Ring cleavage and successive aldol reaction of 3-[(Trialkylsilyl)methyl] cyclobutanones

Article abstract of DOI:10.1021/ol202424p

3-[(Trialkylsilyl)methyl]cyclobutanones reacted with aldehydes by activation with titanium(IV) chloride to give acyclic β,γ;- unsaturated β′-hydroxyketones.

Full text of DOI:10.1021/ol202424p

ORGANIC
LETTERS
2011
Vol. 13, No. 22
5986–5989
Ring Cleavage and Successive
Aldol Reaction of
3-[(Trialkylsilyl)methyl]cyclobutanones
Jun-ichi Matsuo,* Kosuke Harada, Mizuki Kawano, Ryosuke Okuno, and
Hiroyuki Ishibashi
School of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health
Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan
jimatsuo@p.kanazawa-u.ac.jp
Received September 7, 2011
ABSTRACT
3-[(Trialkylsilyl)methyl]cyclobutanones reacted with aldehydes by activation with titanium(IV) chloride to give acyclic β,γ-unsaturated β0-
hydroxyketones.
Cyclobutanones are interesting building blocks for or-
ganic synthesis,1 and we have reported on the synthetic
utility of 3-ethoxycyclobutanones for formal [4 þ 2] cy-
cloaddition reactions with aldehydes,2 ketones,2 N-Ts
imines,3 allylsilanes,4 and silyl enol ethers5 to give the
corresponding six-membered ring compounds.6ꢀ8 For ex-
ample, 3-ethoxycyclobutanone 1 reacted with benzal-
dehyde to give tetrahydropyrone 2 under the catalysis of
Lewis acid (eq 1).2 In the course of these studies, it was also
found that substitution with a (trialkylsilyl)methyl group
at the 2-position of cyclobutanone facilitated ring cleavage
of the cyclobutanone ring.9 We then tried to investigate the
effect of the (trialkylsilyl)methyl group at the 3-position of
the cyclobutanone and found that a reaction between
3-[(trimethylsilyl)methyl]cyclobutanone 3 and an aldehyde
gave an acyclic aldol product 4 bearing a β,γ-unsaturated
group, which would be difficult to prepare by the regioselec-
tive aldol reaction of β,γ-unsaturated ketone 5 (Scheme 1).10
We would like to describe here this unique ring cleavage and
aldol reaction of 3-[(trialkylsilyl)methyl]cyclobutanones.
(1) (a) Conia, J. M.; Robson, M. J. Angew. Chem., Int. Ed. Engl. 1975,
ꢀ
14, 473. (b) Bellus, D.; Ernst, B. Angew. Chem., Int. Ed. Engl. 1988, 27,
797. (c) Lee-Ruff, E.; Mladenova, G. Chem. Rev. 2003, 103, 1449. (d)
Namyslo, J. C.; Kaufmann, D. E. Chem. Rev. 2003, 103, 1485.
(2) Matsuo, J.; Sasaki, S.; Tanaka, H.; Ishibashi, H. J. Am. Chem.
Soc. 2008, 130, 11600.
(3) Matsuo, J.; Okado, R.; Ishibashi, H. Org. Lett. 2010, 12, 3266.
(4) Matsuo, J.; Sasaki, S.; Hoshikawa, T.; Ishibashi, H. Org. Lett.
2009, 11, 3822.
(5) Matsuo, J.; Negishi, S.; Ishibashi, H. Tetrahedron Lett. 2009, 50,
5831.
(6) Matsuo, J.; Sasaki, S.; Hoshikawa, T.; Ishibashi, H. Chem.
Commun. 2010, 46, 934.
The 3-[(trialkylsilyl)methyl]cyclobutanones 7aꢀh em-
ployed in this study were prepared by a [2 þ 2] cycloaddi-
tion reaction between allylsilane and a keteneiminium salt
(7) Reaction of donorꢀacceptor cyclobutanes: (a) Allart, E. A.;
Christie, S. D. R.; Pritchard, G. J.; Elsegood, M. R. J. Chem. Commun.
2009, 7339. (b) Parsons, A. T.; Johnson, J. S. J. Am. Chem. Soc. 2009,
131, 14202. (c) Moustafa, M. M. A.; Pagenkopf, B. L. Org. Lett. 2010,
12, 4732. (d) Moustafa, M. M. A.; Stevens, A. C.; Machin, B. P.;
Pagenkopf, B. L. Org. Lett. 2010, 12, 4736. (e) Stevens, A. C.; Palmer,
C.; Pagenkopf, B. L. Org. Lett. 2011, 13, 1528.
(9) Matsuo, J.; Kawano, M.; Okuno, R.; Ishibashi, H. Org. Lett.
2010, 12, 3960.
(10) (a) Mahrwald, R. Chem. Rev. 1999, 99, 1095. (b) Mahrwald, R.
Modern Aldol Reaction; Wiley-VCH: Weinheim, 2004. (c) Trost, B. M.;
Fleming, I.; Semmelhack, M. F. In Comprehensive Organic Synthesis;
Pergamon Press: New York, 1991; Vol. 2, Chapter 1.4ꢀ1.9. (d) Mukaiyama,
T. Org. React. 1982, 28, 203.
(8) Related reaction: Shan, G.; Liu, P. F.; Rao, Y. Org. Lett. 2011, 13,
1746.
r
10.1021/ol202424p
Published on Web 10/18/2011
2011 American Chemical Society

(Table 2). It was found that the use of titanium(IV)
chloride gave β,γ-unsaturated aldol product 8 in 93%
yield, while the use of titanium(IV) bromide gave R,β-
unsaturated 9 in 34% yield (entries 1 and 2).12 It was
assumed that enone 9 was formed by isomerization of the
initially formed product 8. Catalysis of tin(IV) chloride
gave 8 in only 4% yield (entry 3). Even ring cleavage of 7a
was not observed in the case of other Lewis acids such as
BF3ꢀOEt2 and Sc(OTf)3.
Scheme 1. Regioselective Formation of Aldol Adduct 4 from
Cyclobutanone 3
which was generated from the corresponding pyrrolidine
amide 6 (Table 1).11 2,2-Dialkyl- and 2-monoalkyl-sub-
stituted 3-[(trimethylsilyl)methyl]cyclobutanones 7aꢀf were
prepared in good yields. Cyclobutanones having tert-
butyldimethylsilyl and triisopropylsilyl groups 7g,h were
prepared by the same method. Attempted preparation of
cyclobutanone 7i which had no substituents at its 2-posi-
tion gave an inseparable mixture of 7i and byproducts by
this procedure. Therefore, 7i was prepared by another
route: [2 þ 2] cycloaddition between dichloroketene and
allyltrimethylsilane followed by dechlorination afforded
pure 7i in good yield (Scheme 2).
Table 2. Effect of Lewis Acid on Reaction between 7a and
Benzaldehyde
entry
Lewis acid
8 (% yield)
9 (% yield)
1
2
3
TiCl4
TiBr4
SnCl4
93
ꢀ
4
ꢀ
34
ꢀ
Table 1. Preparation of 3-[(Trialkylsilyl)mthyl]cyclobutanones
7aꢀh
Next, the scope and limitations of the reaction of
3-[(trialkylsilyl)methyl]cyclobutanones and aldehydes were
studied using titanium(IV) chloride as a Lewis acid. Ben-
zaldehyde derivatives with methyl, methoxy, or halogens
at the para positions of the benzene ring were employed
first. It was found that substitution with halogens gave
high yields of the desired products 10aꢀc (Table 3, entries
1ꢀ3) whereas reactions of methyl or methoxy-substituted
benzaldehyde gave the desired compounds 10d,e in 80 and
54% yields, respectively (entries 4 and 5). Therefore, the
electrophilicity of the aldehydes affected the efficiency of
this reaction. The reaction with 1-naphthyl aldehyde pro-
ceeded sluggishly to afford 10f in 55% yield, but that of
2-naphthyl aldehyde gave the corresponding product 10g
in 88% yield (entries 6 and 7). Notable differences were
observed in the reaction with 1- and 2-naphthyl aldehydes
suggesting that this reaction was influenced easily by steric
effects. Aliphatic aldehydes such as octanal and 3-phenylpro-
panal gave the desired products 10h,i in high yields (entries 8
and 9), while increased steric hindrance in aldehydes such as
isobutyl aldehyde, isopropyl aldehyde, and tert-butyl aldehyde
caused decreased yields of the desired products 10jꢀl (entries
10ꢀ12). When the reactions were carried out at higher reac-
tion temperatures, the β,γ-unsaturated aldol products 10
isomerized to the corresponding R,β-unsaturated ones. The
reaction with ketones such as acetophenone did not proceed.
yield
entry
7
R1
Me
R2
SiR3
SiMe3
(%)
1
2
3
4
5
6
7
8
7a
7b
7c
7d
7e
7f
Me
Et
77
75
85
88
77a
64a
85
75
Et
SiMe3
-(CH2)4-
-(CH2)5-
Me
SiMe3
SiMe3
H
SiMe3
CH2Ph
Me
H
SiMe3
7g
7h
Me
Me
SiMe2t-Bu
Si(i-Pr)3
Me
a Mixture of diastereomers: 7e (84:16), 7f (93:7).
Scheme 2. Preparation of Cyclobutanone 7i
(11) (a) Houge, C.; Frisque-Hesbain, A. M.; Mockel, A.; Ghosez, L.;
Declercq, J. P.; Germain, G.; Van Meerssche, M. J. Am. Chem. Soc.
1982, 104, 2920. (b) Marko, I.; Ronsmans, B.; Hesbain-Frisque, A. M.;
Dumas, S.; Ghosez, L.; Ernst, B.; Greuter, H. J. Am. Chem. Soc. 1985,
107, 2192.
First, we screened Lewis acids which promoted the
reaction between cyclobutanone 7a and benzaldehyde
(12) Other regioisomers were not obtained.
Org. Lett., Vol. 13, No. 22, 2011
5987

Table 3. TiCl4-Promoted Reaction between 7a and Various
Aldehydesa
Table 4. TiCl4-Promoted Reaction of Various 3-(Silylmeth-
yl)cyclobutanones 7bꢀi with Benzaldehydea
entry
R
10
yield (%)
1
4-FC6H4
4-ClC6H4
4-BrC6H4
4-MeC6H4
4-MeOC6H4
1-Naph
10a
10b
10c
10d
10e
10f
86
93
96
80
54
55
88
93
83
49
17
0
2
3
4
5
6b
7
2-Naph
10g
10h
10i
8
CH3(CH2)6
Ph(CH2)2
i-PrCH2
i-Pr
9
10
11
12
10j
10k
10l
t-Bu
a Cyclobutanone 7a (1.4 equiv), Aldehyde (1.0 equiv), and TiCl4
(1.4 equiv) were employed. b Reaction temperature: ꢀ78 to ꢀ18 °C, 3 h.
The reaction of other 2,2-dialkylcyclobutanones such as
diethylcyclobutanone 7b and spirocyclobutanones 7c,d
with benzaldehyde proceeded smoothly at ꢀ78 °C to afford
β,γ-unsaturated aldol products 11aꢀc in good to high
yields (Table 4, entries 1ꢀ3). The reaction of 2-monoalk-
ylcyclobutanones 7e,f required a slightly elevated tempera-
ture (ꢀ45 °C), and that of 2-nonsubstituted cyclobutanone
7i needed to be carried out at ꢀ20 °C for efficient conver-
sion (entries 4ꢀ6). More substituted cyclobutanones re-
acted at lower temperatures. Moderate syn selectivities
were observed in the products 11d,e (entries 4 and 5). It
was noted that cyclobutanones bearing other trialkylsily
groups such as TBS and TIPS groups 7g,h gave the aldol
product 8 (entries 7 and 8). These results suggested that
even sterically hindered trialkylsilyl groups reacted in this
reaction.
a For reaction conditions, see Table 3 unless otherwise noted. b syn/
anti = 80:20. c syn/anti = 70:30. d 7i (1.4 equiv) and TiCl4 (2.1 equiv)
were employed.
A plausible mechanism for the present ring cleavage and
aldol reaction of 3-[(trialkylsilyl)methyl]cyclobutanones is
shown in Scheme 3. Activation of cyclobutanone 12 with
titanium(IV) chloride gave bicyclobutonium ion 13,13 and
the chloride ion attacked the trialkylsilyl group to form a
trichlorotitanium enolate 14, whose formation was con-
sistent with syn selectivity for the aldol reaction of a
trichlorotitanium enolate.14 The regioselectivity for the
formation of 14 was controlled by formation of the more
substituted bicyclobutonium ion 13, and the regioselectiv-
ity was preserved during the reaction. The aldol reaction of
14 with aldehyde proceeded to give 15.
Scheme 3. Plausible Reaction Mechanism
The synthetic utility of the β,γ-unsaturated aldol ad-
ducts was exemplified by transformation of 8 to the
(13) Olah, G. A.; Reddy, V. P.; Prakash, G. K. S. Chem. Rev. 1992,
92, 69.
(14) Nakamura, E.; Kuwajima, I. Tetrahedron Lett. 1983, 24, 3343.
5988
Org. Lett., Vol. 13, No. 22, 2011

In conclusion, 3-[(trialkylsilyl)methyl]cyclobutanones
react with aldehydes upon activation with titanium(IV)
chloride to afford β,γ-unsaturated aldol adducts. Regio-
selective formation of a β,γ-unsaturated trichlorotitanium
enolate was proposed. The present method for generation
of this unique enolate will likely be applicable to reactions
with other electrophiles.
Scheme 4. An Example of Transformation of 8
Acknowledgment. This work was supported by a
Grant-in-Aid for Scientific Research from the Ministry
of Education, Culture, Sports, Science, and Technology,
Japan.
tetrahydropyrone 17 (Scheme 4). Epoxidation of β,γ-un-
saturated aldol adduct 8 with mCPBA gave epoxide 16 in
92% yield. Treatment of epoxide 16 with boron trifluoride
etherate gave tetrahydropyrone 17 in 87% yield.
Supporting Information Available. Detailed experimen-
tal procedures and full spectroscopic characterization
data for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 22, 2011
5989