Preparation of 2-silicon-substituted 1,3-dienes and their diels-alder/cross-coupling reactions

Article abstract of DOI:10.1021/jo901919m

(Chemical Equation Presented) 2-Triethoxysilyl-substituted 1,3-butadiene has been prepared in 30-g quantities from chloroprene via a simple synthetic procedure. Silatrane- and catechol-substituted analogues of this main group element substituted diene wer

Full text of DOI:10.1021/jo901919m

pubs.acs.org/joc
Preparation of 2-Silicon-Substituted 1,3-Dienes and Their Diels-Alder/
Cross-Coupling Reactions
Ramakrishna R. Pidaparthi, Christopher S. Junker, Mark E. Welker,* Cynthia S. Day, and
Marcus W. Wright
Department of Chemistry, Wake Forest University, P.O. Box 7486, Winston-Salem, North Carolina 27109
welker@wfu.edu
Received September 13, 2009
2-Triethoxysilyl-substituted 1,3-butadiene has been prepared in 30-g quantities from chloroprene via
a simple synthetic procedure. Silatrane- and catechol-substituted analogues of this main group
element substituted diene were then prepared on a 10-g scale by ligand exchange and characterized by
X-ray crystallography in addition to standard spectroscopic techniques. 2-Dimethylphenylsilyl-1,3-
butadiene has also been prepared from chloroprene on an 8-g scale. Diels-Alder reactions of these
dienes are reported as well as subsequent TBAF-assisted/Pd-catalyzed Hiyama cross-coupling
reactions of those Diels-Alder adducts. Silicon-substituted cycloadducts and cross-coupled pro-
ducts were also characterized by NMR spectroscopy and, in two cases, by X-ray crystallography.
Introduction
known propensity of trialkoxysilyl aryls and alkenyls to
participate in fluoride-assisted, metal-catalyzed cross-cou-
pling reactions,8 we felt that an easily accessible preparation
of 2-trialkoxysilyl 1,3-dienes would be subsequently useful
for tandem Diels-Alder/cross-coupling chemistry. We re-
ported our initial studies in this area in 20079 and in the work
that follows we provide more details of our subsequent work
in this area of chemistry. Roush’s group has also indepen-
dently reported related intramolecular Diels-Alder chemis-
try of silicon substituted dienes and dienophiles.10,11
Reports of main group element substituted 1,3-dienes and
their reaction chemistry are not widespread in organic
chemistry. In 2008, we published a review which covered
boron- and silicon-substituted diene preparation and reac-
tion chemistry up through 2007.1 In general, reports of
2-trialkylsilyl-substituted 1,3-dienes2 are 3- to 4-fold less
frequent than their 1-substituted counterparts, and reports
of 2-trialkoxysilyl-1,3-dienes are rarer still. We found a
report of the use of the Ganem and Batt protocol3 to make
2-trimethoxysilyl- and 2-triethoxysilyl-1,3-butadiene in
19844 and then a report of the polymerization of these
materials in 1989.5 There are a few other reports of some
chemistry of 2-silyl-substituted 1,3-dienes.6,7 Given the
Results and Discussion
2-Trialkoxysilyl-Substituted 1,3-Diene Preparation and
Characterization. 2-Triethoxysilyl-1,3-butadiene (2) was pre-
pared in high yield by the nucleophilic addition of 1,3-
butadienyl-2-magnesium chloride (generated in situ from
chloroprene (1) and Mg) to triethoxysilyl chloride.5,12 The
title compound (2) was isolated as a colorless liquid after
distillation under reduced pressure. This compound slowly
polymerized on standing at room temperature over a period
(1) Welker, M. E. Tetrahedron 2008, 64, 11529–11539.
(2) Zhang, H. Y., X.; Cai, M. J. Chem. Res. 2008, 305–307.
(3) Batt, D. G.; Ganem, B. Tetrahedron Lett. 1978, 3323–3324.
(4) Sato, F.; Uchiyama, H.; Samaddar, A. K. Chem. Ind. 1984, 743–744.
(5) Takenaka, K. H., T.; Hirao, A.; Nakahama, S. Macromolecules 1989,
22, 1563–1567.
(6) Daniels, R. G.; Paquette, L. A. Organometallics 1982, 1, 1449–1453.
(7) (a) Ikeda, Z.; Oshima, K.; Matsubara, S. Org. Lett. 2005, 7, 4859–
4861. (b) Patel, P. P.; Zhu, Y. X.; Zhang, L.; Herndon, J. W. J. Organometal.
Chem. 2004, 689, 3379. (c) Tonogaki, K.; Mori, M. Tetrahedron Lett. 2002,
43, 2235. (d) Kim, Y. J.; Lee, D. Org. Lett. 2006, 8, 5219. (e) Ye, P. W. X.; Cai,
M. J. Chem. Res. 2007, 319. (f) Yeh, M. C. P.; Sheu, P. Y.; Ho, J. X.; Chiang,
Y. L.; Chiu, D. Y.; Rao, U. N. J. Organometal. Chem. 2003, 675, 13. (g) Cai,
M. Z.; Zhou, Z.; Wang, P. P. Synthesis-Stuttgart 2006, 789.
(8) Hiyama, T.; Shirakawa, E. Cross-Coupling Reactions 2002, 219,
61–85.
(9) Pidaparthi, R. R.; Welker, M. E.; Day, C. S.; Wright, M. W. Org. Lett.
2007, 9, 1623–1626.
(10) Halvorsen, G. T.; Roush, W. R. Org. Lett. 2007, 9, 2243–2246.
(11) Halvorsen, G. T.; Roush, W. R. Org. Lett. 2008, 10, 5313–5316.
(12) Nunomoto, S.; Yamashita, Y. J. Org. Chem. 1979, 44, 4788–4791.
8290 J. Org. Chem. 2009, 74, 8290–8297
Published on Web 10/13/2009
DOI: 10.1021/jo901919m
r
2009 American Chemical Society

Pidaparthi et al.
JOCArticle
of 10-15 days but is quite stable at low temperature (-20 °C).
In practice, for the larger scale ligand-exchange reactions we
report here, we made this diene on ∼30 g scale and used it
subsequently at ∼90% purity (contained ∼10% residual
reaction solvent). 2-Triethoxysilyl-1,3-butadiene (2) can be
used in ligand-exchange reactions to make other siloxy
dienes (3, 4) as air-stable crystalline solids, and here we
report their preparation on a 10- to 15-g scale. Alcoholysis
of compound 2 with triethanolamine in the presence of a
catalytic amount of KOH resulted in the formation of (buta-
1,3-dien-2-yl)silatrane (3) as a white solid. Treatment of
2 with catechol in the presence of KOH yielded potassium
[bis(1,2-benzenediolato)-1,3-butadien-2-yl]silicate (4) as a
white amorphous powder. At room temperature, com-
pounds 3 and 4 show no signs of decomposition over a
period of months.
We also used the same general synthetic sequence which
provided compound 2 to produce a 2-dimethylphenylsilyl-
substituted diene (5) in 97% yield on an 8-g scale. This diene
is a liquid rather than the solid forms of 3 and 4 so it has some
practical disadvantages compared to them. However, we
wanted to compare a 2-alkyl- or arylsilyl-substituted diene
to these 2-trialkoxysilyl dienes in Diels-Alder chemistry. All
of the silyl butadienes (2-5) (Scheme 1) were structurally
characterized by 1D and 2D NMR techniques, and com-
pounds 3 and 4 were also characterized by X-ray crystal-
lography.6
however, we isolated an almost quantitative yield of cycload-
duct 9 from the reaction after heating in a sealed tube at 90 °C
for 4 h.
Cycloadduct 8 was also characterized by X-ray crystal-
lography (for details, see the Supporting Information). The
Si-sp2C bond length (Si(1)-C(13)) in this compound
˚
(1.876(4) A) was slightly shorter than what we had seen in
9
the starting diene (4) (1.889(5) A). In this cycloadduct, as in
˚
the original diene (4), the O-Si-O bond angles between
adjacent oxygens are all in the 85-88° range. The overall
geometry around silicon here is a significantly distorted
square-based pyramid as can be seen from the O(4)-Si-
O(1) and O(3)-Si-O(2) bond angles of 133.91(15) and
163.90(15)°, respectively. For comparison, these same bond
angles in diene 4 were 136.48(15) and 162.32(16)°.13
Next, we wanted to get an idea of the relative reactivity of
the most reactive silicon substituted dienes (3 or 4) in
comparison to known, reactive dienes such as Danishefsky’s
diene (1-methoxy-3-trimethylsiloxy-1,3-butadiene).14 We
found that silatrane diene (3) reacted with N-phenylmaleimide
at 0 °C with a kobs of 3.7 ꢀ 10-2 min-1 and t1/2 of 18.8 min
whereas Danishefsky’s diene reacted under identical conditions
with a kobs of 2.1ꢀ10-2 min-1 and a t1/2 of 33 min. This data
suggests the silatrane diene (3) is almost twice as reactive as
Danishefsky’s diene.
Single point energy, semiempirical (AM1) calculations of
HOMO energies for a number of dienes while constraining
the 1,3-diene dihedral angles to 0°, were also performed using
SPARTAN 2.0. 1,3-Butadiene, 2-methoxybutadiene, and
Danishefsky’s diene have HOMO energies of -9.35,
-9.09, and -8.82 eV respectively. Dienes 2, 3, and 4 have
HOMO energies of -9.21, -7.87, and -5.04 eV respectively.
These energies are consistent with our observations that 2 is
less reactive than Danishefsky’s diene, where 3 is more
reactive than Danishefsky’s diene, and diene 3 is less reactive
than diene 4.
SCHEME 1
SCHEME 3
Diels-Alder Reactions. We initially compared dienes 2-5
in reactions with N-phenylmaleimide. We found that while
the 2-triethoxysilyl diene (2) showed only a 2% conversion to
cycloadduct 6 by 1H NMR after 30 min at 25 °C in THF, the
silatrane (3) and catechol containing dienes (4) showed
complete conversion to cycloadducts 7 and 8 under the same
1
conditions by H NMR, and the cycloadducts were subse-
quently isolated in almost quantitative yield (Scheme 2). The
2-dimethylphenylsilyl diene (5) proved unreactive at 25 °C;
Additional Diels-Alder reactions with symmetrical and
unsymmetrical dienophiles were then performed to assess
any differences in rate or regioselectivity of cycloaddition
reactions. The silatrane substituted diene (3) produced a
2.0:1 mixture of para:meta regioisomers (10a:11a) in 78%
isolated yield after heating to 120 °C in THF for 48 h with
citraconic anhydride (Scheme 3, Table 1, entry a). The
catechol silane substituted diene (4) reacted under slightly
milder conditions (90 °C for 36 h) to produce a 4.8:1 mixture
of 10b:11b with this same dienophile in 78% isolated yield
(Table 1, entry b). The aforementioned general trend of the
bis catechol silyl diene (4) being slightly more reactive than
SCHEME 2
(13) Johnson, C. R.; Kadow, J. F. J. Org. Chem. 1987, 52, 1493–1500.
(14) Danishefsky, S.; Kitahara, T.; Yan, C. F.; Morris, J. J. Am. Chem.
Soc. 1979, 101, 6996–7000.
J. Org. Chem. Vol. 74, No. 21, 2009 8291

Pidaparthi et al.
JOCArticle
TABLE 1. Diels-Alder Reactions
entry
Ln
R1
R2
R3
temp (°C)
time (h)
10:11
% yield
a)
b)
c)
d)
e)
f)
N(CH2CH2O)3
(C6H4O2)2Kþ
N(CH2CH2O)3
(C6H4O2)2Kþ
N(CH2CH2O)3
(C6H4O2)2Kþ
-C(O)-
-C(O)-
CO2Et
CO2Et
CO2Et
CO2Et
-OC(O)-
-OC(O)-
H
H
CO2Et
CO2Et
Me
Me
H
H
H
120
90
150
90
150
90
48
36
90
28
110
29
2.0:1
4.8:1
4.0:1
3.6:1
NA
78
78
99
94
73
70
H
NA
SCHEME 4
the silatrane diene (3) was noted for the two other dieno-
philes tried here as well (compare Table 1 entries c and d as
well as e and f). These dienes are similar in reactivity and
regioselectivity to previously reported thermal Diels-Alder
reactions of 2-phenyl-1,3-butadiene.13,15 This diene is known
to react with di- and trisubstituted dienophiles at 80-110 °C
for 24-36 h. The synthetic advantage here is that one
cycloadduct can be converted to a variety of aryl substituted
cycloadducts via the cross-coupling chemistry described
below.
Major and minor isomer regiochemistry assignments
for 10a and 11a were originally performed using
NOESY data, and this assignment was subsequently
confirmed for the major isomer (10a) by X-ray crystallogra-
phy.9 The regiochemistry of the major isomer from the
reactions with ethyl acrylate (Supporting Information,
10c and 10d) was confirmed by the presence of a strong
HMBC cross peak between C2 and H4 of the major cycload-
duct.
benzonitrile (20), and 2-iodothiophene (21), which produced
cross-coupled cycloadducts in more moderate yields around
50-60%. All these cross-coupled products were character-
ized by 1H and 13C NMR techniques, and the cross-coupled
product from 2-fluoroiodobenzene (16) was also character-
ized by X-ray crystallography (for details, see the Supporting
Information).
However, when we tried these cross-coupling conditions
with a biscatechol silyl substituted cycloadduct such as 10d
and iodobenzene, we isolated the desired cross-coupled
product (22d) as well as the homocoupled product, biphenyl,
in a 1:1 ratio. We subsequently optimized cross-coupling
conditions to the use of [Pd(allyl)Cl]2, S-Phos, and KF in
DMF for the biscatechol silyl substituted cycloadduct 10d
and then used these optimized conditions for cross coupling
cycloadducts 10c-f to produce cross-coupled products
22c-f Scheme 5).
SCHEME 5
Diels-Alder/Cross Coupling. Recent papers from the Lee
group16 as well as from Yorimitsu, Oshima, et al.17 have
demonstrated that it is possible to effect palladium-catalyzed
cross couplings of 1,3-butadienyl species. We have demon-
strated that it is possible to effect Hiyama cross-coupling
reactions of silicon-substituted Diels-Alder cycloadducts as
well. Silatrane-substituted cycloadduct (7) was treated with a
wide variety of aryl iodides substituted with electron-donat-
ing and electron-withdrawing substituents in the presence of
Pd(II), PPh3, and TBAF (Scheme 4). Most of these cross-
coupling reactions proceeded in excellent yield with the
exception of the reactions with 2-iodoanisole (13), 3-iodo-
Conclusions
In summary, we have prepared new, stable, crystalline
silyl-substituted dienes in high yield and find that they read-
ily participate in Diels-Alder/cross-coupling tandem reac-
tions. We will report the transition-metal-catalyzed reaction
chemistry of these main group element substituted dienes in
much more detail in due course.
(15) Georgian, V. L., J. J. Org. Chem. 1964, 29, 40–44.
(16) Kim, S.; Seomoon, D.; Lee, P. H. Chem. Commun. 2009, 1873–1875.
(17) Imoto, J.; Hayashi, S.; Hirano, K.; Yorimitsu, H.; Oshima, K. Bull.
Chem. Soc. Jpn. 2009, 82, 393–400.
8292 J. Org. Chem. Vol. 74, No. 21, 2009

Pidaparthi et al.
JOCArticle
Experimental Section
was brought to reflux. After 2.5 h, reflux was stopped, and
the hot solution was gravity filtered. Precipitation with
pentane (50 mL) yielded a white solid which was collected
and dried by vacuum filtration. The white powder (11.89 g,
0.035 mol, 76.3%) was recrystallized by dissolving in a
minimum quantity of hot THF, cooling to room temperature,
and cooling at -40 °C for 1 h. The resulting white flaky
solid was collected and dried by vacuum filtration fol-
lowed by drying overnight under high vacuum (8.49 g,
0.025 mol, 54.5%).
General experimental details can be found in the prelimin-
ary communication on this work.9 Silatrane containing
compounds should be handled with care with appropriate
skin protection inside a fume hood.18 For all 1H-1H 2-D
spectra, the spectral width was 4432.6 Hz. 2-D 1H-1H
gradient selected COSY and NOESY spectra were acquired
with 2048 complex points in t2, 256 points in t1, and 16
transients with a pulse repetition delay of 1.5 s. The 2-D
NOESY spectra were collected with a mixing time of tm=600
ms. Data sets were multiplied with a 90° phase shifted
squared-sinebell apodization function and zero-filled to 512 ꢀ
512 data points before Fourier transformation.
Large-Scale Synthesis of Buta-1,3-dien-2-yltriethoxysilane 2.
To a dried 250-mL two-neck round-bottom flask equipped
with a stir bar, reflux condenser, and addition funnel and
charged with magnesium turnings (7.271 g, 0.299 mol) was
added 1,2-dibromoethane (1.8 mL, 0.02 mol) dissolved in
THF (25 mL). After 5 min, anhydrous zinc chloride (1.413 g,
0.010 mol) dissolved in THF (10 mL) was added dropwise,
followed by additional THF (35 mL). The reaction mixture was
then brought to reflux, and a solution of chloroprene (1)
in 50% xylenes (36.5 mL, 0.207 mol) and 1,2-dibromoethane
(4.0 mL, 0.05 mol) in THF (40 mL) was added dropwise over
30 min. The reaction mixture was refluxed for an additional
45 min and then cooled to room temperature. The mixture was
then transferred via double-ended needle into a 500-mL round-
bottom flask equipped with a stir bar and containing triethoxy-
chlorosilane (36.0 mL, 0.180 mol) dissolved in THF (125 mL)
and brought to reflux. After 1 h, the reaction was cooled to
room temperature and the solution poured into a separatory
funnel containing 0.5 M HCl (150 mL). The organic compo-
nents were extracted with pentane (2ꢀ100 mL) and washed
successively with 0.5 M HCl (250 mL) and distilled H2O
(350 mL). The organic extracts were then dried over MgSO4
and concentrated by rotary evaporation. The resulting light
yellow liquid (52.703 g) contains buta-1,3-dien-2-yltriethoxy-
silane (2) (33.71 g, 0.156 mol, 86.6% by 1H NMR integration)
(identical by spectroscopic comparison to material we have
reported previously)9 in xylenes and residual THF. This crude
mixture was used in the syntheses described below without
further purification.
Large-Scale Synthesis of (Buta-1,3-dien2-yl)silatrane 3. To a
dried 500-mL round-bottom flask equipped with a stir bar and
reflux condenser were added buta-1,3-dien-2-yltriethoxysilane
(2) in xylenes (29.85 g) described above (containing the diene
(19.28 g, 0.089 mol) by 1H NMR integrations), triethanolamine
(10.51 g, 0.070 mol), and a catalytic amount of KOH (0.439 g,
7.825 mmol), and the mixture was dissolved in THF (250 mL).
The solution was brought to reflux and, after 2.5 h, cooled to
room temperature and condensed by rotary evaporation to
remove approximately half of the solvent. The product was
then precipitated with pentane (100 mL) and collected by
vacuum filtration followed by drying overnight under high
vacuum to yield a white, fluffy solid (13.34 g, 0.059 mol,
83.4%) identical by spectroscopic comparison to material we
have reported previously.9
Large-Scale Synthesis of Potassium Bis(5,50-benzenediolato)-
(1,3-butadien-2-yl)silicate (4). To a dried 500-mL round-bot-
tom flask equipped with a stir bar and reflux condenser was
added catechol (10.21 g, 0.092 mol), and the mixture was
dissolved in THF (125 mL). Buta-1,3-dien-2-yltriethoxysi-
lane (2) in xylenes (18.18 g) described above (containing the
diene (11.74 g, 0.054 mol) by 1H NMR integrations) and
KOH (2.66 g, 0.047 mol) were then added, and the solution
Synthesis of (Buta-1,3-dien-2-yl)dimethyl(phenyl)silane (5).
General Main Group Diene Synthesis Procedure. An oven-
dried, 100 mL, two-neck, round-bottom flask equipped with
a magnetic stir bar, addition funnel, and reflux condenser
was charged with magnesium (1.6 equiv) followed by the
addition of dibromoethane (11.0 mol %) in THF (5 mL).
After the mixture was stirred for ∼ca. 5 min (initiation of
magnesium activation can be noticed by its silver color and
ethane gas liberation), 3.0 mol % of anhydrous ZnCl2 in
THF (5 mL) was added. This mixture was added with
additional THF (30 mL) and resulted in a whitish-gray
solution which was brought to gentle reflux over a period
of 15 min. Chloroprene (in 50% xylenes) (1.0 equiv) and
dibromoethane (23.0 mol %) in THF (25 mL) were added
dropwise to the refluxing reaction mixture over 30 min. After
the addition, refluxing was continued for another 45 min.
The greenish-gray Grignard solution was transferred by canula
into a 250-mL, one-neck, round-bottom flask containing
triethoxychlorosilane (0.95 equiv) in THF (25 mL) at room
temperature. The reaction mixture was refluxed (1 h), poured
into 0.5 M HCl solution (100 mL), and extracted with pentane
(2ꢀ75 mL). The combined colorless, clear organic layers were
washed successively with 0.5 M HCl (75 mL) and water (2 ꢀ
100 mL). After drying over MgSO4, the solvent was removed
under reduced pressure to yield the 2-substituted silyl diene with
xylenes as a colorless liquid. This compound was subjected to
fractional vacuum distillation to remove xylenes and then
purified by flash chromatography. Chloroprene (1) (4.575 g,
51.69 mmol) and phenyldimethylchlorosilane (8.034 g,
47.06 mmol) were used according to the procedure above to
yield a light yellow crude product (14.38 g) as a mixture of diene
and xylenes. The crude product was subjected to fractional
distillation at reduced pressure (20 mm, 45 °C) to produce a
brown liquid, which was further purified by flash chromato-
graphy (100% pentanes) to yield the title compound as a light
yellow liquid in pure form (5) (8.36 g, 44.39 mmol, 96.8%): Rf
0.63 (100% pentanes); 1H NMR (500 MHz, CDCl3) δ 7.49-7.55
(m, 2H), 7.31-7.37 (m, 3H), 6.46 (dd, J=17.7, 10.9 Hz, 1H),
5.88 (d, J=3.2 Hz, 1H), 5.51 (d, J=3.2 Hz, 1H), 5.10 (d, J=17.7
Hz, 1H), 5.00 (d, J=10.9 Hz, 1H), 0.43 (s, 9H); 13C NMR (75
MHz, CDCl3) δ 147.6, 141.1, 138.2, 133.9, 130.4, 129.0, 127.8,
-2.3; HRMS calcd for C12H16Si (Mþ) 188.1021, found
188.1020.
Synthesis of 3a,4,7,7a-Tetrahydro-5-[dimethyl(phenyl)silyl]-2-
phenyl-2H-isoindole-1,3-dione (9). Diene 5 (0.302 g, 1.603 mmol)
and N-phenylmaleimide (0.103 g, 0.595 mmol) were dissolved
in THF (5 mL) in a sealed tube and purged with N2. After being
heated for 4 h at 90 °C, the reaction mixture was filtered
through a cotton plug, and volatiles were removed by rotary
evaporation. The resulting yellow residue was purified by flash
chromatography with the excess diene eluting as a light yellow
solution (0.151 g, 0.802 mmol, 50% recovery: Rf 0.84, pentane/
diethyl ether, 1:1) followed by the cycloadduct 9 which after
solvent removal was isolated as a colorless, clear viscous liquid
(0.204 g, 0.564 mmol, 97.6%): Rf 0.29 (pentane/diethyl ether,
1:1); 1H NMR (500 MHz, CDCl3) δ 7.41-7.54 (m, 4H),
7.29-7.41 (m, 4H), 7.09-7.20 (m, 2H), 6.34 (p, J = 3.2 Hz,
1H), 3.18-3.30 (m, 2H), 2.71-2.88 (m, 2H), 2.22-2.36
(18) Seganish, W. M.; DeShong, P. J. Org. Chem. 2004, 69, 6790–6795.
J. Org. Chem. Vol. 74, No. 21, 2009 8293

Pidaparthi et al.
JOCArticle
(m, 2H), 0.36 (s, 3H), 0.35 (s, 3H); 13C NMR (75 MHz, CDCl3)
δ 179.1, 178.7, 140.7, 138.4, 137.0, 133.9, 132.0, 129.2, 129.0,
128.4, 127.8, 126.3, 39.3, 39.2, 26.4, 25.0, -3.88, -3.89; HRMS
calcd for C22H23NO2Si (Mþ) 361.1498, found 361.1490. Anal.
Calcd for C22H23NO2Si: C, 73.10; H, 6.42. Found: C, 72.63; H,
6.38.
Synthesis of Potassium Bis(7,70-benzenediolato)-[4-(eth-
oxycarbonyl)cyclohex-1-enyl]silicate (10d) and Potassium
Bis(7,70-benzenediolato)[3-(ethoxycarbonyl)cyclohex-1-enyl)-
silicate (11d).
5.7 Hz, 6H); 13C NMR (125.7 MHz, CDCl3) δ 177.0, 137.7,
133.7, 57.9, 40.3, 30.6, 26.3, 25.2, 14.4; HRMS [M þ Na]þ calcd
for C15H25NO5Si þ Na 350.1400, found 350.1394. Regioisomer
ratio 4.0:1.0 (based on GC integrations). Anal. Calcd for
C15H25NO5Si: C, 55.02; H, 7.70. Found: C, 55.50; H, 8.14.
Synthesis of Potassium Bis(7,70-benzenediolato)[3,4-bis-
(ethoxyxarbonyl)cyclohex-1-enyl]silicate (10f). Diene 4 (0.98 g,
2.91 mmol) and diethyl maleate (731 μL, 4.50 mmol) were
dissolved in THF (40 mL) and used in the cycloaddition reaction
according to the general procedure. After being stirred for 29 h
at 90 °C, the reaction vessel was cooled to room temperature and
the solution condensed by rotary evaporation. Additional drying
under high vacuum resulted in a dark brown flaky solid (1.53 g).
Based on 1H NMR integrations, this product contains the title
compound 10f (1.04 g, 2.04 mmol, 70.3%) and excess diethyl
maleate. 10f: 1H NMR (500 MHz, DMSO-d6) δ 6.54-6.52 (m,
4H), 6.46-6.43 (m, 4H), 5.83 (m, 1H), 3.97-3.87 (m, 4H),
2.81-2.74 (m, 2H), 2.45-2.37 (m, 1H), 2.35-2.27 (m, 1H),
2.26-2.12 (m, 2H), 1.06 (t, J=7.1 Hz, 3H), 1.03 (t, J=7.2 Hz,
3H); 13C NMR (125.7 MHz, DMSO-d6) δ 173.0, 172.9, 150.6,
150.5, 137.8, 131.8, 117.1, 117.1, 109.5, 109.4, 59.6, 59.4, 38.5,
28.6, 26.4, 13.8, 13.8. This crude product was used as is for the
cross-coupling reactions described below.
Synthesis of [3,4-Bis(ethoxycarbonyl)cyclohex-1-enyl]silatr-
ane (10e). Diene 3 (0.546 g, 2.40 mmol) and diethyl maleate
(414 μL, 2.55 mmol) were dissolved in THF (25 mL) in a sealed
tube purged with N2. After being stirred for 110 h at 150 °C, the
reaction vessel was cooled to room temperature and the solution
condensed by rotary evaporation. Additional drying under
reduced pressure resulted in a light yellow residue (0.995 g).
On the basis of 1H NMR integrations, this product contains the
title compound 10e (0.695 g, 1.74 mmol, 72.5%) and excess
diethyl maleate. This crude product was used as is for the cross-
coupling reactions described below.
General Procedure for the Cross-Coupling Reactions of Cy-
cloadduct 7. Diels-Alder cycloadduct (1.0 equiv), Pd(OAc)2
(10 mol %), PPh3 (20 mol %), and aryl halide (1.2 equiv) were
taken up in a sealed tube charged with a micro stir bar and
DMF (5 mL). This transparent yellow reaction mixture was
stirred followed by addition of TBAF (1.2 equiv) dissolved in
THF (0.5 mL). The reaction mixture turned dark brown, was
purged with N2, and was heated in an oil bath for 2 h at 90 °C.
During the course of the reaction, the reaction mixture
turned to dark black, and the formation of active palladium
species (PdII f Pd0) was also noticed as the catalyst slowly
turned to a black solid. The reaction mixture was then
quenched with water (50 mL) and extracted with Et2O (4ꢀ
30 mL). The combined organic layers were again washed
with water (2ꢀ75 mL) and dried over MgSO4, and volatiles
were removed by rotary evaporation. The resulting cross-
coupled cycloadduct residue was purified by flash chroma-
tography.
Diene (4) (0.500 g, 1.48 mmol) and ethyl acrylate (245 μL,
2.25 mmol) were dissolved in THF (20 mL) in a sealed tube and
purged with N2. After being stirred for 28 h at 90 °C, the reaction
vessel was cooled to room temperature, and the solvent was
removed by rotary evaporation. Additional drying under va-
cuum overnight to remove excess ethyl acrylate produced
cycloadducts 10d and 11d as a light brown fluffy powder
(0.610 g, 1.39 mmol, 94.1%): mp 239 °C dec. Major isomer
1
(10d): H NMR (500 MHz, DMSO-d6) δ 6.54-6.52 (m, 4H),
6.45-6.43 (m, 4H), 5.85 (m, 1H), 3.99 (q, J = 6.9 Hz, 2H),
2.31-2.25 (m, 1H), 2.09-1.99 (m, 3H), 1.94-1.83 (m, 1H),
1.77-1.70 (m, 1H), 1.32-1.24 (m, 1H), 1.12 (t, J = 6.9 Hz,
3H);13C NMR (125.7 MHz, DMSO-d6) δ 175.3, 150.7, 150.6,
139.8, 131.8, 117.2, 117.1, 109.5, 109.4, 59.6, 38.6, 28.4, 27.3,
25.4, 14.0; HRMS [MþK]þ calcd for C21H21KO6Si 475.0382,
found 475.0382. Regioisomer ratio 3.6:1.0 (based on 1H NMR
integrations).
Synthesis of [4-(Ethoxycarbonyl)cyclohex-1-enyl]silatrane
(10c) and [3-(Ethoxycarbonyl)cyclohex-1-enyl]silatrane (11c).
Synthesis of (3aR,7aS)-5-(2-Methoxyphenyl)-2-phenyl-3a,4,-
7,7a-tetrahydro-1H-isoindole-1,3(2H)-dione (13). Cycloadduct
7 (0.101 g, 0.252 mmol), Pd(OAc)2 (0.020 g, 0.034 mmol),
PPh3 (0.024 g, 0.092 mmol), 2-iodoanisole (0.084 g, 0.359
mmol), and TBAF (0.110 g, 0.349 mmol) were used according
to the general procedure mentioned above. The resulting
brown oily crude reaction mixture was subjected to flash
chromatography to yield the cross-coupled product 13 as a
brownish-yellow crystalline solid (0.048 g, 0.144 mmol,
57.1%): mp 128-132 °C dec; Rf 0.42 (diethyl ether/hexanes,
Diene 3 (0.520 g, 2.28 mmol) and ethyl acrylate (360 μL,
3.30 mmol) were dissolved in THF (20 mL) in a sealed tube and
purged with N2. After being stirred for 90 h at 150 °C, the
reaction vessel was cooled to room temperature and the solution
condensed by rotary evaporation. Additional drying under
vacuum overnight to remove excess ethyl acrylate led to the
formation of the cycloadducts 10c and 11c as a white, flaky solid
(0.745 g, 2.27 mmol, 99.4%): mp 77-80 °C. Major isomer 10c:
1H NMR (500 MHz, CDCl3) δ 6.24 (m, 1H), 4.10 (q, J=7.0 Hz,
2H), 3.80 (t, J=5.8 Hz, 6H), 2.82 (t, J=5.9 Hz, 6H), 2.52-2.44
(m, 1H), 2.36-2.23 (m, 3H), 2.20-2.10 (m, 1H), 2.00-1.91
(m, 1H), 1.66-1.54 (m, 1H), 1.23 (t, J=7.0, 4H); 13C NMR
(125.7 MHz, CDCl3) δ 176.8, 138.9, 132.6, 60.1, 58.0, 51.2, 39.7,
1
2:1); H NMR (500 MHz, CDCl3) δ 7.44 (t, J=8.1 Hz, 2H),
7.37 (t, J=7.5 Hz, 1H), 7.18-7.25 (m, 3H), 7.08 (d, J=7.5 Hz,
1H), 6.90 (t, J=7.5 Hz, 1H), 6.83 (d, J=8.1 Hz, 1H), 6.03 (p, J=
3.4 Hz, 1H), 3.67 (s, 3H), 3.36 (ddd, J=9.1, 7.7, 2.4 Hz, 1H),
3.32 (ddd, J=9.1, 6.7, 2.6 Hz, 1H), 3.07 (dd, J=15.4, 2.4 Hz,
1H), 2.94 (ddd, J=15.4, 6.7, 2.6 Hz, 1H), 2.63 (ddt, J=15.4, 7.7,
1
29.0, 27.7, 26.0, 14.4. Minor isomer 11c, diagnostic peaks: H
NMR (500 MHz, CDCl3) δ 3.74 (t, J=5.7 Hz, 6H), 2.78 (t, J=
8294 J. Org. Chem. Vol. 74, No. 21, 2009

Pidaparthi et al.
JOCArticle
2.4 Hz, 1H), 2.37-2.50 (m, 1H); 13C NMR (75 MHz, CDCl3) δ
179.2, 178.8, 156.5, 139.5, 132.3, 130.9, 129.2, 129.0, 128.8,
128.5, 126.7, 125.1, 120.6, 110.5, 54.9, 40.0, 39.8, 28.9, 24.5;
HRMS calcd for C21H19NO3Cs (M þ Csþ) 466.0419, found
466.0430.
126.3, 126.1 (q, JC-F=5.2 Hz), 124.2 (q, JC-F=273.6 Hz),
39.9, 38.8, 29.6 (q, 5JC-F=1.7 Hz), 24.7; 19F NMR (300 MHz,
CDCl3) δ -58.2; HRMS calcd for C21H16F3NO2Cs (M þ Csþ)
504.0187, found 504.0219.
3
1
Synthesis of (3aR,7aS)-2-Phenyl-5-(3-(trifluoromethyl)phe-
nyl)-3a,4,7,7a-tetrahydro-1H-isoindole-1,3(2H)-dione (18). Cyc-
loadduct 7 (0.100 g, 0.25 mmol), Pd(OAc)2 (0.018 g, 0.030 mmol),
PPh3 (0.018 g, 0.069 mmol), 1-iodo-3-(trifluoromethyl)benzene
(0.096 g, 0.353 mmol), and TBAF (0.092 g, 0.292 mmol) were
used according to the general procedure mentioned above. The
resulting brown oily crude reaction mixture was subjected to flash
chromatography toyield the cross-coupled product 18 asa brown
liquid (0.084 g, 0.226 mmol, 90.3%): Rf 0.16 (diethyl ether/
hexanes, 1:1); 1H NMR (500 MHz, CDCl3) δ 7.60 (s, 1H), 7.54
(d-overlapped, J=7.9 Hz, 1H), 7.52 (d-overlapped, J=8.1 Hz,
1H), 7.39-7.48 (m, 3H), 7.36 (att, J=7.3, 1.4 Hz, 1H), 7.15 (d, J=
7.3 Hz, 2H), 6.30 (p, J=3.5 Hz, 1H), 3.47(ddd, J=9.4, 6.9, 2.7 Hz,
1H), 3.37 (ddd, J=9.4, 7.5, 2.5 Hz, 1H), 3.25 (dd, J=15.4, 2.7 Hz,
1H), 2.97 (ddd, J=15.6, 6.9, 2.5 Hz, 1H), 2.67 (ddt, J=15.4, 6.9,
2.5 Hz, 1H), 2.47 (dddd, J=15.6, 6.2, 3.7, 2.5 Hz, 1H); 13C NMR
(75 MHz, CDCl3) δ 178.8, 178.6, 141.1, 138.9, 131.8, 131.0
(q, 2JC-F=32.2 Hz), 129.13, 129.11, 128.7 (q, 4JC-F=1.7 Hz),
Synthesis of (3aR,7aS)-5-(3-Methoxyphenyl)-2-phenyl-3a,-
4,7,7a-tetrahydro-1H-isoindole-1,3(2H)-dione (14). Cycload-
duct 7 (0.100 g, 0.250 mmol), Pd(OAc)2 (0.028 g, 0.047 mmol),
PPh3 (0.024 g, 0.088 mmol), 3-iodoanisole (0.126 g, 0.538 mmol),
and TBAF (0.128 g, 0.406 mmol) were used according to the
general procedure mentioned above. The resulting brown oily
crude reaction mixture was subjected to flash chromatography
to yield the cross-coupled product 14 as a brown oil (0.073 g,
1
0.219 mmol, 87.7%): Rf 0.15 (diethyl ether/hexanes, 2:1); H
NMR (500 MHz, CDCl3) δ 7.41 (at, J=8.1 Hz, 2H), 7.35 (at, J=
8.1 Hz, 1H), 7.19-7.25 (m, 1H), 7.16 (ad, J = 8.1 Hz, 2H),
6.91-7.02 (m, 1H), 6.90 (at, J=2.1 Hz, 1H), 6.81 (dd, J=8.3,
2.5 Hz, 1H), 6.22 (p, J=3.4 Hz, 1H), 3.80 (s, 3H), 3.44 (ddd, J=
9.4, 7.0, 2.5 Hz, 1H), 3.34 (ddd, J=9.4, 7.2, 2.5 Hz, 1H), 3.24
(dd, J=15.3, 2.5 Hz, 1H), 2.93 (ddd, J=15.3, 7.0, 2.5 Hz, 1H),
2.64 (ddt, J=15.3, 7.0, 2.3 Hz, 1H), 2.37-2.51 (m, 1H); 13C
NMR (75 MHz, CDCl3) δ 179.0, 178.8, 159.8, 141.9, 140.0,
132.0, 129.5, 129.1, 128.6, 126.4, 123.4, 118.0, 113.1, 111.2, 55.5,
40.1, 39.5, 27.7, 25.3; HRMS calcd for C21H19NO3Cs (M þ Csþ)
466.0419, found 466.0444.
128.6, 126.3, 125.0, 124.2 (q, 3JC-F=4.0 Hz), 124.0 (q, 1JC-F
=
273.0 Hz), 122.4 (q, JC-F=4.0 Hz), 40.0, 39.2, 27.5, 25.3; 19F
3
NMR (300 MHz, CDCl3)
δ -63.2; HRMS calcd for
C21H17F3NO2 (M þ H)þ 372.1211, found 372.1211.
Synthesis of (3aR,7aS)-5-(2-Fluorophenyl)-2-phenyl-3a,4,7,-
7a-tetrahydro-1H-isoindole-1,3(2H)-dione (16). Cycloadduct 7
(0.135 g, 0.337 mmol), Pd(OAc)2 (0.023 g, 0.039 mmol), PPh3
(0.024 g, 0.092 mmol), 1-iodo-2-fluorobenzene (0.126 g,
0.568 mmol), and TBAF (0.132 g, 0.418 mmol) were used
according to the general procedure mentioned above. The
resulting brown oily crude reaction mixture was subjected to
flash chromatography to yield the cross-coupled product 16 as a
light-yellow, amorphous solid (0.091 g, 0.283 mmol, 84.3%): mp
(neat) 110-112 °C; Rf 0.27 (diethyl ether/hexanes, 1:1); 1H
NMR (500 MHz, CDCl3) δ 7.44 (t, J=7.6 Hz, 2H), 7.37 (tt,
J=7.6, 1.3 Hz, 1H), 7.15-7.25 (m, 4H), 7.09 (td, J=7.6, 1.0 Hz,
1H), 7.04 (ddd, J=10.7, 8.2, 1.0 Hz, 1H), 6.21 (p, J=3.2 Hz, 1H),
3.41 (ddd, J=9.5, 6.9, 2.5 Hz, 1H), 3.35 (ddd, J=9.5, 6.9, 2.5 Hz,
1H), 3.16 (dd, J=15.5, 1.6 Hz, 1H), 2.94 (ddd, J=15.5, 6.9,
2.5 Hz, 1H), 2.73 (ddq, J=15.5, 7.3, 1.3 Hz, 1H), 2.47 (dddd, J=
15.5, 6.6, 3.5, 2.5 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 178.9,
178.7, 159.7 (d, 1JC-F=247.7 Hz), 135.3, 132.0, 129.1, 128.99 (d,
3JC-4F=5.7 Hz), 128.91 (d, 3JC-F=5.7 Hz), 128.79, 128.6, 127.2
Synthesis of (3aR,7aS)-2-Phenyl-5-(4-(trifluoromethyl)phe-
nyl)-3a,4,7,7a-tetrahydro-1H-isoindole-1,3(2H)-dione (19). Cyc-
loadduct 7 (0.099 g, 0.247 mmol), Pd(OAc)2 (0.023 g,
0.039 mmol), PPh3 (0.024 g, 0.092 mmol), 1-iodo-
4-(trifluoromethyl)benzene (0.132 g, 0.485 mmol), and TBAF
(0.098 g, 0.311 mmol) were used according to the general
procedure mentioned above. The resulting brown oily crude
reaction mixture was subjected to flash chromatography to yield
the cross-coupled product 19 as a yellow-brown liquid (0.082 g,
1
0.221 mmol, 89.3%): Rf 0.35 (diethyl ether/hexanes, 2:1); H
NMR (500 MHz, CDCl3) δ 7.58 (d, J=8.4 Hz, 2H), 7.46 (d, J=
8.4 Hz, 2H), 7.42 (t, J=7.5 Hz, 2H), 7.36 (t, J=7.5 Hz, 1H), 7.14
(t, J=7.5 Hz, 2H), 6.31 (p, J=3.4 Hz, 1H), 3.47 (ddd, J=9.4, 6.7,
2.5 Hz, 1H), 3.38 (ddd, J=9.4, 7.1, 2.3 Hz, 1H), 3.27 (dd, J=
15.3, 2.5 Hz, 1H), 2.99 (ddd, J=15.6, 7.1, 2.3 Hz, 1H), 2.65 (ddt,
J = 15.3, 6.7, 2.5 Hz, 1H), 2.37-2.54 (m, 1H); 13C NMR
5
(75 MHz, CDCl3) δ 178.8, 178.7, 143.7 (q, JC-F = 1.1 Hz),
2
139.1, 131.8, 129.5 (q, JC-F = 32.8 Hz), 129.1, 128.6, 126.3,
4
125.8, 125.5 (q, 3JC-F=4.0 Hz), 125.4, 124.1 (q, 1JC-F=271.8 Hz),
40.0, 39.2, 27.4, 25.3; 19F NMR (300 MHz, CDCl3) δ -63.0;
HRMS calcd for C21H16F3NO2Cs (M þ Csþ) 504.0187, found
504.0222.
(d, JC-F = 3.4 Hz), 126.4, 124.2 (d, JC-F = 3.4 Hz), 115.9
(d, 2JC-F=22.4 Hz), 40.0, 39.3, 28.6 (d, 4JC-F=2.3 Hz), 25.0;
19F NMR (300 MHz, CDCl3) δ -116.3; HRMS calcd for
C20H16FNO2Cs (M þ Csþ) 454.0219, found 454.0238. Anal.
Calcd for C20H16FNO2: C, 74.75; H, 5.02. Found: C, 74.47;
H, 5.08.
Synthesis of 3-[(3aR,7aS)-1,3-Dioxo-2-phenyl-2,3,3a,4,7,7a-
hexahydro-1H-isoindol-5-yl]benzonitrile (20). Cycloadduct 7
(0.15 g, 0.375 mmol), Pd(OAc)2 (0.027 g, 0.046 mmol), PPh3
(0.024 g, 0.088 mmol), 3-iodobenzonitrile (0.118 g, 0.515 mmol),
and TBAF (0.143 g, 0.453 mmol) were used according to the
general procedure mentioned above. The resulting brown oily
crude reaction mixture was subjected to flash chromatography
to yield the cross-coupled product 20aslightyellowsolid (0.066 g,
0.201 mmol, 53.7%): mp (neat) 157-159 °C; Rf 0.51 (100%
diethyl ether); 1H NMR (500 MHz, CDCl3) δ 7.63 (t, J=1.5 Hz,
1H), 7.58 (dt, J=7.9, 1.5 Hz, 1H), 7.54 (dt, J=7.9, 1.5 Hz, 1H),
7.39-7.48 (m, 3H), 7.63 (tt, J=7.4, 1.3 Hz, 1H), 7.15 (app d, J=
7.4 Hz, 2H), 6.29 (p, J=3.4 Hz, 1H), 3.48(ddd, J=9.4, 6.8, 2.5 Hz,
1H), 3.38 (ddd, J=9.4, 7.6, 2.5 Hz, 1H), 3.22 (dd, J=15.3, 2.5 Hz,
1H), 2.98 (ddd, J=15.7, 7.0, 2.5 Hz, 1H), 2.64 (ddt, J=15.3, 6.8,
2.5 Hz, 1H), 2.47 (dddd, J=15.7, 7.6, 3,6, 2.5 Hz, 1H); 13C NMR
(75 MHz, CDCl3) δ 178.7, 178.5, 141.4, 138.3, 131.8, 131.0, 129.8,
129.5, 129.2, 128.7, 126.3, 125.7, 118.7, 112.9, 40.0, 39.1, 27.2,
25.4; HRMS calcd for C21H16N2O2Cs (M þ Csþ) 461.0266,
found 461.0280.
Synthesis of (3aR,7aS)-2-Phenyl-5-(2-(trifluoromethyl)phe-
nyl)-3a,4,7,7a-tetrahydro-1H-isoindole-1,3(2H)-dione (17). Cyc-
loadduct 7 (0.158 g, 0.394 mmol), Pd(OAc)2 (0.022 g,
0.037 mmol), PPh3 (0.020 g, 0.076 mmol), 1-iodo-2-(trifluor-
omethyl)benzene (0.122 g, 0.448 mmol), and TBAF (0.126 g,
0.399 mmol) were used according to the general procedure
mentioned above. The resulting brown oily crude reaction
mixture was subjected to flash chromatography to yield the
cross-coupled product 17 as a yellow-brown liquid (0.11 g,
1
0.296 mmol, 75.1%): Rf 0.68 (diethyl ether/hexanes, 1:1); H
NMR (500 MHz, CDCl3) δ 7.63 (d, J=7.8 Hz, 1H), 7.43-7.54
(m, 3H), 7.40 (tt, J=7.6, 2.0 Hz, 1H), 7.36 (t, J=7.8 Hz, 1H),
7.29 (dt, J=7.6, 2.0 Hz, 1H), 7.10 (d, J=7.8 Hz, 1H), 5.95 (p, J=
3.4 Hz, 1H), 3.40 (ddd, J=9.4, 7.0, 2.6 Hz, 1H), 3.39 (ddd, J=
9.4, 7.0, 2.6 Hz, 1H), 2.81-2.98 (m, 2H), 2.66-2.80 (m, 1H),
2.40-2.57 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 179.0, 178.8,
141.2 (q, 3JC-F=2.3 Hz), 138.4, 132.0, 131.8, 129.9, 129.1, 128.6,
2
5
127.8 (q, JC-F =29.9 Hz), 127.3, 126.5 (q, JC-F =1.7 Hz),
J. Org. Chem. Vol. 74, No. 21, 2009 8295

Pidaparthi et al.
JOCArticle
Synthesis of (3aR,7aS)-2-Phenyl-5-(thiophene-2-yl)-3a,4,7,7a-
data mirror that of the product 22d mentioned above. Regioi-
somer ratio 3.9:1.0 (based on GC integrations).
tetrahydro-1H-isoindole-1,3(2H)-dione (21). Cycloadduct
7
(0.15 g, 0.375 mmol), Pd(OAc)2 (0.022 g, 0.037 mmol), PPh3
(0.026 g, 0.099 mmol), 2-iodothiophene (0.126 g, 0.60 mmol),
and TBAF (0.129 g, 0.409 mmol) were used according to the
general procedure mentioned above. The oily crude reaction
mixture was purified by flash chromatography to yield the cross-
coupled product 21 as a brown oily substance (0.059 g, 0.191
Cross-Coupling Reaction of 10f) Resulting in the Synthesis of
Diethyl 4-Phenylcyclohex-4-ene-1,2-dicarboxylate (22f). The
crude compound 10f (0.304 g) which contains the cycloadduct
1
(0.206 g, 0.405 mmol) by H NMR integrations, [Pd(allyl)Cl]2
(0.020 g, 0.055 mmol), S-Phos (0.107 g, 0.224 mmol), iodoben-
zene (67.0 μL, 0.601 mmol), KF (0.120 g, 2.06 mmol), and DMF
(20 mL) were used according to the general procedure men-
tioned above. The resulting brown residue was subjected to flash
chromatography using silica gel and 6:1 hexanes/ethyl acetate to
yield the cross-coupled product 22f as a light brown oil (0.043 g,
0.142 mmol, 35.1%): Rf 0.25 (hexanes/ethyl acetate 6:1); 1H
NMR (500 MHz, CDCl3) δ 7.39 (m, 2H), 7.31 (m, 2H), 7.24
(m, 1H), 6.05 (m, 1H), 4.17 (q, J=7.14 Hz, 4H), 3.21-3.18 (td,
J=6.30 Hz, 3.62 Hz, 1H), 3.11-3.08 (td, J=6.30 Hz, 3.62 Hz,
1H), 3.03-2.95 (m, 1H), 2.79-2.70 (m, 2H), 2.58-2.51 (m, 1H),
1.25 (t, J=7.12 Hz, 6H); 13C NMR (125.7 MHz, CDCl3) δ 173.0,
173.0, 141.3, 135.2, 128.2, 127.0, 125.2, 122.3, 60.66, 60.63, 40.4,
39.5, 28.0, 26.4, 14.18, 14.16; GC/MS m/z (relative) 302 (3) [Mþ],
257 (8), 228 (29), 199 (2), 156 (16), 155 (100), 154 (19), 153 (8),
141 (3), 129 (5), 128 (6), 115 (8), 103 (1), 91 (7), 77 (9), 51 (2);
HRMS [M þ H]þ calcd for C18H22O4 303.1596, found 303.1595.
Cross-Coupling Reaction of 10e Resulting in the Synthesis of
Diethyl 4-Phenylcyclohex-4-ene-1,2-dicarboxylate (22e). Crude
compound 10e (0.251 g) which contains the cycloadduct (0.175 g,
0.439 mmol), [Pd(allyl)Cl]2 (0.028g, 0.077mmol), S-Phos(0.102 g,
0.214 mmol), iodobenzene (67.0 μL, 0.601 mmol), TBAF (1.5 mL,
1.5 mmol), and DMF (20 mL) were used according to the general
procedure mentioned above. The resulting brown residue was
subjected to flash chromatography using silica gel and 6:1
hexanes/ethyl acetate to yield the cross-coupled product 22e as
a light brown oil (0.088 g, 0.291 mmol, 66.3%). Characterization
data mirrors that of the product 22f mentioned above.
1
mmol, 50.9%): Rf 0.22 (diethyl ether/hexanes, 1:1); H NMR
(300 MHz, CDCl3) δ 7.30-7.47 (m, 3H), 7.10-7.22 (m, 3H),
7.05 (ad, J=3.4 Hz, 1H), 6.97 (at, J=4.3 Hz, 1H), 6.28 (p, J=
3.4 Hz, 1H), 3.40 (ddd, J=9.6, 7.0, 2.8 Hz, 1H), 3.31 (ddd, J=
9.6, 7.0, 2.6 Hz, 1H), 3.22 (dd, J=15.3, 2.8 Hz, 1H), 2.87 (ddd,
J=15.8, 7.0, 2.6 Hz, 1H), 2.67 (ddt, J=15.3, 7.0, 2.3 Hz, 1H),
2.38-2.55 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 178.8, 178.4,
143.9, 133.3, 131.9, 129.0, 128.5, 127.5, 126.4, 124.2, 123.0,
121.4, 39.7, 39.3, 27.5, 24.8; HRMS calcd for C18H15NO2SCs
(M þ Csþ) 441.9878, found 441.9891.
General Procedure for Optimized Cross-Coupling Reactions of
10-11(c-f). Diels-Alder cycloadduct (compounds 10-11-
(c-f)), [Pd(allyl)Cl]2, and 2-dicyclohexylphosphino-20,60-di-
methoxy-1,10-biphenyl (S-Phos) were taken up in a single-neck
round-bottom flask fitted with a reflux condenser and dissolved
in DMF. After the solution was purged with argon for 5 min,
iodobenzene and the fluoride source were added, and the
reaction was heated to 100 °C. After the specified time, the
reaction was quenched with distilled water (100 mL) and
extracted with Et2O (4ꢀ75 mL). The combined organic layers
were washed with distilled water (2 ꢀ 150 mL), dried over
MgSO4, and condensed by rotary evaporation. The resulting
residue was purified by flash chromatography on silica gel.
Cross-Coupling Reaction of 10d and 11d Resulting in the
Synthesis of Ethyl 4-Phenylcyclohex-3-enecarboxylate (22d
Major) and Ethyl 3-Phenylcyclohex-3-enecarboxylate (22d
Minor). Compounds 10d and 11d (0.220 g, 0.504 mmol),
[Pd(allyl)Cl]2 (0.026 g, 0.071 mmol), S-Phos (0.105 g, 0.220 mmol),
iodobenzene (67.0 μL, 0.600 mmol), KF (0.099 g, 1.70 mmol),
and DMF (20 mL) were used according to the general procedure
mentioned above. The resulting brown residue was subjected to
flash chromatography using silica gel and 10:1 hexane/ethyl
acetate as eluent to yield the cross-coupled product (22d major
and minor) as a colorless oil (0.081 g, 0.352 mmol, 69.8%): Rf
0.30 (hexanes/ethyl acetate, 10:1). Major isomer 22d: 1H NMR
(300 MHz, CDCl3) δ 7.31 (m, 5H), 6.10 (m, 1H), 4.17 (q, J=
7.06 Hz, 2H), 2.73-2.39 (m, 5H), 2.25-2.13 (m, 1H), 1.92-1.76
(m, 1H), 1.28 (t, J = 7.07 Hz, 3H); 13C NMR (125.7 MHz,
CDCl3) δ 175.0, 142.0, 136.6, 128.5, 127.1, 125.3, 122.9, 60.7,
39.4, 28.5, 27.1, 25.9, 14.6. Minor isomer 22d, diagnostic peaks:
1H NMR (300 MHz, CDCl3) δ 4.18 (q, J=7.06 Hz, 2H), 2.32
(m), 2.05 (m); 13C NMR (125.7 MHz, CDCl3) δ 176.0, 142.1,
135.5, 125.4, 124.2, 40.3, 30.0, 25.5, 25.1; GC/MS m/z (relative)
(major isomer 22d) 230 (15) [Mþ], 157 (28), 156 (100), 155 (31),
141 (11), 129 (17), 115 (16), 91 (26), 77 (8); (minor isomer 22d)
231 (6), 230 (38) [Mþ], 184 (9), 158 (13), 157 (100), 156 (99), 155
(53), 141 (21), 129 (26), 115 (33), 91 (54), 77 (11); HRMS [M þ H]þ
calcd for C15H18O2 231.1385, found 231.1387. Regioisomer
ratio 3.8:1.0 (based on GC integrations).
Brief Experimental Description of X-ray Characterization of
Compound 8. Weakly diffracting colorless needle-shaped crys-
tals of K[Si(O2C6H4)2(C14H12NO2)]-MeCN are, at 213(2) K,
monoclinic, space group P21/c - C52h (No. 14) with a =
˚
˚
˚
10.141(8) A, b=12.072(10) A, c=21.290(14) A, β=95.56(2)°,
V=2594(3) A , and Z=4 [dcalcd=1.410 g cm-3; μa(Mo KR)=
3
˚
0.298 mm-1]. Repeated recrystallization attempts to obtain
better quality crystals were unsuccessful. A full hemisphere of
diffracted intensities (1968 30-s frames with an ω scan width of
0.30°) was measured using graphite-monochromated Mo KR
˚
radiation (λ=0.71073 A) on a Bruker SMART APEX CCD
single-crystal diffraction system. X-rays were provided by a fine-
focus sealed X-ray tube operated at 50 kV and 30 mA.
Lattice constants were determined with the Bruker SAINT
software package using peak centers for 1493 reflections having
7.72° e 2θ e 39.09°. A total of 19509 integrated reflection
intensities having 2θ(Mo KR) e 50.00° were produced using
the Bruker program SAINT; 4548 of these were unique and gave
Rint =0.106 with a coverage which was 99.6% complete. The
data were corrected empirically for scaling and variable absorp-
tion effects using Bruker SADABS software; the relative trans-
mission factors ranged from 0.609 to 0.746.
The Bruker software package SHELXTL was used to solve
the structure using “direct methods” techniques. All stages of
weighted full-matrix least-squares refinement were conducted
Cross-Coupling Reaction of 10c and 11c Resulting in the
Synthesis of Ethyl 4-Phenylcyclohex-3-enecarboxylate (22c Major)
and Ethyl 3-Phenylcyclohex-3-enecarboxylate (22c Minor).
Compounds 10c and 11c (0.051 g, 0.156 mmol), [Pd(allyl)Cl]2
(0.010 g, 0.027 mmol), S-Phos (0.047 g, 0.099 mmol), iodoben-
zene (20.5 μL, 0.184 mmol), TBAF (0.45 mL, 0.450 mmol), and
DMF (6 mL) were used according to the general procedure
mentioned above. The resulting brown residue was subjected to
flash chromatography using silica gel and 10:1 hexane/ethyl
acetate as eluent to yield the cross-coupled product 22c as a
colorless oil (0.025 g, 0.109 mmol, 69.8%). Characterization
2
using Fo data with the SHELXTL Version 2008/3 software
package. The resulting structural parameters have been refined
to convergence [R1 (unweighted, based on F)=0.0749 for 3164
independent reflections having 2θ(Mo KR) < 50.00° and F2 >
2σ(F2)] [R1 (unweighted, based on F) = 0.1146 and wR2
(weighted, based on F2)=0.1570 for all 4548 reflections] using
counter-weighted full-matrix least-squares techniques and a
structural model which incorporated anisotropic thermal para-
meters for all nonhydrogen atoms. The hydrogen atoms were
8296 J. Org. Chem. Vol. 74, No. 21, 2009

Pidaparthi et al.
JOCArticle
included in the structural model as fixed atoms (using idealized
sp2- or sp3-hybridized geometry and C-H bond lengths of
The final structural model incorporated anisotropic thermal
parameters for all non-hydrogen atoms and isotropic thermal
parameters for all hydrogen atoms. The hydrogen atoms were
included in the structural model as fixed atoms (using idealized
sp2- or sp3-hybridized geometry and C-H bond lengths of
˚
0.94-0.99 A) “riding” on their respective carbon atoms. The
isotropic thermal parameters for all hydrogen atoms were fixed
at a value 1.2(nonmethyl) or 1.5(methyl) times the equivalent
isotropic thermal parameter of the carbon atom to which they
are covalently bonded. A total of 343 parameters were refined
using no restraints and 4548 data. The largest shift/s.u. was
0.000 in the final refinement cycle. The final difference map had
˚
0.95-1.00 A) “riding” on their respective carbon atoms. The
isotropic thermal parameter of each hydrogen atom was fixed at
a value 1.2 times the equivalent isotropic thermal parameter of
the carbon atom to which it is covalently bonded. A total of 217
parameters were refined using no restraints and 4776 data. Final
agreement factors at convergence are: R1(unweighted, based on
F)=0.059 for 3533 independent “observed” reflections having
2θ(Mo KR) < 60.10° and I > 2σ(I); R1(unweighted, based on
F)=0.078 and wR2(weighted, based on F2)=0.169 for all 4776
independent reflections having 2θ(Mo KR) < 60.10°. The
largest shift/su was 0.000 in the final refinement cycle. The final
difference map had maxima and minima of 0.363 and -0.172
-
3
˚
maxima and minima of 0.348 and -0.409 e /A , respectively.
Brief Experimental Description of X-ray Characterization of
Compound 16. CIF File Deposition Code CCDC 745626:. Large
colorless plate-shaped crystals of C20H16FNO2 are, at 193(2) K,
monoclinic, space group P21/n [an alternate setting of P21/c -
C2h (No. 14)] (1) with a = 14.649(1) A, b = 6.6182(6) A, c =
5
˚
˚
3
˚
˚
17.212(2) A, β=99.662(1)°, V=1645.1(3) A , and Z=4 formula
units [dcalcd =1.297 g/cm3; μa(Mo KR)=0.091 mm-1]. A full
hemisphere of diffracted intensities (1968 20 s frames with a
ω scan width of 0.30°) was measured for a single domain
specimen using graphite-monochromated Mo KR radiation
-
3
˚
e /A , respectively.
Acknowledgment. We thank the National Science Foun-
dation for their support of this work (CHE-0450722 and
0749759) and for the NMR instrumentation used to char-
acterize the compounds reported here. The UNC Center for
Mass Spectrometry performed high-resolution mass spectral
analyses. We thank Professor Al Rives for assistance with the
HOMO energy calculations for the dienes.
˚
(λ= 0.71073 A) on a Bruker SMART APEX CCD single crystal
diffraction system (2). X-rays were provided by a fine-focus
sealed X-ray tube operated at 50 kV and 30 mA.
Lattice constants were determined with the Bruker SAINT
software package using peak centers for 4453 reflections having
7.81° e 2θ e 53.84°. A total of 17395 integrated reflection
intensities having 2θ(Mo KR) < 60.10° were produced using the
Bruker program SAINT (3); 4776 of these were unique and
gave Rint=0.029 with a coverage which was 98.8% complete.
The Bruker software package SHELXTL was used to solve the
structure using “direct methods” techniques. All stages of
weighted full-matrix least-squares refinement were conducted
Supporting Information Available: 1H and 13C NMR spec-
tra of all novel compounds produced. Experimental procedures
for many of the Diels-Alder and cross-coupling reactions other
than the representative examples included here and X-ray
crystallographic data for 8 and 16. This material is available
free of charge via the Internet at http://pubs.acs.org.
2
using Fo data with the SHELXTL Version 6.12 software
package (4).
J. Org. Chem. Vol. 74, No. 21, 2009 8297