Powerful Claisen condensation and Claisen-aldol tandem reaction of α,α-dialkylated esters promoted by ZrCl4-iPr2NEt

Article abstract of DOI:10.1039/b104185c

Powerful Claisen ester condensations of α,α-dialkylated esters mediated by ZrCl₄-ⁱPr₂NEt were performed to give the corresponding thermodynamically unfavorable α,α-dialkylated β-ketoesters, and Claisen-aldol tandem reactions between an intermediary Zr-enolate of a α,α-dialkylated β-ketoester and aldehydes also proceeded.

Full text of DOI:10.1039/b104185c

Powerful Claisen condensation and Claisen–aldol tandem reaction of
a,a-dialkylated esters promoted by ZrCl4–iPr2NEt
Yoo Tanabe,* Ryota Hamasaki and Syunsuke Funakoshi
School of Science, Kwansei Gakuin University, 1-1-155 Uegahara, Nishinomiya, Hyogo 662-8501, Japan
Received (in Cambridge, UK) 14th May 2001, Accepted 19th July 2001
First published as an Advance Article on the web 7th August 2001
Powerful Claisen ester condensations of a,a-dialkylated
esters mediated by ZrCl4–iPr2NEt were performed to give
the corresponding thermodynamically unfavorable a,a-
dialkylated b-ketoesters, and Claisen–aldol tandem reac-
tions between an intermediary Zr-enolate of a a,a-dialkyl-
ated b-ketoester and aldehydes also proceeded.
3 (Scheme 1). However, a,a-dialkylated esters 4 could not
undergo this type of the condensation, because 4 lacks the
ability to force the formation of a stable enolate.1,2 Actually, the
reversible equilibrium barely shifts from 4 to the unfavorable
production of the b-ketoesters 5. Thermodynamics dictate that
the starting a,a-dialkylated esters 4 are more stable than the
desired b-ketoesters 5, namely, the retro-Claisen condensation
of esters 5 should predominate.1,2 Although two methods for the
Claisen condensation of alkyl 2-methylpropanoate using strong
bases (Ph3C2·Na+ or KH)3,4 have been reported, the yields were
moderate to low ( ~ 35%).† In addition, these methods describe
the sole example of the condensation of alkyl 2-methylpropa-
noate.
The Claisen ester condensation is recognized as a fundamental
and useful C–C bond-forming reaction.1 Traditional Claisen
condensations using alkali-metal basic reagents such as NaOR,
NaH, LDA and LiHMDS are widely applied to a-mono-
alkylated esters 1 giving the corresponding dimeric b-ketoesters
Recently, Ti–Claisen condensations were demonstrated5–9
and proved to be more reactive and practical between a-
monoalkylated esters than the representative method using NaH
or LDA.‡ However, this method is unfortunately limited to the
case of a-monoalkylated esters 1. Here we introduce the
powerful Claisen ester condensation of a,a-dialkylated esters 4
promoted by the ZrCl4–iPr2NEt reagent and its extension to the
Claisen–aldol tandem reaction.
First, the Claisen condensation of a,a-dialkylated esters is
described. Although ethyl 2-methylpropanoate was inert (no
i
reaction) to ZrCl4–amine (Et3N, Bu3N, or Pr2NEt) reagent,
successful results were obtained using a slightly more acidic
substrate, phenyl 2-methylpropanoate (4a). Treatment of 4a
with ZrCl4–iPr2NEt afforded the desired phenyl 2,2,4-tri-
methyl-3-oxopentanoate (5a) in 72% yields under optimized
conditions.§ Table 1 summarizes the results of the Zr–Claisen
condensation of a,a-dialkylated esters 4a–e. Replacement of
phenyl ester 4b for 4-chlorophenyl analog 4e increased the
yield. On the other hand, TiCl4–Bu3N agent (with or without
cat. TMSCl or cat. TMSOTf) failed to drive the reaction (no
reaction).
Phenyl esters are readily prepared by several methods and, in
addition, are smoothly hydrolyzed under milder conditions
compared with alkyl esters.10 A little higher acidity of phenyl
esters than that of alkyl esters is suggested by the following two
experiments: (a) 1H NMR chemical shifts of a-hydrogen of 4a
Table 1 Claisen condensations of a,a-dialkylated esters promoted by
ZrCl4–aminea
4
R1
R2
Ar
Amine
Yield (%)
4a
4a
4a
4a
4b
4c
4d
4e
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
Et
Et
Et
Ph
Ph
Ph
Ph
Et3N
Bu3N
6
19
Trace
72
44
29
22
55
TMEDA
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
Ph
2-Cl-Ph
2-MeO-Ph
4-Cl-Ph
a In CH2Cl2 at 215 to 220 °C for 3 h. Molar ratio; 4–ZrCl4–amine =
1.0+2.0+3.0.
Scheme 1
1674
Chem. Commun., 2001, 1674–1675
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b104185c

Table 2 Claisen–aldol tandem reactions of phenyl 2-methylpropanoate (4a)
with aldehydes promoted by ZrCl–iPr2NEt–(catalytic TMSCl)a
2-methylpropanoate (0.21 g, 1.8 mmol). The second method4 using KH
lacks generality; this reaction failed to proceed in several of our experiments
when ethyl 2-methylpropanoate was employed as the substrate.
‡ For an example of the Claisen condensation of methyl dec-9-enoate using
NaH by the reported method,11 the desired b-ketoester was obtained in ca.
75% (DME, reflux, 20 h). The Ti–Claisen condensation proceeded with a
93% yield (toluene, 0–5 °C, 1 h).8 Accordingly, the Ti–Claisen condensa-
tion clearly has the advantage of a high yield, mild conditions and a shorter
reaction time. Related Dieckmann condensation using AlCl3 is also
reported.12
R3
Product Yield
R3
Product Yieldb (%)
§ A typical procedure is as follows. iPr2NEt (388 mg, 3.0 mmol) in CH2Cl2
(0.5 cm3) was added to a stirred suspension of ZrCl4 (466 mg, 2.0 mmol)
and phenyl 2-methylpropanoate (164 mg, 1.0 mmol) in CH2Cl2 (2.5 cm3) at
215 to 220 °C. After stirring at the same temperature for 3 h, the mixture
was quenched with water (5 cm3) and 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–ether = 30+1) to give phenyl 2,2,4-trimethyl-
3-oxopentanoate (84 mg, 72%). Colorless oil. 1H NMR (400 MHz, CDCl3)
d 1.17 (6H, d, J = 7.2 Hz), 1.53 (6H, s), 3.01–3.11 (1H, m), 7.05–7.09 (2H,
m), 7.22–7.26 (2H, m), 7.37–7.41 (2H, m). 13C NMR (100 MHz, CDCl3) d
20.42, 21.85, 36.98, 56.33, 121.11, 126.08, 129.51, 150.51, 172.35, 212.12.
Ph
7a
7b
7c
7d
71
59
61
57
PhCHNCH
2-Naphthyl 7f
n-Pr
iPr
7e
57
4-Cl-Ph
4-NO2-Ph
4-MeO-Ph
43 (54)
54 (74)
31 (61)
7g
7h
a In CH2Cl2 at 215 to 220 °C for 3 h. Molar ratio; 4a–ZrCl4–amine–
aldehyde
catalytic TMSCl (0.05 equiv.).
=
1.0+2.0+3.0+1.0. b Parentheses indicate the yields using
and ethyl 2-methylpropanoate were located at 2.80 and 2.53
ppm, respectively; and (b) when equimolar mixtures of 4a and
ethyl 2-methylpropanoate in THF were treated with 1 equiv. of
LDA at 0–5 °C for 1 h, followed by quenching with D2O, the
ratio of a-deuterated esters was ca. 9+1 by the 1H NMR
measurement.
The successful results using the Zr reagent suggest that the
strong chelation effect of zirconium toward two carbonyl
oxygens and longer bond length between Zr–O than that
between Ti–O contribute to drive the reactions, releasing steric
constraint around the crowded Zr-intermediate 6.
Next, the intermediary Zr-enolate 6a was utilized for further
C–C bond formation. Namely, the first Claisen–aldol tandem
reaction between 2 equiv. of phenyl 2-methylpropanoate 4a and
several aldehydes successfully proceeded in a one-pot manner
through intermediary Zr-enolate 6a, eventually affording pyran-
2,4-diones 7 with a concomitant lactonization.¶ Table 2
summarizes these results. It should be noted that catalytic
TMSCl significantly affects the second aldol addition step for
some aldehydes.7
IR (film) 2980, 2938, 1763, 1717, 1196, 1121 cm21
.
¶ A typical procedure is as follows. In place of quenching with water,
TMSCl (0.006 cm3, 0.05 mmol) and isobutyraldehyde (72 mg, 1.0 mmol)
were successively added to a stirred reaction mixture at 0–5 °C. The mixture
was stirred for 2 h, and was then quenched with water (5 cm3) and extracted
twice with AcOEt. The combined organic phase was washed with water,
brine, dried (Na2SO4) and concentrated. The obtained crude crystals were
purified by SiO2-column chromatography (hexane–AcOEt
= 20+1 ?
10+1) to give 3,3,5,5-tetramethyl-6-(1-methylethyl)pyran-2,4-dione (65
mg, 61%). Colorless crystals; mp 34.0–34.5 °C. 1H NMR (400 MHz,
CDCl3) d 1.08 (3H, d, J = 6.8 Hz), 1.13 (3H, s), 1.14 (3H, d, J = 6.8 Hz),
1.22 (3H, s), 1.43 (3H, s), 1.44 (3H, s), 2.08–2.16 (1H, m), 4.12 (1H, d, J =
3.2 Hz). 13C NMR (100 MHz, CDCl3) d 17.15, 18.21, 20.60, 22.50, 23.88,
25.63, 28.93, 47.59, 50.03, 83.97, 174.79, 211.36. IR (film) 2978, 2942,
1750, 1711, 1290, 1152, 1024 cm21
.
1 J. March, Advanced Organic Chemistry, Benjamin, New York, 4th edn.,
1992, p. 491.
2 For example,K. P. C. Vollhardt and N. E. Schore, Organic Chemistry,
3rd edn., Freeman, New York, 1999, p. 1039.
3 C. R. Hauser and W. B. Renfrow, Jr., J. Am. Chem. Soc., 1937, 59,
1823.
Thus, we achieved an efficient, powerful and practical Zr–
Claisen condensation and the first Claisen–aldol tandem
reaction of a,a-dialkylated esters 4.
4 C. A. Brown, Synthesis, 1975, 326.
5 Y. Tanabe, Bull. Chem. Soc. Jpn., 1988, 62, 1917.
6 Y. Yoshida, R. Hayashi, H. Sumihara and Y. Tanabe, Tetrahedron Lett.,
1997, 38, 8727.
7 Y. Yoshida, N. Matsumoto, R. Hamasaki and Y. Tanabe, Tetrahedron
Lett., 1999, 40, 4227.
This work was partially supported by a Grant-in-Aid for
Scientific Research on Priority Areas (A) “Exploitation of
Multi-Element Cyclic Molecules” and on Basic Areas (C) from
the Ministry of Education, Culture, Sports, Science and
Technology, Japan.
8 R. Hamasaki, S. Funakoshi, T. Misaki and Y. Tanabe, Tetrahedron,
2000, 56, 7423.
9 W. Oppolzer and I. Rodriguez, Helv. Chem. Acta, 1993, 76, 1275.
10 T. W. Green and P. G. M. Wuts, Protective Groups in Organic
Synthesis, 3rd edn., Wiley, New York, 1999, p. 414.
11 J. E. McMurry, M. P. Fleming, K. L. Kees and L. R. Krepski, J. Org.
Chem., 1978, 17, 3255.
Notes and references
† In the first method,3 preparation of the Ph3C2·Na+ reagent includes a
tedious procedure from a practical and green chemical standpoint: ca. 9.3 g
of 1% Na(Hg) vs. 0.28 g (1 mmol) of Ph3CCl is used for ethyl
12 S. Tamai, H. Ushirogochi, S. Sano and Y. Nagao, Chem. Lett., 1955,
295.
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