Intramolecular Tandem Michael-Type Addition/Aldol Cyclization Induced by TiCl4-R4NX Combinations

Article abstract of DOI:10.1021/ol026413h

(Matrix Presented) Treatment of formyl α,β-enones with a TiCl₄-R₄NX combination induces an intramolecular aldol cyclization to furnish 2-acyl-3-halocyclohexanol with three controlled consecutive stereogenic centers. The reaction of b

Full text of DOI:10.1021/ol026413h

ORGANIC
LETTERS
2002
Vol. 4, No. 18
3111-3114
Intramolecular Tandem Michael-Type
Addition/Aldol Cyclization Induced by
TiCl4−R NX Combinations
4
Kazunari Yagi, Takayuki Turitani, Hiroshi Shinokubo,* and Koichiro Oshima*
Department of Material Chemistry, Graduate School of Engineering, Kyoto UniVersity,
Kyoto 606-8501, Japan
oshima@fm1.kuic.kyoto-u.ac.jp
Received June 23, 2002
ABSTRACT
Treatment of formyl r,â-enones with a TiCl4−R NX combination induces an intramolecular aldol cyclization to furnish 2-acyl-3-halocyclohexanol
4
with three controlled consecutive stereogenic centers. The reaction of bis-r,â-enones with the combination provides cyclic diketones with
high stereoselectivity via an intramolecular Michael addition reaction.
Efficient and stereoselective cyclization is a powerful means
to construct cyclic structures of natural and nonnatural
compounds. In this context, stereoselective tandem conjugate
addition-cyclization reactions have been extensively ex-
plored.1 In particular, intramolecular aldol and Michael
cyclizations are useful strategies.2 We have recently devel-
oped a highly stereoselective coupling reaction between R,â-
unsaturated ketones and aldehydes via a sequential Michael
addition-aldol reaction with the use of halides as nucleo-
philes (Scheme 1).3,4 We then anticipated that this reaction
Scheme 1
(1) (a) Little, R. D.; Masjedizadeh, M. R.; Wallquist, O.; McLoughlin,
J. I. Org. React. 1995, 47, 315. (b) Ho, T. L. Tandem Organic Reactions;
Wiley: New York, 1992. (c) Tietze, L. F.; Beifuss, U. Angew. Chem., Int.
Ed. Engl. 1993, 32, 131. (d) Ihara, M.; Fukumoto, K. Angew. Chem., Int.
Ed. Engl. 1993, 32, 1010.
(2) For recent examples of aldol and Michael cyclizations, see: (a)
Enholm, E. J.; Xie, Y.; Abboud, K. A. J. Org. Chem. 1995, 60, 1112. (b)
Baik, T.-G.; Luis, A. L.; Wang, L. C.; Krische, M. J. J. Am. Chem. Soc.
2001, 123, 5112. (c) Chiu, P.; Szeto, P.-C.; Geng, Z.; Cheng, K.-F. Org.
Lett. 2001, 3, 1901. (d) Nagaoka, Y.; Tomioka, K. Org. Lett. 1999, 1, 1467.
(e) Ono, M.; Nishimura, K.; Nagaoka, Y.; Tomioka, K. Tetrahedron Lett.
1999, 40, 6979. (f) Ono, M.; Nishimura, K.; Tsubouchi, H.; Nagaoka, Y.;
Tomioka, K. J. Org. Chem. 2001, 66, 8199. (g) Kamenecka, T. M.;
Overman, L. E.; Ly Sakata, S. K. Org. Lett. 2002, 4, 79. (h) Suwa, T.;
Nishino, K.; Miyatake, M.; Shibata, I.; Baba, A. Tetrahedron Lett. 2000,
41, 3403. (i) Emiabata-Smith, D.; McKillop, A.; Mills, C.; Motherwell, W.
B.; Whitehead, A. J. Synlett 2001, 1302.
would be applied to an intramolecular variant. Herein, we
describe a highly stereoselective intramolecular aldol reaction
of formyl R,â-enones to furnish 2-acyl-3-halocycloalkanols
with three consecutive stereogenic centers by the action of
a TiCl4-R4NX combination.5 This combination also achieved
a stereoselective cyclization of bis-R,â-enones via an in-
tramolecular double-Michael addition reaction.
Under an argon atmosphere, a solution of TiCl4 (1.0 M in
CH2Cl2, 0.6 mL, 0.6 mmol) was added dropwise to a solution
(3) For the use of combinations of TiCl4-R4NI and related mixtures in
similar reactions, see: (a) Uehira, S.; Han, Z.; Shinokubo, H.; Oshima, K.
Org. Lett. 1999, 1, 1383. (b) Han, Z.; Uehira, S.; Shinokubo, H.; Oshima,
K. J. Org. Chem. 2001, 66, 7854. (c) Shi, M.; Feng, Y.-S. J. Org. Chem.
2001, 66, 406. (d) Shi, M.; Jiang, J.-K.; Cui, S.-C.; Feng, Y.-S. J. Chem.
Soc., Perkin Trans. 1 2001, 390.
(4) For the use of TiX4 alone as both a Lewis acid and a halogen source
for Michael-type addition/aldol reactions, see: (a) Li, G.; Wei, H.-X.; Gao,
J. J.; Caputo, T. D. Tetrahedron Lett. 2000, 41, 1. (b) Li, G.; Gao, J.; Wei,
H.-X.; Enright, M. Org. Lett. 2000, 2, 617. (c) Wei, H.-X.; Kim, S. H.;
Caputo, T. D.; Purkiss, D. W.; Li, G. Tetrahedron 2000, 56, 2397.
10.1021/ol026413h CCC: $22.00 © 2002 American Chemical Society
Published on Web 08/03/2002

of n-Bu4NI (222 mg, 0.6 mmol) in CH2Cl2 (3 mL) at 0 °C,
and the resulting dark-red solution was stirred for 10 min.
To the reaction mixture was added a solution of 1a (101
mg, 0.5 mmol) in CH2Cl2 (2 mL) at 0 °C. After being stirred
for 1 h at 0 °C, the reaction mixture was poured into saturated
aqueous ammonium chloride (30 mL). Extraction followed
by silica gel column purification afforded adduct 2a in 85%
yield with high stereoselectivity (Scheme 2). None of the
other isomers were detected in the reaction mixture.6
Scheme 3a
Scheme 2
We examined several formyl R,â-enones (Scheme 3) to
clarify the scope and limitations. Several characteristics of
this cyclization are noteworthy. Benzylammonium chloride
also worked efficiently as a halide source, and achieved
excellent stereoselectivity (eq 1). The use of benzylammo-
nium bromide provided the corresponding bromide in 53%
yield along with chloride 2a′ (27%). The addition of
ammonium halide is essential. In the absence of ammonium
halide, treatment of 1a with TiCl4 at 0 °C provided the
desired product 2a′ in a low yield (<10% yield). Starting
from alkylidencyclohexanone 1b afforded spiro compound
2b in good yield (eq 2). The reaction of â-substituted
cyclohexenone 1c was sluggish and yielded a Decalin
derivative 2c in a low yield (eq 3). Formyl R,â-enone 1e
provided seven-membered hydroxy ketone 2e in good yield
as a single isomer (eq 5). In the case of 1f, five-membered
hydroxy ketone 2f was not so stable and dehydration and
dehydrochlorination products accompanied (eq 6). Diketone
1g also furnished hydroxy ketone 2g in good yield. The
product was decomposed during silica gel column purifica-
tion via a retro-aldol reaction. The reaction of 1h provided
a complex mixture containing mainly the starting material.
The stereochemistry of the hydroxy ketones was assigned
by the examination of the coupling constants on the basis of
the Karplus relationship2b and confirmed by X-ray crystal-
lographic analysis in the case of 2b (Figure 1).8
a Condition A: enone (0.5 mmol), TiCl4 (0.6 mmol), n-Bu4NI
(0.6 mmol), CH2Cl2 (5 mL), 0 °C. Condition B: enone (0.5 mmol),
TiCl4 (0.6 mmol), BnNEt3Cl (0.6 mmol), CH2Cl2 (5 mL), 0 °C.
b NMR yield with Bn2O as an internal standard.
lecular Baylis-Hillman-type cyclization (Scheme 4).7,8 Treat-
ment of dimethyl acetal 3 with the TiCl4-n-Bu4NI combi-
Treatment of 1a with Et2AlI instead of TiCl4-n-Bu4NI
provided unsaturated ketone 4 in 80% yield via intramo-
(5) (a) Taniguchi, M.; Hino, T.; Kishi, Y. Tetrahedron Lett. 1986, 27,
4767. (b) Yachi, K.; Maeda, K.; Shinokubo, H.; Oshima, K. Tetrahedron
Lett. 1997, 38, 5161. (c) Tsuritani, T.; Shinokubo, H.; Oshima, K.
Tetrahedron Lett. 1999, 40, 8121. (d) Tsuritani, T.; Ito, S.; Shinokubo, H.;
Oshima, K. J. Org. Chem. 2000, 65, 5066. (e) Han, Z.; Uehira, S.; Tsuritani,
T.; Shinokubo, H.; Oshima, K. Tetrahedron 2001, 57, 987. (f) Tsuritani,
T.; Shinokubo, H.; Oshima, K. Synlett 2002, 978.
1
(6) The diastereomer could not be detected by H or 13C NMR.
(7) For the use of Et2AlI in Michael-type addition reactions, see: Itoh,
A.; Ozawa, S.; Oshima, K.; Nozaki, H. Bull. Chem. Soc. Jpn. 1981, 54,
274. For Michael/aldol cyclization with Et2AlSPh, see: Itoh, A.; Ozawa,
S.; Oshima, K.; Nozaki, H. Tetrahedron Lett. 1980, 21, 361.
(8) For recent examples of Baylis-Hilman cyclization, see: (a) Frank,
S. A.; Mergott, D. J.; Roush, W. R. J. Am. Chem. Soc. 2002, 124, 2404.
(b) Wang, L. C.; Luis, A. L.; Agapiou, K.; Jang, H.-Y.; Krische, M. J. J.
Am. Chem. Soc. 2002, 124, 2402 and references therein.
Figure 1. ORTEP drawing of 2b.
Org. Lett., Vol. 4, No. 18, 2002
3112

The use of oxygen-tethered diketone 6d lowered the stereo-
selectivity. The stereochemistry of the cyclized diketones
were assigned by the examination of the coupling constants
and confirmed by X-ray crystallographic analysis in the case
of 7e (Figure 2).11
Scheme 4
nation afforded the decomposed product containing aldehyde
1a. However, the use of excess TiCl4 yielded the cyclized
product 5 in good yield.9 It is notable that the major isomer
has the opposite stereochemistry to 2a at the methoxy-
substituted carbon atom, although the stereoselectivity is not
satisfactory.
Figure 2. ORTEP drawing of 7e.
The TiCl4-ammonium halide combination also effects the
cyclization of bis-R,â-enones 6, providing cyclic diketones
7 with high stereoselectivity via an intramolecular Michael
addition.10 The results are summarized in Scheme 5. Treat-
We propose a plausible mechanism to explain the stereo-
chemical outcome of these processes (Scheme 6).12 1,4-
Scheme 6
Scheme 5a
a Diketone (0.5 mmol), TiCl4 (0.6 mmol), ammonium salt (0.6
mmol), CH2Cl2 (5 mL), 0 °C.
Addition of titanium iodide species to the R,â-enone moiety
furnishes iodo titanium enolate 9. The enolate 9 then
undergoes the intramolecular aldol reaction via a chelated
six-membered transition state 10 and provides hydroxy
ketone with the axial hydroxy group. In the case of 6a, iodo
titanium enolate cyclizes to diketone with an all-equatorial
orientation via an intramolecular Michael addition.
ment of unsymmetrical diketone 6c yielded 7c predominantly
via enolate formation at the phenyl-substituted R,â-enone.
(9) This result can be explained as follows: TiCl4-n-Bu4NI affords an
iodo titanium enolate, and the excess TiCl4 converts dimethoxy acetal to
an oxocarbenium ion. The TiCl4-n-Bu4NI combination does not have
enough Lewis acidity to activate an acetal.
(10) General Procedure. To a solution of n-Bu4NI (222 mg, 0.6 mmol)
in CH2Cl2 (3 mL) was added TiCl4 (0.6 mL, 1.0 M solution in CH2Cl2,
0.6 mmol) dropwise at 0 °C. After 10 min, a solution of 6a (152 mg, 0.5
mmol) in CH2Cl2 (2.0 mL) was introduced dropwise for 1 min at 0 °C.
The reaction mixture was stirred for 1 h at 0 °C and poured into saturated
aqueous NH4Cl (30 mL). The mixture was extracted with ether, and the
organic layer was washed with brine and dried over anhydrous Na2SO4.
Concentration and purification afforded 7a (214 mg) in 99% yield.
(11) Crystallographic data for the structures reported herein have been
deposited with the Cambridge Crystallographic Data Center (CCDC 186739
and 186740 for 2b and 7e, respectively). Copies of this data can be obtained,
free of charge, upon application to the Director, CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK. Fax: 44-1223-3360033. E-mail: deposit@
ccdc.cam.ac.uk.
(12) A similar model to account for the stereochemical outcome has been
proposed. See ref 2h.
Org. Lett., Vol. 4, No. 18, 2002
3113

In conclusion, we have developed a highly stereoselective
cyclization via intramolecular aldol and Michael reactions
with a TiCl4-R4NX combination.
nology, Japan. We thank Prof. Tamejiro Hiyama and Dr.
Masaki Shimizu (Kyoto University) for X-ray analysis.
Supporting Information Available: Experimental pro-
cedures and compound data. This material is available free
of charge via the Internet at http://pubs.acs.org.
Acknowledgment. This work was supported by a Grant-
in-Aid for Scientific Research on Priority Areas (No. 412:
Exploitation of Multi-Element Cyclic Molecules) from the
Ministry of Education, Culture, Sports, Science, and Tech-
OL026413H
3114
Org. Lett., Vol. 4, No. 18, 2002