Asymmetric synthesis of chromanones via N-heterocyclic carbene catalyzed intramolecular crossed-benzoin reactions

Article abstract of DOI:10.1055/s-2006-950403

The enantioselective synthesis of 3-hydroxy-4-chromanones bearing a quaternary stereocenter via an N-heterocyclic carbene catalyzed intramolecular crossed-benzoin reaction is described. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-950403

LETTER
2431
Asymmetric Synthesis of Chromanones via N-Heterocyclic Carbene Catalyzed
Intramolecular Crossed-Benzoin Reactions
A
symmetric Synth
i
esis of
e
Chromanon
t
e
s
er Enders,* Oliver Niemeier, Gerhard Raabe
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany
Fax +49(241)8092127; E-mail: enders@rwth-aachen.de
Received 10 July 2006
4-chromanone derivative (S)-eucomol19 (4), we herein
report our studies on the catalytic asymmetric synthesis of
various 3-hydroxy-4-chromanones brought about by the
chiral triazolium salts 1–3 as pre-catalysts (Figure 1).
Abstract: The enantioselective synthesis of 3-hydroxy-4-chro-
manones bearing a quaternary stereocenter via an N-heterocyclic
carbene catalyzed intramolecular crossed-benzoin reaction is de-
scribed.
Key words: organocatalysis, N-heterocyclic carbenes, asymmetric
synthesis, benzoin reaction, chromanones
Ph
Ph
N+
Ph
N+ N
N+
N
.
.
N
–
N
BF4
–
BF4
.
–
Since the discovery of stable carbenes in the last decade
of the 20th century,1 N-heterocyclic carbenes have played
an important role in the rapidly growing area of organo-
catalysis.2 Beginning with the thiazolium unit of the co-
enzyme thiamine (vitamin B1) the enormous catalytic
potential of N-heterocyclic carbenes has enabled new
organic reactions such as conjugate nucleophilic acyla-
tions,3 transesterifications,4 polymerizations,5 b-alkyla-
tions,6 hydroacylations,7 trifluoromethylations,8 and sila-
Stetter reactions.9 Asymmetric variants of carbene-cata-
lyzed reactions such as the enantioselective benzoin con-
densation,10 the asymmetric intramolecular Stetter
reaction,11 and the enantioselective intermolecular alde-
hyde-imine cross-coupling12 exemplify their broad appli-
cability in asymmetric organocatalysis.
N
N
BF4
t-Bu
O
TIPSO
.
.
1
2
3
OH
O
OH
HO
O
4
OMe
Figure 1 Enantiopure pre-catalysts 1–3 and (S)-eucomol (4)
The sterically different pre-catalysts 1–3 were chosen in
order to adjust the catalyst system to the steric and elec-
tronic properties of the substrates 5. Therefore the alde-
hyde ketone 5a20 was investigated as a test substrate to
determine appropriate conditions that favor the desired
carbene-catalyzed cyclization to the chromanone 6a in
comparison to the base-catalyzed aldol condensation to
the 3-hydroxy benzofuran 7 (Scheme 1).
Intermolecular benzoin reactions are usually limited to the
synthesis of homobenzoins; recently, however, crossed
versions have been developed via cyanide- or phosphite-
catalyzed cross-silyl13 and enzyme-catalyzed14 reactions.
Concerning the intramolecular crossed-benzoin cycliza-
tions we15b and Suzuki et al.15a,c reported protocols utiliz-
ing commercial thiazolium salts as pre-catalysts to form
different five- and six-membered a-hydroxy ketones.
Enantioselective reactions of this type remained an un-
solved problem until 2006, when we published a break-
through with the first enantioselective intramolecular
crossed-benzoin reaction employing new chiral tetracy-
clic and pyroglutamic acid based triazolium salts 1 and 2
as pre-catalysts.16 a-Hydroxy tetralones were obtained
bearing a quaternary stereocenter17 with high yields and
excellent enantiomeric excesses of up to 98%.
Unfortunately, the conditions that successfully yielded a-
hydroxy tetralones with tetracyclic pre-catalyst 116a [t-
BuOK as base in THF (0.1 M) at r.t.] resulted in an almost
1:1 mixture of the desired chromanone 6a and the benzo-
furan 7, albeit accompanied by a high enantiomeric excess
of 91% (Table 1). A screening of the reaction conditions
indicated 10 mol% of the tetracyclic pre-catalyst 1 and
substoichiometric amounts of KHMDS (9 mol%) as base
at room temperature were suitable. A higher dilution (0.05
M) was also found to suppress the aldol reaction.
With the enantioselective intramolecular benzoin reaction
established as a synthetic tool, and in combination with
our efforts in the synthesis of bioactive natural products
bearing a quaternary a-hydroxy ketone unit,18 such as the
The ethyl-substituted chromanone 6a was obtained with a
high yield (90%) and an excellent asymmetric induction
of 91% ee, that could be further increased to 94% ee by
performing the reaction at 5 °C. Utilizing the TIPS-substi-
tuted triazolium salt 2 only the undesired aldol product
was obtained and the more bulky pre-catalyst 3 showed a
very low activity.
SYNLETT 2006, No. 15, pp 2431–2434
1
8
.0
9
.2
0
0
6
Advanced online publication: 08.09.2006
DOI: 10.1055/s-2006-950403; Art ID: G22906ST
© Georg Thieme Verlag Stuttgart · New York

2432
D. Enders et al.
LETTER
Table 1 Optimization of the Asymmetric Intramolecular Benzoin Reactiona
Entry
Pre-catalyst (mol%) Base (mol%)
Temp
r.t.
Time (h)
24
Yield of 6a (%) Yield of 7 (%) ee (%)b (configuration)c
1
2
3
4
5
6
7
8
1 (20)
1 (10)
1 (10)
1 (20)
1 (10)
1 (20)
2 (10)
3 (20)
t-BuOK (20)
t-BuOK (9)
DBU (9)
42d,e
81e
18
–
54e
19e
77
11e
2e
91 (S)
r.t.
48
91 (S)
r.t.
48
–
Et3N (20)
r.t.
96
–
KHMDS (9)
KHMDS (19)
KHMDS (9)
KHMDS (20)
r.t.
48
90
88
–
91 (S)
5 °C
r.t.
48
6e
94 (S)
16
90e
8e
–
–
r.t.
72
18
a Conditions: THF (0.05 M) and 5a.
b Determined by chiral stationary phase GC (Lipodex E).
c The absolute configuration was confirmed by X-ray analysis of the corresponding (S)-camphanyl ester of (S)-6a.21
d Reaction in THF (0.1 M).
e Conversion determined by GC.
hyde ketones 5c and 5d could be cyclized revealing a
broad tolerance of steric demand at the ketone function.
O
Et
OH
Activated substrates only required short reaction times
and could also be converted with the bulkier catalyst 3, re-
sulting in most cases in better inductions. 2,4-Dibromo-
substituted substrates 5e and 5f could be cyclized to the
corresponding chromanones in high yields with the tetra-
cyclic catalyst 1 at 0 °C, which were found to be the best
conditions with the isobutyl-substituted substrate 5f (92%
ee). In contrast the ethyl-substituted aldehyde ketone 5e
showed the best results with catalyst 3 at room tempera-
ture (86% ee). Even complete asymmetric induction could
be obtained utilizing the 2-nitro-substituted substrate 5g.
In this case the competing aldol reactions allowed only
moderate yields of the chromanone 6g (51%). These acti-
vated substrates enable the synthesis of both enantiomers,
as the pre-catalysts 1 and 3 generate enantiomeric config-
urations at the newly formed stereocenter.
O
O
(S)-6a
precat. 1–3,
O
Et
base, THF (0.05 M)
.
.
.
OH
O
Et
O
5a
O
7
Scheme 1 Optimization studies of the chromanone synthesis
(Table 1)
After the adjustment of the reaction parameters several al-
dehyde ketones 5a–i were transformed into the corre-
sponding 3-hydroxy-4-chromanones 6a–i (Scheme 2,
Table 2).
Utilizing 10 mol% tetracyclic catalyst 1 and substoichio-
metric amounts of KHMDS (9 mol%) in THF at room
temperature, the methyl-substituted chromanone 6b could
be obtained in a good yield (70%) and high enantiomeric
excess (90%). The asymmetric induction could be further
improved to 93% ee accompanied by a slightly decreased
yield by running the reaction at 5 °C and employing 20
mol% catalyst 1.
Sterically demanding functionalizations at the aromatic
part of substrates 5 caused much lower conversions with
pre-catalyst 1 even after long reaction times. The 2,4-di-
tert-butyl-substituted aldehyde ketone 5h showed a rather
low activity and chromanone 6h was obtained in only
30% yield accompanied by a reduced ee of 82%. By run-
ning the reaction at 45 °C the conversion could be im-
proved to 50% with a minimal decrease of the
enantiomeric excess (78%).
The increased steric demand at the ketone function of sub-
strates 5 resulted in an increase in the enantiomeric ex-
cesses up to 95% accompanied by moderate to good
yields. The isobutyl- and the cyclohexyl-substituted alde-
Furthermore the piperonyl-type aldehyde ketone 5i, bear-
ing a motif that can often be found in natural products,
was also used as a substrate in the intramolecular benzoin
reaction. Again higher temperatures were necessary to
yield the desired chromanone 6i with improved yields
(43%) and a satisfactory ee of 88%. The TIPS-substituted
catalyst 2 was tested with this highly functionalized sub-
strate too. Chromanone 6i could be synthesized at room
temperature with an improved yield of 61% but a signifi-
cant drop of the enantiomeric excess to 71%.
O
O
10 mol% precat. 1–3,
9 mol% KHMDS,
THF (0.05 M)
1
R2
OH
R2
O
2
3
R1
.
.
*
.
.
O
O
24–93%
4
R1
5a–i
6a–i
71–99% ee
Scheme 2 Scope of chromanones 6 (Table 2)
Synlett 2006, No. 15, 2431–2434 © Thieme Stuttgart · New York

LETTER
Asymmetric Synthesis of Chromanones
2433
Table 2 Scope of the Intramolecular Crossed-Benzoin Reaction of 5 to Yield Chromanones 622
Product 6 R1
R2
Precatalyst
Temp
5 °C
r.t.
Time (h)
48
Yield (%)
88c
70
ee (%)a (configuration)b
94 (S)
a
b
b
c
c
d
e
e
f
H
Et
1
1
1
1
1
1
1
3
1
3
1
3
1
1
1
1
2
H
Me
18
90 (S)
H
Me
5 °C
r.t.
48
62c
78d
46c
53c
92c
87c
93c
84c
54
93 (S)
H
i-Bu
i-Bu
c-Hex
Et
40
92 (S)
H
5 °C
r.t.
24
95 (S)
H
72
94 (S)
2,4-dibromo
2,4-dibromo
2,4-dibromo
2,4-dibromo
2-nitro
0 °C
r.t.
18
76 (S)
Et
18
86 (R)
i-Bu
i-Bu
i-Bu
i-Bu
Me
0 °C
5 °C
5 °C
5 °C
r.t.
24
92 (S)
f
24
81 (R)
g
g
h
h
i
19
89 (S)
2-nitro
65
51
99 (R)
2,4-di-t-Bu
2,4-di-t-Bu
2,3-methylenedioxo
2,3-methylenedioxo
2,3-methylenedioxo
65
30c
50c
24
82 (S)
Me
45 °C
r.t.
24
78 (S)
n-Pr
n-Pr
n-Pr
72
91 (S)
i
45 °C
r.t.
72
43c
61c
88 (S)
i
48
71 (S)
a Determined by chiral stationary phase GC (Lipodex E) or HPLC (Daicel Chiralpak AD).
b The absolute configuration was confirmed by X-ray analysis of the corresponding (S)-camphanyl esters of (S)-6a and (S)-6f.21
c Reaction with 20 mol% pre-catalyst and 19 mol% KHMDS.
d Reaction with 12 mol% pre-catalyst and 9 mol% KHMDS.
The absolute configuration of chromanone 6a and 6f was um salts as pre-catalysts enabled the adaptation of the cat-
assigned by X-ray analysis of the corresponding (S)-cam- alyst system to the steric and electronic demands of the
phanyl esters (Figure 2).21 Thus, the absolute configura- substrates. The application of our protocol in the organo-
tion of the quaternary stereocenter was determined to be S catalytic asymmetric synthesis of natural products bearing
utilizing pre-catalyst 1, which is in accordance with our this key structural motif, such as (S)-eucomol (4), is
postulated transition state.16a
currently in progress.
In conclusion we have developed an efficient N-hetero-
cyclic carbene catalyzed asymmetric intramolecular
crossed-benzoin reaction yielding the title 3-hydroxy-4-
chromanones. The application of three different triazoli-
Acknowledgment
This work was supported by the Deutsche Forschungsgemeinschaft
(Schwerpunktprogramm 1179 Organokatalyse) and the Fonds der
Chemischen Industrie. We thank Degussa AG, BASF AG, Bayer
AG, and Wacker Chemie for the donation of chemicals and Dr. C.
W. Lehmann, MPI Mülheim, for the X-ray data of 6f.
References and Notes
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Figure 2 X-ray structure of the (S)-camphanyl ester of (S)-6f
Synlett 2006, No. 15, 2431–2434 © Thieme Stuttgart · New York

2434
D. Enders et al.
LETTER
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a-bromo ketones in DMF at r.t.
(21) CCDC 607797 (6a) and CCDC 607796 (6f) contain the
supplementary crystallographic data for this paper. These
data can be obtained free of charge from the Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
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Enantioselective Intramolecular Crossed-Chromanone
Cyclization to 6a; Typical Procedure
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In a Schlenk tube under argon at r.t. the pre-catalyst 1 (39.0
mg, 0.104 mmol, 20 mol%) was suspended in anhyd THF
(9.5 mL). KHMDS (0.5 M in toluene; 198 mL, 0.099 mmol,
19 mol%) was added slowly, and the solution stirred for 15
min. The yellow solution was cooled to 5 °C and the
aldehyde ketone 5a (100 mg, 0.520 mmol) dissolved in
anhyd THF (1.0 mL) was added to the carbene solution. The
reaction mixture was stirred for 48 h, diluted with CH2Cl2,
quenched with H2O, extracted twice with CH2Cl2, and dried
over MgSO4. The solvent was evaporated and the crude
product was purified by flash chromatography on silica gel
(Et2O–n-pentane, 1:8) to yield 6a (88 mg, 88%) as a
colorless solid; mp 48 °C; ee 94% [determined by chiral
stationary phase GC (Lipodex E)]; [a]D23 –10.3 (c 1.2,
CHCl3). IR (KBr): 3853, 3742, 3482, 2973, 2361, 2340,
1837, 1690, 1610, 1558, 1465, 1382, 1311, 1215, 1134,
1021, 942, 862, 758, 670, 533. 1H NMR (300 MHz, CDCl3,
TMS): d = 0.95 (t, 3 H, J = 7.4 Hz, CH3), 1.81 (q, 2 H, J =
7.5 Hz, CH3CH2), 3.68 (s, 1 H, OH), 4.17 (d, 1 H, J = 11.4
Hz, CHH), 4.40 (d, 1 H, J = 11.4 Hz, CHH), 6.96–7.08 (m,
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2 H, Ar), 7.48–7.54 (m, 1 H, Ar), 7.86–7.89 (m, 1 H, Ar). 13
C
NMR (75 MHz, CDCl3): d = 6.8 (CH3), 27.6, 72.8 (CH2),
73.0 (C), 117.9 (CH), 118.4 (C), 127.5, 136.5 (CH), 161.4
(C), 196.8 (CO). MS (EI): m/z (%) = 192 (M+, 11), 122 (7),
121 [(M+ + 1) – 72, 100], 120 (11), 93 (7), 92 (18), 77 (5), 65
(6). Anal. Calcd for C11H12O3: C, 68.75; H, 6.29. Found: C,
68.69; H, 6.28.
Synlett 2006, No. 15, 2431–2434 © Thieme Stuttgart · New York