Diastereoselective synthesis of 3-hydroxyindanones via N-heterocyclic carbene catalyzed [4+1] annulation of phthalaldehyde and 1,2-diactivated Michael acceptors

Article abstract of DOI:10.1055/s-0030-1259707

The diastereoselective synthesis of 2,2-disubstituted-3-hydroxy-indanones was realized by the N-heterocyclic carbene catalyzed [4+1] annulation of phthalaldehyde and 1,2-diactivated Michael acceptors, which involves a tandem process of Stetter reaction, p

Full text of DOI:10.1055/s-0030-1259707

LETTER
1005
Diastereoselective Synthesis of 3-Hydroxyindanones via N-Heterocyclic
Carbene Catalyzed [4+1] Annulation of Phthalaldehyde and 1,2-Diactivated
Michael Acceptors
3
-Hydroxyind
a
n
HC-Cataly
g
ze
d
[4+1] An
-
nulationGang Sun, Song Ye*
Key Laboratory of Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences,
Beijing 100190, P. R. of China
Fax +86(10)62554449; E-mail: songye@iccas.a.cn
Received 17 November 2010
Dedicated to Professors Lixin Dai and Xiyan Lu for their inspiration and encouragement on my personal (S. Ye) career in organic
chemistry
when we try to expand the substrate to 1,2-diactivated
Abstract: The diastereoselective synthesis of 2,2-disubstituted-3-
Michael acceptors, the corresponding hydroxyindanone
was formed exclusively instead of hydroxytetralones
(Scheme 1, b). Here we wish to report the primitive results
of this tandem [4+1]-annulation reaction.
hydroxy-indanones was realized by the N-heterocyclic carbene cat-
alyzed [4+1] annulation of phthalaldehyde and 1,2-diactivated
Michael acceptors, which involves a tandem process of Stetter reac-
tion, proton shift, and aldol reaction.
Key words: [4+1] annulation, tandem reaction, N-heterocyclic car-
benes, indanone, Stetter reaction
O
COR
[4+2] annulation
(a)
COR
ref. 14
Indanones are presented widely in many natural and un-
natural bioactive compounds, various drugs and pharma-
ceutical candidates.1 Thus, many methods have been
developed for their construction,2 including the classic in-
tramolecular Friedel–Crafts acylation3 and Nazarov cy-
clization.4 In addition, many interesting approaches have
been reported in recent years, such as the Pd-catalyzed cy-
clization of 3-(2-iodoaryl)propanenitriles,5 Rh-catalyzed
[5+1+2+1] cycloaddition of vinylcyclopropane, alkynes,
and CO,6 Rh-catalyzed hydroacylation of 2-vinyl benzal-
dehyde,7 and other reactions.8
OH
hydroxytetralone
CHO
CHO
NHC
O
[4+1] annulation
this work
(b)
COPh
CO2Et
EtO2C
COPh
OH
hydroxyindanone
Scheme 1 NHC-catalyzed tandem reactions of phthalaldehyde and
Michael acceptors
As a subunit of indanones, 3-hydroxyindanones show in-
teresting bioactivity and are useful intermediates for or-
ganic synthesis.9 However, the efficient methods for rapid
construction of 3-hydroxyindanones are far less devel-
oped. There are only a few examples which synthesize 3-
hydroxyindanones from simple starting materials.10 Rep-
resentative examples include Hallberg et al.’s Heck–aldol
reaction of salicylic aldehydes with vinyl ether11 and Grée
et al.’s intramolecular isomerisation–aldolization of allyl-
ic alcohols.12
It was found that thiazolium NHC 4a¢, generated in situ
from thiazolium salt 4a in the presence of Cs2CO3, could
catalyze the reaction of phthalaldehyde (1) and 1,2-diacti-
vated Michael acceptor 2a to give the [4+1]-annulation
product of 3-hydroxyindanone 3a in 96% yield with ex-
clusive cis selectivity (Table 1, entry 1). It is interesting
that thiazolium salt 4b with N-ethyl substituent showed
similar catalytic activity with 4a, but salt 4c without a free
hydroxy group resulted in very low yield (entries 2 and 3).
Solvent screening revealed that reaction worked well in
THF, toluene, or dichloromethane but did not in diethyl
ether (Table 1, entries 1, 4–6). Base screening showed
K2CO3 and DBU worked as well as Cs2CO3 (Table 1, en-
tries 7–9).
Tandem reactions, which allow two or more reactions oc-
cur consecutively in one pot, are of great interest in mod-
ern synthesis.13 Recently, Gravel et al. reported a NHC-
catalyzed tandem Stetter–Michael reaction,14 and You et
al. reported a tandem aza-benzoin–Michael reaction with
interesting on-site reversal of the reactivity of N-Boc im-
ines.15,16 We reported a N-heterocyclic carbene (NHC)-
catalyzed tandem Stetter–aldol reaction of phthalaldehyde
and Michael acceptors to give hydroxytetralones as the
[4+2]-annulation products (Scheme 1, a).17 Interestingly,
With the optimized reaction conditions in hand, the scope
of the 1,2-diactivated Michael acceptors was briefly in-
vestigated (Table 2). Michael acceptors 2b,c with elec-
tron-withdrawing group (4-O2NC6H4, 4-ClC6H4) worked
much better than 2d,e with electron-donating group (4-
MeC6H4, 4-MeOC6H4) (Table 2, entries 1–5). Michael
acceptors 2f,g with bulky substituent (2-ClC6H4, 2-naph-
thyl) also worked well (Table 2, entries 6 and 7). Consid-
ering the low yield of reaction of Michael acceptors 2d,e
SYNLETT 2011, No. 7, pp 1005–1009
x
x.
x
x.
2
0
1
1
Advanced online publication: 08.03.2011
DOI: 10.1055/s-0030-1259707; Art ID: W32110ST
© Georg Thieme Verlag Stuttgart · New York

1006
F.-G. Sun, S. Ye
LETTER
Table 1 Optimization of Reaction Conditions
O
COPh
CHO
COPh
CO2Et
4, base
+
solvent, r.t.
CHO
1 (1.5 equiv)
CO2Et
OH
2a
3a
R2
N+
4a R1 = HO(CH2)2, R2 = Bn, X = Cl
X–
4b R1 = HO(CH2)2, R2 = Et, X = I
4c R1 = Me, R2 = Bn, X = Cl
S
R1
Entry
4
Base (mol%)a
Cs2CO3 (20)
Cs2CO3 (20)
Cs2CO3 (20)
Cs2CO3 (20)
Cs2CO3 (20)
Cs2CO3 (20)
Cs2CO3 (10)
K2CO3 (10)
DBU (10)
Solvent
THF
Yield (%)b
1
2
3
4
5
6
7
8
9
4a
4b
4c
4a
4a
4a
4a
4a
4a
96
95
20
89
94
24
95
94
95
Figure 1 X-ray crystal structure of hydroxyindanone 3a
THF
THF
The cis stereochemistry of hydroxyindanone 3a was un-
ambiguously assigned by the X-ray analysis of its crystal
(Figure 1). It is worthwhile to note that only cis isomer of
the hydroxyindanone was detected for all the reactions ex-
amined in Table 2.
toluene
CH2Cl2
Et2O
The resulted highly functionalized indanones offer oppor-
tunities for further chemical transformations. For exam-
ple, indanone 6a could be prepared smoothly from
hydroxyindanone 3a via a two-step dehydroxy process
(Scheme 2).
THF
THF
THF
a The NHC 4¢ was generated from the corresponding thiazolium salt 4
in situ in the presence of the noted base.
O
O
b Isolated yields of pure cis isomer of 3a. No trans-3a was detected.
ClCOCO2Et
DMAP
COPh
CO2Et
OCOCO2Et
COPh
CO2Et
CH2Cl2, r.t.
90%
with an electron-rich aryl group, it is better than expected
that Michael acceptors with 2-furyl and 2-thienyl gave the
corresponding hydroxyindanone in very good yields (en-
tries 8 and 9). Michael acceptor 2j with diketo group also
showed good reactivity (entry 10). The spirocyclic hy-
droxyindanone 3k could be obtained in reasonable yield
(46%) when N-phenylmaleimide was used as the substrate
(Table 2, entry 11).
OH
3a
5a
O
COPh
Bu3SnH, AIBN
CO2Et
toluene, 75 °C
66%
6a
Scheme 2 Synthesis of indanone 6a from hydroxyindanone 3a
Table 2 Synthesis of 3-Hydroxyindanones via NHC-Catalyzed Tandem Reaction of Phthalaldehyde and Michael Acceptors 2
O
Z2
4a, Cs2CO3
(10 mol%)
CHO
Z1
Z2
+
THF, r.t.
CHO
Z1
OH
1 (1.5 equiv)
3
2
Z1, Z2 = electron-withdrawing group
Entry
2
3
Yield (%)a
X
O
O
O
EtO2C
1
95
CO2Et
OH
X
2a X = H
3a X = H
2
3
2b X = NO2
2c X = Cl
3b X = NO2
97
95
3c X = Cl
Synlett 2011, No. 7, 1005–1009 © Thieme Stuttgart · New York

LETTER
3-Hydroxyindanones via NHC-Catalyzed [4+1] Annulation
1007
Table 2 Synthesis of 3-Hydroxyindanones via NHC-Catalyzed Tandem Reaction of Phthalaldehyde and Michael Acceptors 2 (continued)
O
Z2
4a, Cs2CO3
(10 mol%)
CHO
Z1
Z2
+
THF, r.t.
CHO
Z1
OH
1 (1.5 equiv)
3
2
Z1, Z2 = electron-withdrawing group
Entry
2
3
Yield (%)a
4
5
2d X = Me
3d X = Me
3e X = OMe
58
50
2e X = OMe
Cl
O
Cl
O
O
EtO2C
6
92
CO2Et
2f
OH
3f
O
O
O
7
8
EtO2C
93
98
CO2Et
OH
2g
3g
X
O
O
O
X
EtO2C
CO2Et
OH
2h X = O
2i X = S
3h X = O
3i X = S
9
95
65
O
Ph
O
O
Ph
10
Ph
COPh
OH
O
2j
3j
O
N
O
O
N
O
11
46
O
OH
2k
3k
a Isolated yields of pure cis isomer of 3 and no trans-3 was detected for all entries.
A possible catalytic cycle of this NHC-catalyzed [4+1]- proton shift occurs to provide another zwitterionic C
annulation reaction is depicted in Scheme 3. The addition which is stabilized by the additional electron-withdrawing
of NHC to phthalaldehyde gives the Breslow intermediate group (Z2), hydroxy and thiazolium group. The intramo-
A, which reacts with Michael acceptor 2 affording zwitte- lecular aldol reaction and fragmentation of intermediate C
rion B. As we reported previously, zwitterion B reacts via affords final [4+1]-annulation product of hydroxyin-
an intramolecular aldol reaction to give [4+2]-annulation danone and regenerates the N-heterocyclic carbene.18
product if no additional withdrawing group is installed in
In conclusion, the synthesis of 2,2-disubstituted 3-hy-
the Michael acceptor (Z2 = H). However, when the addi-
droxyindanones was realized by a NHC-catalyzed tandem
tional withdrawing group is present in the b-position of
reaction of phthalaldehyde and 1,2-diactivated Michael
the Michael acceptor (Z2 = electron-withdrawing group),
acceptors. The additional electron-withdrawing group in
Synlett 2011, No. 7, 1005–1009 © Thieme Stuttgart · New York

1008
F.-G. Sun, S. Ye
LETTER
Supporting Information for this article is available online at
O
CHO
http://www.thieme-connect.com/ejournals/toc/synlett.
Z1
Z2
CHO
N
••
NHC
S
Me
1
OH
Acknowledgment
3
Financial support from National Natural Science Foundation of
China (No. 21072195, 20932008) and the Chinese Academy of Sci-
ences is gratefully acknowledged.
aldol reaction
O
CHO
Z1
OH
S
–
Z2
S
Me
References and Notes
HO
Me
proton shift
N
N
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A
O
stetter reaction
Z1
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C
–
Z2
S
HO
2
N+
Me
B
Z2 = H – NHC
OH
Z1
O
Z1, Z2 = electron-withdrawing group
Scheme 3 Proposed catalytic cycle
the Michael acceptor facilitates the proton shift of the in-
termediate of the Stetter reaction and thus results in a
[4+1]-annulation product. This tandem reaction features
several advantages, including exclusive cis diastereose-
lectivity, readily available starting materials, and catalyst,
and construction of two C–C bonds in one pot, which
makes it potentially useful for the synthesis of the 3-hy-
droxyindanones.
Typical Procedure of the NHC-Catalyzed [4+1] Annulation
To an oven-dried 50 mL Schlenk tube equipped with a stir bar was
charged with thiazolium salt 4a (12.7 mg, 0.047 mmol) and phthal-
aldehyde (94.9 mg, 0.71 mmol). The tube was closed with a septum,
evacuated, and back-filled with argon. To this mixture was added
solvent THF (4.7 mL) and Michael acceptor 2a (96.3 mg, 0.47
mmol). Then, Cs2CO3 (15.4 mg, 0.047 mmol) was added to the
tube. The mixture was further stirred overnight, then diluted with
EtOAc and passed through a short silica pad. The solvent was re-
moved under reduced pressure, and the residue was purified by
chromatography on silica gel (EtOAc–PE, 1:3) to give 151.6 mg
(95%) of hydroxyindanone 3a as a white solid; Rf = 0.22 (PE–
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Synlett 2011, No. 7, 1005–1009 © Thieme Stuttgart · New York

LETTER
3-Hydroxyindanones via NHC-Catalyzed [4+1] Annulation
1009
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