First sequential Mukaiyama-Michael reaction/crossed-Claisen condensation using two molar ketene silyl acetals and one molar α,β-unsaturated esters promoted by a NaOH catalyst

Article abstract of DOI:10.1039/c0cc01110j

The NaOH-catalyzed first sequential Mukaiyama-Michael reaction/crossed- Claisen condensation is developed using two molar ketene silyl acetals and one molar α,β-unsaturated esters in either a stepwise or one-pot manner.

Full text of DOI:10.1039/c0cc01110j

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First sequential Mukaiyama–Michael reaction/crossed-Claisen
condensation using two molar ketene silyl acetals and one molar
a,b-unsaturated esters promoted by a NaOH catalystw
Hiroaki Tamagaki, Yuuya Nawate, Ryohei Nagase and Yoo Tanabe*
Received 25th April 2010, Accepted 9th June 2010
DOI: 10.1039/c0cc01110j
The NaOH-catalyzed first sequential Mukaiyama–Michael
reaction/crossed-Claisen condensation is developed using two
molar ketene silyl acetals and one molar a,b-unsaturated esters
in either a stepwise or one-pot manner.
the simple and mild reaction conditions. (ii) Aliphatic, aromatic,
and a 2-furyl a,b-unsaturated esters were applicable as the
acceptor. (iii) Terminal double bond, THPO-, and even free
HO- groups in R1 were compatible (entries 4–8).
(iv) The yield and reactivity using aromatic a,b-unsaturated
esters were somewhat higher than those using aliphatic esters
(entries 9–18). (v) Diastereoselectivity of the products 2
derived from 1b was ca. 1 : 1. Thus, substrate-generality of
the present simple LiOH (or NaOH)-catalyzed method is equal
or better than that of the hitherto reported methods.3,4
We next investigated a stepwise M–M reaction/crossed-
Claisen condensation between KSAs 1-B and the M–M
adducts 2. The reported method of NaOH-catalyzed crossed-
Claisen condensation of KSAs with methyl esters5a,d was
applied for this objective.6 The crossed-Claisen condensation
of KSAs 1a–1d as 1-B with 2 proceeded smoothly to give the
desired 1,3,7-tricarbonyl products 3 in good to excellent yield.
Table 2 lists the successful results.z It is noteworthy that the
present condensation occurred at the less stereocongested
methyl ester side with complete regioselectivity, which is
consistent with a characteristic feature that Claisen condensation
that it is strongly affected by a steric environment.
The Michael reaction and Claisen condensation reaction are
well-recognized fundamental C–C bond forming protocols in
organic syntheses. For the Michael reaction, there are a
number of reported methods using a,b-unsaturated ketones,
aldehydes, and sometimes esters as the acceptor.1 The
Mukaiyama–Michael (M–M) reaction using silyl enolates is
a superb variant because of its mild reaction conditions and
conjugate addition regioselectivity.2 The M–M-reaction,
however, lacks substrate-generality for intrinsically less reactive
a,b-unsaturated ester acceptors.3,4 Three crossed-Claisen
condensations using silyl enolates with carboxylic acid equivalents
(esters and acid chlorides) were exploited, wherein less accessible
a,a-dialkylated b-ketoesters were readily prepared.5
This background led us to investigate an efficient M–M
reaction of ketene silyl acetals (KSAs) 1-A with a,b-unsaturated
esters to give 1,5-diesters 2, followed by crossed-Claisen
condensation of KSAs 1-B with 2 (Scheme 1). Here, we
disclose a mild but powerful LiOH (or NaOH)-catalyzed
method between KSAs 1-A and a wide range of a,b-unsaturated
esters to afford the corresponding 1,5-diesters 2 and subsequent
regioselective NaOH-catalyzed crossed-Claisen condensation,
which could be performed in a stepwise or one-pot manner to
produce less accessible and uniquely functionalized 1,3,7-
tricarbonyl compounds 3. This is the first report of a sequential
(tandem) M–M reaction/crossed-Claisen condensation.
For the M–M reaction step, an initial attempt was guided
using KSA 1a (R2 = R3 = Me) as 1-A and methyl crotonate
(R1 = Me) in DMF at 0–5 1C. Among the readily available
inorganic base catalysts, LiOH and NaOH produced the best
results; Li2CO3 (18%), K2CO3 (42%), KOH (70%), NaOH
(71%, 81% at rt), and LiOH (93%, 80% at rt).6
Based on these successful results, we envisioned a one-pot
sequential (tandem) M–M reaction/crossed-Claisen condensation
promoted by a NaOH catalyst. Table 3 lists the successful
results using 2 molar amounts of the same two KSA 1a
(1-A and 1-B) with a,b-unsaturated esters.z To our delight,
all five examples examined produced good to excellent yields.
In the present sequential (tandem) version, the M–M reaction
step predominates over the crossed-Claisen condensation step;
when using 1a and methyl crotonate under controlled conditions
(0 C, for 3 h), intermediary M–M adduct 2a was isolated in ca.
50% yield with tandem adduct 3a in 45% yield.
Encouraged by our results, we next focused our attention on
a more challenging one-pot sequential (tandem) reaction using
different two KASs, that is, 1-A (the M–M reaction nucleophile)
and 1-B (the crossed-Claisen nucleophile) (Table 4)z.
Table 1 lists the successful results of the LiOH (or NaOH)-
promoted reaction of KSAs 1a and 1b (R2 = Et) with various
a,b-unsaturated esters.z The salient features are as follows.
(i) Due to the high reactivity of the present system, good to
excellent yield was obtained in all examples examined despite
Department of Chemistry, School of Science and Technology,
Kwansei Gakuin University, 2-1 Gakuen, Sanda, Hyogo, 669-1337,
Japan. E-mail: tanabe@kwansei.ac.jp; Fax: (+81) 79-565-9077;
Tel: (+81) 79-565-8394
w Electronic supplementary information (ESI) available: Experimental
details and NMR spectra. See DOI: 10.1039/c0cc01110j
Scheme 1 Sequential Mukaiyama–Michael reaction/crossed-Claisen
condensation.
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Table 1 LiOH (or NaOH)-catalyzed Mukaiyama–Michael reaction
of KSAs 1-A with a,b-unsaturated estersa
Table 3 NaOH-catalyzed one-pot sequential (tandem) Mukaiya-
ma–Michael/crossed-Claisen condensation of the same two KSAs 1a
(1-A, 1-B) with a,b-unsaturated estersa
Entry
R1
KSA (R2)
Product
Yield/%
1
2
3
4
Me
1a (Me)
1b (Et)
1a
2a
2b
2c
2d
77
68
77
75
Entry
R1
Product
Yield/%
n-Pr
1
2
3
4
5
Me
Ph
3a
3e
3h
3i
57
85
80
80
48
1b
(4-MeO)C6H4
(4-Cl)C6H4
[3,4-(MeO)2]C6H3
5
1a
2e
70
6
7
8
9
1b
1a
1a
1a
2f
2g
2h
2i
69
74
3j
THPO(CH2)4
HO(CH2)4
Ph
56b
a
a,b-Unsaturated ester : 1a : NaOH = 1.0 : 3.3 : 0.3.
93c (70)d
70e (81)e
98c
10
11
12
13
14
15
16
17
18
1b
1a
1b
1a
1b
1a
1b
1a
1b
2j
2k
2l
2m
2n
2o
2p
2q
2r
Table 4 NaOH-catalyzed one-pot sequential (tandem) Mukaiya-
ma–Michael/crossed Claisen condensation of different two KSAs 1-
A and 1-B with a,b-unsaturated estersa
(4-MeO)C6H4
(4-Cl)C6H4
96c
81c
86c
83c
[3,4-(MeO)2]C6H3
2-Furyl
81c
92c
79
81
1-A
(R3)
1-B
(R4, R5)
a
b
Entry R1
Product Yield/%
a,b-Unsaturated ester : 1 : LiOH = 1.0 : 1.5 : 0.3. 2.4 equiv. of 1a
was used to give its TMS ether. 1.2 equiv. of 1 was used. Carried
c
d
e
out at rt for 3 h. NaOH catalyst was used instead LiOH at rt for 3 h.
1
Ph
1a (Me) 1e (Me, Et)
1a
1a
3m
3n
60
60
48
65
70
69
59
70
52
52
53
69
53
55
46
35
i
2
3
4
5
6
7
8
9
1f (Me, Pr)
t
1g (Me, Bu) 3o
1b (Et, Me) 3p
1a (Me, Me) 3q
1a
1e (Et)
1f (iPr)
Table 2 NaOH-catalyzed crossed-Claisen condensation of KSAs 1-B
with Mukaiyama–Michael adducts 2a
1a
1g (tBu) 1a
3r
3s
3t
(4-MeO)C6H4 1e
1f
1a
1a
1a
1b
1a
1a
1a
1a
1a
3u
3v
3w
3x
3y
3z
3a
3b
10
11
12
13
14
15
16
1g
1a
1e
1f
1g
1e
1g
(4-Cl)C6H4
Me
Entry R1
2
1-B (R4, R5) Product Yield/%
1
2
3
4
Me
2a 1a
(Me, Me)
1b
3a
3b
3c
3d
74
84
64
92
a
a,b-Unsaturated ester: KSA 1-A : KSA 1-B : NaOH
1.0 : 1.2 : 2.0 : 0.4.
=
(Et, Me)
1c
t
(Me, Bu)
cinnamates (R1 = aromatic) produced better yield (entries
1–14) than those using methyl crotonate (R1 = Me). (iii) The
1d
(OTBS, Me)
5
6
7
8
Ph
2i
1a
1b
1c
3e
3f
3g
3h
3i
3j
3k
3l
96
88
86
81
72
98
84
80
i
t
variation between Me or Et and Pr or Bu ester moieties
affords differentiation for further synthetic functionalization.
Scheme 2 illustrates a plausible mechanism for the present
one-pot reaction exemplified by Table 4, entry 7. Initially, the
NaOH catalyst reacts with KSA 1g to form Na-enolate I with
the release of 1/2(TMS)2O and H2O. I couples with methyl
cinnamate to give Na-enolate adduct intermediate II, which in
turn captures a TMS group from 1a to give intermediary TMS
enolate III by reforming I. III is protonated by in situ-generated
(4-MeO)C6H4
(4-Cl)C6H4
[3,4-(MeO)2]C6H3 2o 1a
2k 1a
2m 1a
9
10
11
12
1b
1c
a
2 : 1 : NaOH = 1.0 : 2.4 : 0.3.
Gratifyingly, under carefully optimized conditions (molar
ratio, temperature, and period), various reactions proceeded in
reasonable yield with excellent regioselectivity to produce
highly multi-functionalized 1,3,7-tricarbonyl compounds
3m–3z, 3a, and 3b.7 The salient features of the reaction are
as follows. (i) The success is ascribed to the smooth and a high
yielding M–M reaction, followed by a highly regiocontrolled
crossed-Claisen condensation. (ii) Reactions using methyl
H2O to form 2s. Finally, consistent with
speculation,5a,d 2s condenses with 2 equiv. of 1b to produce
a reported
1,3,7-dicarbonyl compound 3s.
In conclusion, we developed a sequential Mukaiyama–
Michael reaction and regioselective crossed-Claisen condensation
to yield unique 1,3,7-tricarbonyl structural scaffolds. The present
method provides a new useful avenue for organic synthesis.
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1M-HCl–MeOH was added to the reaction mixture to deprotect the
TMS group and the mixture was stirred at the same temperature for
0.5 h. A similar work-up gave the crude product, which was purified by
silica-gel column chromatography (hexane : Et2O = 4 : 1) to give the
desired product 3e (142 mg, 85%).
A typical procedure of Table 4, entry 1: 1a (105 mg, 0.6 mmol) was
added to a stirred solution of methyl cinnamate (81 mg, 0.5 mmol),
NaOH (crushed powder, prepared under dry atmosphere; 8 mg,
0.2 mmol) in DMF (0.1 mL) at 20–25 1C under an Ar atmosphere,
and the mixture was stirred at the same temperature for 1.5 h. Next, 1e
(188 mg, 1.0 mmol) was added to the mixture, which was stirred at the
same temperature for 2 h. 1M-HCl–MeOH was added to the reaction
mixture to deprotect the TMS group and the mixture was stirred at the
same temperature for 0.5 h. A similar work-up gave the crude product,
which was purified by silica-gel column chromatography (hexane :
Et2O = 4 : 1) to give the desired product 3m (105 mg, 60%).
1 For examples, (a) E. D. Bergmann, D. Ginsburg and R. Rappo, in
Org. React., Wiley, New York, 1959, vol. 10, p. 179; (b) M. B. Smith
and J. March, in March’s Advanced Organic Chemistry, Wiley, New
York, 6th edn, 2007, p. 1110; (c) L. Kurti and B. Czako, Strategic
´
¨
Applications of Named Reactions in Organic Synthesis, Elsevier,
Burlington, 2005, p. 286.
Scheme 2 Plausible mechanism.
2 (a) K. Narasaka, K. Soai, Y. Aikawa and T. Mukaiyama, Bull.
Chem. Soc. Jpn., 1976, 49, 779; Original TiCl4–promoted method.
(b) T. Nakagawa, H. Fujisawa, Y. Nagata and T. Mukaiyama, Bull.
Chem. Soc. Jpn., 2005, 78, 236; Recent base-catalyzed method.
Other references cited therein.
3 (a) V. M. Swamy and A. Sarkar, Tetrahedron Lett., 1998, 39, 1261;
(b) F.-Y. Zhang and E. J. Corey, Org. Lett., 2001, 3, 639;
(c) J. Boyer, R. J. P. Corriu, R. Perz and Reya, Tetrahedron,
1983, 39, 117; (d) P. G. Klimko and D. A. Singleton, J. Org. Chem.,
1992, 57, 1733; (e) M. O. Ratnikov, V. V. Tumanov and W. A. Smit,
Angew. Chem., Int. Ed., 2008, 47, 9739.
This research was partially supported by Grant-in-Aids for
Scientific Research on Basic Areas (B) ‘‘18350056’’, Priority
Areas (A) ‘‘17035087’’ and ‘‘18037068’’, and Exploratory
Research ‘‘17655045’’ from the Ministry of Education, Culture,
Sports, Science and Technology (MEXT).
Notes and references
z A typical procedure of Table 1, entry 1: Methyl crotonate (methyl
but-2-enoate) (100 mg, 1.0 mmol) and methoxy-2-methyl-1-(trimethyl-
siloxy)propene 1a (261 mg, 1.5 mmol) were successively added to a
stirred suspension of LiOH (8 mg, 0.3 mmol) in DMF (commercially
technical grade; 1.0 mL) at 0–5 1C under an Ar atmosphere, followed
by being stirred at the same temperature for 3 h. Water was added to
the reaction mixture, which was extracted with ether. The organic
phase was washed with water, brine, dried (Na2SO4), and concentrated.
The obtained crude product was purified by silica-gel column
chromatography (hexane : ether = 5 : 1) to give the desired product
2a (156 mg, 77%).
A typical procedure of Table 2, entry 1: 1a (209 mg, 1.20 mmol) was
added to a stirred solution of 2a (101 mg, 0.5 mmol) and NaOH
(crushed powder, prepared under dry atmosphere; 2 mg, 0.05 mmol) in
DMF (0.2 mL) at 20–25 1C under an Ar atmosphere, and the mixture
was stirred at the same temperature for 3 h. A similar work-up gave
the crude product, which was purified by silica-gel column chromato-
4 Contrary to general belief, a literature survey indicates that the
M–M reaction using a,b-unsaturated esters has not been fully
investigated with regard to substrate-generality, compared with
a,b-unsaturated ketones or aldehydes.
A
notable method
involves ca. 10 examples using a clay montmorillonite catalyst:
M. Kawai, M. Onaka and Y. Izumi, Bull. Chem. Soc. Jpn., 1988,
61, 2157.
5 (a) A. Iida, K. Takai, T. Okabayashi, T. Misaki and Y. Tanabe,
Chem. Commun., 2005, 3171; (b) A. Iida, S. Nakazawa,
T. Okabayashi, A. Horii, T. Misaki and Y. Tanabe, Org. Lett.,
2006, 8, 5215; (c) A. Iida, J. Osada, R. Nagase, T. Misaki and
Y. Tanabe, Org. Lett., 2007, 9, 1859; (d) K. Takai, Y. Nawate,
T. Okabayashi, H. Nakatsuji, A. Iida and Y. Tanabe, Tetrahedron,
2009, 65, 5596.
6 LiOH is more reactive than NaOH for the M–M step. Use of
powdered LiOH is convenient and robust enough under bench-top
handling due to its less-hygroscopic property. The next crossed
Claisen condensation step, however, failed to proceed using a LiOH
catalyst. NaOH was therefore employed to link M–M reaction and
crossed-Claisen condensation.
7 A related double nucleophilic reactions are reviewed by Shimizu’s
group; M. Shimizu, I. Hachiya and I. Mizota, Chem. Commun.,
2009, 874.
graphy (hexane : Et2O
(100 mg, 74%).
= 6 : 1) to give the desired product 3a
A typical procedure of Table 3, entry 2: 1a (288 mg, 1.65 mmol) was
added to a stirred solution of methyl cinnamate (81 mg, 0.5 mmol),
NaOH (crushed powder, prepared under dry atmosphere; 8 mg,
0.2 mmol) in DMF (0.1 mL) at 20–25 1C under an Ar atmosphere,
and the mixture was stirred at the same temperature for 1.5 h.
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This journal is The Royal Society of Chemistry 2010
5932 | Chem. Commun., 2010, 46, 5930–5932