Diversity-oriented approach to novel spirocyclics via enyne metathesis, diels-alder reaction, and a [2+2+2] cycloaddition as key steps

Article abstract of DOI:10.1055/s-0033-1339489

A simple protocol for the synthesis of indane-based spirocyclics has been developed via enyne metathesis, Diels-Alder reaction, and a [2+2+2] cycloaddition as key steps starting from indane-1,3-dione. The key diene building block was assembled by enyne metathesis. In this sequence, rongalite is used as a green reagent to prepare the sultine intermediate, which is a useful precursor to generate the transient diene.

Full text of DOI:10.1055/s-0033-1339489

LETTER
▌1921
lDettierversity-Oriented Approach to Novel Spirocyclics via Enyne Metathesis,
Diels–Alder Reaction, and a [2+2+2] Cycloaddition as Key Steps
Diversity-Oriented Approach to Novel 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: 20.03.2013; Accepted after revision: 09.07.2013
This paper is dedicated to the memory of Professor A. Srikrishna, Department of Organic Chemistry, Indian Institute of Science, Banga-
lore, India.
H
Abstract: A simple protocol for the synthesis of indane-based spi-
rocyclics has been developed via enyne metathesis, Diels–Alder re-
action, and a [2+2+2] cycloaddition as key steps starting from
indane-1,3-dione. The key diene building block was assembled by
enyne metathesis. In this sequence, rongalite is used as a green re-
agent to prepare the sultine intermediate, which is a useful precursor
to generate the transient diene.
N
O
HO
H
H
H
H
O
O
OH
OH
O
MeO
O
Keywords: spirocyclic compounds, [2+2+2]-cycloaddition reac-
tion, rongalite, enyne metathesis, Diels–Alder reaction
fredericamycin (1)
fenestrindane (2)
Figure 1
Indane derivatives1 are useful building blocks for the syn-
thesis of several natural and non-natural products.2
Hudlicky has remarked that generation of a spiro center is
a highly difficult task because it involves the creation of a
quaternary center.3 Many intricate compounds, such as
fredericamycin,4 fenestrindane5 (Figure 1), alicyclic
[5.5.5.5]fenestrane,6 and spiranes,7 contain the spiro link-
age as a core structural element.
There are several approaches to synthesize spirocycles.8
These methods include alkylation,9 transition-metal-
based strategies,10 rearrangement-based approaches,11
radical-mediated procedures,12 and ring-closing metathe-
sis.13 However, some of these methods have severe limi-
tations due to functional-group incompatibility and may
also be restricted to a limited substitution pattern. There-
fore, there remains a need to design new and simple syn-
thetic strategies to spirocyclics where the newly generated
functionality at the end of the sequence can be used for ad-
ditional synthetic transformations. Several intricate natu-
ral and non-natural products have been synthesized using
an atom-economic ring-closing enyne metathesis as a key
step.14 In connection with our interest to generate new
synthetic methods to spirocyclics,8f we had shown that the
diene building block 3 can provide linearly annulated spi-
ro indane derivatives with various dienophiles such as di-
methyl acetylenedicarboxylate 4 when the aromatized
product 5 was obtained directly under toluene reflux con-
ditions.16d Alternatively, a [2+2+2]-cycloaddition se-
quence was also applied to synthesize linearly annulated
indane-based spiro derivatives containing silicon substit-
uents (Scheme 1).
To expand the building-block approach8c to various spiro-
cyclics, we have identified that the diene building blocks
9 and 10 are suitable to generate a library of spiro indane
O
O
CO2Me
CO2Me
Δ
+
CO2Me
CO2Me
O
O
5
3
4
O
O
O
TMS
TMS
CpCo(CO)2
+
TMS
TMS
O
7
6
8
Scheme 1 Indane-based spirocyclic compounds by [4+2] and [2+2+2] approach
SYNLETT 21709013, 2415, 1921–1926
Advanced online publication: 14.08.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1339489; Art ID: ST-2013-D0252-L
© Georg Thieme Verlag Stuttgart · New York

1922
S. Kotha et al.
LETTER
derivatives (Figure 2) by the application of the Diels– the monoallylation of 11, various conditions involving the
Alder reaction.
different bases were attempted. However, under these
conditions the formation of the diallyl compound seems to
be unavoidable. After considerable experimentation, by
using 20% aq KOH as a base and catalytic amount of cop-
per powder, monoallylated product (34%) along with un-
identified material was obtained. Therefore, we attempted
initial monopropargylation followed by allylation to syn-
thesize the enyne building block 12. First we performed
the propargylation reaction with 20% aqueous KOH and a
catalytic amount of copper powder at room temperature
for 24 hours but obtained the dipropargylated compound
as a major product. However, when the dione 11 was
treated with 10% aqueous KOH and a catalytic amount of
copper powder at room temperature for 72 hours, we ob-
tained the monopropargylated compound 17 in 56% yield
(Scheme 3). Next, we successfully generated the enyne
building block 12 by allylation of 17 using K2CO3 as a
base (Scheme 3).
O
O
O
O
9
10
Figure 2 Building blocks identified in our present strategy
To this end, we envisaged a new and general methodology
for assembling linearly as well as angularly fused indane
derivatives starting with the indane-1,3-dione 11 by using
a sequential enyne metathesis and Diels–Alder reactions
(Scheme 2, route A) or alternatively a [2+2+2] cycloaddi-
tion and Diels–Alder reaction (Scheme 2, route B) as key
steps.
In the Diels–Alder based sequence, it is necessary to use
dienophiles containing electron-withdrawing groups (e.g.,
4) and thus transformation of 5 into 14 requires protection
and deprotection steps. On the other hand, following the
[2+2+2]-cycloaddition strategy, it is possible to employ 2-
butyne-1,4-diol (15). Therefore, a [2+2+2]-cycloaddition
strategy to generate the key building block 14 avoids pro-
tection–deprotection steps and thus incorporates redox
and step-economy into the overall process.15,16
The enyne building block 12 was then subjected to the
ring-closing enyne metathesis. Initially, by using the
Grubbs first-generation (G-I) or Grubbs second-genera-
tion (G-II) catalyst without any additives, the desired
product was obtained in low yield [G-I (19%) and G-II
(27%)]. Based on Fürstner’s report,17 to facilitate the me-
tathesis, we used a catalytic amount of titanium
isopropoxide18 and better yields of the diene 9 [G-I (32%)
and G-II (34%)] were observed. In addition, Mori’s
group19 has reported that ethylene has a beneficial effect
in metathesis sequence and, in this instance, the yield in-
creased to 48% (Scheme 4).
Our strategy towards the synthesis of an angularly func-
tionalized indane-based spirocyclic system such as 13 be-
gan with the monoallylation or monopropargylation of the
commercially available indane-1,3-dione 11. To realize
O
O
O
O
route A
O
6
9
OH
OH
O
O
O
13
12
11
O
O
O
O
route B
OH
OH
10
O
O
14
16
Scheme 2 Retrosynthetic analysis of indane-based spirocyclics
O
O
O
10% aq KOH
Cu powder
K2CO3, TBAHS
allyl bromide
MeCN, r.t., 12 h
68%
11
propargyl bromide
r.t., 72 h, 56%
O
12
17
Scheme 3 Synthesis of enyne building block 12
Synlett 2013, 24, 1921–1926
© Georg Thieme Verlag Stuttgart · New York

LETTER
Diversity-Oriented Approach to Novel Spirocyclics
1923
R
O
O
O
O
R
G-II (7.5 mol%)
Ti(Oi-Pr)4
R
(i) toluene, Δ
+
ethylene
CH2Cl2, r.t.
16 h, 48%
(ii) MnO2
1,4-dioxane
Δ, 49–81%
R
O
O
18
12
9
Scheme 4 Diels–Alder reaction of diene 9 with various dienophiles
O
O
K2CO3, TBAHS
RhCl(PPh3)3
MeCN
15, Ti(Oi-Pr)4
6
11
propargyl bromide
reflux, 12 h, 78%
EtOH, reflux
24 h
O
O
25 (7%)
+
Br
Br
OH
OH
O
O
O
O
rongalite
TBAB
PBr3
O
S
benzene
O
DMF, r.t.
6 h, 75%
r.t., 26 h
54%
O
O
26
27
Δ
14 (46%)
O
O
O
i. toluene
R
R
R
ii. DDQ, toluene
Δ, 61–81%
R
O
28
10
Scheme 5 Synthesis of spiro-indane derivatives via diene 10
Next, the inner–outer diene building block 920 has been dehydrogenated with 2,3-dichloro-5,6-dicyano-1,4-ben-
subjected to Diels–Alder reaction with various dieno- zoquinone (DDQ) in refluxing toluene to deliver the aro-
philes in refluxing toluene to generate the corresponding matized products (Table 2).
adducts shown in Scheme 4 (R = electron-withdrawing
In conclusion, we have developed a highly efficient and
group). Since the adducts were contaminated with the aro-
simple method for the synthesis of linearly as well as an-
matized product, no attempt has been made to character-
gularly annulated indane-based spirocyclic compounds
ize them. Instead they were subjected to oxidation with
starting from indane-1,3-dione 11. This strategy generates
MnO2 in 1,4-dioxane to deliver the corresponding aroma-
complex architectures in reasonable overall yield in a di-
tized spirocyclics (Table 1). Towards the synthesis of the
versity-oriented manner.23 Since there are several diversi-
linearly functionalized indane-based spirocyclics such as
ty points incorporated in our strategy, this approach can
16 the same starting material indane-1,3-dione 11
provide a library of spirocycles and the multiple bond-
(Scheme 5) was used and the dipropargylated compound
forming sequence increases the brevity and diversity.
6 was obtained under propargyl bromide/K2CO3 condi-
Overall, these protocols provide a new way of
tions in good yield.16d Subsequently, a [2+2+2] cycloaddi-
benzannulation24 involving spirocyclic molecules. For the
tion of compound 6 with 2-butyne-1,4-diol (15) in dry
first time, we have shown that Ti(Oi-Pr)4 plays a useful
ethanol in the presence of Wilkinson’s catalyst gave diol
role in the Wilkinson’s catalyst mediated [2+2+2]-cyclo-
addition sequence.
14 in 39% yield along with a small amount (4%) of the di-
mer 25. Since Ti(Oi-Pr)4 facilitates enyne metathesis, a
similar role in a [2+2+2]-cycloaddition sequence was an-
Acknowledgment
ticipated. When Ti(Oi-Pr)4 was used in catalytic amount,
the yield of diol 14 increased to 46% along with a minor
amount (7%) of dimer 25. Compound 14 was then con-
R.A. thanks the University Grants Commission, New Delhi for the
award of research fellowship. S.K. thanks the Department of Sci-
verted into the dibromo derivative 26 using PBr3 in dry ence and Technology for the award of a J. C. Bose fellowship. We
also thank DST-New Delhi for the financial support and the review-
ers for their valuable suggestions.
benzene at room temperature for 26 hours, and the dibro-
mide was converted into the sultine derivative 27 by treat-
ing with rongalite in dimethylformamide.21 The diene
intermediate 10 was generated from sultine 27 in reflux-
ing toluene and trapped with various dienophiles to deliv-
er the corresponding adducts. These adducts were
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1921–1926

1924
S. Kotha et al.
LETTER
Table 2 Diels–Alder Reaction of 10 with Different Dienophiles
Table 1 Diels–Alder Products of 9 with Different Dienophiles
Entry Dienophile Product
Yield
(%)
Entry Dienophile
Product
Yield
(%)
O
CO2Me
CO2Me
O
CO2Me
CO2Me
CO2Me
CO2Me
76a
1
63a
1
O
O
CO2Me
O
O
CO2Me
29
19
20
O
O
O
O
O
2
61a
2
57a
O
O
O
O
O
O
O
16
O
N
O
Ph
O
O
N
O
Ph
3
4
68a
O
O
O
O
3
49a
O
30
CN
CN
O
O
NC
NC
CN
CN
CN
21
81
CN
O
31
O
a Combined yield of Diels–Alder reaction and aromatization steps.
O
O
4
55a
O
References and Notes
O
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13
22
Ph
O
N
O
O
O
O
5
65a
N
Ph
O
Ph
O
N
O
O
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N
O
N
N
N
622
81
60
N
Ph
O
O
30
31
CN
(3) Hudlicky, T.; Reed, J. W. The Way of Synthesis; Wiley-
VCH: Weinheim, 2007, 98.
NC
O
CN
CN
NC
NC
CN
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CN
O
a Combined yield of Diels–Alder reaction and aromatization steps.
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Synlett 2013, 24, 1921–1926
© Georg Thieme Verlag Stuttgart · New York

LETTER
Diversity-Oriented Approach to Novel Spirocyclics
1925
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1988, 46, 416.
HRMS (ESI, Q-ToF): m/z calcd for C15H13O2 [M + H]+:
225.0916; found: 225.0912.
General Procedure for the Diels–Alder Reaction of 9 and
Subsequent Aromatization
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To a solution of diene building block 9 in toluene (20 mL)
was added dienophile (1.5 equiv), and the reaction mixture
was heated at 110–120 °C for 24–36 h. Then, the solvent was
concentrated under reduced pressure, and the crude product
was purified by silica gel column chromatography by using
EtOAc–PE (40:60) to afford the Diels–Alder adduct. Later,
aromatization of the Diels–Alder adduct was carried out
with 10 equiv activated MnO2 in 1,4-dioxane (25 mL) at
reflux temperature for 20–24 h. The solvent was then
removed at reduced pressure, and the crude product was
purified by column chromatography using EtOAc–PE
(40:60) to afford aromatized products.
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Garratt, S.; Fawcett, J.; Russell, D. R.; Ghosh, S. Angew.
Chem. Int. Ed. 1998, 37, 3298. (b) Kotha, S.; Manivannan,
E.; Sreenivasachary, N.; Ganesh, T.; Deb, A. C. Synlett
1999, 1618.
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S.; Meshram, M.; Tiwari, A. Chem. Soc. Rev. 2009, 38,
2065. (e) Kotha, S.; Mandal, K. Chem. Asian J. 2009, 4, 354.
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Rev. 2009, 38, 3010.
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100, 2901. (c) Kotha, S.; Sreenivasacharry, N. Bioorg. Med.
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Compound 13
Yellow solid; mp 171–173 °C; Rf = 0.50 (silica gel, 40%
EtOAc–PE). 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). 13C NMR (100 MHz, CDCl3): δ = 39.37, 43.47,
59.29, 124.02, 128.35, 129.47, 129.53, 129.68, 129.80,
130.27, 130.33, 130.62, 134.58, 135.27, 135.34, 136.31,
141.72, 143.20, 149.91, 183.06, 184.37, 202.68. IR (KBr):
1706, 1739, 2846, 2920, 3055 cm–1. HRMS (ESI, Q-ToF):
m/z calcd for C29H17O4 [M + H]+: 429.1127; found:
429.1138.
General Procedure for [2+2+2] Cycloaddition
A solution of compound 6 (500 mg, 2.25 mmol) and 15 (968
mg, 11.25 mmol) in dry EtOH (50 mL) was degassed with
nitrogen for 15 min, afterwards Wilkinson’s catalyst (62 mg,
3.0 mol%) and Ti(Oi-Pr)4 (103 mg, 25 mol%) were added,
and the reaction mixture was heated at 75–80 °C for 24 h.
After completion of the reaction (TLC monitoring), the
solvent was concentrated at reduced pressure, and the crude
product was purified by silica gel column chromatography
using EtOAc–PE (20:80) to give the white solid compound
25 (70 mg, 7%) and continued elution with EtOAc–PE
(60:40) gave a white solid 14 (320 mg, 46%)
Compound 14
Mp 112–114 °C; Rf = 0.32 (silica gel, 40% EtOAc–PE).
1H NMR (400 MHz, CDCl3): δ = 3.29 (s, 4 H), 4.69 (s, 4 H),
7.27 (s, 2 H), 7.95–8.03 (m, 4 H). 13C NMR (100 MHz,
CDCl3): δ = 41.30, 60.34, 63.15, 124.62, 125.20, 137.42,
139.65, 141.52, 142.88, 204.50. IR (KBr): 1598, 1744, 2987,
3054, 3304 3692 cm–1. HRMS (ESI, Q-ToF): m/z calcd for
C19H16O4Na [M + Na]+: 331.0946; found: 331.0933.
Compound 25
(19) (a) Mori, M.; Sakakibara, N.; Kinoshita, A. J. Org. Chem.
1998, 63, 6082. (b) Kitamura, T.; Mori, M. Org. Lett. 2001,
3, 1161.
Mp 187–190 °C; Rf = 0.60 (silica gel, 40% EtOAc–PE). 1H
NMR (400 MHz, CDCl3): δ = 1.74–1.75 (br, 1 H), 2.73–2.74
(br, 2 H), 3.07 (s, 2 H), 3.08 (s, 4 H), 6.78–6.80 (m, 3 H),
7.73–7.75 (m, 2 H), 7.80–7.84 (m, 4 H), 7.92–7.94 (m, 2 H).
13C NMR (100 MHz, CDCl3) δ = 24.00, 40.30, 40.52, 58.85,
58.93, 71.65, 78.48, 123.06, 123.77, 123.99, 125.73, 129.00,
134.00, 135.96, 136.03, 139.26, 140.77, 141.52 142.77,
202.36, 202.92. IR (KBr): 1708, 1738, 2160, 2929, 3054 cm–
1. HRMS (ESI, Q-ToF): m/z calcd for C30H21O4 [M + H]+:
445.1440; found: 445.1425.
(20) Preparation of 9
The enyne 12 (140 mg, 0.63 mmol) in dry CH2Cl2 (20 mL)
was degassed with nitrogen for 10 min, G-II catalyst (39 mg,
7.5 mol%) and Ti(Oi-Pr)4 (23 mg, 20 mol%) were added,
and the reaction vessel was kept under ethylene pressure
(balloon pressure). The reaction mixture was stirred at r.t. for
16 h. After completion of the reaction (TLC monitoring), the
solvent was concentrated, and the crude product was purified
by silica gel column chromatography using EtOAc–PE
(3:93) to give the white solid compound 9 (67 mg, 48%); mp
123–124 °C; Rf = 0.41 (silica gel, 20% EtOAc–PE). 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. IR (KBr): 1597, 1742, 2854, 2923, 3011 cm–1.
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