Thiazolium ylide-catalyzed intramolecular aldehyde-ketone benzoin-forming reactions: Substrate scope

Article abstract of DOI:10.1002/adsc.200404092

The scope and limitations of intramolecular benzoin-forming reactions of aldehydes and ketones catalyzed by the combination of a thiazolium salt and a base are described. After optimization of the reaction conditions, five- and six-membered cyclic acyloins were obtained in good to excellent yields and competing reactions such as intramolecular aldol reactions were suppressed. The analogous closure of seven-membered rings proved difficult.

Full text of DOI:10.1002/adsc.200404092

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Thiazolium Ylide-Catalyzed Intramolecular AldehydeꢀKetone
Benzoin-Forming Reactions: Substrate Scope
Yoshifumi Hachisu,a Jeffrey W. Bode,b Keisuke Suzukia,*
a
ꢀ
Department of Chemistry, Tokyo Institute of Technology and CREST JSTAgency, 2-12-1, O-okayama, Meguro-ku,
Tokyo 152-8551, Japan
Fax: 81-3-5734-2788, e-mail: ksuzuki@chem.titech.ac.jp
Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA 93106-9510, USA
b
Received: March 23, 2004; Accepted: July 5, 2004
Dedicated to the memory of the late Professor Oyo Mitsunobu.
Supporting Information for this article is available on the WWW under http://asc.wiley-vch.de or from the author.
Abstract: The scope and limitations of intramolecu-
lar benzoin-forming reactions of aldehydes and ke-
tones catalyzed by the combination of a thiazolium
salt and a base are described. After optimization of
the reaction conditions, five- and six-membered cy-
clic acyloins were obtained in good to excellent
yields and competing reactions such as intramolecu-
lar aldol reactions were suppressed. The analogous
closure of seven-membered rings proved difficult.
Keywords: benzoin; cyclization; ketones; organic
catalysis; tertiary alcohols
It has long been known that thiazolium salts, in the pres-
ence of bases, catalyze benzoin-type reactions[1] of alde-
hydes via the mechanism proposed by Breslow in 1957
(Scheme 1).[2,3] Although the catalytically generated ac-
tivated intermediate is broadly considered to be an acyl
Scheme 1. Proposed mechanism of thiazolium ylide-cata-
lyzed reaction.
anion equivalent,[4] the electrophilic reaction partners
have been essentially limited to aldehydes,[5] imines[6]
or Michael acceptors, such as enones.[7]
Recently, we reported a cyclization via benzoin-type
aldehyde–ketone coupling, affording tetracyclic prod-
ucts with an a-ketol function (Scheme 2).[8,9] This proc-
ess, which proceeded with high efficiency under mild
and convenient reaction conditions, enabled a novel
and stereoselective approach to complex anthraquinone
precursors. In addition to the utility of the products, we
found it remarkable that, prior to our investigations, ke-
tones had not been employed as electrophiles in ben-
zoin-type couplings.[10] While we initially believed that
our highly rigid systems were uniquely oriented for in-
tramolecular reaction, thus allowing the use of ketones
Scheme 2.
We now report that a wide variety of keto-aldehyde
as electrophiles, we sought to explore these reaction substrates cyclize in good yields under optimized reac-
conditions for further examples of intramolecular alde- tion conditions. Remarkably, our preliminary results
hyde–ketone benzoin-forming reactions.
suggest that neither preorientation of the functional
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DOI: 10.1002/adsc.200404092
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Scheme 4.
Table 1. Reactions of biaryl substrate 3.
Entry X [mol %] Y [mol %] Time [h] Yield [%]
4
5
1
2
3
20
20
25
70
40
20
1.5
1
1
65
81
90
26
9
5
Figure 1. Competing reaction pathways.
Scheme 5.
Table 2. Optimization of reaction conditions for keto-alde-
hyde 6.
Scheme 3. Intermolecular benzoin-forming reaction.
groups nor absence of enolizable aldehydes are prereq- Entry
uisites for high reactivity. The expected by-products, di-
X
Base
Y
Solvent
Time [h] Yield
[%]
meric benzoins and/or aldol products, are largely sup-
pressed by improvements in the reaction conditions
(Figure 1). Taken together, these results document a
broad and highly useful scope for the intramolecular ke-
tone–aldehyde benzoin-forming reactions under mild,
convenient reaction conditions.
We first sought to examine whether ketones can gen-
erally serve as electrophiles in intermolecular benzoin-
type reactions, a previously unreported process. Not un-
expectedly, however, no isolable cross-coupled products
were observed upon exposure of a mixture of benzalde-
1
2
3
4
5
6
7
8
20 DBU
50 DBU
50 Et3N
70 t-BuOH
40 t-BuOH
40 t-BuOH 24
1
0.5
63[a]
81
78
78
66
68
81
89
50 t-BuOK 40 t-BuOH
0.5
1
0.5
1
50 DBU
50 DBU
50 DBU
25 DBU
40 EtOH
40 DMF
40 THF
20 t-BuOH
2
[a]
The aldol product 8 was obtained in 8% yield.
hyde and cyclohexanone to benzoin catalysts and typical in the overall basicity of the reaction medium, leading to
reaction conditions. Only benzoin 2 was obtained in a suppression of the undesired intramolecular aldol
50% yield (Scheme 3).
process.[11]
We therefore concentrated on the intramolecular re-
We were pleased to find that the reaction was not lim-
actions, and started with the reaction of the simple biaryl ited to ketones alpha to an aromatic ring, as exemplified
keto-aldehyde 3 (Scheme 4). Under our previously re- by substrate 6 (Scheme 5, Table 2). Again, the relative
ported conditions,[9] the desired product 4 was obtained amounts of thiazolium salt and base proved important
in low yield, accompanied by a significant amount of al- (Entries 1 and 2). While the use of excess base gave
dol product 5 (Table 1, Entry 1). After some experimen- the aldol side product, this competing process could be
tation, a simple means of suppressing the competing al- completely suppressed simply by reducing the relative
dol reaction was found: the employment of DBU in sub- amount of DBU, giving cyclized product 7 in 81% yield
stoichiometric quantities relative to the thiazolium salt (Entry 2). The use of other bases was also possible: tri-
(Entries 2 and 3). This presumably results in a decrease ethylamine and potassium t-butoxide proved effective,
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Intramolecular Aldehyde–Ketone Benzoin-Forming Reactions
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Scheme 6.
Scheme 9.
Table 3. Reaction of keto-aldehyde 17.
Entry X [mol %] Base (Y [mol %]) Time [h] Yield [%]
18
19
1
2
3
25
25
50
DBU (20)
t-BuOK (20)
t-BuOK (40)
9
6
1
59
54
73
14
7
5
Scheme 7.
Scheme 8.
Scheme 10.
although the reaction with triethylamine required a sig- selectivity (Scheme 8). Aldol 16 was obtained in 5%
nificantly longer reaction time (Entry 3). t-BuOH and yield. It should also be noted that the potentially sensi-
THF were found to be the preferred solvents (Entries 2, tive b-hydroxyketone moiety in the substrate remained
5–7). The use of lower catalyst loadings (25 mol %1 and intact under these conditions.
20 mol % DBU) permitted a clean reaction to provide 7
in optimal yield (Entry 8).
This reaction was highly stereoselective, a feature ra-
tionalized by the steric repulsion of the activated alde-
Encouraged by these results, the formation of six- hyde and the 19-methyl group adjacent to the ketone.
membered rings from other simple keto-aldehydes was The relative stereochemistry was determined by com-
examined. Keto-aldehyde 9 cyclized in 42% yield under parison of the spectroscopic data of 3-O-acetyl deriva-
these conditions to give the expected six-membered ring tives of 15b and 15a with those of the reported com-
ketone 10 (Scheme 6). The reaction of other simple pounds.[13]
keto-aldehydes, however, proved to be capricious. For
Five-membered ring formation was achieved with
example, substrate 11 underwent cyclization in only keto-aldehyde 17[14] (Scheme 9, Table 3). The initially
21% yield, and the dimeric benzoin adduct 13 was ob- disappointing yield, due to the formation of elimination
tained as the major product (Scheme 7).
product 19, could be overcome by employing t-BuOK as
Fortunately, the use of more complex substrates the base in place of DBU, although increased catalyst
proved feasible. Keto-aldehyde 14 derived from choles- loadings were needed to attain a rapid and clean reac-
terol[12] gave ketol 15 in moderate yield with high stereo- tion (Entries 2 and 3).
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Yoshifumi Hachisu et al.
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Two attempts to make larger rings were met with frus- References and Notes
tration. Aldehyde 20 gave only homo-coupled product
[1] T. Ukai, R. Tanaka, S. Dokawa,J. Pharm. Soc. Jpn. 1943,
63, 269.
[2] a) R. Breslow, Chem. Ind. (London) 1957, 893; b) R.
Breslow, J. Am. Chem. Soc. 1958, 80, 3719.
[3] Triazolium salt is also the active catalyst for benzoin-type
reactions; for recent examples of the chiral triazolium
salt-catalyzed enatioselective reactions, see: a) D. En-
ders, T. Balensiefer, Acc. Chem. Res. ACS ASAP, and
references cited therein; b) M. S. Kerr, J. R. de Alaniz,
T. Rovis, J. Am. Chem. Soc. 2002, 124, 10298; c) R. L.
Knight, F. J. Leeper, J. Chem. Soc. Perkin. Trans. 1 1998,
1891.
21 in 69% yield [Scheme 10, Eq. (1)]. Keto-aldehyde
22 provided neither the desired product nor the homo-
coupled product, even at higher temperature.
Although the intramolecular ketone–aldehyde ben-
zoin-forming reaction is not without its limitations, the
mild reaction conditions, tolerance of sensitive function-
alities (including b-hydroxy ketones), operational sim-
plicity, and commercially available catalysts render
this process an attractive means of carbon–carbon
bond formation for the synthesis of complex molecules.
Furthermore, given the long history of this process, in-
cluding extensive mechanistic studies, it is remarkable
that the use of ketones as electrophiles has not been ex-
ploited prior to our work.[16]
[4] J. S. Johnson, Angew. Chem. Int. Ed. 2004, 43, 1326.
[5] H. Stetter, Org. Synth. 1984, 62, 170.
´
[6] a) J. Castells, F. Lopez-Calahorra, M. Bassedas, P. Urrios,
Synthesis 1988, 314; b) A. R. Katritzky, D. Cheng, R. P.
Musgrave, Heterocycles 1996, 42, 273; c) J. A. Murry,
D. E. Frantz, A. Soheili, R. Tillyer, E. J. J. Grabowski,
P. J. Reider, J. Am. Chem. Soc. 2001, 123, 9696.
[7] H. Stetter, H. Kuhlmann, Org. React. (N. Y.) 1991, 40,
407.
Experimental Section
Typical Procedure for the Benzoin-Forming Reaction
[8] a) J. W. Bode, Y. Hachisu, T. Matsuura, K. Suzuki, Tetra-
hedron Lett. 2003, 44, 3555; b) J. W. Bode, Y. Hachisu, T.
Matsuura, K. Suzuki, Org. Lett. 2003, 5, 391; c) T. Mat-
suura, J. W. Bode, Y. Hachisu, K. Suzuki, Synlett 2003,
1746.
2-Hydroxy-2-methyl-3,4-dihydro-2H-naphthalen-1-one (7):
To a solution of keto-aldehyde 6 (104 mg, 0.590 mmol) in t-
BuOH (4.5 mL) was added thiazolium salt 1 (37.5 mg,
0.149 mmol), and the temperature was raised to 408C. To the
resulting suspension was added DBU (18.0 mg, 0.118 mmol)
in t-BuOH (1.5 mL) at this temperature, and stirring was con-
tinued for 2 h. The reaction mixture was poured into saturated
aqueous NH4Cl solution, and the products were extracted with
EtOAc (ꢁ3). The combined organic extracts were washed
with brine, dried (Na2SO4) and concentrated under vacuum.
The residue was purified by flash chromatography (hexane/
EtOAc¼72/28) to afford product 7 as a colorless oil; yield:
92.3 mg (89%); 1H NMR (CDCl3): d¼8.04 (d, 1H, J¼
8.0 Hz), 7.52 (dd, 1H, J¼7.7, 7.5 Hz), 7.35 (dd, 1H, J¼7.7,
8.0 Hz), 7.26 (d, 1H, J¼7.5 Hz), 3.87 (s, 1H), 2.97–3.18 (m,
2H), 2.17–2.31 (m, 2H), 1.40 (s, 3H); 13C NMR (CDCl3): d¼
201.8, 143.4, 134.0, 129.9, 129.0, 128.0, 126.9, 73.6, 35.8, 26.8,
23.9; IR (neat): n¼3489, 3066, 2972, 2933, 2864, 1689, 1603,
[9] Y. Hachisu, J. W. Bode, K. Suzuki, J. Am. Chem. Soc.
2003, 125, 8432.
[10] An extensive literature search has uncovered a single ex-
ample of a benzoin-type reaction employing ketone elec-
trophiles, namely the decarboxylative cyclization of 2,6-
dioxoheptanoic acid cited in: H. Dugas, Bioorganic
Chemistry, 3rd edn., Springer, New York, 1996, p. 568.
[11] We have made preliminary efforts to establish the role of
a retro-aldol-benzoin processes as a key pathway for the
apparent preference of intramolecular benzoin-type re-
actions over the corresponding aldol. So far, these ex-
periments have been inconclusive. For example, treat-
ment of aldol 5 under typical benzoin-forming reaction
conditions gave the elimination product (4%) and the re-
covered aldol adduct (94%).
1455, 1371, 1290, 1222, 1155, 1097, 971, 796, 742 cmꢀ1 [15]
.
[12] K. Jaworski, L. L. Smith, J. Org. Chem. 1988, 53, 545.
[13] P. Yates, S. Stiver, Can. J. Chem. 1987, 65, 2203.
[14] J. P. Richard, R. W. Nagorski, J. Am. Chem. Soc. 1999,
121, 4763.
Supplementary Information
General experimental conditions, preparation and characteri-
zation of compounds 4, 10, 12, 15, and 18.
´
[15] A. Solladie-Cavallo, O. Sedy, M. Salisova, M. Biba, C. J.
´
Welch, L. Nafie, T. Freedman, Tetrahedron: Asymmetry
2001, 12, 2703.
[16] After submission of this paper, we were informed of an
independent, related by Enders et al. [Synlett, submit-
ted]. We thank Professor Dieter Enders for the kind in-
formation.
Acknowledgements
Partial financial support by 21st Century COE program is grate-
fully acknowledged.
1100
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Adv. Synth. Catal. 2004, 346, 1097–1100