Design and synthesis of angularly annulated spirocyclics via enyne metathesis and the Diels-Alder reaction as key steps

Article abstract of DOI:10.1055/s-0034-1378280

We have developed a simple and an efficient route to a range of angularly fused spirocycles by the application of enyne metathesis and the Diels-Alder reaction as key steps. The enyne metathesis protocol has been further extended to the dibenzylation of indane-1,3-dione by using cross-enyne metathesis in the presence of hexa-1,5-diene with the aid of Grubbs' 1st generation catalyst followed by an aromatization sequence with DDQ. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0034-1378280

PAPER
▌2471
paper
Design and Synthesis of Angularly Annulated Spirocyclics via Enyne Metathesis
and the Diels–Alder Reaction as Key Steps
Design and Synthesis of Angularly Annulated Spirocyclics
Sambasivarao Kotha,* Rashid Ali, Arti Tiwari
Department of Chemistry, Indian Institute of Technology-Bombay, Powai, Mumbai 400076, India
Fax +91(22)25727152; E-mail: srk@chem.iitb.ac.in
Received: 12.02.2014; Accepted after revision: 15.05.2014
OHC
O
Abstract: We have developed a simple and an efficient route to a
range of angularly fused spirocycles by the application of enyne
metathesis and the Diels–Alder reaction as key steps. The enyne
metathesis protocol has been further extended to the dibenzylation
of indane-1,3-dione by using cross-enyne metathesis in the presence
of hexa-1,5-diene with the aid of Grubbs’ 1st generation catalyst
followed by an aromatization sequence with DDQ.
OH
OH
OH
AcO
H2N
HO
OH
2 (+)-valienamine
1 ( )-guanacastepene A
O
Key words: active methylene compounds, cross-metathesis, Diels–
O
Alder reaction, enyne metathesis, spirocyclic compounds
O
H
O
Since the development of ruthenium catalysts,1 several
metathesis protocols have opened up new and useful
retrosynthetic strategies.2 These advances have elevated
organic synthesis to a higher level. The ring-closing enyne
metathesis3 (RCEM) protocol discovered by Katz in 1985
generate inner-outer 1,3-dienes, which are suitable for the
Diels–Alder reaction. Generally, in the enyne metathesis
sequence the alkylidene part migrates from the alkene to
the alkyne carbon to deliver a conjugated diene and this
skeletal reorganization is known as alkylidene migration
reaction. Although ring-closing metathesis (RCM) is a
useful route for the construction of carbon–carbon bonds,
ring-closing enyne metathesis is unique and it is useful for
the construction of conjugated 1,3-dienes containing polar
functional groups in a single step. Over the last two de-
cades, the metathesis sequence has been applied to gener-
ate challenging ring systems in natural products,3k,4 in
particular macrocyclic compounds and other biologically
relevant substances. A number of selected bioactive natu-
ral products prepared by the enyne metathesis sequence
are shown in Figure 1.5 A simple access to dienes helps to
expand the scope of the Diels–Alder reaction in prepara-
tive organic chemistry. It is worth noting that the Diels–
Alder reaction is a powerful tool that enhances molecular
diversity immensely in a single step.
O
O
H
O
3 ( )-differolide
4 (–)-dihydroxanthatin
Figure 1 Some important natural products synthesized by the me-
tathesis protocol
tures. Although, a number of synthetic methods8 are
reported for the construction of linearly fused spirocy-
clics, only a limited number of strategies are available for
the synthesis of angularly annulated spirocyclics. In our
preliminary report,9 we reported a simple synthetic strate-
gy for the angularly annulation of indane-based spirocy-
clics starting with indane-1,3-dione (5) (Scheme 1, Figure
3).10 Here, we report the full details of our preliminary
work and also its extension to the generation of a library
of angularly fused spirocyclics. We have assembled di-
verse spirocyclics by the sequential use of enyne meta-
thesis and the Diels–Alder reaction which are atom-
economic. We have also expanded the metathesis se-
quence to a dibenzylated product by employing a cross-
enyne metathesis and aromatization sequence. The active
methylene components and the Grubbs’ catalysts used in
our study are shown in Figure 2.
Our investigation started with the selective monoallyla-
tion of active methylene compounds. To achieve the
monoallylation of 5, different conditions were examined.
However, our attempts clearly indicated that the forma-
tion of the diallylated compound is unavoidable (Scheme
1, Table 1). After extensive experimentation, we found
that monoallylated product 7 was obtained in 34% yield
along with a small amount of unidentified compound by
using 20% aqueous potassium hydroxide and a catalytic
amount of copper powder at room temperature (entry 2).
We have also found an alternative route i.e. monopropar-
gylation followed by allylation of indane-1,3-dione is a
better route than the allylation followed propargylation to
Spirocyclics2b,6 have attracted the attention of synthetic
organic chemists because they constitute core structural
units in several biologically important targets.7 Molecules
containing angularly fused aromatic systems with an ex-
tended π-framework are useful in designing electronic or-
ganic materials. These systems can create intricate
molecular frameworks due to their unusual packing ar-
rangement, which is difficult in linearly annulated struc-
SYNTHESIS 2014, 46, 2471–2480
Advanced online publication: 25.06.2014
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1
1
4
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DOI: 10.1055/s-0034-1378280; Art ID: ss-2014-n0101-op
© Georg Thieme Verlag Stuttgart · New York

2472
S. Kotha et al.
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Alder adducts in refluxing 1,4-dioxane gave the corre-
sponding aromatized products (Figure 3).
O
O
O
O
O
O
EtO
Table 1 Various Conditions Attempted for the Monoallylation of 5
EtO
O
MeO
Entry Reaction conditions
Yielda (%)
5
6a
6b
6c
6d
7
8
PCy3
N
N
1
2
10% aq KOH, Cu powder, r.t., 8 h
20
34
30
6
–
Ph
Cl
Cl
Ph
Ru
20% aq KOH, Cu powder, r.t., 8 h
25% aq KOH, Cu powder, r.t., 8 h
KF-Celite, MeCN, reflux, 12 h
KF-Celite, MeCN, r.t., 12 h
NaH, THF, r.t., 2 h
–
Cl
Cl
Ru
PCy3
(G-II)
PCy3
3
–
4
52
43
59
40
51
63
55
(G-I)
5
15
18
24
8
Figure 2 Active methylene components and the Grubbs’ catalysts
used in our strategy
6
7
NaH, THF, r.t., 0.5 h
generate the enyne building block 10. Having the monoal-
lylated compound 7 in hand, it was successfully converted
into the enyne building block 10. Later, different condi-
tions were attempted to generate the diene building block
11 using a metathesis protocol in dry dichloromethane in
the presence of Grubbs’ 1st generation (G-I) or Grubbs’
2nd generation (G-II) catalyst. Since, the groups of Fürst-
ner and Mori have reported the effects of titanium
isopropoxide11 and ethylene12 in the facilitation of the me-
tathesis sequence, we used a catalytic amount of titanium
isopropoxide under ethylene atmosphere in dry dichloro-
methane in presence of Grubbs’ 2nd generation catalyst,
and the diene 11 was obtained in 48% yield (Table 2). The
diene 11 was subjected to the Diels–Alder sequence with
various dienophiles to generate cycloaddition products.
During the Diels–Alder sequence a small amount of aro-
matized products was also obtained. Therefore, we did not
isolated the Diels–Alder adducts and they were directly
subjected to the aromatization sequence. Subsequent de-
hydrogenation with manganese(IV) oxide of these Diels–
8
K2CO3, TBAHS, MeCN, reflux, 4 h
K2CO3, TBAHS, MeCN, r.t., 12 h
K2CO3, TBAHS, MeCN, 0 °C, 8 h
9
13
9
10
a Isolated yields.
Table 2 Different Conditions Attempted for Enyne Metathesis of
Building Block 10
Entry Reaction conditions
Yielda
(%)
1
2
3
4
5
G-I (5 mol%), CH2Cl2, r.t., 15 h
19
G-I (5 mol%), Ti(Oi-Pr)4, CH2Cl2, r.t., 15 h
G-II (7.5 mol%), CH2Cl2, r.t., 16 h
32
27
34
G-II (7.5 mol%), Ti(Oi-Pr)4, CH2Cl2, r.t., 16 h
G-II (7.5 mol%), Ti(Oi-Pr)4, ethylene, CH2Cl2, r.t., 16 h 48
a Isolated yield along with some unidentified polymerized material.
O
c
a
O
7
8
O
R
O
O
O
O
O
R
R
R
f
e
5
O
O
O
10
11
12
d
b
O
9
Scheme 1 Construction of angularly fused spirocyclics of 5; Reagents and conditions: (a) conditions shown in Table 1; (b) 10% aq KOH, Cu
powder, propargyl bromide, r.t., 72 h, 56%; (c) K2CO3, TBAHS, propargyl bromide, MeCN, r.t., 16 h, 75%; (d) K2CO3, TBAHS, allyl bromide,
MeCN, r.t., 24 h, 68%; (e) conditions shown in Table 2 (f) 1. dienophiles, toluene, reflux, 12–24 h; 2. MnO2, 1,4-dioxane, reflux, 24 h, 49–76%.
Synthesis 2014, 46, 2471–2480
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Design and Synthesis of Angularly Annulated Spirocyclics
2473
AMC
14a–d
R
R
a
b
c
d
H
H
+
AMC
AMC
AMC
AMC
AMC
13a–d
6a–d
16a–d
17a–d
H
15a–d
Scheme 2 Synthesis of spirocyclics of 6a–d; Reagents and conditions: (a) NaH, allyl bromide, THF, r.t., 1.5–12 h, monoallyl product 39–
63%, diallyl product 13–26%; (b) NaH, propargyl bromide, THF, r.t., 12–20 h, 61–79%; (c) G-II (7.5 mol%), Ti(Oi-Pr)4(20 mol%), ethylene,
CH2Cl2, r.t., 5–16 h, 51–68%; (d) 1. dienophile, toluene, reflux, 8–24 h; 2. DDQ, toluene, reflux, 24 h, 59–75%.
To extend this strategy to other angularly fused spirocy- ucts (Figure 3). We also extended this strategy to other ac-
clics, we prepared several dienes by varying the active tive methylene compounds with only one carbonyl group
methylene compound. In this regard, we used commer- such as indan-1-one and 1-tetralones to deliver angularly
cially available and inexpensive starting material such as fused spirocyclics. In case of 2,3-dihydro-1H-inden-1-one
diethyl malonate (6a). The monoallyl compound 13a was (6b), monoallylation gave 13b in 39% yield under sodium
obtained in 63% yield along with the diallylated product hydride/allyl bromide conditions (Scheme 2, Table 3).
14a (24% yield) using sodium hydride and allyl bromide Along similar lines, 3,4-dihydronaphthalen-1(2H)-one
in tetrahydrofuran (Scheme 2, Table 3). Next, the mono- (6c) gave monoallylated compound 13c in 54% yield us-
allylated compound 13a was successfully transformed ing similar reaction conditions. In addition, we have also
into the enyne building block 15a using sodium hydride observed that, 6-methoxy-3,4-dihydronaphthalen-1(2H)-
and propargyl bromide in 79% yield. Subsequently, enyne one (6d) delivered the monoallylated compound in 57%
metathesis in dry dichloromethane in the presence of yield (Table 3). These monoallylated compounds 13b–d
Grubbs’ 2nd generation catalyst gave the diene 16a in were converted into the corresponding enyne building
65% yield, which was further subjected to Diels–Alder re- blocks 15b–d; the propargylation of monoallylated com-
action with various dienophiles followed by aromatiza- pound 13b gave a small amount of unexpected product
tion with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone 15b′ (Table 3, Scheme 3, the monoallylated compound
(DDQ) in refluxing toluene to afford the aromatized prod- 13b was contaminated by a small amount of starting ma-
Table 3 Various Diene Building Blocks Prepared Using the Enyne Metathesis Sequence
13a–d
(yield)
14a–d
(yield)
Time 15a–d (
(h) yield)
Time 16a–d
Time
(h)
(h)
(yield)
O
O
O
O
O
O
EtO
EtO
EtO
EtO
EtO
EtO
EtO
EtO
12
16
12
O
O
13a (63%)
15a (79%)
16a (65%)
14a (24%)
O
O
O
O
1.5
12
15
16
8
13b (39%)
15b (61%) + 15b′ (6%)a
16b (51%)
14b (26%)
O
O
O
O
3
13c (54%)
16c (68%)
15c (78%)
14c (18%)
O
O
O
O
6
20
5
MeO
MeO
MeO
MeO
16d (58%)
13d (57%)
15d (71%)
14d (13%)
a Minor amount of unexpected product 15b′ isolated along with desired product
© Georg Thieme Verlag Stuttgart · New York
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2474
S. Kotha et al.
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terial that could not be separated by column chromatogra- Our goal to generate the bis-diene 34 started with di-
phy) which was also isolated and confirmed by 1H and 13C propargylation of 1H-indane-1,3(2H)-dione (5) under po-
NMR spectral data and further supported by mass spectral tassium carbonate/propargyl bromide conditions, the
data. Next, these enyne building blocks 15b–d were sub- dialkyne building block 33 was obtained in 85% yield.
jected to ring-closing enyne metathesis to generate the in- The diyne 33 was treated with ethylene in the presence of
ner-outer dienes 16b–d. Treatment of these dienes 16b–d Grubbs’ 1st and 2nd generation catalysts in dry dichloro-
with various dienophiles delivered the expected Diels– methane. To our surprise, 33 failed to deliver the bis-diene
Alder adducts. Since these Diels–Alder adducts were con- 34. However, when compound 33 was treated with hexa-
taminated with a minor amount of aromatized products, 1,5-diene in the presence of Grubbs’ 1st generation cata-
no effort was made to characterize these impure Diels– lyst in dry dichloromethane, compound 35 was obtained
Alder adducts. Subsequently, these Diels–Alder adducts in 59% yield. Surprisingly, treatment of compound 35
were subjected dehydrogenation with DDQ in refluxing with various dienophiles such as dimethyl acetylenedicar-
toluene to deliver the corresponding aromatized products boxylate, tetracyanoethylene, 1,4-benzoquinone, and 1,4-
(Figure 3).
naphthoquinone did not afford the desired Diels–Alder
Ph
O
O
O
O
N
O
O
O
O
O
O
O
O
O
O
O
O
18 (57%)
19 (49%)
20 (55%)
21 (65%)
Ph
O
N
CO2CH3
CO2CH3
CN
NC CN
O
NC
O
O
O
O
CN
CN
CN
N
O
EtO
EtO
N
CN
O
O
O
22 (76%)
23 (60%)
24 (81%)
25 (85%)
MeO2C
CO2Me
CO2Me
CO2Me
O
CO2Me
CO2Me
O
CN
EtO
EtO
O
O
NC
CN
CN
O
26 (73%)
28 (59%)
CO2Me
29 (69%)
27 (72%)
CN CN
MeO2C
CN CN
NC
CN
NC
CN
O
O
O
MeO
MeO
30 (91%)
31 (75%)
32 (79%)
Figure 3 Diverse angularly fused spirocyclics assembled via enyne metathesis and Diels–Alder reaction
H
O
NaH
nucleophilic attack
O
– H2O
+
HO
+
O
O
O
C3H3Br
O
Mixture of compounds
15b'
Scheme 3 Plausible mechanism for the formation of unexpected product 15b′
Synthesis 2014, 46, 2471–2480
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Design and Synthesis of Angularly Annulated Spirocyclics
2475
O
O
O
O
b
a
O
O
f
34
33
5
c
R
O
O
O
d
e
R
R
O
O
O
R
35
36
Scheme 4 Dibenzylation of 1H-indene-1,3(2H)-dione (5) using cross enyne metathesis; Reagents and conditions: (a) K2CO3, TBAHS, prop-
argyl bromide, MeCN, r.t., 7 h, 85%; (b) G-I/G-II (10 mol%), ethylene, CH2Cl2, r.t., 20 h; (c) G-I (10 mol%), hexa-1,5-diene, CH2Cl2, r.t., 6 h,
59%; (d) dienophiles (R = electron withdrawing group), toluene, reflux; (e) DDQ, toluene, reflux, 18 h, 94%; (f) K2CO3, TBAHS, BnBr, MeCN,
r.t., 12 h, 79%.
for development. Column chromatography was performed using
Acme silica gel (100–200 mesh) with EtOAc–PE. Yields refer to
the isolated yields after column chromatography. Grubbs’ catalysts
were purchased from Sigma Aldrich. Infrared spectra were recorded
on Nicolet Impact-400 FT IR spectrophotometer in KBr/(neat). 1H
NMR (400 MHz and 500 MHz) spectra and 13C NMR (100 MHz
and 125.8 MHz) spectra were recorded on a Bruker spectrometer.
HRMS measurements were carried out by using electrospray ion-
ization (ESI), (Q-ToF) spectrometer. Melting points were recorded
on a Büchi B-545 melting point apparatus.
adducts. On the other hand, dehydrogenation of com-
pound 35 with DDQ in refluxing toluene gave the aroma-
tized product 36 in 94% yield (Scheme 4). To establish the
structure of compound 36, an independent synthesis was
undertaken by treating compound 5 with benzyl bromide
using potassium carbonate as the base in acetonitrile to
deliver 36 in 79% yield (Scheme 4). The spectral data of
the dibenzylated compound obtained by this route was
found to be identical to that of the compound obtained by
the earlier route.
2-Allyl-1H-indene-3(2H)-dione (7)
To 20% aq KOH solution were added 5 (3.5 g, 23.97 mmol) and Cu
powder (1.2 g, 19.05 mmol), and the mixture was stirred at r.t. for
15 min. Allyl bromide (3 mL, 34.66 mmol) was added dropwise us-
ing a dropping funnel and stirring was continued at this temperature
for 8 h. At the conclusion of the reaction (TLC monitoring), Cu
powder was filtered through a sintered funnel, dil HCl was added at
0 °C (pH 2–3) to the mixture and the aqueous layer was extracted
with CH2Cl2. The solvent was removed under reduced pressure and
the crude product was purified by column chromatography (silica
gel, 5% EtOAc–PE) to afford 7 (1.5 g, 34%) as a yellow viscous liq-
uid. 1H and 13C NMR spectra matched with the literature data.14
We have demonstrated a simple and useful method for the
construction of angularly fused spirocyclics by the appli-
cation of enyne metathesis and the Diels–Alder reaction
as key steps. A variety of dienes were prepared by the
enyne metathesis sequence and reacted with several di-
enophiles such as dimethyl acetylenedicarboxylate, tetra-
cyanoethylene, 1,4-benzoquinone, 1,4-naphthoquinone,
1,4-anthraquinone, 4-phenyl-1,2,4-triazoline-3,5-dione,
and N-phenylmaleimide to generate a library of angularly
fused spirocyclic compounds. Further, the enyne metath-
esis sequence was expanded to generate dibenzylated
product 36 involving cross enyne metathesis in the pres-
ence of hexa-1,5-diene with the aid of Grubbs 1st genera-
tion catalyst in dry dichloromethane. Advantageously, all
the starting materials are simple, commercially available
and the final products are found to be a key structural ele-
ments present in various biologically active substances.
Our strategy may be applicable for the synthesis of highly
functionalized spirocyclics of chemically and biologically
interest in a diversity oriented fashion.13
Monoallyl Products 13a–d; General Procedure
To a suspension of NaH (3 equiv) in anhyd THF (25–30 mL), 6a–d
was added and the mixture was stirred at r.t. for 10 min. Then allyl
bromide (1.1–1.2 equiv) was added and stirring was continued for
1.5–12 h at this temperature. At the conclusion of the reaction (TLC
monitoring), the mixture was diluted with EtOAc and the aqueous
layer was extracted with CH2Cl2. The solvent was removed under
reduced pressure and the crude products were purified by column
chromatography (silica gel, 1–2% EtOAc–PE) to afford the desired
products 13a–d.
Diethyl 2-Allylmalonate (13a) and Diethyl 2,2-Diallylmalonate
(14a)
Following the general procedure gave 13a (1.52 g, 63%) as a thick
colorless liquid and 14a (693 mg, 24%) also as a thick colorless liq-
uid. The 1H and 13C NMR spectra matched with the literature data.15
Commercially available reagents were used without purification
and reactions involving air sensitive reagents or catalysts were per-
formed in degassed solvents. TBAHS = tetrabutylammonium hy-
drogensulfate Moisture sensitive materials were transferred using
standard syringe-septum techniques and the reactions were main-
tained under a N2 atmosphere. Analytical TLC was performed on
(7.5 × 2.5 cm) glass plates coated with Acme silica gel GF 254 (con-
taining 13% CaSO4 as a binder) using EtOAc–petroleum ether (PE)
2-Allyl-2,3-dihydro-1H-inden-1-one (13b) and 2,2-Diallyl-2,3-
dihydro-1H-inden-1-one (14b)
Following the general procedure gave 13b (353 mg, 39%) as a thick
yellow liquid and 14b (297 mg, 26%) also as a thick yellow liquid.
The 1H and 13C NMR spectra matched with the literature data.16
© Georg Thieme Verlag Stuttgart · New York
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IR (neat): 1608, 1640, 1710, 2187, 2922, 3077, 3301 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.88 (t, J = 2.64 Hz, 1 H), 2.38–
2.50 (m, 4 H), 3.12, 3.25 (ABq, J = 17.41 Hz, 2 H), 4.98–5.13 (m,
2 H), 5.52–5.63 (m, 1 H), 7.35–7.39 (m, 1 H), 7.45–7.47 (m, 1 H),
7.59–7.63 (m, 1 H), 7.75 (d, J = 7.68 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 26.48, 36.87, 41.32, 51.67, 70.51,
80.56, 119.19, 124.27, 126.61, 127.64, 132.89, 135.32, 136.29,
153.15, 208.73.
2-Allyl-3,4-dihydronaphthalen-1(2H)-one (13c) and 2-Diallyl-
3,4-dihydronaphthalen-1(2H)-one (14c)
Following the general procedure gave 13c (624 mg, 54%) as a thick
yellow liquid, 14c (320 mg, 18%) also as a thick yellow liquid, and
recovered starting material (290 mg). The 1H and 13C NMR spectra
matched with the literature data.17
2-Allyl-6-methoxy-3,4-dihydronaphthalen-1(2H)-one (13d) and
2-Diallyl-6-methoxy-3,4-dihydronaphthalen-1(2H)-one (14d)
Following the general procedure gave 13d (358 mg, 57%) as a thick
yellow liquid, 14d (96 mg, 13%) also as a thick yellow liquid, and
recovered starting material (492 mg). The 1H and 13C NMR spectra
matched with the literature data.18
HRMS (ESI, Q-ToF): m/z [M + H]+ calcd for C15H15O: 211.1123;
found: 211.1117.
Compound 15b′
Yellow solid; mp 122–124 °C; Rf = 0.48 (silica gel, 5% EtOAc–PE).
IR (neat): 1606, 1640, 1709, 2118, 2124, 2846, 3017, 3307 cm–1.
2-Allyl-2-prop-2-ynyl-1H-inden-1,3(2H)-dione (10)
To a solution of 7 (480 mg, 2.58 mmol) in MeCN (20 mL) were add-
ed K2CO3 (750 mg, 5.43 mmol) and TBAHS (150 mg, 0.44 mmol)
and the mixture was stirred at r.t. for 15 min. Propargyl bromide (0.6
mL, 6.73 mmol) was added and the stirring was continued at the this
temperature for 16 h. At the conclusion of the reaction (TLC moni-
toring), excess K2CO3 was filtered off through a sintered funnel and
the aqueous layer was extracted with CH2Cl2. The solvent was re-
moved under reduced pressure and the crude product was purified
by column chromatography (silica gel, 4% EtOAc–PE) to afford 10
(435 mg, 75%) as a thick yellow liquid; mp 107–109 °C; Rf = 0.46
(PE–EtOAc, 80:20).
1H NMR (400 MHz, CDCl3): δ = 2.04 (t, J = 2.60 Hz, 2 H), 2.54–
2.70 (m, 4 H), 2.73–2.90 (m, 2 H), 3.41, 3.55 (ABq, J = 17.58 Hz,
2 H), 4.95 (dd, J1 = 0.84 Hz, J2 = 9.24 Hz, 1 H), 5.14 (dd, J1 = 1.56
Hz, J2 = 16.96 Hz, 1 H), 5.55–5.62 (m, 1 H), 6.47 (s, 1 H), 6.93–6.95
(m, 1 H), 7.12–7.19 (m, 2 H), 7.41–7.48 (m, 2 H), 7.61–7.66 (m, 2
H), 7.83 (d, J = 7.64 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 25.34, 25.40, 37.93, 41.39, 51.74,
53.62, 70.58, 70.75, 81.10, 119.05, 120.82, 122.80, 124.38, 125.56,
126.55, 127.55, 127.81, 132.84, 135.42, 136.72, 137.98, 141.90,
144.21, 149.52, 152.66, 207.12.
IR (KBr): 1597, 1706, 2923, 3001 cm–1.
HRMS (ESI, Q-ToF): m/z [M + H]+ calcd for C27H23O: 363.1749;
found: 363.1753.
1H NMR (400 MHz, CDCl3): δ = 1.74 (t, J = 2.64 Hz, 1 H), 2.54 (d,
J = 7.44 Hz, 2 H), 2.67 (d, J = 2.64 Hz, 2 H), 4.94 (dd, J1 = 1.68 Hz,
J2 = 10.04 Hz, 1 H), 5.08 (dd, J1 = 1.68 Hz, J2 = 16.98 Hz, 1 H),
5.43–5.53 (m, 1 H), 7.84–7.89, (m, 2 H), 7.97–8.03 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 23.06, 38.57, 56.86, 71.53, 78.41,
120.17, 123.33, 130.96, 136.04, 142.39, 202.10.
2-Allyl-2-prop-2-ynyl-3,4-dihydronaphthalen-1(2H)-one (15c)
Following the general procedure gave 15c (479 mg, 78%) as a yel-
low liquid; Rf = 0.78 (silica gel, 5% EtOAc–PE).
IR (neat): 1601, 1639, 1680, 2118, 2931, 3074, 3301 cm–1.
1H NMR (400 MHz, CDCl3): δ = 2.01 (t, J = 2.68 Hz, 1 H), 2.16–
2.32 (m, 2 H), 2.36–2.42 (m, 1 H), 2.49–2.60 (m, 3 H), 2.94–3.13
(m, 2 H), 5.06–5.11 (m, 2 H), 5.67–5.78 (m, 1 H), 7.24 (d, J = 7.72
Hz, 1 H), 7.32 (t, J = 7.44 Hz, 1 H), 7.48 (dt, J1 = 1.40 Hz, J2 = 8.84
Hz, 1 H), 8.04 (dd, J1 = 1.16 Hz, J2 = 7.88 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 25.06, 25.20, 30.99, 38.27, 47.70,
71.19, 81.01, 119.05, 126.95, 128.26, 128.93, 131.64, 133.09,
133.57, 143.23, 199.93.
HRMS (ESI, Q-ToF): m/z [M + H]+ calcd for C15H13O2: 225.0916;
found: 225.0907.
Monoallyl-monopropargyl Products 15a–d; General Procedure
To a suspension of NaH (3 equiv) in anhyd THF (20 mL), 13a–d
was added and the mixture was stirred at r.t. for 15 min. Then
propargyl bromide (2–3 equiv) was added and stirring was contin-
ued for 12–20 h at this temperature. At the conclusion of the reac-
tion (TLC monitoring), the mixture was diluted with EtOAc and the
aqueous layer was extracted with CH2Cl2. The solvent was removed
under reduced pressure and the crude products were purified by col-
umn chromatography (silica gel, 2–3% EtOAc–PE) to afford the de-
sired enyne building blocks 15a–d.
HRMS (ESI, Q-ToF): m/z [M + Na]+ calcd for C16H16NaO:
247.1093; found: 247.1093.
2-Allyl-6-methoxy-2-prop-2-ynyl-3,4-dihydronaphthalen-
1(2H)-one (15d)
Following the general procedure gave 15d (582 mg, 71%) as a yel-
low liquid; Rf = 0.77 (silica gel, 5% EtOAc–PE).
Diethyl 2-Allyl-2-prop-2-ynylmalonate (15a)
Following the general procedure gave 15a (943 mg, 79%) as a yel-
low liquid. The 1H and 13C NMR spectra matched with the literature
data.19
IR (neat): 1600, 1673, 1728, 2117, 2939, 3007, 3075, 3296 cm–1.
1H NMR (400 MHz, CDCl3): δ = 2.01 (t, J = 2.60 Hz, 1 H), 2.13–
2.30 (m, 2 H), 2.34–2.40 (m, 1 H), 2.47–2.59 (m, 3 H), 2.89–3.05
(m, 2 H), 3.86 (s, 3 H), 5.07–5.10 (m, 2 H), 5.68–5.76 (m, 1 H), 6.68
(d, J = 2.20 Hz, 1 H), 6.83 (dd, J1 = 2.40 Hz, J2 = 8.76 Hz, 1 H), 8.01
(d, J = 8.76 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 25.21, 25.64, 31.04, 38.57, 47.41,
55.63, 71.10, 81.20, 112.55, 113.63, 118.88, 125.27, 130.73,
133.33, 145.75, 163.76, 198.71.
2-Allyl-2-prop-2-ynyl-2,3-dihydro-1H-inden-1-one (15b) and 2-
(1-Allyl-2-propy-2-ynyl-1H-inden-1-yl)-2-prop-2-ynyl-2,3-di-
hydro-1H-inden-1-one (15b′)
To a suspension of NaH (280 mg, 8.72 mmol) in anhyd THF (20
mL), 13b (500 mg, 2.91 mmol) was added and the mixture was
stirred at r.t. for 15 min. Then, propargyl bromide (0.80 mL, 8.72
mmol) was added and stirring was continued for 12 h at this temper-
ature. At the conclusion of the reaction (TLC monitoring), the mix-
ture was diluted with EtOAc and the aqueous layer was extracted
with CH2Cl2. The solvent was removed under reduced pressure and
the crude product was purified by column chromatography (silica
gel, 3% EtOAc–PE) to afford 15b as a thick yellow liquid (372 mg,
61%) along with unexpected compound 15b′ (63 mg, 6%) as a yel-
low solid.
HRMS (ESI, Q-ToF): m/z [M + Na]+ calcd for C17H18NaO2:
277.1199; found: 277.1193.
Enyne Metathesis of 10 and 15a–d; General Procedure
The solution of enynes 10 and 15a–d in CH2Cl2 (20 mL) was
degassed with N2 for 10 min, after that, G-II (7.5 mol%) and
Ti(Oi-Pr)4 (20 mol%) were added and the reaction vessel was kept
under ethylene pressure (balloon pressure). The mixture was stirred
at r.t. for 5–16 h. At the conclusion of the reaction (TLC monitor-
Compound 15b
Rf = 0.53 (silica gel, 5% EtOAc–PE).
Synthesis 2014, 46, 2471–2480
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Design and Synthesis of Angularly Annulated Spirocyclics
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ing), the solvent was removed under reduced pressure and the crude
products were purified by column chromatography (silica gel, 3–
5% EtOAc–PE) to afford the desired dienes 11 and 16a–d.
Diels–Alder Reaction of 11, 16a–d and Subsequent Aromatiza-
tion; General Procedure
To a solution of diene 11, 16a–d in toluene, dienophile (1.5 equiv)
was added and the mixture was refluxed for 8–24 h. At the conclu-
sion of the reaction (TLC monitoring), the solvent was removed un-
der reduced pressure and the crude products were purified by
column chromatography (silica gel, EtOAc–PE) to afford the Diels–
Alder adducts. Aromatization of the Diels–Alder adducts was car-
ried out with activated MnO2 (10 equiv, 100% conversion) in 1,4-
dioxane or DDQ (4 equiv, 100% conversion) in toluene at reflux
temperature for 20–24 h. Then, the solvent was removed under re-
duced pressure and the crude products were purified by column
chromatography (silica gel, EtOAc–PE) to deliver aromatized prod-
ucts.
3-Vinylspiro[cyclopent-3-ene-1,2′-indene]-1′,3′-dione (11)
Following the general procedure gave 11 (67 mg, 48%) as a white
solid; mp 123–124 °C; Rf = 0.41 (PE–EtOAc, 80:20).
IR (KBr): 1597, 1742, 2854 , 2923, 3011 cm–1.
1H NMR (400 MHz, CDCl3): δ = 2.85–2.87 (m, 4 H), 5.03 (d, J =
17.52 Hz, 1 H), 5.12 (d, J = 10.72 Hz, 1 H), 5.72–5.73 (br, 1 H),
6.54–6.62 (m, 1 H), 7.86–7.88 (m, 2 H), 8.01–8.03 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 39.70, 41.56, 57.77, 115.51,
123.78, 127.58, 132.34, 135.96, 140.68, 141.76, 203.50.
HRMS (ESI, Q-ToF): m/z [M + H]+ calcd for C15H13O2: 225.0916;
found: 225.0912.
Compound 18
Following the general procedure using MnO2 gave 18 (21 mg, 57%)
as a yellow solid; mp 168–170 °C; Rf = 0.40 (silica gel, 40%
EtOAc–PE).
Diethyl 3-Vinylcyclopent-3-ene-1,1-dicarboxylate (16a)
Following the general procedure gave 16a (130 mg, 65%) as a thick
colorless liquid. The 1H and 13C NMR spectra matched with the lit-
erature reported spectral data.20
IR (KBr): 1593, 1664, 1710, 1745, 2929, 3056 cm–1.
1H NMR (400 MHz, CDCl3): δ = 3.42 (s, 2 H), 3.79 (s, 2 H), 6.88
(d, J = 10.28 Hz, 1 H), 6.95 (d, J = 10.32 Hz, 1 H), 7.61 (d, J = 7.85
Hz, 1 H), 7.91–7.94 (m, 2 H), 8.02–8.07 (m, 3 H).
13C NMR (100 MHz, CDCl3): δ = 39.35, 42.51, 59.11, 124.01,
127.21, 127.93, 129.39, 131.90, 136.35, 138.49, 139.07, 141.62,
142.33, 149.74, 185.01, 186.55, 202.50.
3-Vinylspiro[cyclopent-3-ene-1,2′-inden]-1′(3′H)-one (16b)
Following the general procedure gave 16b (178 mg, 51%) as a yel-
low liquid; Rf = 0.47 (silica gel, 10% EtOAc–PE).
IR (neat): 1608, 1640, 1701, 2926, 3017 cm–1.
1H NMR (400 MHz, CDCl3): δ = 2.38–2.48 (m, 2 H), 2.98 (d, J =
14.40 Hz, 2 H), 3.19 (s, 2 H), 5.04 (dd, J1 = 10.64, Hz, J2 = 18.16
Hz, 2 H), 5.71(s, 1 H), 6.56 (dd, J1 = 10.60, Hz, J2 = 17.41 Hz, 1 H),
7.37–7.45 (m, 2 H), 7.58–7.62 (m, 1 H), 7.79 (d, J = 7.64 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 43.58, 45.50, 45.55, 55.62,
114.81, 124.40, 126.62, 127.65, 128.35, 133.09, 134.98, 136.25,
141.17, 152.81, 210.15.
HRMS (ESI, Q-ToF): m/z [M + H]+ calcd for C21H13O4: 329.0814;
found: 329.0813.
Compound 19
Following the general procedure using MnO2 gave 19 (18 mg, 49%)
as a yellow solid; mp 174–176°C; Rf = 0.44 (silica gel, 40% EtOAc–
PE).
IR (KBr): 1593, 1671, 1700, 1742, 2917, 3066 cm–1.
HRMS (ESI, Q-ToF): m/z [M + K]+ calcd for C15H14KO: 249.0676;
1H NMR (400 MHz, CDCl3): δ = 3.46 (s, 2 H), 3.93 (s, 2 H), 7.66
(d, J = 7.88 Hz, 1 H), 7.72–7.76 (m, 2 H), 7.90–7.94 (m, 2 H), 8.02–
8.07 (m, 2 H), 8.20–8.22 (m, 1 H), 8.28–8.31 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 39.31, 43.28, 59.26, 124.01,
127.18, 127.25, 128.08, 129.59, 129.64, 133.47, 133.57, 133.97,
134.11, 134.19, 136.31, 141.67, 143.00, 149.91, 183.19, 184.55,
202.59.
found: 249.0688.
3-Vinyl-3′,4′-dihydrospiro[cyclopent-3-ene-1,2′-naphthalen]-
1′-one (16c)
Following the general procedure gave 16c (54 mg, 68%) as a yellow
liquid; Rf = 0.76 (silica gel, 5% EtOAc–PE).
IR (neat): 1601, 1681, 2931, 3019 cm–1.
1H NMR (400 MHz, CDCl3): δ = 2.16–2.22 (m, 2 H), 2.43–2.55 (m,
2 H), 2.95–3.06 (m, 4 H), 5.01–5.10 (m, 2 H), 5.63 (s, 1 H), 6.49–
6.57 (m, 1 H), 7.21–7.36 (m, 2 H), 7.43–7.47 (m, 1 H), 8.06 (dd, J1 =
1.04, J2 = 7.80 Hz, 1 H).
13C NMR (125.8 MHz, CDCl3): δ = 26.17, 35.10, 39.98, 41.84,
52.02, 114.43, 126.85, 127.95, 128.44, 128.83, 131.69, 133.31,
133.38, 140.41, 143.59, 201.03.
HRMS (ESI, Q-ToF): m/z [M + H]+ calcd for C25H15O4: 379.0970;
found: 379.0980.
Compound 20
Following the general procedure using MnO2 gave 20 (21 mg, 55%)
as a yellow solid; mp 171–173 °C; Rf = 0.50 (silica gel, 40%
EtOAc–PE).
HRMS (ESI, Q-ToF): m/z [M + Na]+ calcd for C16H16NaO:
IR (KBr): 1618, 1672, 1706, 1739, 2846, 2920, 3055 cm–1.
247.1093; found: 247.1091.
1H NMR (400 MHz, CDCl3): δ = 3.47 (s, 2 H), 3.97 (s, 2 H), 7.64–
7.68 (m, 3 H), 7.90–7.94 (m, 2 H), 8.05–8.09 (m, 4 H), 8.36 (d, J =
7.88 Hz, 1 H), 8.82 (s, 1 H), 8.72 (s, 1 H).
6′-Methoxy-3-vinyl-3′,4′-dihydrospiro[cyclopent-3-ene-1,2′-
naphthalen]-1′-one (16d)
13C NMR (100 MHz, CDCl3): δ = 39.37, 43.47, 59.29, 124.02,
128.35, 129.46, 129.53, 129.68, 129.80, 130.27, 130.32, 130.61,
134.57, 135.26, 135.33, 136.31, 141.71, 143.19, 149.90, 183.05,
184.36, 202.68.
HRMS (ESI, Q-ToF): m/z [M + H]+ calcd for C29H17O4: 429.1127;
found: 429.1138.
Following the general procedure gave 16d (69 mg, 58%) as a yellow
liquid; Rf = 0.74 (silica gel, 50% EtOAc–PE).
IR (neat): 1609, 1640, 1710, 2843, 2922, 3077 cm–1.
1H NMR (400 MHz, CDCl3): δ = 2.15–2.20 (m, 2 H), 2.46–2.59 (m,
2 H), 2.95–3.05 (m, 4 H), 3.86 (s, 3 H), 5.00–5.30 (m, 2 H), 5.64 (s,
1 H), 6.50–6.58 (m, 1 H), 6.68 (d, J = 2.24 Hz, 1 H), 66.83 (dd, J1 =
1.56, J2 = 8.76 Hz, 1 H), 8.04 (d, J = 8.80 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 26.42, 35.12, 40.07, 41.94, 51.59,
55.49, 112.35, 113.35, 114.23, 125.09, 127.91, 130.66, 133.30,
140.31, 145.96, 163.45, 199.91.
Compound 21
Following the general procedure using MnO2 gave 21 (29 mg, 65%)
as a yellow solid; mp 108–110 °C; Rf = 0.42 (silica gel, 40%
EtOAc–PE).
HRMS (ESI, Q-ToF): m/z [M + H]+ calcd for C17H19O2: 255.1380;
found: 255.1379.
IR (KBr): 1593, 1714, 1742, 2925, 3055 cm–1.
© Georg Thieme Verlag Stuttgart · New York
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1H NMR (400 MHz, CDCl3): δ = 3.46 (s, 2 H), 3.71 (s, 2 H), 7.37–
7.43 (m, 3 H), 7.48–7.52 (m, 2 H), 7.63 (d, J = 7.57 Hz, 1 H), 7.85
(d, J = 7.56 Hz, 1 H), 7.91–7.94 (m, 2 H), 8.03–8.06 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 39.01, 40.03, 59.36, 123.47,
124.11, 126.82, 127.30, 128.22, 129.28, 129.70, 131.33, 131.92,
136.50, 139.26, 141.53, 149.85, 167.51, 202.05.
HRMS (ESI, Q-ToF): m/z [M + Na]+ calcd for C19H18N4NaO4:
389.1220; found: 389.1226.
Compound 26
Following the general procedure using DDQ gave 26 (146 mg,
73%) as a thick colorless liquid; Rf = 0.44 (silica gel, 25% EtOAc–
PE).
HRMS (ESI, Q-ToF): m/z [M + H]+ calcd for C25H16NO4: 394.1079;
found: 394.1088.
IR (neat): 1591, 1730, 2854, 2926, 3019 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.25 (t, J = 7.12 Hz, 6 H), 3.63 (s,
2 H), 3.66, (s, 2 H), 3.87, (s, 3 H), 3.93, (s, 3 H), (q, J1 = 7.08 Hz,
J2 = 14.20 Hz, 4 H), 7.32 (d, J = 7.88 Hz, 1 H), 7.43 (d, J = 7.88 Hz,
1 H).
13C NMR (100 MHz, CDCl3): δ = 14.07, 39.34, 40.43, 52.59, 52.69,
60.07, 62.10, 125.75, 128.37, 129.02, 130.40, 139.44, 145.61,
166.99, 168.56, 171.07.
Compound 22
Following the general procedure using MnO2 gave 22 (62 mg, 76%)
as a yellow solid; mp 119–120°C; Rf = 0.42 (silica gel, 50% EtOAc–
PE).
IR (KBr): 1597, 1709, 1722, 2923, 3049 cm–1.
1H NMR (400 MHz, CDCl3): δ = 3.40 (s, 2 H), 3.43, (s, 2 H), 3.86,
(s, 3 H), 3.89, (s, 3 H), 7.35–7.37 (m, 1 H), 7.77 (d, J = 7.89 Hz, 1
H), 7.89–7.52 (m, 2 H), 8.01–8.05 (m, 2 H).
HRMS (ESI, Q-ToF): m/z [M + Na]+ calcd for C19H22NaO8:
401.1207; found: 401.1209.
13C NMR (100 MHz, CDCl3): δ = 40.04, 40.27, 52.65, 52.71, 58.54,
123.98, 125.95, 129.17, 129.36, 130.10, 136.31, 140.03, 141.52,
146.08, 167.28, 168.39, 202.21.
HRMS (ESI, Q-ToF): m/z [M + H]+ calcd for C21H17O6: 365.1025;
found: 365.1024.
Compound 27
Following the general procedure gave 27 (58 mg, 72%) as a white
solid; mp 126–127 °C; Rf = 0.77 (silica gel, 50% EtOAc–PE).
IR (neat): 1643, 1708, 2254, 2944, 3165 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.96–2.07 (m, 1 H), 2.51 (d, J =
16.6 Hz, 1 H), 2.72 (dd, J1 = 8.44, Hz, J2 = 13.04 Hz, 1 H), 2.93 (d,
J = 16.61 Hz, 1 H), 3.16–3.32 (m, 4 H), 3.95–3.99 (br, 1 H), 5.68–
5.70 (br, 1 H), 7.42–7.47 (m, 2 H), 7.66 (dt, J1 = 1.16 Hz, J2 = 7.60
Hz, 1 H), 7.79 (d, J = 7.64 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 33.76, 38.53, 38.71, 42.04, 42.79,
43.64, 52.91, 109.23, 110.53, 110.84, 111.45, 112.93, 124.92,
126.57, 128.35, 134.68, 135.91, 139.20, 152.01, 208.19.
Compound 23
Following the general procedure gave 23 (19 mg, 60%) as a yellow
solid; mp 148–149 °C; Rf = 0.41 (silica gel, 40% EtOAc–PE).
IR (KBr): 1597, 1742, 2925, 3060 cm–1.
1H NMR (400 MHz, CDCl3): δ = 2.31 (t, J = 12.7 Hz, 1 H), 2.48–
2.53 (m, 1 H), 2.80–2.93 (m, 2 H), 3.19–3.32 (m, 2 H), 3.98–3.99
(br, 1 H), 5.74–5.75 (m, 1 H), 7.91–7.96 (m, 2 H), 8.02–8.08 (m, 2
H).
HRMS (ESI, Q-ToF): m/z [M + Na]+ calcd for C21H14N4NaO:
361.1060; found: 361.1063.
13C NMR (100 MHz, CDCl3): δ = 33.61, 36.42, 36.99, 38.36, 42.33,
44.16, 55.48, 108.16, 110.29, 110.54, 111.08, 113.69, 123.92,
124.19, 136.67, 136.71, 137.33, 140.60, 141.40, 200.07, 201.90.
HRMS (ESI, Q-ToF): m/z [M + Na]+ calcd for C21H12N4O2Na:
375.0858; found: 375.0862.
Compound 28
Following the general procedure using DDQ gave 28 (39 mg, 59%)
as a white solid; mp 110–112 °C; Rf = 0.64 (silica gel, 50% EtOAc–
PE).
IR (neat): 1639, 1730, 2944, 3004 cm–1.
Compound 24
Following the general procedure gave 24 (38 mg, 81%) as a white
solid; mp 245–247 °C; Rf = 0.5 (silica gel, 50% EtOAc–PE).
1H NMR (400 MHz, CDCl3): δ = 2.90–2.99 (m, 2 H), 3.14–3.24 (m,
2 H), 3.48–3.57 (m, 2 H), 3.88 (s, 3 H), 3.89 (s, 3 H), 7.35 (d, J =
7.80 Hz, 1 H), 7.38–7.46 (m, 2 H), 7.62–7.66 (m, 1 H), 7.81 (dd,
J1 = 7.64, Hz J2 = 14.88 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 43.71, 43.76, 43.86, 44.57, 52.64,
57.37, 124.63, 125.89, 126.81, 127.96, 128.15, 129.07, 130.87,
135.41, 136.02, 140.88, 147.35, 152.43, 167.11, 168.85, 208.21.
IR (KBr): 1599, 1742, 1772, 2920, 3060 cm–1.
1H NMR (400 MHz, CDCl3): δ = 2.38 (t, J = 11.8 Hz, 1 H), 2.86–
2.96 (m, 3 H), 4.18 (d, J = 16.6 Hz, 1 H), 4.53 (d, J = 16.7 Hz, 1 H),
4.79 (br, 1 H), 5.89 (br, 1 H), 7.44–7.60 (m, 5 H), 7.99–8.00 (m, 2
H), 8.10–8.12 (br, 2 H).
13C NMR (100 MHz, CDCl3): δ = 35.22, 39.26, 43.02, 56.78, 57.69,
113.54, 123.86, 124.09, 125.72, 128.36, 129.33, 131.24, 136.37,
136.47, 137.52, 141.11, 141.70, 151.73, 153.90, 202.00, 202.98.
HRMS (ESI, Q-ToF): m/z [M + Na]+ calcd for C21H18NaO5:
373.1046; found: 373.1046.
Compound 29
HRMS (ESI, Q-ToF): m/z [M + H]+ calcd for C23H18N3O4:
400.1297; found: 400.1280.
Following the general procedure using DDQ gave 29 (11 mg, 69%)
as a white semi solid; Rf = 0.72 (silica gel, 50% EtOAc–PE).
IR (neat): 1650, 1719, 2987, 3054 cm–1.
Compound 25
Following the general procedure gave 25 (110 mg, 85%) as a thick
colorless liquid; Rf = 0.52 (silica gel, 25% EtOAc–PE).
1H NMR (400 MHz, CDCl3): δ = 2.22 (t, J = 6.52 Hz, 2 H), 2.96–
3.13 (m, 4 H), 3.45 (d, J = 16.76 Hz, 1 H), 3.61 (d, J = 16,73 Hz, 1
H), 3.88 (s, 6 H), 7.31–7.35 (m, 3 H), 7.51 (t, J = 7.40 Hz, 1 H), 7.75
(d, J = 7.88 Hz, 1 H), 8.04 (d, J = 7.84 Hz, 1 H).
13C NMR (125 MHz, CDCl3): δ = 26.17, 34.10, 40.05, 41.71, 52.60,
52.67, 53.57, 126.10, 127.08, 128.09, 128.51, 128.97, 128.99,
130.98, 131.48, 133.70, 140.45, 143.41, 147.30, 167.21, 169.04,
199.88.
IR (neat): 1655, 1730, 2984, 3020 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.06 (dt, J1 = 4.12 Hz, J2 = 7.16
Hz, 6 H), 2.25–2.32 (m, 1 H), 2.99–3.08 (m, 1 H), 3.12–3.25 (m, 4
H), 3.45–3.49 (br, 1 H), 4.19–4.32 (m, 4 H), 5.68 (t, J = 2.24 Hz, 1
H).
13C NMR (100 MHz, CDCl3): δ = 14.04, 14.07, 33.48, 36.17, 37.83,
38.40, 42.35, 43.73, 57.18, 62.60, 62.76, 108.43, 110.48, 110.64,
111.19, 113.69, 136.89, 169.61, 170.61.
HRMS (ESI, Q-ToF): m/z [M + Na]+ calcd for C22H20NaO5:
387.1203; found: 387.1202.
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Design and Synthesis of Angularly Annulated Spirocyclics
2479
Synthesis of Compound 30
gel, 5% EtOAc–PE) to deliver 35 (87 mg, 59%) as a white solid; mp
138–139 °C; Rf = 0.73 (silica gel, 5% EtOAc–PE).
IR (neat): 1596, 1705, 1741, 2936, 3017 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.49–1.54 (m, 4 H), 1.76–1.81 (m,
4 H), 2.58 (s, 4 H), 5.30–5.54 (m, 6 H), 7.73 (dd, J1 = 2.64 Hz, J2 =
5.72 Hz, 2 H), 7.85 (dd, J1 = 3.08 Hz, J2 = 5.64 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 21.78, 22.24, 41.55, 60.55,
122.62, 125.84, 126.99, 127.79, 130.87, 135.19, 143.52, 204.22.
To a solution of diene 16c (50 mg, 0.22 mmol) in toluene (20 mL),
tetracyanoethylene (43 mg, 0.33 mmol) was added and the mixture
was refluxed for 12 h. At the conclusion of the reaction (TLC mon-
itoring), the solvent was removed under reduced pressure and the
crude product was purified by column chromatography ( silica gel,
40% EtOAc–PE) to furnish 30 (71 mg, 91%) as a white semisolid;
Rf = 0.73 (silica gel, 50% EtOAc–PE).
IR (neat): 1601, 1678, 2255, 2929, 3020 cm–1.
HRMS (ESI, Q-ToF): m/z [M + H]+ calcd for C23H23O2: 331.1693;
found: 331.1694.
1H NMR (400 MHz, CDCl3): δ = 1.81 (t, J = 11.96 Hz, 1 H), 2.22
(t, J = 6.20 Hz, 2 H), 2.47 (d, J = 17.45 Hz, 1 H), 2.72–2.77 (m, 1
H), 3.01–3.25 (m, 5 H), 3.71 (br, 1 H), 5.63 (s, 1 H), 7.27 (d, J =
7.28 Hz, 1 H), 7.35 (t, J = 7.52 Hz, 1 H), 7.53 (t, J = 6.96 Hz, 1 H),
8.06 (d, J = 7.72 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 26.45, 33.73, 35.47, 38.17, 38.46,
39.14, 42.82, 43.88, 50.59, 109.04, 110.56, 110.89, 111.51, 112.85,
127.33, 128.62, 128.93, 130.35, 134.23, 138.97, 143.17, 199.93.
2,2-Dibenzyl-1H-indene-1,3(2H)-dione (36)
The solution of 35 (50 mg, 0.15 mmol) and DDQ (50 mg, 0.15
mmol) in toluene (20 mL) was refluxed for 18 h. At the conclusion
of the reaction (TLC monitoring), the solvent was removed under
reduced pressure and the crude product was purified by column
chromatography (silica gel, 4% EtOAc–PE) to furnish 36 (46 mg,
94%) as a white solid. The 1H and 13C NMR spectra matched with
the literature data.22
HRMS (ESI, Q-ToF): m/z [M + Na]+ calcd for C22H16NaN4O:
375.1216; found: 375.1214.
Compound 31
Acknowledgment
Following the general procedure using DDQ gave 31 (47 mg, 75%)
as a white solid; mp 130–132 °C; Rf = 0.36 (silica gel, 40% EtOAc–
PE).
We are grateful to DST-New Delhi for the financial support. R.A.
thanks University Grants Commission, New Delhi for the award of
research fellowship. S.K. thanks the Department of Science and
Technology for the award of a J. C. Bose fellowship. We are also
thankful to SAIF IIT Bombay for providing the spectral data.
IR (neat): 1671, 1725, 2952, 3020 cm–1.
1H NMR (500 MHz, CDCl3): δ = 2.18 (t, J = 6.40 Hz, 2 H), 2.93–
3.10 (m, 4 H), 3.44 (d, J = 16.75 Hz, 1 H), 3.59 (d, J = 16.70 Hz, 1
H), 3.86 (s, 3 H), 3.87 (s, 3 H), 3.88 (s, 3 H), 6.70 (s, 1 H), 6.85 (dd,
J1 = 1.85 Hz, J2 = 8.65 Hz, 1 H), 7.31 (d, J = 7.80 Hz, 1 H), 7.74 (d,
J = 7.85 Hz, 1 H), 8.02 (d, J = 8.75 Hz, 1 H).
13C NMR (125.8 MHz, CDCl3): δ = 26.50, 34.13, 40.19, 41.82,
52.58, 52.64, 53.27, 55.63, 112.58, 113.70, 124.96, 126.04, 127.86,
128.89, 130.88, 130.93, 140.52, 145.88, 147.46, 163.85, 167.17,
169.08, 198.74.
Supporting Information for this article is available online
at
http://www.thieme-connect.com/products/ejournals/journal/
10.1055/s-00000084.SunogIpimrfiantoSuIpg
n
fonirtat
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References
HRMS (ESI, Q-ToF): m/z [M + Na]+ calcd for C23H22NaO6:
417.1309; found: 417.1308.
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Compound 32
Following the general procedure gave 32 (54 mg, 79%) as a white
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2,2-Bis[(cyclohexa-1,5-dienyl)methyl]-1H-indene-3(2H)-dione
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© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 2471–2480

2480
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Synthesis 2014, 46, 2471–2480
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