Synthesis of spiro bis-indanes via domino Stetter-aldol-Michael and Stetter-aldol-aldol reactions: Scope and limitations

Article abstract of DOI:10.1055/s-0030-1260031

The synthesis of spiro bis-indanes by means of N-heterocyclic carbene (NHC) catalysis is reported. The dimerization of various o-formylchalcone substrates or their combination with phthaldialdehyde derivatives under the catalysis of thiazolium-derived carbenes afforded Stetter-aldol-Michael products and Stetter-aldol-aldol products, respectively. The use of poor Michael acceptors in conjunction with an N-alkyltriazolium-derived catalyst furnished a variety of dibenzo[8]annulene products. This work highlights the interplay of a variety of factors affecting competing pathways in NHC-catalyzed domino reactions. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1260031

1896
PAPER
Synthesis of Spiro Bis-Indanes via Domino Stetter–Aldol–Michael and
Stetter–Aldol–Aldol Reactions: Scope and Limitations
N
HC-Catalyzed
d
Spir
o
Bis-In
u
dane Synthe
a
sis rdo Sánchez-Larios, Janice M. Holmes, Crystal L. Daschner, Michel Gravel*
Department of Chemistry, University of Saskatchewan, 110 Science Place, Saskatoon, SK, S7N 5C9, Canada
Fax +1(306)9664730; E-mail: michel.gravel@usask.ca
Received 16 March 2011
tion. The postulated mechanistic rationale for the
formation of 9a is similar to that of the synthesis of in-
danes (Scheme 2b). Once the acyl anion equivalent I is
generated,6 it attacks the electron-poor olefin portion of a
Abstract: The synthesis of spiro bis-indanes by means of N-hetero-
cyclic carbene (NHC) catalysis is reported. The dimerization of var-
ious o-formylchalcone substrates or their combination with
phthaldialdehyde derivatives under the catalysis of thiazolium-
derived carbenes afforded Stetter–aldol–Michael products and second equivalent of 6a leading to the formation of the
Stetter–aldol–aldol products, respectively. The use of poor Michael
acceptors in conjunction with an N-alkyltriazolium-derived catalyst
furnished a variety of dibenzo[8]annulene products. This work
termediate III. Under the basic reaction conditions, ke-
highlights the interplay of a variety of factors affecting competing
pathways in NHC-catalyzed domino reactions.
enolate intermediate II. An aldol reaction then takes
place,7 along with elimination of the catalyst to furnish in-
tone III is deprotonated to form enolate intermediate IV,
which cyclizes to 10a. Finally, dehydration of this inter-
Key words: NHC, organocatalysis, Stetter, umpolung, domino re-
mediate affords the spiro bis-indane product 9a.
actions, Michael, aldol
In late 2010, we disclosed this highly efficient synthesis of
spiro bis-indanes.8 This work began with studies aimed at
finding the optimal reaction conditions and scope of the
In recent years, N-heterocyclic carbene (NHC)-catalyzed
reactions have been the subject of intensive research.1 In
2009, our group reported the diastereoselective synthesis
of indanes via a domino2 Stetter–Michael reaction.3,4 We
proposed that this reaction proceeds through the addition
of an acyl anion equivalent derived from 1 onto an elec-
tron-poor olefin 2, which generates an enolate intermedi-
ate 3 in situ. Subsequently, the enolate in 3 is trapped
intramolecularly by a second electron-poor olefin to fur-
nish the desired indane 4 (Scheme 1).
Stetter–aldol–Michael (SAM) reaction (Table 1). The
first step consisted in screening the main families of
NHCs (not shown), of which thiazolium salt 11 gave the
best results at 30 mol% loading. In order to achieve the
best yield and diastereocontrol in this transformation, we
surveyed various bases and found 1,8-diazabicyc-
lo[5.4.0]undec-7-ene (DBU) to be optimum (Table 1, en-
tries 1–5). Using this base, the catalyst loading could be
reduced to 10 mol% without significantly affecting the
yield or selectivity (entry 6). Having set the optimized
conditions, the scope of the reaction was then studied. In
general, aromatic ketone acceptors give excellent yield
and diastereoselectivity (entries 6–8). Whereas electron-
withdrawing groups on the aromatic ring provide a faster
reaction and a decreased diastereomeric ratio, electron-
donating substituents result in a slower and incomplete re-
action, albeit with an improved diastereomeric ratio (en-
tries 7, 8). We attribute the effect of the aromatic
substituent on the diastereomeric ratio to a retro-Michael
reaction that reduces the initially high diastereomeric ratio
observed.8 The reactivity of aryl ketone substrates is also
greatly influenced by the type and position of the substit-
Following the success of this indane synthesis, we became
interested in the application of this concept towards the
synthesis of benzo[b]furans 7 via a domino acyloin–oxa-
Michael reaction and isoindolines 8 via a domino aza-
acyloin–aza-Michael reaction (Scheme 2a).5 At the outset
of our studies, we investigated both domino processes by
employing furfural (5) and o-formylchalcone 6a. Unfortu-
nately, neither product 7 nor 8 were obtained. More inter-
estingly, we obtained a complex spirocyclic structure 9a,
which is derived from two equivalents of 6a. This exciting
discovery allows the formation of three new carbon–car-
bon bonds and a quaternary center in one synthetic opera-
O
COAr2
O
Ar2
Ar3
O
Ar2
Ar3
NHC
base
COAr3
+
Ar1
H
COAr1
4
O–
Ar1
O
O
1
3
2
Scheme 1 NHC-catalyzed diastereoselective synthesis of indanes via a domino Stetter–Michael reaction
SYNTHESIS 2011, No. 12, pp 1896–1904
x
x.
x
x
.
2
0
1
1
Advanced online publication: 06.05.2011
DOI: 10.1055/s-0030-1260031; Art ID: C29911SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
NHC-Catalyzed Spiro Bis-Indane Synthesis
1897
uent (R1) incorporated on the left portion of the acceptor 6 ond aldol ring-closing step. In order to test our hypothesis,
(entries 9–12). The picture emerging from these results is we performed a model reaction employing o-phthaldial-
that electron-withdrawing groups (relative to the alde- dehyde (12a) and o-formylchalcone 6a that smoothly fur-
hyde) accelerate the reaction. Particularly interesting are nished SAA product 13. Unfortunately, the product was
the results from entries 6 and 11 which show a faster reac- obtained as an inseparable 1:1 mixture of diastereomers.
tion in the case of p-methoxy-substituted chalcone 6f. Therefore, we decided to oxidize the diastereomeric mix-
These observations support the notion that formation of ture of alcohols to a single diketone 14 in order to facili-
the Breslow intermediate I is slower than subsequent steps tate the isolation and analysis of the product (Table 2).
in the SAM sequence.
During the optimization of the reaction conditions, we
also found that better yields could be obtained by employ-
ing two equivalents of acceptor 6. In this manner, the SAA
reaction could proceed to completion despite the compet-
ing SAM process forming dimer 9.
The use of aliphatic ketones results in good yield and
moderate diastereoselectivity (entry 13). Finally, thioester
acceptor 6i afforded the bis spiro-indane product with
good diastereoselectivity, but in a modest yield (entry 14).
A screening of other families of acceptors revealed that The scope of the SAA reaction is shown in Table 2. The
esters, sulfones, and nitriles do not afford the desired use of electron-withdrawing groups (EWGs) on the aryl
product under our optimized conditions. Thus, the scope ketone portion of the acceptor 6 is well tolerated (entry 2).
of the SAM reaction seems limited to ketone and thioester In contrast, electron-donating groups (EDGs) consider-
acceptors.
ably affect the rate of the reaction, resulting in a modest
yield (entry 3). The use of EDGs on C3 of the acceptor 6f
(R2 = 3-OMe) also showed a notable decrease in the reac-
tivity, affording the product in poor yield (entry 4). On the
other hand, acceptors 6d and 6j bearing EWGs enhanced
the electrophilicity of the Michael acceptor, reducing the
reaction time and increasing the yield of the product (en-
tries 5 and 6). Finally, the effect of substituents on the o-
Based on our understanding of the SAM reaction mecha-
nism, we developed an analogous Stetter–aldol–aldol
(SAA) process. This proposed domino transformation re-
lies on the reactivity of o-phthaldialdehydes, in which one
formyl group would be involved in the Stetter reaction
and the second formyl group would be involved in a sec-
a)
COPh
NHC, base
7
O
O
O
Ph
COR
+
H
R
COPh
H
5 R = 2-furyl
p-Ts-NH2, NHC, base
O
6a
NTs
8
COR
PhOC
NHC, base
9a
O
COPh
COPh
b)
COPh
O
O
6
S
HO
Ph
NEt
O–
aldol
OH
Stetter
COPh
Ph
S
NEt
O
OH
I
II
III
base
COPh
O
PhOC
Ph
O–
dehydration
Michael
COPh
OH
O
COPh
O
COPh
OH
9a
10a
IV
Scheme 2 a) Domino Stetter reaction; b) mechanistic rationale for the domino Stetter–aldol–Michael reaction
Synthesis 2011, No. 12, 1896–1904 © Thieme Stuttgart · New York

1898
E. Sánchez-Larios et al.
PAPER
phthaldialdehyde partner was probed (entries 7 and 8). In- We initiated our investigations by assessing the reactivity
terestingly, the use of methoxy-substituted dialdehyde of ester substrate 16a using standard conditions for the
substrate 12b furnishes product 14g as a single regioiso- Stetter reaction. Unfortunately, the spiro bis-indane prod-
mer prior to the oxidation step (entry 7). Again, this out- uct 17a was not obtained using either thiazolium salt 11 or
come can be attributed to the dual nature of alkoxy triazolium salt 15 as precatalyst (Scheme 3a). This failure
substituents as electron-donating and electron-withdraw- prompted us to explore a different type of NHC. In 2008,
ing at the para and meta positions, respectively. Surpris- Enders and co-workers reported the use of the N-benzyl-
ingly, the use of electron-poor o-phthaldialdehyde substituted triazolium salt 18 in their asymmetric intermo-
substrate 12c (R1 = F) resulted in a very sluggish transfor- lecular Stetter reactions.9 In their case, 18 was shown to be
mation, requiring the use of a highly reactive SAA partner a more reactive NHC compared to other families of nu-
in order to achieve a synthetically useful yield (entry 8).
cleophilic carbenes such as thiazolylidenes or N-aryltria-
zolylidenes. Unexpectedly, when 16a was reacted with
triazolium salt 18 a dibenzo[8]annulene product 19a was
obtained. Similarly, when sulfone 16b and cyanide 16c
were reacted with catalysts 18 and 11, respectively, diben-
zo[8]annulenes 19b and 19c10 were obtained.11 These
products presumably arise from sequential inter- and
intramolecular Stetter reactions. We postulate that forma-
Based on our experimental results in the SAM reaction,
we could observe that o-formylchalcone derivatives 6a–i
were very reactive Stetter acceptors. Therefore, we decid-
ed to further study electron-withdrawing groups that are
known for being less reactive in intermolecular Stetter re-
actions, such as esters and a-alkyl-a,b-unsaturated ke-
tones.1f
Table 1 Optimization and Scope of the Domino Stetter–Aldol–Michael (SAM) Reaction
R1
3
4
R2OC
COR2
+
EtN
4
3
11 (10 mol%),
DBU (30 mol%)
–Br
S
R1
H
CH2Cl2 (0.5 M)
23 °C
R1
Me
(CH2)2OH
11
O
COR2
O
9a–i
6a–i
Entry
1e
2f
R1
H
R2
Time (min)
Producta
Yield (%)b,c
drd
Ph
19 h
10
5 h
45
35
15
5
9a
9a
9a
9a
9a
9a
9b
9c
9d
9e
9f
(<10)
n.r.g
(<5)
77
>20:1
–
H
Ph
3h
4i
H
Ph
–
H
Ph
5:1
5j
H
Ph
75
20:1
17:1
12:1
>20:1
11:1
16:1
>20:1
10:1
7:1
6
H
Ph
79
7
H
4-ClC6H4
86
8
H
4-MeOC6H4
Ph
45
5
68
9
4-F
4-F
64
10
11
12
13
14
4-ClC6H4
Ph
15
9
80
3-MeO
3-MeO
H
85
4-ClC6H4
Me
5
9g
9h
9i
81
195
120
75
H
SEt
31
13:1
a The relative configuration was determined by X-ray crystallography (see ref. 8).
b Combined yield of pure isolated product diastereomers.
c Numbers in parentheses represent conversion.
d Determined from 1H NMR analysis of the crude reaction mixture.
e Conditions: 30 mol% of 11 and 1 equiv of i-Pr2NEt.
f Conditions: 30 mol% of 11 and 27 mol% of tetramethylguanidine (TMG).
g n.r. = no reaction.
h Conditions: 10 mol% of 11 and 9 mol% of Cs2CO3.
i Conditions: 30 mol% of 11 and 1 equiv of DBU.
j Conditions: 30 mol% of 11 and 27 mol% of DBU.
Synthesis 2011, No. 12, 1896–1904 © Thieme Stuttgart · New York

PAPER
NHC-Catalyzed Spiro Bis-Indane Synthesis
1899
tion of 19 is mainly driven by rapid protonation of inter- worthy due to the stereoselective formation of four
mediate V forming intermediate VI. Apparently, this contiguous stereocenters. With the aim of improving the
process occurs more rapidly than the aldol ring closure yield, several reaction parameters were varied such as the
leading to intermediate VI¢. Subsequently, intermediate solvent (toluene, N,N-dimethylformamide, ethanol, and
VI releases the NHC to give intermediate VII, which un- tetrahydrofuran), the catalyst (11, 18), and even portion-
dergoes a second Stetter reaction to form the eight-mem- wise addition of catalyst 11. However, no more than a
bered ring 19a (Scheme 3b).
trace amount of product was obtained in each case due to
low conversion. Only when dichloroethane was used as
solvent and by employing forcing conditions was it possi-
ble to obtain the desired product in low yield. The detec-
tion of only one diastereomer in the crude reaction
mixture suggests a highly diastereoselective SAA reac-
tion.
To date, it has been particularly difficult to perform inter-
molecular Stetter reactions on linear a-alkyl substituted
Stetter acceptors.12 This difficulty is presumably due to
the reduced reactivity caused by the steric interaction of
the a-alkyl substituent and the loss of conjugation be-
tween the a,b-double bond and the ketone. Knowing
about the high reactivity of o-formylchalcone derivatives, Another type of acceptor that was investigated was the
we decided to investigate the use of substrate 20 with cat- double Michael acceptor 24, which was previously em-
alyst 11. To our surprise, the dibenzo[8]annulene 21 was ployed in our synthesis of indanes.4 We hypothesized this
obtained in low yield (Scheme 4). In this case, the com- highly electrophilic acceptor would undergo a Stetter–
peting aldol step is probably slowed due to steric hin- Michael–aldol reaction in analogy to the SAA reaction
drance, thus leading to preferential protonation and (Scheme 6). Satisfyingly, the desired product was ob-
subsequent formation of the eight-membered ring. Never- tained in moderate yield as a single diastereomer, again
theless, the most remarkable feature of this transformation indicating the possibility of selectively forming four con-
is that sequential Stetter reactions occurred to form the C2- tiguous stereocenters.
symmetric diastereomers.
While studying the scope of the SAA reaction, we inves-
Motivated by the sequential Stetter reaction on 20, we tigated the reactivity of ester acceptor 16a with o-phthal-
turned our attention to diketone 22 for use in the SAA re- dialdehyde (12a). When using catalyst 11, no reaction was
action. This acceptor was expected to be less reactive in observed. In contrast, o-phthaldialdehyde (12a) was com-
the SAA reaction due to the increased steric hindrance in pletely consumed and acceptor 16a remained intact when
both the Stetter and the first aldol steps. To this end, ac- catalyst 18 was used (Scheme 7a). The product isolated
ceptor 22 was prepared and reacted with phthaldialdehyde from the reaction mixture was found to be a dimer of 12a.
(12a) (Scheme 5), affording the nondehydrated SAA ad- The same unidentified dimeric product was obtained
duct 23. Despite the low yield, this transformation is note- when the reaction was performed with dialdehyde 12a
Table 2 Domino Stetter–Aldol–Aldol (SAA) Reaction
R2
4
3
1) 11 (30 mol%)
O
O
X
DBU (1 equiv)
CH2Cl2 [0.5 M]
23 °C
4
R2
H
H
+
H
R3
R1
R1
2) IBX, MeCN
80 °C, 2 h
3
R3
O
O
2 equiv
O
O
13 X = H, OH
14 X = O
12a–c
6a–f,j
Entry
R1
R2
R3
Time (min)a
Product
13a
Yield (%)b
1c
2
3
4
5
6
7
8
H
H
H
20
30
60
100
5
71
58
25
36
72
75
42
50
H
H
4-Cl
14b
14c
H
H
4-OMe
H
H
3-OMe
4-F
4-OMe
H
14d
13e
H
H
H
4-Cl
H
15
35
60
14f
OMe
F
14g
4-F
4-Cl
14h
a Reaction time for the Stetter–aldol–aldol (SAA) step.
b Yield of pure isolated product.
c Reaction performed on a gram scale.
d Each diastereomer of products 13a and 13e was isolated prior to the oxidation step.
Synthesis 2011, No. 12, 1896–1904 © Thieme Stuttgart · New York

1900
E. Sánchez-Larios et al.
PAPER
–BF4
a)
N
O
11 or
N
N
C6F5
+
EtO
(30 mol%)
DBU (27 mol%)
15
CH2Cl2, 23 °C, 2 h
EWG
17a
O
OEt
O
N
H
Ph
N
N
+
EWG
O
–BF4
O
OTBDPS
18 (30 mol%)
16a EWG = COOEt
16b EWG = SO2Ph
16c EWG = CN
DBU (27 mol %)
CH2Cl2, 23 °C
19a: 42%, dr 1:1
O
EWG
19b: 64%, dr >20:1
19c: 13%, dr >20:1
(11 was used instead of 18)
b)
CO2Et
CO2Et
CO2Et
N
N
N
N
H-B
fast
N
N
HO
HO
HO
NBn
slow
NBn
O–
NBn
O
CO2Et
OEt
OEt
O
O
O–
V
VI
VI'
N
base – NHC
base (DBU) =
O
N
EtO2C
CO2Et
O
Stetter
+ NHC
O
CO2Et
CO2Et
O
19a
VII
Scheme 3 a) Synthesis of dibenzo[8]annulenes 19a–c; b) proposed mechanism for the synthesis of 19a
O
O
O
O
O
Ph
Ph
11 (50 mol%)
Ph
DBU (50 mol%)
H
H
H
+
H
CH2Cl2, r.t., 25 h
8%, dr 2:1
Ph
Ph
O
20
O
O
O
O
21
21'
Scheme 4 C2-Symmetric dibenzo[8]annulene products from a-methyl o-formylchalcone 2013
O
O
HO
11 (50 mol%)
DBU (50 mol%)
Ph
H
H
+
OH
Ph
Ph
DCE
78 °C, 30 h
11%
O
O
Ph
O
O
12a
22
23
Scheme 5 Stetter–aldol–aldol reaction using benzoylchalcone 22
alone with catalyst 18 (Scheme 7b). Very recently, Cheng X-ray crystallography confirmed their structural assign-
and co-workers disclosed a dimerization of phthaldialde- ment of the dimeric product as lactol 27, whose NMR
hydes catalyzed by N,N¢-dibenzylimidazolylidene (26).14 spectra matched those of our unknown product.
Synthesis 2011, No. 12, 1896–1904 © Thieme Stuttgart · New York

PAPER
NHC-Catalyzed Spiro Bis-Indane Synthesis
1901
O
O
O
O
HO
11 (30 mol%)
DBU (1 equiv)
Ph
Ph
O
H
H
+
CH2Cl2
23 °C, 48 h
23%
Ph
O
O
Ph
12a
24
25
Scheme 6 Domino Stetter–Michael–aldol reaction
11 (20 mol%)
DBU (20 mol%)
a)
O
CH2Cl2, 23 °C
CO2Et
H
+
H
H
HO
18 (20 mol%)
DBU (20 mol%)
O
16a
O
+ 16a
12a
CH2Cl2, 23 °C
5 min
O
OH
O
27
b)
O
HO
H
H
conditions
O
O
OH
O
12a
27
ii) Cheng conditions:
i) our conditions:
18 (20 mol%)
DBU (20 mol%)
CH2Cl2, 23 °C
5 min, 70%
BnN
NBn
26 (20 mol%)
NaH (20 mol%)
CH2Cl2, 23 °C
60 min, 90%
Scheme 7 Domino acyloin-aldol-aldol reaction
in a melting point apparatus and are uncorrected. Anhydrous sol-
vents were dried using a Braun Solvent Purification System and
stored under N2 over 3 Å molecular sieves.15 Unless otherwise not-
ed, commercially available reagents were used without further pu-
rification. All reactions were carried out under an inert atmosphere.
In conclusion, we have reported a series of highly efficient
NHC-catalyzed domino transformations that allow the
formation of three carbon–carbon bonds and up to four
contiguous stereogenic centers. Various Michael accep-
tors were surveyed for the domino SAM and SAA reac-
tions. Thioesters and ketones were shown to lead to the
desired spiro bis-indane products in contrast to esters, sul-
fones, and nitriles. Under appropriate conditions, these
and other weaker acceptors led to dibenzo[8]annulene
products via a double Stetter sequence. A highly diastere-
oselective domino Stetter–Michael–aldol reaction was
also demonstrated for the first time. Taken together, these
results show the importance of subtle variations in the re-
Spiro Bis-Indanes via Domino SAM; General Procedure
To a stirred a solution of aldehyde 6a–i (1 equiv) and 3-ethyl-5-(2-
hydroxyethyl)-4-methylthiazol-3-ium bromide (11; 0.1 equiv) in
anhyd CH2Cl2 (0.5 M) placed in a 5 mL oven-dried Schlenk tube fit-
ted with a septum was added DBU (0.3 equiv). After stirring the
mixture at r.t. for the time indicated in Table 1, the reaction was
quenched with sat. aq NH4Cl (2 mL) and extracted with CH2Cl2 (3
× 5 mL). The combined organic extracts were filtered through a
small pipette column containing anhyd Na2SO4/silica gel, and the
action conditions on the outcome of domino NHC-cata- solvent was removed in vacuo. The crude product was purified by
flash column chromatography employing the indicated eluent.
lyzed reactions.
rel-(1¢R,3S)-2¢-Benzoyl-3-(2-oxo-2-phenylethyl)-1,2¢-spirobi[in-
TLC was performed on Merck Silica Gel 60 F254 and was visual-
ized with UV light and 5% phosphomolybdic acid (PMA). Silica gel
SI 60 (40–63 mm) used for column chromatography was purchased
from Silicycle Chemical Division. NMR spectra were measured in
CDCl3 solution at 500 MHz for 1H and 125 MHz for 13C. The resid-
ual solvent protons (1H) or the solvent carbons (13C) were used as
internal standards for chemical shifts. High-resolution mass spectra
(HRMS) were obtained on a double focusing high-resolution spec-
trometer. EI ionization was accomplished at 7 eV. IR spectra were
recorded on a Fourier transform interferometer using a diffuse re-
flectance cell (DRIFT); only diagnostic and/or intense peaks are re-
ported. All samples were prepared as a film on a KBr disc or pellet
using KBr (IR grade) for IR analysis. Melting points were measured
den]-1(3H)-one (9a) (Major Diastereomer)
Reaction carried out on 0.21 mmol scale; yield: 67 mg (79%); dr =
17:1; white crystals; mp 187–189 °C, Rf = 0.25 (30% EtOAc in
hexanes).
IR (KBr film): 1716, 1682, 1629 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.97–7.91 (m, 3 H), 7.72 (ddd,
J = 7.6, 7.6, 1.0 Hz, 1 H), 7.63–7.60 (m, 1 H), 7.59–7.53 (m, 3 H),
7.61–7.54 (m, 3 H), 7.53–7.48 (m, 4 H), 7.47–7.43 (m, 1 H), 7.37
(d, J = 7.3 Hz, 1 H), 7.32–7.27 (m, 2 H), 7.19 (ddd, J = 7.5, 7.5, 1.0
Hz, 1 H), 7.13 (ddd, J = 7.5, 7.5, 1.2 Hz, 1 H), 6.82 (d, J = 7.5 Hz,
1 H), 4.93 (dd, J = 9.3, 5.3 Hz, 1 H), 3.41 (dd, J = 17.1, 9.3 Hz, 1
H), 3.34 (dd, J = 17.1, 5.4 Hz, 1 H).
Synthesis 2011, No. 12, 1896–1904 © Thieme Stuttgart · New York

1902
E. Sánchez-Larios et al.
PAPER
13C NMR (125 MHz, CDCl3): d = 200.8, 197.6, 191.6, 155.4, 148.6,
145.5, 144.7, 143.7, 138.9, 137.3, 136.8, 135.4, 133.1, 132.2, 129.5,
128.6, 128.5, 128.4, 128.2, 128.1, 127.8, 125.5, 125.4, 125.0, 72.4,
40.6, 39.1.
HRMS (EI+): m/z [M]+ calcd for C32H22O3: 454.1569; found:
454.1566.
quenched with sat. aq NH4Cl (0.5 mL) and the mixture was extract-
ed with CH2Cl2 (3 × 2 mL) and the combined organic layers were
filtered through a short pipette plug of anhyd Na2SO4/silica gel. The
solvent was removed in vacuo and the crude product was purified
by flash column chromatography (20% EtOAc in hexanes) to fur-
nish the title product as an inseparable mixture of diastereomers
(dr = 5.3:1) in 42% yield (41 mg) as colorless needle-like crystals;
mp 135–139 °C; Rf = 0.28 (20% EtOAc in hexanes).
Spiro Bis-indanes via Domino SAA; General Procedure
To a stirred a solution of phthaldialdehyde 12a–c (1 equiv), o-
formylchalcone derivative 6a–f, j (2 equiv), and 11 (0.3 equiv) in
anhyd CH2Cl2 (0.5 M) in a 5 mL oven-dried Schlenk tube fitted with
a septum was added DBU (1 equiv). After stirring the mixture at r.t.
for the indicated time, the reaction was quenched with sat. aq NH4Cl
(4 mL) and extracted with CH2Cl2 (3 × 5 mL). The combined organ-
ic extracts were filtered through a small pipette column containing
anhyd Na2SO4/silica gel. The solvent was removed in vacuo. The
crude product was purified by flash column chromatography em-
ploying the indicated eluent.
IR (KBr film): 2980, 1725, 1714, 1490, 1094 cm–1.
1H NMR (500 MHz, CDCl3): d (major diastereomer) = 7.36 (d,
J = 7.5 Hz, 2 H), 7.31 (dd, J = 7.3, 7.3 Hz, 2 H), 7.24 (ddd, J = 7.5,
7.5, 1.2 Hz, 2 H), 7.10 (d, J = 7.2 Hz, 2 H), 5.75 (dd, J = 9.3, 4.5
Hz, 2 H), 4.20 (dddd, J = 7.2, 2.1, 2.0, 1.8 Hz, 4 H), 3.10 (dd,
J = 15.1, 9.4 Hz, 2 H), 2.59 (dd, J = 15.2, 4.6 Hz, 2 H), 1.24 (dd,
J = 7.2, 7.2 Hz, 6 H); d (minor diastereomer) = 7.37 (d, J = 7.5 Hz,
2 H), 7.32–7.39 (m, 2 H), 7.26–7.22 (m, 2 H), 7.09 (d, J = 7.4 Hz,
2 H), 5.70 (dd, J = 9.4, 4.7 Hz, 2 H), 4.22–4.16 (m, 4 H), 3.14 (dd,
J = 14.9, 9.4 Hz, 2 H), 2.76 (dd, J = 14.9, 4.7 Hz, 2 H), 1.20 (dd,
J = 7.2, 7.2 Hz, 6 H).
13C NMR (125 MHz, CDCl3): d (major diastereomer) = 170.4,
132.0, 131.6, 128.6, 128.1, 126.9, 124.1, 120.3, 74.4, 60.9, 39.9,
14.4.
HRMS (EI+): m/z [M]+ calcd for C24H24O6: 408.1572; found:
408.1575.
rel-(1R,1¢R)-2¢-Benzoyl-1-hydroxy-1,2¢-spirobi[inden]-3(1H)-
one (13a)
Reaction carried out on 3.7 mmol scale; yield: 432 mg (33%); dr =
1:1.1; light yellow crystals; mp 152–154 °C; Rf = 0.35 (10% EtOAc
in toluene).
IR (KBr pellet): 3421, 3066, 1716, 1552, 1341, 1064, 758 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.92 (d, J = 7.6 Hz, 1 H), 7.84–
7.80 (m, 4 H), 7.73 (s, 1 H), 7.60–7.56 (m, 3 H), 7.47 (dd, J = 7.6,
7.6 Hz, 2 H), 7.37 (dd, J = 7.4, 7.4 Hz, 1 H), 7.31 (dd, J = 7.4, 7.4
Hz, 1 H), 6.98 (d, J = 7.4 Hz, 1 H), 5.74 (d, J = 12.0 Hz, 1 H), 4.43
(d, J = 12.0 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 200.3, 195.6, 155.5, 149.4, 149.3,
141.9, 138.5, 136.2, 135.8, 132.9, 129.9, 129.6, 128.6, 128.5, 126.6,
125.2, 124.7, 121.8, 77.4, 74.3.
2,2¢-Bis(phenylsulfonylmethyl)(3,4,7,8-tetrahydrodiben-
zo[8]annulene) (19b)
Following the typical procedure for 19a, the reaction was per-
formed with (E)-2-[2-(phenylsulfonyl)vinyl]benzaldehyde (16b; 50
mg, 0.18 mmol, 1 equiv) and 189 (31 mg, 0.055 mmol, 0.3 equiv) in
CH2Cl2 (0.37 mL, 0.5 M) and DBU (7.5 mL, 0.05 mmol, 0.27 equiv)
for 10 min. The crude product was filtered and rinsed with CH2Cl2
(6 × 5 mL) to furnish the title product as an off-white solid (dr =
>20:1) in 64% yield (32 mg); Rf = 0.20 (30% EtOAc in hexanes).
1H NMR (500 MHz, CDCl3): d = 8.03 (dd, J = 7.6, 7.6 Hz, 4 H),
7.75 (q, J = 7.2, 7.2, 7.2 Hz, 2 H), 7.64 (dd, J = 7.2, 7.2 Hz, 4 H),
7.25–7.25 (m, 6 H), 7.02–7.00 (m, 2 H), 3.65–3.54 (m, 4 H).
HRMS (EI+): m/z [M]+ calcd for C24H16O3: 352.1099; found:
352.1100.
rel-(1S,1¢R)-2¢-Benzoyl-1-hydroxy-1,2¢-spirobi[inden]-3(1H)-
one (epi-13a)
Yield: 492 mg (38%); light pink crystals; mp 241–244 °C;
Rf = 0.15 (10% EtOAc in toluene).
2,2¢-(3,4,7,8-Tetrahydrodibenzo[8]annulene)diacetonitrile
(19c)
Following the typical procedure for 19a, the reaction was per-
formed with (E)-3-(2-formylphenyl)acrylonitrile (16c; 25 mg, 0.15
mmol, 1 equiv) and 11 (12 mg, 0.048 mmol, 0.3 equiv) in CH2Cl2
(0.32 mL, 0.5 M) and DBU (6.4 mL, 0.04 mmol, 0.27 equiv) for 90
min. The crude product was purified by flash column chromatogra-
phy to furnish the title product as a light yellow oil (dr = >20:1) in
13% yield (3.2 mg); Rf = 0.25 (30% EtOAc in hexanes).
1H NMR (500 MHz, CDCl3): d = 7.98 (d, J = 7.6 Hz, 2 H), 7.78 (dd,
J = 7.6, 7.4 Hz, 2 H), 7.67 (dd, J = 8.2, 7.6 Hz, 4 H), 5.67 (dd,
J = 6.4, 5.7 Hz, 2 H), 3.10 (dd, J = 16.8, 5.1 Hz, 2 H), 2.94 (dd,
J = 16.8, 7.0 Hz, 2 H).
IR (KBr pellet): 3428, 1690, 1621, 1553, 1343, 1292, 727 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.90 (dd, J = 7.6, 7.6 Hz, 2 H),
7.86 (d, J = 7.6 Hz, 2 H), 7.81 (dd, J = 7.3, 7.6 Hz, 1 H), 7.75 (s, 1
H), 7.61–7.57 (m, 3 H), 7.50 (dd, J = 7.7, 7.7 Hz, 2 H), 7.37 (dd,
J = 7.6, 7.6 Hz, 1 H), 7.23 (dd, J = 7.6, 7.6 Hz, 1 H), 6.77 (d,
J = 7.6 Hz, 1 H), 6.07 (d, J = 9.2 Hz, 1 H), 1.96 (dd, J = 9.2, 6.7 Hz,
1 H).
13C NMR (125 MHz, CDCl3): d = 197.8, 191.5, 154.0, 147.1, 146.6,
144.1, 143.5, 138.7, 136.9, 135.7, 132.4, 129.5, 129.2, 129.1, 129.0,
128.6, 125.9, 125.8, 124.8, 123.1, 75.6, 73.6.
HRMS (EI+): m/z [M]+ calcd for C24H16O3: 352.1099; found:
352.1095.
HRMS (EI+): m/z [M]+ calcd for C20H14N2O2: 314.1055; found:
314.1048.
Diethyl 2,2¢-(3,4,7,8-Tetrahydrodibenzo[8]annulene)diacetate
(19a); Typical Procedure
2,2¢-(3,4,7,8-Tetrahydrodibenzo[8]annulene)bis(1-phenylpro-
pan-1-one) (21)
A flame-dried Schlenk tube was charged with (E)-ethyl 3-(2-
formylphenyl)acrylate (16a; 50 mg, 0.24 mmol, 1 equiv) and (S)-
2-benzyl-5-[(tert-butyldiphenylsilyloxy)methyl]-6,7-dihydro-5H-
pyrrolo[2,1-c][1,2,4]triazol-2-ium tetrafluoroborate (18;9 40 mg,
0.072 mmol, 0.3 equiv). The tube was evacuated three times and re-
filled with dry N2, and then the solids were dissolved in CH2Cl2
(0.24 mL, 1 M). Lastly, DBU (9.7 mL, 0.065 mmol, 0.27 equiv) was
added to the solution at r.t. The reaction was monitored by TLC
(20% EtOAc in hexanes). Upon completion (10 min), it was
Following the typical procedure for 19a, the reaction was per-
formed with (E)-2-(2-methyl-3-oxo-3-phenylprop-1-enyl)benzal-
dehyde (20; 50 mg, 0.20 mmol, 1 equiv) and 11 (25 mg, 0.10 mmol,
0.5 equiv) in CH2Cl2 (0.24 mL, 1 M) and DBU (15 mL, 0.10 mmol,
0.5 equiv) for 25 h. The crude product was purified by flash column
chromatography (20% EtOAc in hexanes) to furnish the title prod-
uct as an inseparable mixture of diastereomers (dr = 2:1) in 8% yield
(8.3 mg) as a light yellow oil; Rf = 0.3 (20% EtOAc in hexanes)
Synthesis 2011, No. 12, 1896–1904 © Thieme Stuttgart · New York

PAPER
NHC-Catalyzed Spiro Bis-Indane Synthesis
1903
IR (KBr film): 2979, 2938, 1766, 1680, 1287, 1216, 972, 702 cm–1.
H), 7.59–7.52 (m, 2 H), 7.51–7.41 (m, 5 H), 7.33 (d, J = 7.5 Hz, 1
H), 7.24 (dd, J = 7.4, 7.4 Hz, 1 H), 7.04 (dd, J = 7.4, 7.4 Hz, 1 H),
6.44 (d, J = 7.7 Hz, 1 H), 5.18 (d, J = 3.8 Hz, 1 H), 4.79 (d, J = 4.8
Hz, 1 H), 4.45 (ddd, J = 13.4, 10.0, 5.3 Hz, 1 H), 3.78 (dd, J = 17.6,
8.3 Hz, 1 H), 3.71 (dd, J = 17.6, 5.5 Hz, 1 H), 2.89 (d, J = 4.2 Hz,
1 H).
13C NMR (125 MHz, CDCl3): d = 203.2, 201.8, 198.9, 153.7, 146.5,
139.7, 137.1, 135.8, 135.1, 133.9, 133.4, 129.5, 129.2, 129.1, 128.8,
128.4, 127.2, 125.7, 125.3, 125.1, 124.3, 73.6, 73.4, 55.8, 46.0,
45.4.
1H NMR (500 MHz, CDCl3): d (major diastereomer) = 7.99 (d,
J = 7.1 Hz, 2 H), 7.93–7.87 (m, 4 H), 7.68 (d, J = 4.5 Hz, 2 H),
7.63–7.46 (m, 8 H), 7.33 (d, J = 7.8 Hz, 2 H), 5.91, (d, J = 8.8 Hz,
2 H), 3.68 (ddd, J = 15.8, 7.1, 7.1, 7.1 Hz, 2 H), 1.54 (d, J = 7.0 Hz,
6 H); d (minor diastereomer) = 7.93–7.87 (m, 6 H), 7.63–7.46 (m,
12 H), 5.97 (d, J = 5.1 Hz, 2 H), 4.10 (ddd, J = 12.3, 5.1, 5.1, 5.1
Hz, 2 H), 1.10 (d, J = 7.2 Hz, 6 H).
13C NMR (125 MHz, CDCl3): d (major diastereomer) = 201.5,
170.3, 149.1, 135.9, 134.4, 134.0, 129.6, 129.1, 128.6, 126.2, 125.9,
123.4, 82.3, 47.1, 16.3.
HRMS: m/z [M]+ calcd for C32H24O4: 472.1674; found: 472.1675.
HRMS: m/z [M]+ calcd for C34H28O4: 500.1987; found: 500.1987.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
2¢-Benzoyl-1,3¢-dihydroxy-3¢-phenyl-2¢,3¢-dihydro-1,2¢-spiro-
bi[inden]-3(1H)-one (23)
A flame-dried Schlenk tube was charged with (E)-3-(2-benzoylphe-
nyl)-1-phenylprop-2-en-1-one (22; 50 mg, 0.16 mmol, 1 equiv), o-
phthaldialdehyde (12a; 32.2 mg, 0.24 mmol, 1.5 equiv), and 11
(20.2 mg, 0.08 mmol, 0.5 equiv) in 1,2-dichloroethane (0.16 mL, 1
M). The mixture was heated to 78 °C, and then DBU was added (12
mL, 0.08 mmol, 0.5 equiv) and heated for 30 h. The reaction was
quenched with sat. aq NH4Cl (0.5 mL) and the mixture was extract-
ed with CH2Cl2 (3 × 2 mL) and filtered through a short pipette plug
of anhyd Na2SO4/silica gel. The solvent was removed in vacuo and
the crude product was purified by flash column chromatography
(30% EtOAc in hexanes) to furnish the title product in 11% yield
(7.7 mg) as an orange solid; mp 191–194 °C; Rf = 0.22 (30% EtOAc
in hexanes).
Acknowledgment
We thank the Natural Sciences and Engineering Research Council
(NSERC) of Canada (Discovery Grant to M.G. and Postgraduate
Scholarship to J.M.H.), the Canada Foundation for Innovation, and
the University of Saskatchewan for financial support.
References
(1) For reviews on NHC catalysis, see: (a) Enders, D.;
Balensiefer, T. Acc. Chem. Res. 2004, 37, 534.
(b) Berkessel, A.; Gröger, H. Asymmetric Organocatalysis;
Wiley-VCH: Weinheim, 2005. (c) Zeitler, K. Angew. Chem.
Int. Ed. 2005, 44, 7506. (d) Enders, D.; Niemeier, O.;
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IR (KBr film): 3412, 3061, 1715, 1605, 1447, 1218, 957, 735, 713
cm–1.
1H NMR (500 MHz, CDCl3): d = 7.89 (d, J = 7.4 Hz, 2 H), 7.80 (d,
J = 7.8 Hz, 1 H), 7.78 (d, J = 7.8 Hz, 1 H), 7.71 (dd, J = 7.4, 7.4 Hz,
1 H), 7.62 (d, J = 7.3 Hz, 2 H), 7.48 (dd, J = 7.3, 7.3 Hz, 1 H), 7.46
(dd, J = 7.5, 7.5 Hz, 1 H), 7.37 (dd, J = 7.4, 7.4 Hz, 2 H), 7.33 (dd,
J = 7.7, 7.7 Hz, 2 H), 7.28 (dd, J = 7.3, 7.3 Hz, 1 H), 7.24 (dd,
J = 7.5, 7.5 Hz, 1 H), 7.17 (ddd, J = 7.6, 1.1, 1.0, 1.0 Hz, 1 H), 6.98
(d, J = 7.5 Hz, 1 H), 6.65 (s, 1 H), 6.57 (d, J = 7.6 Hz, 1 H), 5.43 (s,
1 H), 5.34 (s, 1 H).
(2) For reviews on domino reactions, see: (a) Tietze, L. F.
Chem. Rev. 1996, 96, 115. (b) Fogg, D. E.; dos Santos, E. N.
Coord. Chem. Rev. 2004, 248, 2365. (c) Tietze, L. F.;
Brasche, G.; Gericke, K. Domino Reactions in Organic
Synthesis; Wiley-VCH: Weinheim, 2006. (d) Chapman, C.
J.; Frost, C. G. Synthesis 2007, 1. (e) Enders, D.; Grondal,
C.; Hüttl, M. R. M. Angew. Chem. Int. Ed. 2007, 46, 1570.
(3) (a) Stetter, H.; Schreckenberg, M. Angew. Chem., Int. Ed.
Engl. 1973, 12, 81. (b) Stetter, H. Angew. Chem., Int. Ed.
Engl. 1976, 15, 639. (c) Stetter, H.; Kuhlmann, H. Org.
React. 1991, 40, 407.
13C NMR (125 MHz, CDCl3): d = 204.7, 201.7, 153.5, 147.3, 143.7,
142.3, 136.9, 136.3, 135.8, 134.6, 129.5, 129.3, 128.9, 128.8, 128.5,
127.8, 126.5, 126.4, 124.6, 124.3, 123.8, 86.7, 72.7, 70.6, 59.0.
HRMS: m/z [M]+ calcd for C30H22O4: 446.1518; found: 446.1512.
2¢-Benzoyl-1-hydroxy-3¢-(2-oxo-2-phenylethyl)-2¢,3¢-dihydro-
1,2¢-spirobi[inden]-3(1H)-one (25)
(4) Sánchez-Larios, E.; Gravel, M. J. Org. Chem. 2009, 74,
A flame-dried Schlenk tube was charged with (2E,2¢E)-3,3¢-(1,2-
phenylene)bis(1-phenylprop-2-en-1-one) (24;3 50 mg, 0.15 mmol, 1
equiv), o-phthaldialdehyde (12a; 20.1 mg, 0.15 mmol, 1 equiv), and
11 (11.3 mg, 0.045 mmol, 0.3 equiv). The tube was evacuated three
times and refilled with dry N2, the solids were dissolved in CH2Cl2
(0.3 mL, 0.5 M) followed by the addition of DBU (22.4 mL, 0.15
mmol, 1 equiv) at r.t. The reaction was monitored by TLC (30%
EtOAc in hexanes). When no further change was observed (48 h),
the reaction was quenched with sat. aq NH4Cl (0.5 mL) and the
mixture was extracted with CH2Cl2 (3 × 2 mL) and filtered through
a short pipette plug of anhyd Na2SO4/silica gel. The solvent was re-
moved in vacuo and the crude product was purified by flash column
chromatography (30% EtOAc in hexanes) to furnish the title prod-
uct in 23% yield (16 mg) as a light yellow solid; mp 167–169 °C;
Rf = 0.25 (30% EtOAc in hexanes).
7536.
(5) For other domino or one-pot sequences involving a Stetter
reaction, see: (a) Nemoto, T.; Fukuda, T.; Hamada, Y.
Tetrahedron Lett. 2006, 47, 4365. (b) Mattson, A. E.;
Bharadwaj, A. R.; Zuhl, A. M.; Scheidt, K. A. J. Org. Chem.
2006, 71, 5715. (c) He, J.; Tang, S.; Liu, J.; Su, Y.; Pan, X.;
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T.; Wurz, N. E.; Glorius, F. J. Am. Chem. Soc. 2010, 132,
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Acad. Sci. U.S.A. 2010, 107, 20666.
(6) Breslow, R. J. J. Am. Chem. Soc. 1958, 80, 3719.
(7) For domino Stetter-aldol reactions, see: (a) Sun, F.-G.;
Huang, X.-L.; Ye, S. J. Org. Chem. 2010, 75, 273. (b) Sun,
F.-G.; Ye, S. Synlett 2011, 1005. For an aza-benzoin–aldol
reaction, see: (c) Sun, F.-G.; Ye, S. Org. Biomol. Chem.
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(d) Wu, K.-J.; Li, G.-Q.; Li, Y.; Dai, L.-X.; You, S.-L. Chem.
Commun. 2011, 47, 493.
IR (KBr film): 3485, 3062, 1713, 1681, 1596, 1579, 1217, 752, 690
cm–1.
1H NMR (500 MHz, CDCl3): d = 7.99 (d, J = 8.8 Hz, 2 H), 7.97 (d,
J = 10.4 Hz, 2 H), 7.80–7.76 (m, 2 H), 7.73 (dd, J = 7.4, 7.4 Hz, 1
Synthesis 2011, No. 12, 1896–1904 © Thieme Stuttgart · New York

1904
E. Sánchez-Larios et al.
PAPER
(8) Sánchez-Larios, E.; Holmes, J. M.; Daschner, C. L.; Gravel,
M. Org. Lett. 2010, 12, 5772.
(9) Enders, D.; Han, J. H.; Henseler, A. Chem. Commun. 2008,
3989.
(10) The reaction of 16c to produce 19c was performed with
catalyst 11.
(11) HPLC analysis on a chiral stationary phase showed 19a to be
racemic even when the reaction was performed with weaker
bases to avoid racemization.
M.; Dalton, D. M.; Rovis, T. J. Am. Chem. Soc. 2009, 131,
10872.
(13) The relative configuration for 21 and 21¢ was determined by
the coupling constants of the proton a to the carbonyl at
d = 5.91 (d, J = 8.8 Hz) for the major diastereomer and
d = 5.97 (d, J = 5.1 Hz) for the minor diastereomer.
(14) Cheng, Y.; Peng, J.-H.; Li, Y.-J.; Shi, X.-Y.; Tang, M.-S.;
Tan, T.-Y. J. Org. Chem. 2011, 76, 1844.
(15) Williams, D. B. G.; Lawton, M. J. Org. Chem. 2010, 75,
(12) For a recent example of a Stetter reaction on an a,b-disub-
8351.
stituted Michael acceptor, see: DiRocco, D. A.; Oberg, K.
Synthesis 2011, No. 12, 1896–1904 © Thieme Stuttgart · New York