Titanium(IV) chloride-mediated carbon-carbon bond-forming reaction between 3,3-dialkylcyclobutanones and aldehydes

Article abstract of DOI:10.1021/ol101653b

Treatment of 3,3-dialkylcyclobutanones with titanium(IV) chloride in the presence of aldehyde gave β²-chloro-β-hydroxy ketones in high yields. It was speculated that ring cleavage of the cyclobutanone ring with titanium(IV) chloride gave trichlorotitanium enolate having a tertiary alkyl chloride moiety and then aldol reaction of the titanium enolate proceeded. A trialkylsilylmethyl group at the 2-position of cyclobutanone facilitated the ring cleavage. Synthesis of substituted cyclopentenone from an obtained product is also described.

Full text of DOI:10.1021/ol101653b

ORGANIC
LETTERS
2010
Vol. 12, No. 17
3960-3962
Titanium(IV) Chloride-Mediated
Carbon-Carbon Bond-Forming Reaction
between 3,3-Dialkylcyclobutanones and
Aldehydes
Jun-ichi Matsuo,* 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 July 16, 2010
ABSTRACT
Treatment of 3,3-dialkylcyclobutanones with titanium(IV) chloride in the presence of aldehyde gave ꢀ′-chloro-ꢀ-hydroxy ketones in high yields.
It was speculated that ring cleavage of the cyclobutanone ring with titanium(IV) chloride gave trichlorotitanium enolate having a tertiary alkyl
chloride moiety and then aldol reaction of the titanium enolate proceeded. A trialkylsilylmethyl group at the 2-position of cyclobutanone
facilitated the ring cleavage. Synthesis of substituted cyclopentenone from an obtained product is also described.
Cyclobutanones have often been employed as versatile
building blocks in organic synthesis.1 Synthetic utility of
3-alkoxycyclobutanones for preparing six-membered cyclic
compounds was recently reported by our group. Thus, a
zwitterionic intermediate 2, generated by activation of
3-alkoxycyclobutanone 1 with Lewis acid (LA), reacts with
aldehydes,2 ketones,2 imines,3 allylsilanes,4 and silyl enol
ethers5 to afford the corresponding six-membered cyclic
compounds (eq 1).6,7 The presence of the alkoxy group at
the 3-position of the cyclobutanone ring of 1 makes ring
cleavage easy. It was then thought that dialkyl groups at the
3-position of cyclobutanone 4 also promoted formation
of zwitterionic intermediate 5 since the tertiary carbocation-
ic part of 5 was stabilized by the dialkyl groups.8 The
zwitterionic species 5 was considered to react with aldehyde
to give tetrahydro-γ-pyrone 6 as in the case of intermediate
2 (eq 2). However, reaction of 3,3-dialkylcyclobutanone 4
with aldehyde by activation of titanium(IV) chloride did not
give the expected product 6 but afforded ꢀ-hydroxy ketone
(aldol product) bearing a chloride group. We report here this
unique aldol reaction from cyclobutanone 4 and also report
synthesis of a substituted cyclopentenone from the aldol
product.
(1) (a) Conia, J. M.; Robson, M. J. Angew. Chem., Int. Ed. Engl. 1975,
14, 473. (b) Bellusˇ, 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) Intramolecular reaction: Matsuo, J.; Sasaki, S.; Hoshikawa, T.;
Ishibashi, H. Chem. Commun 2010, 46, 934
.
10.1021/ol101653b  2010 American Chemical Society
Published on Web 08/06/2010

Reaction of 2,2,3,3-tetramethylcyclobutanone 7a and ben-
zaldehyde was investigated first by employing various Lewis
acids. Neither boron trifluoride diethyl etherate nor tin(IV)
chloride promoted ring cleavage of cyclobutanone 7a,
whereas activation with titanium(IV) chloride smoothly
cleaved the cyclobutanone ring of 7a in the presence of
benzaldehyde to afford an aldol product 8 bearing a tertiary
alkyl chloride group in 80% yield (Table 1, entry 1).
-18-0 °C, while that of 7c took place immediately at -78
°C. These results suggested that the silylmethyl group at the
2-position promoted cleavage of the cyclobutanone ring with
titanium(IV) chloride. The tert-butyldimethylsilyl group and
triisopropylsilyl group also accelerated the ring cleavage, and
aldol products 8d and 8e were obtained in 85% and 88%
yields, respectively (entries 5 and 6).10,11
Reaction of cyclobutanone 7c with various aldehydes 9
was investigated (Table 2). 4-Chloro- and 4-bromobenzal-
Table 1. Reaction between 3,3-Dimethylcyclobutanones 7a-e
a
and Benzaldehyde by Activation with TiCl4
Table 2. Aldol Reaction between Cyclobutanone 7c with
Various Aldehydes 9a-fa
entry
7
R1
R2
conditions
8b
80
drc
entry
9 (R)
t (°C)
-78
time (min) 10b drc
1
2
3
4
5
6
7a Me
7b Et
7b Et
7c TMSCH2
7d TBSCH2
7e TIPSCH2
Me -78 to 0 °C, 1 h
H
H
H
H
H
-78 to -18 °C, 1.5 h 80
76:24
1
2
3
4
5
9a (4-ClC6H4)
9b (4-BrC6H4)
9c (1-naphthyl) -78 to -45
9d (PhCH2CH2) -78 to -45
40
45
60
90
90
84
95
95:5
97:3
-78 °C, 0.5 h
-78 °C, 0.5 h
-78 °C, 0.5 h
-78 °C, 0.5 h
trace
87
85
88
-78
86:14
71:29
83:17
72 89:11
87 85:15
76 85:15
9e (i-Pr)
-78 to -45
a Cyclobutanone 7 (1.5 equiv), TiCl4 (1.5 equiv), and PhCHO (1.0 equiv)
were employed. b Isolated yield (%). c Syn/anti ratio determined by 1H NMR
of a mixture of diasetereomers.
a For conditions, see Table 1. b Isolated yield (%). c Syn/anti ratio
determined by H NMR.
1
dehyde 9a and 9b reacted smoothly at -78 °C, and the
corresponding aldol products 10a and 10b were obtained in
high yields with high syn-selectivities (entries 1 and 2).
1-Naphthyl aldehyde 9c reacted at -45 °C, and aldol product
10c was obtained in 72% yield with moderate syn-selectivity
(syn/anti ) 89:11, entry 3). Aldol reaction with aliphatic
aldehydes such as 3-phenylpropanal 9d and 2-methylpropanal
9e also proceeded efficiently to afford the corresponding aldol
products 10d and 10e in 87% and 76% yields, respectively
(entries 4 and 5). However, reaction with ketones such as
acetophenone did not proceed.
Some 3,3-dialkyl-2-[(trimethylsilyl)methyl]cyclobutanones
11a-c9 were employed in this reaction with benzaldehyde. 3,3-
Diethylcyclobutanone 11a and spirocyclobutanones 11b and 11c
also reacted with benzaldehyde to afford the corresponding aldol
product bearing a tertiary alkyl chloride group in high yields
with moderate to good syn-selectivities (Table 3).
Tetrahydro-γ-pyrone 6 (R′ ) Me, R ) Ph) was not obtained
at all. A new carbon-carbon bond was formed regioselec-
tively at the more substituted R-position of the carbonyl
group of 7a. Reaction of 3,3-dimethyl-2-ethylcyclobutanone
7b with benzaldehyde also proceeded smoothly to afford
aldol adduct 8b in 80% yield as a mixture of diastereomers
(syn/anti ) 76:24) (entry 2). This result suggested that 3,3-
dialkylcyclobutanone bearing a monoalkyl group at the
2-position was also an effective substrate for the present
reaction. 3,3-Dialkyl groups on the cyclobutanone ring were
found to be necessary for this reaction since ring-opening
of 2,3-dipropylcyclobutanone with titanium(IV) chloride did
not take place. Interestingly, reaction of cyclobutanone 7c9
bearing a 2-(trimethylsilyl)methyl group took place at a lower
temperature (-78 °C) than that of 2,2-dialkyl and 2-alkyl
cyclobutanones 7a and 7b, and the reaction afforded the
corresponding product 8c in 87% yield (syn/anti ) 86:14)
(entry 4). Reaction of 7b at -78 °C gave only a trace amount
of product 8b (entry 3).
The obtained ꢀ′-chloro-ꢀ-hydroxy ketones were precursors
for multisubstituted cyclopentenones. Thus, a mixture of
diastereomers (syn/anti ) 86:14) of adduct 8c was mesylated
by using mesyl chloride and triethylamine, and treatment of
the resulting mesylate with DBU at 45 °C gave dienone 13
in 79% yield in two steps. Nazarov cyclization12 of 13 with
Titanium(IV) chloride-mediated ring-opening of 7a and
7b required raised reaction temperatures from -78 °C to
(7) Formation of zwitterionic intermediates from cyclobutane derivatives:
(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.
(10) Stereochemistry of anti-8d was determined by X-ray crystal-
lography. Stereochemistry of other products 8b-e and 12a-c was deduced
by 1H NMR spectra of syn- and anti-8d. For details, see the Supporting
Information.
(8) (a) Jackson, D. A.; Rey, M.; Dreiding, A. S. Tetrahedron Lett. 1983,
24, 4817. (b) Jackson, D. A.; Rey, M.; Dreiding, A. S. HelV. Chim. Acta
1985, 68, 439.
(11) Ring expansion of silylmethylcyclobutanes: Kno¨lker, H.-J.; Baum,
(9) Compounds 7c-e and 11a-c were prepared by [2+2] cycloaddition
by using carboxylic acid chloride and (3,3-dialky-2-propenyl)trialkylsilane in
the presence of triethylamine. For details, see the Supporting Information.
G.; Graf, R. Angew. Chem., Int. Ed. Engl. 1994, 33, 1612
(12) Habermas, K. L.; Denmark, S. E.; Jones, T. K. Org. React. 1994,
45, 1.
.
Org. Lett., Vol. 12, No. 17, 2010
3961

Table 3. Aldol Reaction between Various
3,3-Dialkyl-2-[(trimethylsilyl)methyl]cyclobutanones 11a-c and
Benzaldehydea
Scheme 2. Proposed Mechanism
16 to form trichlorotitanium enolate 17, which reacts with
aldehydes to afford product 18. Observed moderate to good
syn-selectivity of product 18 is consistent with aldol reaction
of trichlorotitanium enolate.13 It was assumed that the
trialkylsilylmethyl group at the 2-position of the cyclobu-
tanone ring would stabilize bicyclobutonium ion14 during
the formation of zwitterionic intermediate 16.
a For conditions, see Table 1. Reactions were carried out at -78 to
-45 °C for 1-1.5 h. b Isolated yield (%). c Syn/anti ratio determined by
1H NMR.
In conclusion, ꢀ′-chloro-ꢀ-hydroxy ketones were synthe-
sized by the titanium(IV) chloride-mediated reaction between
3,3-dialkylcyclobutanones and aldehydes. Aldol reaction of
in situ formed trichlorotitanium enolate, which was formed
from 3,3-dialkylcyclobutanones and titanium(IV) chloride,
was proposed. Trialkylsilylmethyl substituent at the 2-posi-
tion of cyclobutanone accelerated this reaction, and products
were useful precursors for substituted cyclopentenones.
hydrochloric acid in refluxing ethanol gave cyclopentenone
14 in 73% yield (Scheme 1). The trimethylsilyl group was
removed during this cyclization.
Scheme 1
.
Nazarov Cyclization to Tetrasubstituted
Cyclopentenone 14
Acknowledgment. This study was financially supported
by a Grant from Suntory Institute for Bioorganic Research
and a Grant-in-Aid for Scientific Research from the Ministry
of Education, Culture, Sports, Science, and Technology,
Japan.
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.
Our proposed mechanism for the present reaction between
cyclobutanone 15 and aldehyde is shown in Scheme 2.
Activation of 3,3-dialkylcyclobutanone 15 with titanium(IV)
chloride gives zwitterionic intermediate 16 by cleaving the
carbon-carbon bond between the more substituted C2 and
C3. Chloride ion attacks the tertiary carbocationic center of
OL101653B
(13) Nakamura, E.; Kuwajima, I. Tetrahedron Lett. 1983, 24, 3343.
(14) Olah, G. A.; Reddy, V. P.; Prakash, G. K. S. Chem. ReV. 1992, 92,
69.
3962
Org. Lett., Vol. 12, No. 17, 2010