Synthesis of angularly fused carbocycles via tandem radical cyclization of α-carbonyl radicals

Article abstract of DOI:10.1002/ejoc.200700986

An α-carbonyl radical cyclization approach towards the synthesis of angularly fused tricyclic systems is described. On reduction with tributyltin hydride, bromo ketones yield a α-carbonyl radical that undergoes successive 5-exo-dig/trig cyclizations, resu

Full text of DOI:10.1002/ejoc.200700986

FULL PAPER
DOI: 10.1002/ejoc.200700986
Synthesis of Angularly Fused Carbocycles via Tandem Radical Cyclization of
α-Carbonyl Radicals
Chandran Prakash[a] and Arasambattu K. Mohanakrishnan*[a]
Keywords: Radicals / Cyclization / Polycycles
An α-carbonyl radical cyclization approach towards the syn-
thesis of angularly fused tricyclic systems is described. On
reduction with tributyltin hydride, bromo ketones yield a α-
carbonyl radical that undergoes successive 5-exo-dig/trig cy-
clizations, resulting in two or four contiguous stereocenters.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
to be cumbersome. Additionally, we found it difficult to re-
produce the iodination of silyl enol ether when using the
existing NaI/mCPBA protocol.[9] On the other hand, even
though, in some cases the α-iodo cycloalkanones were pre-
pared using Sha’s procedure in reasonable yields, they are
highly unstable and photo-labile. In particular, tertiary α-
iodo ketone undergoes extensive decomposition even at
room temperature (Figure 1).
Introduction
Tandem-cyclization strategies for the synthesis of angu-
larly fused carbocycles[1,2] have gained considerable promi-
nence since these frameworks exist in many natural prod-
ucts. The tandem construction of the rings can provide an
inherently efficient approach to the synthesis of an angu-
larly fused tricyclic system if the stereochemistry is con-
trolled. Thus, tandem radical cyclization[3] ranks among the
most powerful methods to construct a tricyclic ring system
in a single step from a monocyclic precursor. During the
last fifteen years, Sha and co-workers exploited the α-car-
bonyl radical cyclization strategy to synthesize several natu-
ral products, including (Ϯ)-modhephene,[4a] (–)-dendrobi-
ne,[4b] (–)-5-oxosilphiperfol-6-ene,[4c] dimethyl gloiosphone
A[4d] and (+)-paniculatine.[4e] The syntheses of these natural
products were achieved by homolytic Bu3SnH-mediated
cleavage of the corresponding α-iodo cycloalkanones fol-
lowed by intramolecular cyclization.
Results and Discussion
The angular tricyclic framework has received prominent
attention among synthetic chemists. Several elegant strate-
gies reported[5] for such ring systems are based on a tandem
radical cyclization. Hence, a systematic study was under-
taken to synthesize the angular tricyclic skeletons 1–3 of
the natural products agariblazeispirol C,[6] dankasterone[7]
and laurenene[8] following the α-carbonyl radical cyclization
approach established by Sha and co-workers.[4]
Figure 1. Natural products containing angular tricyclic units.
We believe that the labile nature of α-iodo cycloalk-
anones is a bottleneck for applying the α-carbonyl radical
cyclization strategy to the synthesis of core skeleton of the
above-mentioned natural products. In this regard, we have
recently reported a facile preparation of α-bromo and α-
iodo cycloalkanones using NaX/FeCl3.[10] As expected, rel-
atively, the α-bromo cycloalkanones were found to be more
stable.
Towards the realization of this objective, all our attempts
to prepare the required α-iodo cycloalkanones were found
[a] Department of Organic Chemistry, University of Madras,
Guindy, Campus,
Initially, we tested the tandem radical cyclization ap-
proach with the synthesis of 6–5–5 angular tricyclic sys-
tems[4e] 7a and 7b (Scheme 1). A CuI-promoted 1,4-ad-
Chennai 600025, Tamil Nadu, India
Fax: +91-44-22352494
E-mail: mohan_67@hotmail.com
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C. Prakash, A. K. Mohanakrishnan
FULL PAPER
dition of 4-(trimethylsilyl)-3-butynylmagnesium bromide to
enones[11,12] 4a and 4b followed by trapping of the resulting
enolate with trimethylsilyl chloride afforded silyl enol ether
5a and 5b, which on bromination using KBr/mCPBA or
NaBr/FeCl3 delivered bromo compounds 6a and 6b in good
yields. On treatment of 6a/6b with tributyltin hydride and
AIBN in benzene at reflux temperature through slow ad-
dition using a syringe pump technique (see Exp. Section),
tandem radical cyclization occurred smoothly to afford
angular 6–5–5 tricyclic systems 7a/7b in 62 and 66% yields,
respectively, through a combination of 5-exo-dig and 5-exo-
trig cyclizations.
Scheme 2. Reagents and conditions: (a) (i) 4-(bromobut-1-ynyl)tri-
methylsilane; (ii) CuI, –78 °C; (iii) TMSCl, –78 °C; (iv) Et3N,
–78 °C to room temp., 86%; (b) KBr/mCPBA (dry), THF, 0 °C to
room temp., 8 h, 68%; (c) NaBr/FeCl3, CH3CN, 0 °C to room
temp., 4 h, 74%; (d) Bu3SnH/AIBN, syringe addition pump, 6 h,
benzene, 80 °C, 66 %.
Scheme 1. Reagents and conditions: (a) (i) 4-(bromobut-1-ynyl)tri-
methylsilane; (ii) CuI, –78 °C; (iii) TMSCl, –78 °C; (iv) Et3N,
–78 °C to room temp.; (b) KBr/mCPBA (dry), THF, 0 °C to room
temp., 8 h; (c) NaBr/FeCl3, CH3CN, 0 °C to room temp., 4 h; (d)
Bu3SnH/AIBN, syringe addition pump, 6 h, benzene, 80 °C.
Next, the synthesis of the 6–5–6 angular tricyclic skeleton
of dankasterone was planned. The required enone 8 was
prepared using established procedure.[13] The CuI induced
1,4-addition of Grignard reagent to enone 8 followed by
bromination using KBr/mCPBA or NaBr/FeCl3 gave the
bromo compound 10 in 68 and 74% yields, respectively.
Tandem radical cyclization (TRC) of the bromo compound
10 using Bu3SnH/AIBN under high dilution conditions via
syringe addition pump at benzene reflux temperature af-
forded a bicyclic product 11, instead of the expected tricy-
clic product 12 (Scheme 2). We presume that the bicyclic
vinyl radical intermediate 13 might have formed a stable
propargyl radical 14 via [1,5]-H abstraction as observed by
Malacria and co-workers.[14]
Scheme 3. Reagents and conditions: (a) (i) 4-(bromobut-1-ynyl)tri-
methylsilane; (ii) CuI, –78 °C; (iii) TMSCl, –78 °C; (iv) Et3N,
–78 °C to room temp., 87%; (b) KBr/mCPBA (dry), THF, 0 °C to
room temp., 8 h, 65%; (c) NaBr/FeCl3, CH3CN, 0 °C to room
temp., 4 h, 71%; (d) Bu3SnH/AIBN, syringe addition pump, 6 h,
benzene, 80 °C, 56 %.
clohept-2-enone by means of a thioketone protocol[15] pub-
We devised another synthetic route for the synthesis of lished for a six-membered ring system. A customary 1,4-
6–5–6 angular tricyclic system 19. The required bromo addition, followed by bromination, afforded the bromo
compound 17 was prepared by using a known procedure.[13] compound 22, which underwent successive 5-exo-dig and 5-
However, tandem radical cyclization of bromo compound exo-trig radical cyclizations to give the angular tricycle 23
17 also did not lead to the expected tricyclic product 19; in 68% yield.
only reduction product 18 was isolated (Scheme 3). It
The stereochemistry of 23 was confirmed by X-ray crys-
should be noted that radical cyclization of 17 did not pro- tallography analysis, Figure 2.
duce even the corresponding bicyclic product.
Since the natural product laurenene possesses an angular
To generalize the approach, we undertook tandem radi- methyl group, the required α-bromo ketone 26 was pre-
cal cyclization in
a
seven-membered ring system. pared by using an established procedure. Surprisingly, the
(Scheme 4). The required enone 20 was obtained from cy- tandem radical cyclization of bromo compound 26 also
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Synthesis of Angularly Fused Carbocycles
good yields. When the latter was treated with tributyltin
hydride and AIBN in benzene using the syringe-pump tech-
nique, tandem radical cyclization occurred smoothly to af-
ford tetracycle 31 possessing four contiguous stereocenters
in 50% yield along with the reduction product 32 in 20%
yield.
Scheme 4. Reagents and conditions: (a) (i) 4-(bromobut-1-ynyl)tri-
methylsilane; (ii) CuI, –78 °C; (iii) TMSCl, –78 °C; (iv) Et3N,
–78 °C to room temp., 95%; (b) KBr/mCPBA (dry), THF, 0 °C to
room temp., 8 h, 67%; (c) NaBr/FeCl3, CH3CN, 0 °C to room
temp., 4 h, 74%; (d) Bu3SnH/AIBN, syringe addition pump, 6 h,
benzene, 80 °C, 68 %.
Scheme 6. Reagents and conditions: (a) (i) 4-(bromobut-1-ynyl)tri-
methylsilane; (ii) CuI, –78 °C; (iii) TMSCl, –78 °C; (iv) Et3N,
–78 °C to room temp., 92%; (b) KBr/mCPBA (dry), THF, 0 °C to
room temp., 8 h, 65%; (c) NaBr/FeCl3, CH3CN, 0 °C to room
temp., 4 h, 70%; (d) Bu3SnH/AIBN, syringe addition pump, 6 h,
benzene, 80 °C.
Treatment of compound 31 with 2,4-dinitrophenyl hydra-
zine in the presence of sulfuric acid in catalytic proportion
afforded hydrazone 33 as orange crystals suitable for X-ray
Figure 2. ORTEP view of tricyclic compound 23.
did not afford the expected tricyclic product; always the
corresponding radical-quenched product 27 was isolated
(Scheme 5).
Scheme 5. Reagents and conditions: (a) (i) 4-(bromobut-1-ynyl)tri-
methylsilane; (ii) CuI, –78 °C; (iii) TMSCl, –78 °C; (iv) Et3N,
–78 °C to room temp., 95%; (b) KBr/mCPBA (dry), THF, 0 °C to
room temp., 8 h, 63%; (c) NaBr/FeCl3, CH3CN, 0 °C to room
temp., 4 h, 71%; (d) Bu3SnH/AIBN, syringe addition pump, 6 h,
benzene, 80 °C, 57 %.
Finally, synthesis of angular tetracycle possessing four
contiguous stereocenters was planned (Scheme 6). The CuI-
mediated conjugate addition of 4-(trimethylsilyl)-3-butynyl-
magnesium bromide to enone 28 followed by trapping of
the resulting enolate 29 with TMSCl and bromination with
KBr/mCPBA or NaBr/FeCl3 yielded bromo ketone 30 in Figure 3. ORTEP view of tetracyclic compound 33.
Eur. J. Org. Chem. 2008, 1535–1543
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1537

C. Prakash, A. K. Mohanakrishnan
FULL PAPER
{2-Allyl-3-[4-(trimethylsilyl)but-3-ynyl]cyclohex-1-enyloxy}tri-
methylsilane (5a): To a stirred suspension of Mg turnings (705 mg,
29.41 mmol) in THF (10 mL) was added a solution of 4-bromo-1-
trimethylsilyl-1-butyne (3.01 g, 14.70 mmol) and 1,2-dibromoeth-
ane (0.1 mL) in dry THF (10 mL) with a syringe pump (1 h). After
the addition, the reaction mixture was heated to reflux for 1 h to
ensure the completion of the Grignard formation; it was then di-
luted with dry THF (30 mL) and cooled to –78 °C. CuI (2.80 g,
14.70 mmol) was added. The reaction mixture was stirred for
30 min. To this mixture was added 4a (800 mg, 5.88 mmol) in dry
THF (5 mL) dropwise, followed by chlorotrimethylsilane (0.89 mL,
7.05 mmol) and triethylamine (1.06 mL, 7.64 mmol). The reaction
mixture was warmed to room temperature, stirred for 12 h and
quenched with saturated NaHCO3 solution (10 mL). The resulting
black precipitate was filtered off and washed with hexane (40 mL).
The combined organic layer was washed with NaHCO3 solution
(2ϫ20 mL) and dried (K2CO3). Filtration followed by removal of
the solvent gave crude 5a (1.82 g, 93%) as a pale yellow liquid. IR
crystallography. The stereostructure of the tetracyclic com-
pound 33 was confirmed by the single-crystal X-ray diffrac-
tion analysis, Figure 3.
Conclusions
In conclusion, an efficient α-carbonyl radical-initiated
tandem cyclization for stereo-controlled synthesis of angu-
larly fused tricyclic/tetracyclic systems starting from the re-
spective α-bromo cycloalkanones was described. Attempts
to prepare 6–5–6 angular tricyclic systems were unsuccess-
ful. The synthesis of inaccessible 6–5–6 angular tricyclic
system[16] and other angularly fused polycyclic systems
using various silyl enol ethers and the respective α-bromo
cycloalkanones involving a RCM approach is under investi-
gation.
(film): ν = 2174, 1612, 845, 760 cm–1. 1H NMR (400 MHz, CDCl ):
˜
3
δ = 5.78–5.71 (m, 1 H, CH2CH=CH2), 5.13–4.93 (m, 2 H,
CH2CH=CH2), 2.87 (dd, J = 7.3, 15.7 Hz, 1 H, CHCH=CH2), 2.64
(dd, J = 7.3, 15.7 Hz, 1 H, CHCH=CH2), 2.47–2.35 (m, 1 H,
CH2CHCH2), 2.21–2.04 (m, 4 H, CH2CH2), 1.65–1.52 (m, 6 H,
CH2CH2CH2), 0.17 (s, 9 H, SiMe3), 0.14 (s, 9 H, SiMe3) ppm. 13C
NMR (100.6 MHz, CDCl3): δ = 144.9, 136.9, 116.6, 114.4, 107.5,
84.2, 34.7, 32.2, 31.2, 30.2, 26.0, 19.2, 17.8, 0.60, 0.07 ppm. MS
(EI): m/z (%) = 334 (16) [M]+, 318 (13), 260 (18), 221 (19), 209
(30), 208 (100). HRMS: calcd. for C19H34OSi2 [M]+ 334.2148;
found 334.2153. Crude 5a was used for the next step without fur-
ther purification.
Experimental Section
General Methods: All melting points are uncorrected. IR spectra
were recorded on a Shimadzu FT-IR 8300 instrument. H and 13
C
1
NMR spectra were recorded in CDCl3 using TMS as an internal
standard on a JEOL 400 or 500 spectrometer at 400 and 100 or
125 MHz and Bruker-300 and 75 MHz, respectively. Mass spectra
were recorded on a JEOL DX 303 HF spectrometer. Elemental
analyses were carried out on a Perkin–Elmer 240 B instrument.
High resolution mass analyses were performed using electrospray
ionization (ESI) technique. Single-crystal X-ray analysis was per-
formed on a Bruker Axs Kappa Apex 2 SMART CCD dif-
fractometer.
{4-[2-Allyl-1-methyl-3-(trimethylsilyloxy)cyclohex-2-enyl]but-1-ynyl}-
trimethylsilane (5b): The 1,4-addition was performed using enone
4b (850 mg, 5.66 mmol), Grignard reagent [prepared from Mg
(680 mg, 28.33 mmol), 4-bromo-1-trimethylsilyl-1-butyne (2.90 g,
14.16 mmol)], CuI (2.69 g, 14.16 mmol), TMSCl (0.86 mL,
6.80 mmol) and Et3N (1.03 mL, 7.36 mmol) following the same
procedure as for 5a to afford crude 5b (1.77 g, 90%) as a pale yel-
2-Allyl-3-methylcyclohex-2-enone (4b): To a stirred suspension of
cyclohexane-1,3-dione (5 g, 44.59 mmol) in 20% KOH solution
(30 mL) at 0 °C containing Cu powder (150 mg), allyl bromide
(4.23 mL, 49.05 mmol) was slowly added. The reaction temperature
was gradually raised to room temperature and stirred for 8 h. Then
NaOH (2 g) was added to re-dissolve the precipitate and washed
with diethyl ether (100 mL). The acidification of aqueous layer (dil.
aqueous HCl, 20 mL) gave the 2-allylcyclohexane-1,3-dione. The
crude product was recrystallized from benzene (4.41 g, 65%; m.p.
124 °C). Then 2-allylcyclohexane-1,3-dione was converted into the
respective isobutyl ether using isobutyl alcohol (10 mL) and PTSA
(500 mg) in benzene (80 mL) at reflux involving Dean–Stark for
5 h. A solution of isobutyl ether (2.26 g, 7.71 mmol) was treated
with ethereal solution of CH3MgI (2.5 , 6.5 mL) in dry ether
(50 mL) at 0 °C, raised to room temperature and stirred for 3 h. It
was then quenched with saturated NH4Cl solution and extracted
with diethyl ether (2ϫ30 mL). To a solution of the resulting
low liquid. IR (film): ν = 2174, 1616, 847, 760 cm–1. 1H NMR
˜
(400 MHz, CDCl3): δ = 5.72–5.68 (m, 1 H, CH2CH=CH2), 4.99–
4.85 (m, 2 H, CH2CH=CH2), 2.79 (dd, J = 6.5, 14.4 Hz, 1 H,
CHCH=CH2), 2.55 (dd, J = 6.5, 14.4 Hz, 1 H, CHCH=CH2), 2.04–
1.92 (m, 4 H, CH2CH2), 1.58–1.46 (m, 6 H, CH2CH2CH2), 0.96 (s,
3 H, Me), 0.16 (s, 9 H, SiMe3), 0.13 (s, 9 H, SiMe3) ppm. 13C NMR
(100.6 MHz, CDCl3): δ = 146.2, 138.2, 119.3, 113.5, 108.1, 83.6,
39.2, 37.6, 34.5, 30.6, 30.5, 26.6, 19.0, 15.1, 0.71, 0.08 ppm. MS
(EI): m/z (%) = 348 (13) [M]+, 333 (15), 274 (27), 223 (42), 222
(99). HRMS: calcd. for C20H36OSi2 [M]+ 348.2305; found
348.2311. Crude product 5b was used for the next step without
further purification.
2-Allyl-2-bromo-3-[4-(trimethylsilyl)but-3-ynyl]cyclohexanone (6a):
alcohol (2.16 g, 9.64 mmol) in diethyl ether (15 mL) were added To a stirred suspension of KBr (1.82 g, 15.26 mmol) in dry THF
PTSA (2 g) and water (15 mL) with vigorous stirring for 6 h at
room temperature. Extraction with diethyl ether (2ϫ20 mL), fol-
lowed by flash column chromatographic purification (silica gel, 3%
ethyl acetate in hexane) afforded 4b (838 mg, 58%) as a pale yellow
(15 mL) at 0 °C, a solution of dry m-CPBA (72.5% purity, 2.63 g,
15.26 mmol) in dry THF (10 mL) was added (5 min). The mixture
was warmed to room temp. (10 min) and stirred for 5 min. The
resulting dark brown solution was slowly added to a solution of
silyl enol ether 5a (1.7 g, 5.08 mmol) in THF (5 mL) at 0 °C for
liquid. IR (film): ν = 1665, 1631, 1428, 909, 751 cm–1. 1H NMR
˜
(400 MHz, CDCl3): δ = 5.68–5.61 (m, 1 H, CH2CH=CH2), 4.86– 10 min. It was then quenched (consumption of starting material
4.81 (m, H, CH2CH=CH2), 2.96 (d, 6.0 Hz, H, indicated by TLC) with a solution of Na2S2O3 and reaction mixture
CH2CH=CH2), 2.30–2.26 (m, 4 H, CH2CH2CH2), 1.88–1.82 (m, 5 was extracted with Et2O (3ϫ30 mL). The combined organic layer
2
J
=
2
H, CH2CH2CH2CH) ppm. 13C NMR (100.6 MHz, CDCl3): δ =
197.9, 156.6, 135.5, 132.8, 114.0, 37.4, 32.6, 28.9, 22.0, 20.9 ppm.
MS (EI): m/z (%) = 150 (67) [M]+, 149 (68), 134 (100). C10H14O
(150.10): calcd. C 79.96, H 9.39; found C 79.87, H 9.27.
was washed with NaHCO3 solution (20 mL), brine and dried
(MgSO4). Removal of solvent followed by flash column chromato-
graphic purification (silical gel, 0.5% ethyl acetate in hexane to 1%
ethyl acetate in hexane) afforded 6a (1.29 g, 75%) as a pale yellow
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Synthesis of Angularly Fused Carbocycles
liquid. IR (film): ν = 2171, 1712, 1610, 845, 759 cm–1. 1H NMR
CH2CH), 2.59–2.48 (m, 1 H, CH2CH), 2.29–2.23 (m, 2 H,
(400 MHz, CDCl3): δ = 5.71–5.66 (m, 1 H, CH2CH=CH2), 5.20– CH2CH2), 2.16–2.11 (m, 3 H, CH2CHCH2), 1.92–1.90 (m, 3 H,
˜
5.08 (m, 2 H, CH2CH=CH2), 3.32 (dd, J = 5.6, 5.6 Hz, 1 H,
CHCH=CH2), 3.18 (m, 1 H, CH2CHCH2), 2.78 (dd, J = 8.4,
CH2CHCH2), 1.65 (d, J = 12.0 Hz, 2 H, CH2CH2), 1.32–1.25 (m,
2 H, CH2CH2), 1.05 (d, J = 7.2 Hz, 3 H, Me), 0.12 (s, 9 H, SiMe3)
8.4 Hz, 1 H, CHCH=CH2), 2.42–2.21 (m, 2 H, CH2CH2), 2.02– ppm. 13C NMR (100.6 MHz, CDCl3): δ = 213.2, 161.1, 137.4, 74.0,
1.89 (m, 4 H, CH2CH2CH2), 1.68–1.51 (m, 4 H, CH2CH2CH2), 49.1, 48.0, 45.2, 40.0, 30.7, 24.7, 24.2, 23.1, 21.8, 0.09 ppm. MS
0.15 and 0.12 (2s, 9 H, SiMe3) ppm. 13C NMR (100.6 MHz,
CDCl3): δ = 203.2, 202.9, 133.4, 132.3, 119.8, 119.3, 107.1, 106.1,
76.7, 75.0, 46.4, 43.3, 41.1, 39.9, 37.1, 36.6, 29.8, 27.7, 26.5, 25.9,
24.4, 24.2, 22.0, 19.4, 17.9, 17.3, 0.16, 0.07 ppm. MS (EI): m/z (%)
= 342 (15) [M]+2, 340 (15) [M]+, 308 (12), 261 (78), 170 (65), 129
(82), 73 (100). C16H25BrOSi (340.08): calcd. C 56.30, H 7.38; found
C 56.42, H 7.29.
(EI): m/z (%) = 262 (30) [M]+, 247 (44), 219 (36), 137 (40), 105
(70), 73 (100). HRMS: calcd. for C16H26OSi [M]+ 262.1753; found
262.1747.
(5aS*, 91S*)-2,5a Dimethyl-3-(trimethylsilyl)-4,5,5a,6,7,8-hexahy-
dro-1H-cyclopenta[c]inden-9(2H)-one (7b): The radical cyclization
of 6b (1.20 g, 3.38 mmol) was performed using Bu3SnH (1.1 mL,
4.06 mmol) and AIBN (83 mg, 0.51 mmol) following the same pro-
cedure that of 7a to afford 7b (617 mg, 66%) as a viscous liquid.
2-Allyl-2-bromo-3-methyl-3-[4-(trimethylsilyl)but-3-ynyl]cyclo-
hexanone (6b): Bromination using compound 5b (1.70 g,
4.88 mmol), KBr (1.74 g, 14.65 mmol) and dry m-CPBA (72.5%
purity, 2.52 g, 14.65 mmol) following the same procedure as for 6a
IR (film): ν = 1706, 1615, 846, 760 cm–1. 1H NMR (400 MHz,
˜
CDCl3): δ = 3.15–3.02 (m, 1 H, CH2CH), 2.53–2.42 (m, 1 H,
CH2CH), 2.32–1.63 (m, 5 H, CH2CH2CHCH2), 1.52–1.45 (m, 2 H,
CH2CH2), 1.29–1.10 (m, 4 H, CH2CH2CH2), 0.92 (d, J = 6.8 Hz,
to afford 6b (1.26 g, 73%) as a yellow liquid. IR (film): ν = 2173,
˜
1712, 1613, 848, 762 cm–1. 1H NMR (400 MHz, CDCl3): δ = 5.58– 3 H, Me), 0.75 (s, 3 H, Me), 0.06 (s, 9 H, SiMe3) ppm. 13C NMR
5.52 (m, 1 H, CH2CH=CH2), 5.09–5.00 (m, 2 H, CH2CH=CH2),
3.89 (d, J = 15.0 Hz, 1 H, CHCH=CH2), 2.41 (dd, J = 8.3, 5.4 Hz,
(100.6 MHz, CDCl3): δ = 212.9, 159.4, 137.7, 77.6, 48.7, 43.5, 39.3,
38.3, 37.2, 33.1, 25.1, 22.6, 22.5, 21.8, 0.07 ppm. MS (EI): m/z (%)
1 H, CHCH=CH2), 2.39–2.07 (m, 2 H, CH2CH2), 1.96–1.60 (m, 4 = 276 (16) [M]+, 261 (14), 204 (15), 186 (18), 133 (11), 118 (10), 73
H, CH2CH2CH2), 1.32–1.19 (m, 4 H, CH2CH2CH2), 1.01 and 0.77
(2s, 3 H, Me), 0.13 and 0.11 (2s, 9 H, SiMe3) ppm. 13C NMR
(100.6 MHz, CDCl3): δ = 204.6, 203.1, 132.1, 131.9, 118.5, 118.0,
107.8, 107.1, 84.3, 84.1, 61.3, 58.3, 45.1, 38.9, 38.5, 37.4, 37.3, 36.4,
33.7, 31.4, 31.2, 25.0, 21.8, 21.6, 19.4, 17.7, 15.0, 14.4, 0.16,
0.07 ppm. MS (EI): m/z (%) = 356 (18) [M]+2, 354 (18) [M]+, 341
(14), 278 (23), 253 (65), 190 (35), 116 (76), 82 (100). C17H27BrOSi
(354.10): calcd. C 57.45, H 7.66; found C 57.56, H 7.74.
(100). HRMS: calcd. for C17H28OSi [M]+ 276.1909; found
276.1915.
3-Methyl-2-[4-(trimethylsilyl)but-3-ynyl]cylohex-2-enone (8): To a
solution of tBuLi (1.5 , 16 mL) in dry THF (80 mL) at –78 °C
was added 1,5-dimethoxy-1,4-cyclohexadiene (3 g, 21.4 mmol) and
the resultant solution was stirred at the same temperature for 1 h.
To this, HMPA (5.6 mL, 32.14 mmol) was added. After 10 min,
(4-bromobut-1-ynyl)trimethylsilane (6.6 g, 32.14 mmol) was added.
Representative Procedure for Bromination with NaBr/FeCl3. 2-Allyl- The reaction mixture was slowly raised to room temperature and
2-bromo-3-[4-(trimethylsilyl)but-3-ynyl]cyclohexanone (6a): To
a
stirred for 2 h. It was then quenched with saturated NH4Cl solution
(50 mL) and extracted with hexane (3ϫ50 mL). The crude product
(4.58 g) was dissolved in dry acetone (30 mL, previously purged
with a stream of N2 for 15 min). With vigorous stirring, 1  hydro-
chloric acid (10 mL, previously purged with a stream of N2 for
15 min) was added. The resultant solution was stirred for 1 h. Us-
ual work up followed by flash column chromatographic purifica-
tion (silica gel, 30% ethyl acetate in hexane) afforded a white solid
(2.12 g, 52%), m.p. 140 °C. This was converted into the respective
isobutyl ether with isobutyl alcohol (15 mL), PTSA (500 mg) in
benzene (80 mL) at reflux using a Dean–Stark apparatus for 5 h.
To a solution of isobutyl ether (2.32 g, 7.94 mmol) was treated with
ethereal solution of CH3MgI (2.5 , 4.8 mL) in dry ether (50 mL)
at 0 °C, raised to room temperature and stirred for 3 h. It was then
quenched with saturated NH4Cl solution and extracted with diethyl
ether (2ϫ30 mL). The crude product (2.22 g, 91%) in diethyl ether
(15 mL) was added PTSA (2 g, 15 mL of H2O) with vigorous stir-
ring for 6 h at room temperature. Extraction of the product using
ether (2ϫ20 mL), followed by flash column chromatographic puri-
fication (silica gel, 3% ethyl acetate in hexane) afforded 8 (1.21 g,
solution of FeCl3 (1.55 g, 9.58 mmol) in acetonitrile (20 mL), NaBr
(488 mg, 4.79 mmol) was added and stirred at 0 °C for 15 min. To
this, a solution of silyl enol ether 5a (1.6 g, 4.79 mmol) in acetoni-
trile (10 mL) was added dropwise at 0 °C. The reaction mixture
was warmed to room temperature and stirred for 4 h. It was then
quenched (consumption of starting material indicated by TLC)
with saturated NH4Cl solution and reaction mixture was extracted
with Et2O (2ϫ20 mL). The organic layer was separated and
washed with saturated Na2S2O3 (2ϫ10 mL) solution, water
(20 mL) and dried (Na2SO4). Removal of solvent followed by flash
column chromatographic purification (silical gel, 0.5% ethyl acetate
in hexane to 1% ethyl acetate in hexane) afforded 6a (1.31 g, 81%)
as a pale yellow liquid.
(91S*)-2-Methyl-3-(trimethylsilyl)-4,5,5a,6,7,8-hexahydro-1H-cyclo-
penta[c]inden-9(2H)-one (7a): To a refluxing solution of bromo
compound 6a (1.3 g, 3.82 mmol) in dry benzene (200 mL) under
N2 was added a solution of Bu3SnH (1.2 mL, 4.58 mmol) in dry
benzene (20 mL) containing AIBN (94 mg, 0.57 mmol) with a sy-
ringe pump over 6 h. After addition, the reaction mixture was
heated at reflux for 1 h to ensure the completion of radical cycliza-
tion and then cooled to room temperature. Benzene was removed
in vacuo and the residue was dissolved in Et2O (20 mL), then satu-
rated aqueous KF solution was added. The resulting mixture was
stirred at room temperature for 6 h. Then the organic layer was
separated and washed with saturated aqueous NaHCO3 solution
(20 mL) followed by brine and dried (MgSO4). Removal of solvent
followed by flash column chromatographic purification (silica gel,
1% EtOAc in hexane to 2% EtOAC in hexane) afforded 7a
72%) as a pale yellow liquid. IR (film): ν = 2172, 1668, 859, 758
˜
cm–1. 1H NMR (300 MHz, CDCl3): δ = 2.45–2.43 (m, 2 H,
CH2CH2), 2.29–2.23 (m, 6 H, CH2CH2CH2CH2), 1.94–1.18 (m, 5
H, CH2CH2CH2CH), 0.05 (s, 9 H, SiMe3) ppm. 13C NMR
(75 MHz, CDCl3): δ = 198.5, 157.1, 133.6, 107.1, 84.4, 37.6, 32.8,
24.2, 22.1, 21.7, 19.2, 0.13 ppm. MS (EI): m/z (%) = 234 (34)
[M]+, 219 (46), 195 (27), 163 (52), 127 (71), 98 (33), 57 (100).
C14H22OSi (234.14): calcd. C 71.73, H 9.46; found C 71.80, H 9.57.
Compound 9: The 1,4-addition was performed using enone 8
(840 mg, 3.58 mmol), Grignard reagent [prepared from Mg
(430 mg, 17.94 mmol), 4-bromo-1-trimethylsilyl-1-butyne (1.84 g,
(621 mg, 62%) as a viscous liquid. IR (film): ν = 1704, 1612, 848,
˜
760 cm–1. 1H NMR (400 MHz, CDCl3): δ = 3.18–3.04 (m, 1 H,
Eur. J. Org. Chem. 2008, 1535–1543
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1539

C. Prakash, A. K. Mohanakrishnan
8.97 mmol)], CuI (1.71 g, 8.97 mmol), TMSCl (0.54 mL, CH2CH2CH2) 1.59–1.20 (m, 5 H, CH2CH2CH2CH), 0.96 (s, 3 H,
FULL PAPER
4.31 mmol) and Et3N (0.65 mL, 4.66 mmol) following the same
Me), 0.15 (s, 9 H, SiMe3), 0.12 (s, 9 H, SiMe3) ppm. 13C NMR
(125.7 MHz, CDCl3): δ = 146.0, 132.3, 124.2, 121.6, 108.5, 84.7,
39.6, 34.7, 32.5, 30.9, 27.7, 26.7, 19.4, 19.3, 18.0, 15.4, 0.91,
0.24 ppm. MS (EI): m/z (%) = 376 (33) [M]+, 348 (25), 284 (39),
procedure as for 5a to afford crude 9 (1.33 g, 86%) as a pale yellow
liquid. IR (film): ν 2171), 1612, 845, 759 cm–1. 1H NMR (400 MHz,
˜
CDCl3): δ = 2.46–2.37 (m, 2 H, CH2CH2), 2.34–2.28 (m, 6 H,
CH2CH2CH2CH2), 2.23–1.62 (m, 6 H, CH2CH2CH2CH2), 1.23 (s, 242 (46), 193 (64), 78 (100). Found: C, 70.21; H, 10.81. C22H40OSi2
3 H, Me), 0.17 (s, 9 H, SiMe3), 0.13 (s, 9 H, SiMe3), 0.10 (s, 9 H,
SiMe3) ppm. 13C NMR (100 MHz, CDCl3): δ = 131.6, 122.8, 107.6,
106.2, 85.8, 84.2, 38.4, 32.8, 31.3, 29.6, 26.5, 23.2, 19.8, 19.1, 15.4,
0.86, 0.21 ppm. MS (EI): m/z (%) = 432 (22) [M]+, 386 (37), 341
(19), 284 (42), 192 (61), 95 (45), 64 (100). C24H44OSi3 (432.27):
calcd. C 66.59, H 10.25; found C 66.67, H 10.36. Crude 9 was used
for the next step without further purification.
(376.26) calcd. C 70.14, H 10.70; found C 70.21, H 10.81. Crude
product 16 was used for the next step without further purification.
2-Bromo-3-methyl-2-(pent-3-enyl)-3-[4-(trimethylsilyl)but-3-ynyl]-
cyclohexanone (17): Bromination using compound 16 (1.25 g,
3.32 mmol), KBr (1.18 g, 9.97 mmol) and dry m-CPBA (72.5% pu-
rity, 1.72 g, 9.97 mmol) following the same procedure as for 6a to
afford 17 (827 mg, 65%) as a yellow liquid. IR (film): ν = 2173,
˜
1710, 1616, 845, 760 cm–1. 1H NMR (300 MHz, CDCl3): δ = 5.54–
5 . 3 7 ( m , 2 H , C H 2 C H = C H C H 3 ) , 2 . 4 8– 1 . 9 3 ( m , 8 H ,
CH2CH2CH2CH2CH2), 1.84–1.72 (m, 4 H, CH2CH2CH2), 1.70–
1.24 (m, 5 H, CH2CH2CH2CH), 1.06 and 1.01 (2s, 3 H, Me), 0.13
and 0.07 (2s, 9 H, SiMe3) ppm. 13C NMR (75 MHz, CDCl3): δ =
205.8, 139.2, 116.1, 115.4, 107.7, 107.3, 86.7, 86.5, 73.1, 72.2, 47.8,
47.0, 40.6, 38.3, 38.1, 36.9, 33.6, 25.2, 23.5, 23.1, 20.4, 16.7, 16.4,
15.8, 0.09, 0.06 ppm. MS (EI): m/z (%) = 384 (16) [M]+2, 382 (16)
[M]+, 278 (34), 213 (27), 184 (42), 158 (57), 114 (52), 73 (100).
C19H31BrOSi (382.13) calcd. C 59.51, H 8.15; found C 59.60, H
8.23.
2-Bromo-3-methyl-2,3-bis[4-(trimethylsilyl)but-3-ynyl]cyclohexanone
(10): Bromination using compound 9 (1.20 g, 2.77 mmol), KBr
(991 mg, 8.33 mmol) and dry m-CPBA (72.5% purity, 1.43 g,
8.33 mmol) following the same procedure as for 6a to afford 10
(827 mg, 68%) as a yellow liquid. IR (film): ν = 2173, 1710, 1616,
˜
1
845, 760 cm–1. H NMR (300 MHz, CDCl3): δ = 2.38–2.26 (m, 2
H, CH2CH2), 2.25–2.06 (m, 6 H, CH2CH2CH2CH2), 2.03–1.55 (m,
6 H, CH2CH2CH2CH2), 1.15 and 1.01 (2s, 3 H, Me), 0.14 (s, 9 H,
SiMe3), 0.11 (s, 9 H, SiMe3) ppm. 13C NMR (75 MHz, CDCl3): δ
= 205.5, 106.9, 106.7, 106.4, 106.2, 85.1, 84.5, 82.4, 72.6, 71.2, 46.2,
45.7, 39.5, 38.8, 36.2, 36.1, 32.6, 32.0, 27.6, 27.3, 25.6, 21.3, 21.1,
19.2, 15.6, 15.4, 0.07, 0.05 ppm. MS (EI): m/z (%) = 440 (13) [M
+ 2], 438 (13) [M]+, 383 (21), 356 (26), 262 (35), 197 (36), 135 (64),
82 (100). C21H35BrOSi2 (438.14): calcd. C 57.38, H 8.03; found C
57.45, H 8.14.
3-Methyl-2-(pent-3-enyl)-3-[(4-trimethylsilyl)but-3-ynyl]cyclo-
hexanone (18): Radical cyclization of 17 (820 mg, 2.14 mmol) was
performed using Bu3SnH (0.69 mL, 2.56 mmol) and AIBN (52 mg,
0.32 mmol) following the same procedure that of 7a to afford the
(3aS*,7aS*)-7a-Methyl-3a-[4-(trimethylsilyl)but-3-ynyl]-3-[(trimeth-
ylsilyl)methylene]octahydro-4H-inden-4-one (11): Radical cycliza-
tion of 10 (800 mg, 1.82 mmol) was performed using Bu3SnH
(0.59 mL, 2.19 mmol) and AIBN (44 mg, 0.27 mmol) following the
same procedure as for 7a to afford 11 (433 mg, 66%) as a viscous
radical-quenched product 18 (364 mg, 56%) as a viscous liquid. IR
1
(film): ν = 2173, 1706, 1615, 846, 760 cm–1. H NMR (500 MHz,
˜
CDCl3): δ = 5.38–5.36 (m, 2 H, CH2CH=CHCH3), 2.38–2.07 (m,
7 H, CH2CH2CH2CH2CH), 2.02–1.67 (m, 4 H, CH2CH2CH2),
1.64–1.23 (m, 5 H, CH2CH2CH2CH), 1.02–0.95 (m, 2 H,
CH2CH2), 0.73 (s, 3 H, Me), 0.12 (s, 9 H, SiMe3) ppm. 13C NMR
(125.7 MHz, CDCl3): δ = 213.3, 130.8, 125.6, 107.2, 84.6, 60.7,
57.7, 41.6, 34.3, 33.9, 31.5, 25.0, 24.1, 22.6, 17.9, 14.2, 0.19 ppm.
MS (EI): m/z (%) = 304 (27) [M]+, 279 (18), 232 (35), 197 (43), 158
(54), 82 (100). HRMS: calcd. for C19H32OSi [M]+ 304.2222; found
304.2217.
liquid. IR (film): ν = 2173, 1705, 1610, 760 cm–1. 1H NMR
˜
(300 MHz, CDCl3): δ = 5.79–5.62 (m, 1 H, vinyl CH), 2.44–2.01
(m, 6 H, CH2 CH2CH2CH2), 1.87–1.63 (m, 4 H, CH2CH2CH2),
1.46–1.24 (m, 4 H, CH2CH2CH2), 0.91 (s, 3 H, Me), 0.14 (s, 9 H,
SiMe3), 0.06 (s, 9 H, SiMe3) ppm. 13C NMR (75 MHz, CDCl3): δ
= 214.1, 132.0, 128.2, 107.9, 84.4, 67.6, 45.6, 37.4, 36.6, 32.6, 26.8,
22.0, 17.4, 16.6, 15.0, 0.22, 0.04 ppm. MS (EI): m/z (%) = 360
(16) [M]+, 283 (37), 231 (52), 188 (56), 74 (100). HRMS: calcd. for
C21H36OSi2 [M]+ 360.2305; found 360.2310.
2-Allylcyclohept-2-en-1-one (20): To a solution of NaOMe (pre-
pared from Na, 1.25 g, 5.43 mmol and CH3OH, 30 mL) in meth-
anol (20 mL) was stirred at 0 °C. To this, a solution of methyl thio-
glycolate (4.28 g, 45.45 mmol) in methanol (20 mL) was added. Af-
ter 5 min, cyclohepten-1-one (5 g, 45.45 mmol) dissolved in meth-
anol (20 mL) was added drop wise at the same temperature. The
reaction mixture was slowly raised to room temperature and re-
fluxed for 10 h. Then the solvent was removed in vacuo. Orange
residue was dissolved in diethyl ether (50 mL) and extracted with
2  NaOH (2ϫ30 mL). The combined aqueous layer was acidified
with dilute aqueous HCl (60 mL), extracted with diethyl ether
(2ϫ50 mL) and dried (Na2SO4). Removal of solvent followed by
flash column chromatographic purification (silica gel, 10% EtOAC
3-Methyl-2-(pent-3-enyl)cyclohex-2-enone (15): Following the same
experimental procedure as for 8 to afford 15 as a pale yellow liquid
1
in 63% yield. IR (film): ν = 1667, 1628, 963, 757 cm–1. H NMR
˜
(400 MHz, CDCl3): δ = 5.34–5.31 (m, 2 H, CH2CH=CHCH3),
2.30–2.23 (m,
6 H, CH2CH2CH2CH2), 1.91–1.81 (m, 7 H,
CH2CH2CH2CH2CH), 1.55 (d, J = 4.3 Hz, 3 H, Me) ppm. 13C
NMR (100.6 MHz, CDCl3): δ = 199.8, 156.5, 136.1, 131.9, 125.9,
38.8, 33.8, 32.9, 26.3, 23.2, 22.2, 18.9 ppm. MS (EI): m/z (%) = 178
(46) [M]+, 127 (46), 125 (58), 123 (71), 55 (100). C12H18O (178.13):
calcd. C 80.85, H 10.18; found C 80.93, H 10.30.
Trimethyl{3-methyl-2-(pent-3-enyl)-3-[4-(trimethylsilyl)but-3-ynyl]- in hexane) afforded tetrahydro-cyclohepta[b]thiophene-3,4-dione as
cyclohex-1-enyloxy}silane (16): The 1,4-addition was performed an orange-yellow liquid (4.93 g, 59%). To a solution of the latter
using enone 15 (730 mg, 4.10 mmol), Grignard reagent [prepared (3 g, 16.30 mmol) in dry acetone (70 mL), powdered K2CO3
from Mg (492 mg, 20.50 mmol), 4-bromo-1-trimethylsilyl-1-butyne (11.25 g, 81.52 mmol) was added. Then allyl bromide (5.64 mL,
(2.10 g, 10.25 mmol)], CuI (1.95 g, 10.25 mmol), TMSCl (0.62 mL, 65.21 mmol) was added. The reaction mixture was refluxed for 4 h.
4.92 mmol) and Et3N (0.74 mL, 5.33 mmol) following the same
After completion of the reaction, the solvent was removed in vacuo.
The residue was poured onto ice/water and the crude product was
extracted with diethyl ether (2ϫ100 mL) and dried (Na2SO4). The
procedure as for 5a to afford crude 16 (1.34 g, 87%) as a pale yel-
low liquid. IR (film): ν = 2174, 1616, 847, 760 cm–1. 1H NMR
˜
(500 MHz, CDCl3): δ = 5.43–5.41 (m, 2 H, CH2CH=CHCH3), solvent was removed and the crude product (2.37 g) dissolved in
2.23–1.93 (m, 8 H, CH2CH2CH2CH2CH2), 1.78–1.64 (m, 4 H, diethyl ether (50 mL), then aqueous 5% NaOH (50 mL) was added.
1540
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 1535–1543

Synthesis of Angularly Fused Carbocycles
The reaction mixture was stirred for 4 h at room temperature. Then
276.1914. For single-crystal X-ray analysis of 23, all calculations
the organic layer was separated and washed with saturated were made with SHELXL-97 program.[17] Crystal data of 23:
NaHCO3 solution followed by brine solution (2ϫ50). Removal of
solvent followed by flash column chromatographic purification (sil-
C17H28OSi, MW = 276.48 g/mol, triclinic crystal system, space
group P1 , Z = 2, a = 7.3877(2) Å, b = 10.4954(3) Å, c =
¯
ica gel, 5% ethyl acetate in hexane) afforded 20 (761 mg, 48%) as
11.4520(3) Å, α = 91.7610(10)°, β = 105.7330(10)°, γ =
98.2520(10)°, V = 843.57(4) Å3 and Dx = 1.088 Mg/m3. In total,
4552 independent reflections were collected of which 3244 were
1
a pale yellow liquid. IR (film): ν = 1661, 1622, 859, 756 cm–1. H
˜
NMR (400 MHz, CDCl3 ): δ = 6.43 (t, J = 6.4 Hz, 1 H,
CH2CH=CH), 5.75–5.67 (m, 1 H, CH2CH=CH2), 5.05–4.91 (m, 2 considered as observed [IϾ2σ(I)]. The structure was solved by di-
H, CH2CH=CH2), 2.91–2.89 (m, 2 H, CH2CH2), 2.52–2.49 (m, 2 rect methods and refined by full-matrix least-squares procedures to
H, CH2CH2), 2.34–2.2.28 (m, 2 H, CH2CH2), 1.72–1.64 (m, 4 H, final R value of 5.10%.
CH2CH2CH2) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 204.1,
142.3, 141.6, 136.2, 115.7, 42.4, 36.6, 27.4, 24.9, 21.2 ppm. MS (EI):
m/z (%) = 150 (35) [M]+, 127 (38), 111 (33), 93 (57), 85 (100).
C10H14O (150.10) calcd. C 79.96, H 9.39; found C 80.05, H 9.51.
CCDC-643499 contains the supplementary crystallographic data
for 23. These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
Compound 21: The 1,4-addition was performed using enone 20
(650 mg, 4.33 mmol), Grignard reagent [prepared from Mg
(520 mg, 2.16 mmol), 4-bromo-1-trimethylsilyl-1-butyne (2.22 g,
10.83 mmol)], CuI (2.06 g, 10.83 mmol), TMSCl (0.66 mL,
5.20 mmol) and Et3N (0.79 mL, 5.63 mmol) following the same
2-Allyl-3-methylcyclohept-2-enone (24): To a stirred solution of 2-
allylcyclohept-2-enone (20) (2.5 g, 16.66 mmol) in 20 mL of anhy-
drous ether at –78 °C, ethereal solution of methyllithium (1.56 ,
13 mL) was added dropwise. The resulting solution was warmed to
room temperature, stirred for 2 h and quenched by drop wise ad-
dition of water (10 mL). The organic layer was separated and the
aqueous layer was extracted with diethyl ether (2ϫ20 mL). The
combined ethereal solution was dried (Na2SO4), and solvent was
removed under reduced pressure to afford the corresponding
alcohol (2.62 g, 95%) as viscous oil. The solution of this alcohol
(2.6 g, 15.66 mmol) in dry DCM (20 mL) was added to a magneti-
cally stirred slurry of pyridinium chlorochromate (6.75 g,
31.32 mmol) and celite (10 g) in dry DCM (30 mL). The reaction
mixture was stirred at room temperature for 2 h. Usual work up,
followed by flash column chromatographic purification (silica gel,
procedure as for 5a to afford crude 21 (1.43 g, 95%) as a viscous
1
oil. IR (film): ν = 2174, 1616, 847, 760 cm–1. H NMR (500 MHz,
˜
CDCl3): δ = 5.72–5.66 (m, 1 H, CH2CH=CH2), 5.04–4.92 (m, 2 H,
CH2CH=CH2), 3.04 (dd, J = 5.7, 5.7 Hz, 1 H, CHCH=CH2), 2.48–
2.40 (m, 2 H, CH2CH2), 2.26–2.07 (m, 4 H, CH2CH2CH2), 1.75–
1.55 (m, 6 H, CH2CH2CH2CH2), 1.50–1.35 (m, 2 H, CH2CH2),
0.15 (s, 9 H, SiMe3), 0.13 (s, 9 H, SiMe3) ppm. 13C NMR
(125.7 MHz, CDCl3): δ = 148.6, 137.1, 121.4, 115.1, 107.5, 84.6,
37.7, 37.1, 34.9, 29.7, 29.4, 26.0, 24.9, 18.5, 0.81, 0.26 ppm. MS
(EI): m/z (%) = 348 (6) [M]+, 307 (6), 223 (22), 185 (4), 147 (13),
73 (100). C20H36OSi2 (348.23) calcd. C 68.89, H 10.41; found C
68.76, H 10.33. Crude product 21 was used for the next step with-
out further purification.
3% ethyl acetate in hexane) afforded 24 (1.59 g, 62%) as a pale
1
yellow liquid. IR (film): ν = 1658, 1625, 855, 758 cm–1. H NMR
˜
(500 MHz, CDCl3): δ = 5.70–5.65 (m, 1 H, CH2CH=CH2), 4.88–
4.83 (m, 2 H, CH2 CH=CH2 ), 2.99 (d, J = 5.7 Hz, 2 H,
CH2CH=CH2), 2.48–2.46 (m, 2 H, CH2CH2), 2.34–2.32 (m, 2 H,
CH2CH2), 1.86 (s, 3 H, Me), 1.76–1.59 (m, 4 H, CH2CH2CH2)
ppm. 13C NMR (125.7 MHz, CDCl3): δ = 205.8, 152.0, 136.0,
118.1, 114.3, 41.7, 34.5, 33.0, 24.0, 23.2, 21.5 ppm. MS (EI): m/z
(%) = 164 (42) [M]+, 163 (23), 150 (19), 131 (44), 79 (100). C11H16O
(164.12) calcd. C 80.44, H 9.82; found C 80.52, H 9.95.
2-Allyl-2-bromo-3-[4-(trimethylsilyl)but-3-ynyl]cycloheptanone (22):
Bromination using compound 21 (1.30 g, 3.73 mmol), KBr (1.33 g,
11.20 mmol) and dry m-CPBA (72.5% purity, 1.93 g, 11.01 mmol)
following the same procedure as for 6a to afford 22 (886 mg, 67%)
as a yellow liquid. IR (film): ν = 2175, 1708, 1612, 845, 760 cm–1.
˜
1 H NMR (300 MHz, CDCl 3 ) : δ = 5 . 8 8– 5 . 7 7 ( m , 1 H ,
CH2CH=CH2), 5.12–4.98 (m, 2 H, CH2CH=CH2), 3.34 (dt, J =
2.6, 11.8 Hz, 1 H, CHCH=CH2), 3.12 (dd, J = 7.8, 14.8 Hz, 1 H,
CHCH=CH2), 2.75 (dd, J = 7.8, 14.5 Hz, 1 H, CHCH=CH2), 2.61–
2.34 (m, 4 H, CH2CH2CH2), 2.32–2.14 (m, 2 H, CH2CH2), 1.97–
1.76 (m, 2 H, CH2CH2), 1.63–1.29 (m, 4 H, CH2CH2CH2), 0.15
and 0.12 (2s, 9 H, SiMe3) ppm. 13C NMR (75 MHz, CDCl3): δ =
206.2, 138.5, 119.7, 106.1, 87.4, 71.7, 49.5, 43.3, 38.7, 35.2, 31.5,
30.8, 28.5, 18.7, 0.17, 0.10 ppm. HRMS: calcd. for C17H27BrOSi
[M]+ 354.1015; found 354.1021.
Compound 25: The 1,4-addition was performed using enone 24
(680 mg, 4.14 mmol), Grignard reagent [prepared from Mg
(496 mg, 20.7 mmol), 4-bromo-1-trimethylsilyl-1-butyne (2.15 g,
10.36 mmol)], CuI (1.97 g, 10.36 mmol), TMSCl (0.63 mL,
4.97 mmol) and Et3N (0.75 mL, 5.39 mmol) following the same
procedure as for 5a to afford crude 25 (1.42 g, 95%) as a viscous
1
oil. IR (film): ν = 2172, 1614, 844, 760 cm–1. H NMR (500 MHz,
˜
CDCl3): δ = 5.81–5.77 (m, 1 H, CH2CH=CH2), 5.16–4.98 (m, 2 H,
CH2CH=CH2), 2.57–2.48 (m, 2 H, CH2CH2), 2.34–2.12 (m, 4 H,
CH2CH2CH2), 1.85–1.61 (m, 6 H, CH2CH2CH2CH2), 1.57–1.48
(m, 2 H, CH2CH2), 0.96 (s, 3 H, Me), 0.18 (s, 9 H, SiMe3), 0.13 (s,
9 H, SiMe3) ppm. 13C NMR (125.7 MHz, CDCl3): δ = 149.4, 138.6,
122.1, 117.3, 107.8, 85.3, 39.4, 38.7, 36.3, 30.8, 30.3, 27.6, 25.2,
19.6, 15.7, 0.86, 0.31 ppm. MS (EI): m/z (%) = 362 (13) [M]+, 325
(16), 246 (31), 194 (9), 153 (21), 73 (100). C21H38OSi2 (362.24)
calcd. C 69.54, H 10.56; found C 69.66, H 10.70. Crude 25 was
used for the next step without further purification.
(2R*, 5aS*, 101S*)-2-Methyl-3-(trimethylsilyl)-1,2,5,5a,6,7,8,9-oc-
tahydrocylopenta[c]azulen-10(4H)-one (23): Radical cyclization of
bromo compound 22 (820 mg, 2.31 mmol) was performed using
Bu3SnH (0.75 mL, 2.77 mmol) and AIBN (57 mg, 0.34 mmol) fol-
lowing the same procedure as for 7a to afford 23 (434 mg, 68%) as
white crystals; m.p. 56–57 °C. IR (KBr): ν = 1701, 1610, 842, 760
˜
cm–1 1H NMR (400 MHz, CDCl3): δ = 3.05–3.04 (m, 1 H,
.
CH2CH), 2.81–2.74 (m, 1 H, CH2CH), 2.65 (dd, J = 5.6, 5.6 Hz, 1
H, CH2CH), 2.44–2.32 (m, 4 H, CH2CH2CH2), 2.07–1.96 (m, 2 H,
CH2CH2), 1.89–1.77 (m, 5 H, CH2CH2CH2CH), 1.71–1.62 (m, 2 2-Allyl-2-bromo-3-methyl-3-[4-(trimethylsilyl)but-3-ynyl]cyclo-
H, CH2CH2), 1.14 (d, J = 6.8 Hz, 3 H, Me), 0.06 (s, 9 H, SiMe3) heptanone (26): Bromination of 25 (1.25 g, 3.45 mmol) with KBr
ppm. 13C NMR (100.6 MHz, CDCl3): δ = 213.9, 163.0, 135.9, 75.6, (1.23 g, 10.35 mmol) and dry m-CPBA (72.5 % purity, 1.78 g,
47.9, 47.5, 44.9, 41.5, 33.6, 31.3, 26.5, 24.3, 23.3, 21.6, 0.16 ppm.
MS (EI): m/z (%) = 276 (17) [M]+, 261 (7), 233 (10), 191 (11), 175
(40), 73 (100). HRMS: calcd. for C17H28OSi [M]+ 276.1909; found
10.35 mmol), following the same procedure as for 6a, afforded 26
(802 mg, 63%) as a yellow liquid. IR (film): ν = 2174, 1710, 1614,
˜
1
843, 760 cm–1. H NMR (300 MHz, CDCl3): δ = 5.76–5.64 (m, 1
Eur. J. Org. Chem. 2008, 1535–1543
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1541

C. Prakash, A. K. Mohanakrishnan
FULL PAPER
H, CH2CH=CH2), 5.03–4.87 (m, 2 H, CH2CH=CH2), 3.25 (dt, J
= 3.2, 12.5 Hz, 1 H, CHCH=CH2), 3.06 (dd, J = 8.4, 15.2 Hz, 1
{4-[2-(Cyclohex-2-enyl)-3-methylcyclohex-2-enyl]but-1-ynyl}tri-
methylsilane (29): The 1,4-addition was performed using enone 28
H, CHCH=CH2), 2.56–2.34 (m, 2 H, CH2CH2), 2.27–2.09 (m, 4 (760 mg, 4.31 mmol), Grignard reagent [prepared from Mg
H, CH2CH2CH2), 1.84–1.62 (m, 2 H, CH2CH2), 1.56–1.18 (m, 4
H, CH2CH2CH2), 1.02 and 0.88 (2s, 3 H, Me), 0.13 and 0.10 (2s,
9 H, SiMe3) ppm. 13C NMR (75 MHz, CDCl3): δ = 204.6, 136.5,
(518 mg, 21.59 mmol), 4-bromo-1-trimethylsilyl-1-butyne (2.21 g,
10.79 mmol)], CuI (2.05 g, 10.79 mmol), TMSCl (0.66 mL,
5.18 mmol) and Et3N (0.78 mL, 5.61 mmol) following the same
117.2, 106.4, 85.8, 71.3, 48.4, 42.6, 36.2, 34.5, 30.7, 29.5, 28.5, 17.6, procedure as for 5a to afford crude 29 (1.54 g, 92%) as a viscous
1
15.3, 0.15, 0.11 ppm. HRMS: calcd. for C18H29BrOSi [M]+
368.1171; found 368.1176.
oil. IR (film): ν = 2174, 1616, 847, 760 cm–1. H NMR (400 MHz,
˜
CDCl3): δ = 5.53–5.47 (m, 2 H, CHCH=CHCH2), 3.17–3.15 (m, 1
H, CHCH=CH), 2.21–2.11 (m, 8 H, CH2CH2CH2CH2CH2), 1.96–
1.40 (m, 7 H, CH2CH2CH2CH2CH), 1.22–1.18 (m, 2 H, CH2CH2),
0.12 (s, 9 H, SiMe3), 0.10 (s, 9 H, SiMe3) ppm. 13C NMR
(100 MHz, CDCl3): δ = 144.8, 133.2, 125.6, 122.2, 107.7, 84.6, 37.0,
34.7, 31.4, 30.6, 29.6, 25.8, 24.9, 23.1, 19.3, 18.7, 0.83, 0.13 ppm.
MS (EI): m/z (%) = 389 (13) [M]+, 331 (17), 274 (24), 246 (8), 184
(17), 124 (100). C23H41OSi2 (389.26) calcd. C 70.88, H 10.60; found
C 70.97, H 10.71. Crude product 29 was used for the next step
without further purification.
2-Allyl-3-methyl-3-[4-(trimethylsilyl)but-3-ynyl]cycloheptanone (27):
Radical cyclization of bromo compound 26 (750 mg, 2.03 mmol)
was performed using Bu3SnH (0.66 mL, 2.43 mmol) and AIBN
(50 mg, 0.30 mmol) following the same procedure that of 7a to af-
ford the radical-quenched product 27 (336 mg, 57%) as a viscous
liquid. IR (film): ν = 2175, 1701, 1643, 1247, 842, 756 cm–1. 1H
˜
NMR (500 MHz, CDCl3): δ = 5.74–5.64 (m, 1 H, CH2CH=CH2),
5.02–4.95 (m, 2 H, CH2CH=CH2), 2.52–2.43 (m, 2 H, CH2CH2),
2.34–2.19 (m, 2 H, CH2CH2), 2.10–1.88 (m, 4 H, CH2CH2CH2),
1.83–1.34 (m, 7 H, CH2CH2CH2CH2CH), 1.17 (s, 3 H, Me), 0.11
(s, 9 H, SiMe3) ppm. 13C NMR (125.7 MHz, CDCl3): δ = 214.1,
136.9, 116.5, 106.2, 85.0, 54.7, 44.1, 36.2, 33.1, 32.9, 26.3, 24.2,
23.6, 18.2, 15.3, 0.18 ppm. HRMS: calcd. for C18H30OSi [M]+
290.2066; found 290.2073.
2-Bromo-2-(cyclohex-2-enyl)-3-[4-(trimethylsilyl)but-3-ynyl]cyclo-
hexanone (30): Bromination using compound 29 (1.40 g,
3.59 mmol), KBr (1.28 g, 10.79 mmol) and dry m-CPBA (72.5%
purity, 1.86 g, 10.79 mmol) following the same procedure as for 6a
to afford 30 (891 mg, 65%) as a yellow liquid. IR (film): ν = 2174,
˜
1704, 1610, 842, 760 cm–1. H NMR (300 MHz, CDCl3): δ = 5.96
1
(d, J = 10.8 Hz, 1 H, CHCH=CHCH2), 5.72–5.64 (m, 1 H,
CHCH=CHCH2), 3.59–3.50 (m, 1 H, CHCH=CH), 3.42–3.38 (m,
1 H, CH2CHCH2), 2.47–2.24 (m, 8 H, CH2CH2CH2CH2CH2),
2.16–1.25 (m, 8 H, CH2CH2CH2CH2CH2), 0.15 and 0.11 (2s, 9 H,
SiMe3) ppm. 13C NMR (75 MHz, CDCl3): δ = 204.3, 134.7, 129.5,
107.2, 84.6, 74.5, 45.2, 44.8, 38.2, 33.7, 29.4, 28.2, 27.6, 25.3, 24.7,
18.6, 0.05 ppm. MS (EI): m/z (%) = 382 (12) [M]2+, 380 (12) [M]+,
357 (16), 283 (26), 265 (47), 223 (32), 176 (63), 126 (66), 84 (100).
C19H29BrOSi (380.11) calcd. C 59.83, H 7.66; found C 59.91, H
7.78.
2-(Cyclohex-2-enyl)cyclohex-2-enone (28): To a solution of NaOMe
(prepared from Na, 1.25 g, 5.43 mmol and CH3OH, 30 mL) in
methanol (20 mL) was stirred at 0 °C. To this, a solution of methyl
thioglycolate (5.52 g, 5.21 mmol) in methanol (20 mL) was added.
After 5 min, cyclohexen-1-one (5 g, 5.21 mmol) dissolved in meth-
anol (20 mL) was added drop wise at the same temperature. The
reaction mixture was slowly raised to room temperature and re-
fluxed for 10 h. Then, the solvent was removed in vacuo. Resulting
orange residue was dissolved in diethyl ether (50 mL) and extracted
with 2  NaOH (2 ϫ 30 mL). The combined aqueous layer was
acidified with dilute aqueous HCl (60 mL), extracted with diethyl
ether (2ϫ50 mL) and dried (Na2SO4). Removal of solvent followed
by flash column chromatographic purification (silica gel, 10%
EtOAc in hexane) afforded hexahydro-benzothiophene-3,4-dione
as an orange-yellow liquid (5.66 g, 64%). To a solution of hexahy-
dro-benzothiophene-3,4-dione (3 g, 17.64 mmol) in dry acetone
(70 mL), powdered K2CO3 (12.2, 88.23 mmol) was added. Then 3-
bromocyclohex-1-ene (11.3 g, 70.58 mmol) was added. The reac-
tion mixture was refluxed for 4 h. After completion of the reaction,
the solvent was removed in vacuo. The residue was poured onto
ice/water and the crude product was extracted with diethyl ether
(2ϫ100 mL) and dried (Na2SO4). The solvent was removed and
the crude product (2.37 g) dissolved in diethyl ether (50 mL) and an
aqueous solution of NaOH (5%, 50 mL) was added. The reaction
mixture was stirred for 4 h at room temperature. Then the organic
layer was separated and washed with saturated NaHCO3 solution
followed by brine solution (2ϫ50 mL). Removal of solvent fol-
lowed by flash column chromatographic purification (silica gel, 5%
ethyl acetate in hexane) afforded 28 (800 mg, 48%) as a pale yellow
(4aS*,7aR*,11aS*)-7-Trimethylsilyl-2,3,4,4a,5,6,7a,8,9,10,11,11a-
dodecahydro-1H-indeno[7a,1-a]inden-1-one (31): Radical cyclization
of 30 (880 mg, 2.31 mmol) was performed using Bu3SnH (0.75 mL,
2.77 mmol) and AIBN (57 mg, 0.34 mmol) following the same pro-
cedure as for 7a to afford 31 (349 mg, 50%) and also 32 (139 mg,
20%) as a viscous liquid.
1
31: IR (film): ν = 1704, 1610, 842, 760 cm–1. H NMR (400 MHz,
˜
CDCl3): δ = 3.11–3.04 (m, 1 H, CH2CHCH2), 2.58–2.50 (m, 1 H,
CH2CH), 2.33–2.20 (m, 4 H, CH2CH2CH2), 1.96–1.63 (m, 6 H,
CH2CH2CH2CH2), 1.61–1.53 (m, 5 H, CH2CH2CH2CH), 1.51–
1.38 (m, 2 H, CH2CH2), 1.31–1.16 (m, 2 H, CH2CH2), 0.08 (s, 9
H, SiMe3) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 211.7, 161.3,
133.5, 77.1, 51.7, 45.1, 40.1, 38.8, 31.1, 27.7, 24.8, 24.6, 24.5, 24.2,
22.6, 22.5, 0.07 ppm. HRMS: calcd. for C19H30OSi [M]+ 302.2066;
found 302.2061.
32: IR (film): ν = 2174, 1704, 1610, 842, 760 cm–1 1H NMR
.
˜
(300 MHz, CDCl3): δ = 5.66–5.26 (m, 2 H, CH2CH=CHCH2),
2.68–2.34 (m, 4 H, CH2 CH2 CH2 ), 2.07–1.76 (m, 7 H,
CH2CH2CH2CH2CH), 1.72–1.23 (m, 6 H, CH2CH2CH2CH2), 0.87
(t, J = 7.1 Hz, 2 H, CH2CH), 0.09 (s, 9 H, SiMe3) ppm. 13C NMR
(75 MHz, CDCl3): δ = 214.2, 129.3, 128.8, 128.6, 107.1, 85.6, 61.3,
40.6, 40.1, 38.0, 37.6, 35.2, 34.8, 32.1, 28.5, 27.8, 27.6, 25.5, 24.8,
23.7, 22.8, 21.5, 21.2, 18.4, 18.1, 14.3, 0.08 ppm. HRMS: calcd. for
C19H30OSi [M]+ 302.2066; found 302.2070.
liquid. IR (film): ν = 1668, 1615, 859, 758 cm–1 1H NMR
.
˜
(500 MHz, CDCl3): δ = 6.67 (t, J = 3.8 Hz, 1 H, CH2CH=CH),
5.82–5.80 (m, 1 H, CHCH=CHCH2), 5.40–5.38 (m, 1 H,
CHCH=CHCH2), 3.39–3.42 (m, 1 H, CHCH=CH), 2.40–2.34 (m,
4 H, CH2CH2CH2), 1.96–1.79 (m, 4 H, CH2CH2CH2), 1.53–1.24
(m, 4 H, CH2CH2CH2) ppm. 13C NMR (125.7 MHz, CDCl3): δ =
198.9, 145.7, 143.0, 129.1, 128.9, 38.8, 33.3, 28.9, 26.1, 25.1, 23.1,
Preparation of 2,4-Dinitrophenylhydrazone of 33: To a stirred sus-
20.0 ppm. MS (EI): m/z (%) = 176 (34) [M]+, 156 (41), 132 (23), pension of 2,4-dinitrophenylhydrazine in CH3OH (5 mL) was
112 (54), 73 (100). C12H16O (176.12) calcd. C 81.77, H 9.15; found
C 81.85, H 9.28.
added concentrated H2SO4 (0.15 mL). To this solution was added
a solution of 31 (50 mg, 0.17 mmol) in CH3OH (2 mL) and the
1542
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 1535–1543

Synthesis of Angularly Fused Carbocycles
Rev. 1996, 96, 195–206; c) G. Mehta, A. Srikrishna, Chem. Rev.
1997, 97, 671–720; d) C. Ollivier, P. Renaud, Chem. Rev. 2001,
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Malacria, Top. Curr. Chem. 2006, 264, 1–62.
reaction mixture was heated at 70 °C for 10 min. On cooling, hy-
drazone 33 (44 mg, 56%) was obtained as an orange-yellow solid;
m.p. 191–192 °C. H NMR (300 MHz, CDCl3): δ = 10.97 (s, 1 H,
1
NH), 8.92 (d, J = 2.4 Hz, 1 H, ArCH), 8.02 (dd, J = 2.1, 2.1 Hz,
1 H, ArCH), 7.68 (d, J = 9.6 Hz, 1 H, ArCH), 3.12–3.01 (m, 1 H,
CH2CHCH2), 2.55–2.50 (m, 1 H, CH2CHCH2), 2.13–1.98 (m, 4 H,
CH2CH2CH2), 1.83–1.46 (m, 8 H, CH2CH2CH2CH2CH2), 1.38–
1.28 (m, 5 H, CH2CH2CH2CH), 1.07–0.97 (m, 2 H, CH2CH2), 0.17
(s, 9 H, SiMe3) ppm. 13C NMR (75 MHz, CDCl3): δ = 163.1, 159.8,
145.4, 137.2, 132.2, 129.5, 128.5, 123.3, 116.1, 70.3, 51.3, 45.6, 37.3,
31.8, 27.9, 25.5, 25.3, 24.7, 24.6, 24.5, 22.5, 21.1, 0.20 ppm. HRMS:
calcd. for C25H34N4O4Si [M]+ 482.2349; found 482.2354. For sin-
gle-crystal X-ray analysis of 33, all calculations were made with the
SHELXL-97 program.[17] Crystal data of 33: C25H34N4O4Si, MW
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¯
= 482.65 g/mol, triclinic crystal system, space group P1, Z = 2, a
[4]
[5]
= 10.1028(2) Å, b = 10.9354(2) Å, c = 12.9619(3) Å, α =
94.4180(10)°, β = 107.3150(10)°, γ = 110.6550(10)°, V =
1252.40(4) Å3 and Dx = 1.280 Mg/m3. In total, 6376 independent
reflections were collected of which 4219 were considered as ob-
served [IϾ2σ(I)]. The structure was solved by direct methods and
refined by full-matrix least-squares procedures to final R value of
5.26%.
CCDC-643500 contains the supplementary crystallographic data
for 33. These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
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The authors thank Council of Scientific and Industrial Research
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P. thanks the Council of Scientific and Industrial Research (CSIR)
for a Senior Research Fellowship (SRF). The authors thank the
Department of Science and Technology Fund for Improvement of
Science and Technology (DST-FIST) for a 300-MHz NMR spec-
trometer.
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Received: October 17, 2007
Published Online: February 6, 2008
Eur. J. Org. Chem. 2008, 1535–1543
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1543