Thiazol-2-ylidene catalysis in intramolecular crossed aldehyde-ketone benzoin reactions

Article abstract of DOI:10.1055/s-2004-831306

Intramolecular crossed aldehyde-ketone benzoin-type reactions catalyzed by nucleophilic carbenes, easily generated from commercially available thiazolium salts as precatalysts, are described. Five- and six-membered cyclic acyloins are obtained in moderate to good yields. Depending on the structure of the aldehyde-ketone substrate, an interchange of the alcohol and ketone function of the resulting acyloin is possible. Simple aldehyde-ketones are not good substrates due to the competing intermolecular reaction. Starting from biphenyl-2,2′-dicarbaldehyde, the intermediate acyloin is converted to 9,10-phenanthrenequinone by mild air oxidation.

Full text of DOI:10.1055/s-2004-831306

LETTER
2111
Thiazol-2-ylidene Catalysis in Intramolecular Crossed Aldehyde-Ketone
Benzoin Reactions
I
ntramolecular Cro
i
ssed A
e
ldehyde-K
e
t
tone
B
e
e
nzoin Re
a
r
ctions Enders,* Oliver Niemeier
Institut für Organische Chemie, Rheinisch-Westfälische Technische Hochschule Aachen, Professor-Pirlet-Str. 1, 52074 Aachen, Germany
Fax +49(241)8092127; E-mail: Enders@RWTH-Aachen.de
Received 15 June 2004
Based on our experience with intermolecular benzoin
Abstract: Intramolecular crossed aldehyde-ketone benzoin-type
condensations and the breakthrough of Suzuki et al. we
envisaged to enlarge the scope of the intramolecular ben-
zoin-type reactions by using simple aldehyde-ketones as
reactions catalyzed by nucleophilic carbenes, easily generated from
commercially available thiazolium salts as precatalysts, are de-
scribed. Five- and six-membered cyclic acyloins are obtained in
moderate to good yields. Depending on the structure of the alde- substrates. Our initial efforts centered on aromatic alde-
hyde-ketone substrate, an interchange of the alcohol and ketone
function of the resulting acyloin is possible. Simple aldehyde-ke-
tones are not good substrates due to the competing intermolecular
sizes, in particular five- and six-membered rings. Further-
reaction. Starting from biphenyl-2,2¢-dicarbaldehyde, the interme-
diate acyloin is converted to 9,10-phenanthrenequinone by mild air
hyde-aliphatic ketones of type A and their conversion to
benzanellated cyclic acyloins of type B with diverse ring-
more, aliphatic aldehydes-aromatic ketones of type C
could serve as substrates to yield acyloins D, with inter-
changed alcohol and ketone functionality (Scheme 1). In
addition, we selected even simpler aldehyde-ketones,
lacking an attached benzene ring, as potential substrates
for intramolecular acyloin forming reactions.
oxidation.
Key words: organocatalysis, acyloins, carbenes, thiazolium salts,
keto-aldehydes
The coenzyme thiamine (vitamin B1) is a natural thiazoli-
um salt involved in enzymatic catalysis, e.g. nucleophilic
acylation. Considerable efforts to mimic the active cata-
lytic site, a nucleophilic carbene, have been undertaken.
Common catalytic reactions with inversion of the carbon-
yl polarity1 (Umpolung) are the benzoin2 and the Stetter
reaction.3 Enantioselective versions of these N-heterocy-
clic carbene-catalyzed reactions between aldehydes and
other aldehydes4 or a,b-unsaturated carbonyl compounds5
have been developed recently.6
O
O
CH3
OH
O
CH3
n
n
A
B
.
.
O
HO
R
O
O
R
C
D
In 2002 we published our results regarding asymmetric
benzoin condensations performed in an intermolecular
fashion using a bicyclic triazolium salt as catalyst precur-
sor.4e Benzoin was obtained in good yield (83%) and with
the best enantioselectivity reported so far (ee = 90%).
Various other aromatic aldehydes were screened and pro-
vided the corresponding a-hydroxy ketones in good yields
with excellent enantiomeric excesses of up to 99%.
Scheme 1 General routes of intramolecular crossed aldehyde-
ketone benzoin-type condensations.
Firstly, several aldehyde-ketones 5–8 were synthesized by
ozonolysis of the corresponding cyclic olefins 1–4 in
moderate yields (Scheme 2, Table 1).9,10
R1
O
In marked contrast, there are only few precedents of in-
tramolecular benzoin reactions reported in the literature.7
Until very recently ketones could not be used as electro-
philes in nonenzymatic benzoin-type reactions. In 2003
Suzuki et al. reported such an intramolecular crossed ben-
zoin condensation starting from special aldehyde-ketones
in their synthesis of functionalized preanthraquinones and
employing a commercially available thiazolium salt as
catalyst precursor.8
R2
a, b
R1
.
R2
.
n
n
O
1 – 4
5 – 8
Scheme 2 Reagents and conditions: (a) MeOH, O3, –78 °C; (b)
DMS (4.0 equiv), 24 h, r.t.
Initially, we examined the formation of six-membered
ring acyloins resulting from an aromatic aldehyde and an
aliphatic ketone. It was anticipated, as benzaldehyde is
known to form a Breslow-intermediate with the activated
thiazolium salt,11 that this combination would be the most
promising one. We were pleased to find that the reaction
SYNLETT 2004, No. 12, pp 2111–2114
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1
.1
0
.2
0
0
4
Advanced online publication: 26.08.2004
DOI: 10.1055/s-2004-831306; Art ID: G21004ST
© Georg Thieme Verlag Stuttgart · New York

2112
D. Enders, O. Niemeier
LETTER
Table 1 Ozonolysis of Aromatic Cycloalkenes
Aldehyde-Ketone R1
plained by the increase of the steric bulk due to the phenyl
substituent. Changes made in the reaction conditions,
such as the use of DBU as base in a stoichiometric amount
and t-BuOH as solvent, gave a slightly lower yield (26%)
accompanied with a shorter reaction time of three hours
(Scheme 4, Table 3).
Entry Substrate
R2
Yield (%)
1
2
3
4
1 (n = 0)
2 (n = 1)
3 (n = 1)
4 (n = 1)
5
6
7
8
H
CH3 48
CH3 45
H
CH3
Ph
H
H
27
28
O
HO
R
O
O
a
R
.
.
with keto-aldehyde 5 proceeded in good yield (69%) lead-
ing to the a-hydroxy ketone 9.12 An excess of Et3N as base
(40 mol%) was used in order to allow a quantitative con-
version of the thiazolium salt 11 (20 mol%) to the active
12, R = CH3
13, R = Ph
7, R = CH3
8, R = Ph
Scheme 4 Reagents and conditions: (a) Base, 20 mol% 11, solvent
thiazol-2-ylidene catalyst. A concentration of 0.1 M of the (0.1 M), 60 °C.
substrate was chosen in order to favor an intramolecular
reaction over the competing intermolecular reaction.13,14
Table 3 Aldehyde-Ketones of Type C as Substrates
Moreover, five-membered ring formation was achieved
with aldehyde-ketone 6 to yield the acyloin 10 (Scheme 3,
Table 2). The initially low yield with DMF as solvent and
Et3N as base (18%) could be optimized by employing t-
BuOH as solvent (41%). The use of DBU as base also
generated acyloin 10, but with significantly lower yield.
Entry Substrate Base (mol%) Solvent
Time (h) Yield (%)a
1
2
3
7
8
8
Et3N (40)
Et3N (40)
DBU (20)
DMF
24
24
3
12: 47 (79)
13: 28 (76)
13: 26b (50)
DMF
t-BuOH
a Yield determined by GC is shown in parentheses.
b Reaction at 40 °C.
O
O
CH3
OH
O
CH3
a
The same reaction conditions as used before leading to
short reaction times (t-BuOH, DBU) were employed to
other simple aldehyde-ketones 14 and 15. These sub-
strates cannot lead to the obviously favorable benzannela-
tion in the resulting acyloins. The formation of the desired
acyloins could only be observed in moderate yield in the
case of the methyl-substituted aldehyde-ketone 14 (28%).
The competing intermolecular benzoin products 18 and
19 could also be isolated. The application of the benzyl-
substituted thiazolium salt 20 as precatalyst, which afford-
ed better results with aliphatic aldehydes in the intermo-
lecular benzoin reaction,3,16 gave a slightly higher yield in
both products with aldehyde-ketone 14. The phenyl sub-
stituted substrate 15 again led only to the formation of the
intermolecular product 19 (54%, Scheme 5, Table 4).
.
.
n
n
H3C
5, n = 1
6, n = 0
9, n = 1
10, n = 0
H3C
N
S
HO
Br
11
Scheme 3 Reagents and conditions: (a) 40 mol% base, 20 mol% 11,
solvent (0.1 M), 60 °C.
Table 2 Aldehyde-Ketones of Type A as Substrates
Entry Substrate
Base
Et3N
Et3N
Et3N
DBU
DBU
Solvent
DMF
Time (h) Yield (%)a
1
2
3
4
5
5 (n = 1)
6 (n = 0)
6 (n = 0)
6 (n = 0)
6 (n = 0)
96
24
24
24
24
9: 69 (92)
10: 18 (43)
10: 41 (56)
10: 35
DMF
t-BuOH
DMF
O
O
O
O
R
O
R
a
R
OH
.
+
R
4
.
4
t-BuOH
10: 20
OH
O
a Yield determined by GC is shown in parentheses.
16, R = CH3
17, R = Ph
18, R = CH3
19, R = Ph
.
14, R = CH3
.
15, R = Ph
H3C
Encouraged by these results, we examined the suitability
of substrates with aromatic ketones and aliphatic alde-
hydes as substrates. The aldehyde-ketone 7 under previ-
ously performed conditions gave rise to the acyloin 12 in
a moderate yield (47%). Under similar conditions the phe-
nyl-substituted acyloin 13 was formed with significantly
lower yield (28%) starting from 8.15 This may be ex-
Ph
N
HO
Cl
S
20
Scheme 5 Reagents and conditions: (a) 20 mol% DBU, 20 mol% 11
or 20, t-BuOH (0.1 M), 40 °C, 3 h.
Synlett 2004, No. 12, 2111–2114 © Thieme Stuttgart · New York

LETTER
Intramolecular Crossed Aldehyde-Ketone Benzoin Reactions
2113
Table 4 Aliphatic Aldehyde-Ketones 14 and 15 as Substrates
employing commercially available thiazolium salts as
precatalysts. The optimization and extension as well as an
enantioselective version of this versatile carbon-carbon
bond forming reaction is under investigation in our labo-
ratories.19
Entry Substrate Catalyst Yield of the intra- Yield of the inter-
molecular products molecular products
16 and 17 (%)
18 and 19 (%)
1
2
3
4
14
14
15
15
11
20
11
20
28 (16)
11 (18)
32 (16)
20 (18)
Acknowledgment
–
–
40 (19)
We thank the the Fonds der Chemischen Industrie for financial sup-
port and the companies BASF AG and BAYER AG for the donation
of chemicals.
54 (19)
During our investigation to synthezise conformationally
less flexible aldehyde-ketones, another substrate was test-
ed for its applicability. The aromatic dialdehyde 22, ob-
tained by ozonolysis of phenanthrene (21)17, showed
almost complete conversion (90%) with Et3N as base (40
mol%) and DMF as solvent utilizing the thiazolium salt
11 as precatalyst. The obtained yellow solid turned out not
to be the expected acyloin 23 but 9,10-phenanthrene-
quinone (24). The a-hydroxy ketone 23 is only an inter-
mediate and undergoes air oxidation to the quinone 24
during work up.18 Optimization of the reaction conditions
revealed quantitative conversion to quinone 24 with DBU
as base (30 mol%) and t-BuOH as solvent at 60 °C
(Scheme 6, Table 5). In both cases the reaction time was
significantly shorter than the one observed with the alde-
hyde-ketones. No further conversion could be monitored
by TLC after a few minutes. Thus, this reaction consti-
tutes a C-C-connective ortho-quinone synthesis under
very mild conditions.
References
(1) (a) Short review: Johnson, J. S. Angew. Chem. Int. Ed. 2004,
43, 1326; Angew. Chem. 2004, 116, 1348. (b) Linghu, X.;
Potnick, J. R.; Johnson, J. S. J. Am. Chem. Soc. 2004, 126,
3070.
(2) Ide, W. S.; Buck, J. S. Org. React. 1948, 4, 269.
(3) Stetter, H.; Kuhlmann, H. Org. React. 1991, 40, 407.
(4) (a) Enders, D.; Breuer, K.; Teles, J. H. Helv. Chim. Acta
1996, 79, 1217. (b) Enders, D.; Breuer, K. Comprehensive
Asymmetric Catalysis, Vol. 3; Jacobsen, E. N.; Pfaltz, A.;
Yamamoto, H., Eds.; Springer: Berlin, 1999, 1093.
(c) Teles, H. J.; Breuer, K.; Enders, D. Synth. Commun.
1999, 29, 1. (d) Knight, R. L.; Leeper, F. J. J. Chem. Soc.,
Perkin Trans. 1 1998, 1891. (e) Enders, D.; Kallfass, U.
Angew. Chem. Int. Ed. 2002, 41, 1743; Angew. Chem. 2002,
114, 1822.
(5) (a) Enders, D. Stereoselective Synthesis; Ottow, E.;
Schöllkopf, K.; Schulz, B.-G., Eds.; Springer: Heidelberg,
1994, 63. (b) Enders, D.; Breuer, K.; Runsink, J.; Teles, J. H.
Helv. Chim. Acta 1996, 79, 1899. (c) Kerr, M. S.; de Alaniz,
J. R.; Rovis, T. J. Am. Chem. Soc. 2002, 124, 10298.
(d) Kerr, M. S.; Rovis, T. Synlett 2003, 1934.
O
(6) Review: Enders, D.; Balensiefer, T. Acc. Chem. Res. 2004,
in press.
(7) See for example: Cookson, R. C.; Lane, R. M. J. Chem. Soc.,
Chem. Commun. 1976, 804.
(8) Hachisu, Y.; Bode, J. W.; Suzuki, K. J. Am. Chem. Soc.
2003, 125, 8432.
O
O
OH
c
90–100%
22
23
O2 (air)
(9) General Procedure for the Preparation of the Aldehyde-
Ketones: The corresponding cycloalkene (in some cases,
synthesized by Grignard reaction performed on the
corresponding ketone and subsequent dehydration of the
resulting alcohol )10 was dissolved in MeOH (5 mL/mmol),
placed in an ozonolysis apparatus and flushed with argon.
The solution was cooled to –78 °C and the ozonolysis was
carried out until the color turned blue. After flushing with
argon the solution was transferred to a round-bottomed flask
and DMS (4.0 equiv) was added. The mixture was gradually
warmed to r.t. and stirred for 24 h. The solution was
concentrated, diluted with CH2Cl2, washed with H2O, dried
over MgSO4 and concentrated under reduced pressure.
Purification by flash column chromatography (silica gel,
Et2O–pentane) afforded the aldehyde-ketone.
a, b 70%
.
.
O
O
63–70%
21
24
Scheme 6 Reagents and conditions: (a) MeOH, O3, –30 °C; (b) KI–
HOAc, r.t., 1 h; (c) base, 20 mol% 11, solvent (0.1 M), 60 °C, 24 h
Table 5 Synthesis of 9,10-Phenanthrenequinone (24)
(10) Zubaidha, P. K.; Chavan, S. P.; Racherla, U. S.; Ayyangar,
N. R. Tetrahedron 1991, 47, 5759.
Entry
Base (mol%)
Et3N (40)
Solvent
DMF
Yield (%)
90
(11) Breslow, R. J. Am. Chem. Soc. 1958, 80, 3719.
(12) General Procedure for the Intramolecular Aldehyde-
Ketone Condensation: Catalyst, solvent and the appropiate
aldehyde-ketone were placed under argon atmosphere in a
round-bottomed flask with reflux condenser and heated at
60 °C. Upon completion of the addition of the base the
solution was stirred at this temperature and the reaction
progress was monitored by TLC. The reaction mixture was
1
2
DBU (30)
t-BuOH
100
In conclusion, we succeeded in developing an intramolec-
ular crossed aldehyde-ketone benzoin reaction as an entry
to a variety of five- and six-membered cyclic acyloins,
Synlett 2004, No. 12, 2111–2114 © Thieme Stuttgart · New York

2114
D. Enders, O. Niemeier
LETTER
then poured into H2O, extracted twice with CH2Cl2, dried
over MgSO4 and concentrated under reduced pressure. The
residue was purified by flash chromatography (silica gel,
Et2O–pentane).
4.76 (s, 1 H, OH), 7.01–7.05 (m, 2 H, ArH), 7.18–7.43 (m, 6
H, ArH), 7.79 (m, 1 H, ArH). 13C NMR (75 MHz, CDCl3):
d = 27.40, 33.38, 81.13, 127.00, 127.39, 127.50, 128.33,
128.48, 128.80, 135,94, 138.11, 139.77, 210.15. MS (EI):
m/z (%) = 238 (17), 220 (13), 219 (7), 133 (13), 119 (6), 118
(60), 106 (8), 105 (100), 91 (5), 90 (18), 89 (7), 77 (16).
Anal. Calcd for C16H14O2: C, 80.65; H, 5.92. Found: C,
80.35; H, 6.13.
(13) 2-Hydroxy-2-methyl-3,4-dihydro-2H-naphthalin-1-one(9):
1H NMR (300 MHz, CDCl3): d = 1.41 (s, 3 H, CH3), 2.26 (m,
2 H, CH2), 3.07 (m, 2 H, CH2), 3.91 (s, br, 1 H, OH), 7.25–
8.07 (m, 4 H, ArH). 13C NMR (75 MHz, CDCl3): d = 23.89,
26.81, 35.88, 73.58, 126.88, 128.00, 128.99, 134.05, 129.93,
143.40, 201.75. The spectroscopic data were in accordance
with those reported in the literature.14
(14) Solladié, A.; Sedy, O.; Salisova, M.; Biba, M.; Welch, C. J.;
Nafié, L.; Freedman, T. Tetrahedron: Asymmetry 2001, 12,
2703.
(15) 1-Hydroxy-1-phenyl-3,4-dihydro-1H-naphthalin-2-one(13):
Mp 89 °C. IR: 3469, 3062, 3025, 2948, 2913, 2857, 1962,
1917, 1716, 1601, 1487, 1449, 1402, 1353, 1282, 1215,
1174, 1143, 1055, 980, 931, 914, 873, 836, 758, 701, 630,
593, 554, 505 cm–1. 1H NMR (300 MHz, CDCl3): d = 2.57
(m, 1 H, CHH), 2.74 (m, 1 H, CHH), 2.85 (m, 2 H, CH2),
(16) Stetter, H.; Rämsch, R. Y.; Kuhlmann, H. Synthesis 1976,
733.
(17) Bailey, P. S.; Erickson, R. E. Org. Synth. 1961, 41, 41.
(18) (a) Methoden der Organischen Chemie (Houben Weyl), 4th
ed., Vol. VII/3b; Thieme: Stuttgart, 1979, 90. (b) Mayer, F.
Chem. Ber. 1912, 45, 1105. (c) Dallacker, F.; Leidig, M.
Chem. Ber. 1979, 112, 2672.
(19) When our work was finished (O. Niemeier diploma work,
RWTH Aachen, March 2004) we became aware of a parallel
and independent investigation by K. Suzuki et al. (Adv.
Synth. Cat. 2004, 346, in press).
Synlett 2004, No. 12, 2111–2114 © Thieme Stuttgart · New York