et3N.
d Syn/anti was not assigned.
Acknowledgement
This research was partially supported by a Grant-in-Aid for Scien-
tific Research on Priority Areas (A) “Exploitation of Multi-Element
Cyclic Molecules” and Basic Areas (C) from the Ministry of Edu-
cation, Culture, Sports, Science and Technology, Japan.
ample, yields are good to excellent, the reagents are cheap
and available, and the operation can be performed in a sin-
gle flask method without using less accessible ketene silyl
acetals.
References
(1) (a) Heathcock, C. H. In Comprehensive Organic Synthesis,
Vol. 2; Trost, B. M.; Fleming, I., Eds.; Pergamon: Oxford,
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Organic Chemistry, 5th ed.; Wiley: New York, 2001, 1223.
Synlett 2001, No. 12, 1959–1961 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Stereoselective Aldol-type Additions of Phenyl and Phenylthio Esters
1961
(2) (a) Corey, E. J.; Imwinkelreid, R.; Pikul, S.; Xiang, Y. B. J.
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Hunter, A. D.; Nicklow, R. A. J. Org. Chem. 2000, 65, 6264.
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Tetrahedron Lett. 1997, 38, 8727. (c) Yoshida, Y.;
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(6) Green, T. W.; Wuts, P. G. M. In Protective Groups in
Organic Synthesis, 3rd. ed.; Wiley: New York, 1999, 414.
(7) A typical Experimental Procedure (Table 1, entry 1):
TiCl4 (1.0 M CH2Cl2; 1.2 mL) and Et3N (142 mg, 1.4 mmol)
in CH2Cl2 (0.6 mL) were successively added to a stirred
solution of phenyl propanoate (150 mg, 1.0 mmol) in CH2Cl2
(2.0 mL) at –78 °C under an Ar atmosphere. After stirring at
the same temperature for 30 min, benzaldehyde (127 mg, 1.2
mmol) was added to the mixture, followed by being stirred
at –78 °C for 2 h. The mixture was poured onto ice water
(2 mL) with stirring, and was extracted twice with ether. The
combined organic phase was washed with water, brine, dried
(Na2SO4) and concentrated. The obtained crude oil was
purified by SiO2-column chromatography (hexane–
EtOAc = 15:1 – 5:1) to give phenyl 3-hydroxy-2-methyl-3-
phenylpropanoate (205 mg, 80%; syn:anti = 82:18).
Colorless oil; 1H NMR (300 MHz; CDCl3): = 1.17 (anti,
0.54 H, d, J = 7.1 Hz), 1.32 (syn, 2.46 H, d, J = 7.1 Hz),
3.04–3.11 (1 H, m), 4.86 (anti, 0.18 H, d, J = 8.5 Hz), 5.14
(syn, 0.82 H, d, J = 5.1 Hz), 6.87–7.07 (2 H, m), 7.17–7.27
(1 H, m), 7.25–7.44 (7 H, m); 13C NMR (75 MHz; CDCl3):
= 11.52, 14.40, 46.95, 47.40, 74.18, 76.41, 121.47, 121.56,
125.89, 126.21, 126.67, 127.80, 128.21, 128.40, 128.56,
129.34, 141.39, 150.41, 150.57, 173.88, 174.28; IR(neat):
(10) Mueller, P. M.; Wild, H. J. E.P. Patent 49,222, 1992; Chem.
Abstr. 1992, 117, 150865j.
(11) Reformatsky reaction of ethyl 2-bromoheptanoate with
acetoxy acetone proceeded in 40–50%.
(12) A typical Experimental Procedure (Table 2, entry 1):
TiCl4 (1.0 M CH2Cl2; 1.2 mL) and Et3N (142 mg, 1.4 mmol)
in CH2Cl2 (0.6 mL) were successively added to a stirred
solution of phenylthio propanoate (83 mg, 0.50 mmol) in
CH2Cl2 (1.0 mL) at –78 °C under an Ar atmosphere. After
stirring at the same temperature for 30 min, benzaldehyde
(58 mg, 0.55 mmol) was added to the mixture, followed by
being stirred at –78 °C for 2 h. The mixture was poured onto
ice water (2 mL) with stirring, and was extracted twice with
ether. The combined organic phase was washed with water,
brine, dried (Na2SO4) and concentrated. The obtained crude
oil was purified by SiO2-column chromatography
(hexane:EtOAc = 7:1) to give phenylthio 3-hydroxy-2-
methyl-3-phenylpropanate (135 mg, 99%, syn:anti = 86:14).
Colorless oil. 1H NMR (400 MHz, CDCl3): = 1.11 (anti,
0.42 H, d, J = 7.1 Hz), 1.26 (syn, 2.58 H, d, J = 7.1 Hz), 3.05
(syn, 0.86 H, dq, J = 4.2, 7.1 Hz), 3.12 (anti, 0.14 H, dq,
J = 7.1 Hz, 8.3 Hz), 4.84 (anti, 0.14 H, d, J = 8.3 Hz), 5.14
(syn, 0.86 H, d, J = 4.2 Hz), 7.30–7.43 (10 H, m).
(13) Substituents such as 4-t-Bu, 4-MeO, 4-Cl, and 2-Cl were
examined.
Synlett 2001, No. 12, 1959–1961 ISSN 0936-5214 © Thieme Stuttgart · New York