Organoyttrium-catalyzed sequential cyclization/silylation reactions of nitrogen-heteroaromatic dienes demonstrating 'aryl-directed' regioselectivity

Article abstract of DOI:10.1021/jo0000527

The reaction of 1-allyl-2-vinyl-1H-pyrroles and 1-allyl-2-vinyl-1H- indoles with arylsilanes in the presence of catalytic [Cp(TMS)₂Y(μ-Me)]₂ leads to highly selective cyclization/silylation events. In this process the active catalyst for the reaction, 'Cp(TMS)₂YH', undergoes initial olefin insertion at the vinyl group. Even isopropenyl substituents on the heteroaromatics react in preference to less sterically encumbered allyl groups. Furthermore, the observed regioselectivity reflects an 'aryl- directed' process, whereby the more highly substituted secondary or tertiary organometallic is initially generated. This intermediate undergoes cyclization onto the remaining alkene and subsequent silylation by a σ-bond metathesis reaction, affording the observed products.

Full text of DOI:10.1021/jo0000527

J . Org. Chem. 2000, 65, 3767-3770
3767
Or ga n oyttr iu m -Ca ta lyzed Sequ en tia l Cycliza tion /Silyla tion
Rea ction s of Nitr ogen -Heter oa r om a tic Dien es Dem on str a tin g
“Ar yl-Dir ected ” Regioselectivity
Gary A. Molander*,†,‡ and Monika H. Schmitt‡
Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania,
Philadelphia, Pennsylvania 19104-6323, and Department of Chemistry and Biochemistry,
University of Colorado, Boulder, Colorado 80309-0215
Received J anuary 13, 2000
The reaction of 1-allyl-2-vinyl-1H-pyrroles and 1-allyl-2-vinyl-1H-indoles with arylsilanes in the
presence of catalytic [CpTMS2Y(µ-Me)]2 leads to highly selective cyclization/silylation events. In this
process the active catalyst for the reaction, “CpTMS2YH”, undergoes initial olefin insertion at the
vinyl group. Even isopropenyl substituents on the heteroaromatics react in preference to less
sterically encumbered allyl groups. Furthermore, the observed regioselectivity reflects an “aryl-
directed” process, whereby the more highly substituted secondary or tertiary organometallic is
initially generated. This intermediate undergoes cyclization onto the remaining alkene and
subsequent silylation by a σ-bond metathesis reaction, affording the observed products.
Sch em e 1
The use of group 3 and lanthanide metallocenes as
catalysts for stereoselective cyclization/silylation reac-
tions of substituted 1,5- and 1,6-dienes to functionalized
carbocycles is by now well established.1 Previous inves-
tigations have demonstrated that, despite their recog-
nized Lewis acidity and the propensity to complex with
Lewis bases, these metallocenes can also be utilized for
the synthesis of nitrogen heterocycles either via cycliza-
tion/silylation1d,h or hydroamination protocols.2 Because
this class of catalysts is highly sensitive to steric encum-
brance about the alkene, and because steric factors
predominate in the insertion process,3 nearly all of the
research in this area has focused on monosubstituted
olefins. Disubstituted alkene systems cannot be accom-
modated by sterically crowded catalysts such as Cp*2-
YMe‚THF. This allows exquisite selectivity in compli-
cated, polyunsaturated substrates wherein less sterically
encumbered alkenes react in preference to their more
sterically shielded counterparts.1c
More open ligand arrays about the metal have been
enlisted to allow incorporation of 1,1-disubstituted
alkenes.1b In the current contribution we report the use
of one of this new generation of complexes, [CpTMS2Y(µ-
Me)]2,1c,4 in cyclization/silylation reactions of heteroaro-
matic dienes. This catalyst allows the extension of this
chemistry to 1,1-disubstituted olefins with “aryl-directed”
regioselectivity.
In previous studies on saturated nitrogen heterocycles,
the catalytic cycle depicted in Scheme 1 was estab-
lished.1d,h,5 The precatalyst reacts with the silane via a
σ-bond metathesis reaction6 to generate an organolan-
thanide hydride, the active catalyst for the process. The
hydride catalyst “(CpTMS)2YH”7 preferentially inserts the
least hindered olefin with the same regioselectivity as
hydroboration reactions,8 placing the bulky metal and
associated ligands at the terminus of the carbon chain.
† University of Pennsylvania.
‡ University of Colorado.
(1) (a) Molander, G. A. Chemtracts 1998, 11, 237 and references
therein. (b) Molander, G. A.; Dowdy, E. D.; Schumann, H. J . Org. Chem.
1998, 63, 3386. (c) Molander, G. A.; Nichols, P. J .; Noll, B. C. J . Org.
Chem. 1998, 63, 2292. (d) Molander, G. A.; Nichols, P. J . J . Org. Chem.
1996, 61, 6040. (e) Molander, G. A.; Nichols, P. J . J . Am. Chem. Soc.
1995, 117, 4415. (f) Onozawa, S.; Sakakura, T.; Tanaka, M. Tetrahe-
dron Lett. 1994, 35, 8177. (g) Molander, G. A.; Dowdy, E. D. In Topics
In Organometallic Chemistry; Kobayashi, S., Ed.; Springer-Verlag:
New York, 1999; Vol. 2, pp 120-154. (h) Molander, G. A.; Corrette, C.
P. J . Org. Chem. 1999, 64, 9697.
(2) (a) Gagne´, M. R.; Marks, T. J . J . Am. Chem. Soc. 1989, 111, 4108.
(b) Gagne´, M. R.; Nolan, S. P.; Marks, T. J . Organometallics 1990, 9,
1716. (c) Gagne´, M. R.; Stern, C. L.; Marks, T. J . J . Am. Chem. Soc.
1992, 114, 275. (d) Gagne´, M. R.; Brard, L.; Conticello, V. P.; Giardello,
M. A.; Stern, C. L.; Marks, T. J . Organometallics 1992, 11, 2003. (e)
Li, Y.; Fu, P.-F.; Marks, T. J . Organometallics 1994, 13, 439. (f) Li, Y.;
Marks, T. J . J . Am. Chem. Soc. 1996, 118, 707. (g) Li, Y.; Marks, T. J .
Organometallics 1996, 15, 3770. (h) Li, Y.; Marks, T. J . J . Am. Chem.
Soc. 1996, 118, 9295. (i) Giardello, M. A.; Conticello, V. P.; Brard, L.;
Gagne´, M. R.; Marks, T. J . J . Am. Chem. Soc. 1994, 116, 10241. (j)
Arredondo, V. M.; Tian, S.; McDonald, F. E.; Marks, T. J . J . Am. Chem.
Soc. 1999, 121, 3633. (k) Molander, G. A.; Dowdy, E. D. J . Org. Chem.
1999, 64, 6515. (l) Molander, G. A.; Dowdy, E. D. J . Org. Chem. 1998,
63, 8983.
(4) Schumann, H.; Keitsch, M. R.; Demtschuk, J .; Molander, G. A.
J . Organomet. Chem. 1999, 582, 70.
(5) Nichols, P. J . Ph.D. Thesis, University of Colorado at Boulder,
1997.
(3) Molander, G. A.; Knight, E. E. J . Org. Chem. 1998, 63, 7009.
10.1021/jo0000527 CCC: $19.00 © 2000 American Chemical Society
Published on Web 05/19/2000

3768 J . Org. Chem., Vol. 65, No. 12, 2000
Molander and Schmitt
The hydrocarbyl formed undergoes intramolecular olefin
insertion through a chairlike transition structure before
reacting with the silane via σ-bond metathesis to gener-
ate the desired product. All of the individual steps of this
transformation are well documented.1,2b,9
a chairlike transition structure and σ-bond metathesis
to the organosilane would lead to the desired product.
Initial cyclization reactions on the heteroaromatic
dienes were conducted with 1-allyl-2-vinyl-1H-pyrrole
and 1-allyl-2-vinyl-1H-indole using Cp*2YMe‚THF as a
precatalyst.11 Somewhat unexpectedly, the material iso-
lated after oxidation of the reaction contained none of
the desired products (eqs 1 and 2). Thus, although the
During the early stages of the present work on sub-
stituted vinylpyrrole and -indole systems, relative rate
studies were being carried out on organoyttrium-cata-
lyzed hydrosilylation reactions.3 Somewhat surprisingly,
these investigations revealed that the hydrosilylation of
N-methyl-2-vinylpyrrole was at least 10 times faster than
that of 1-decene. 1-Decene was determined to be the most
reactive of the nonconjugated alkenes investigated. Fur-
thermore, Marks had previously noted that the hydrosi-
lylation of styrene derivatives led to benzylically substi-
tuted silanes.10 This reaction presumably transpired
through a benzylic organometallic via a regioinverted
insertion process on the olefin. The combination of these
prior investigations led us to propose the cycle pictured
in Scheme 2 for heteroaromatic dienes.
Sch em e 2
major product of these reactions had resulted from initial
insertion at the conjugated alkene as expected on the
basis of the relative rate studies, in contrast to the Marks
chemistry the insertion had proceeded predominantly
with the same characteristic regiochemistry of noncon-
jugated, terminal alkenes.
The “aryl-directed” process proposed by Marks10 infers
that the aromatic moiety serves as a Lewis base, inter-
acting with the Lewis acidic metal center. Least motion
insertion of the alkene leads to the benzylic organome-
tallic. Rationalizing that this interaction (as well as the
insertion at the more highly substituted terminus of the
alkene) could be facilitated by a more sterically open
organometallic complex (eq 3), we turned to the use of
Thus according to the relative rate studies, the hydride
catalyst was anticipated to react preferentially with the
vinyl substituent.3 In analogy to the Marks hydrosilyla-
tion chemistry of styrene derivatives,10 the regioselectiv-
ity of this process was expected to create a secondary
organometallic intermediate. Subsequent cyclization via
[CpTMS2Y(µ-Me)]2 as a catalyst for the remainder of our
study. This catalyst had previously proven effective for
cyclization/silylation reactions of a variety of 1,1-disub-
stituted dienes,1b a class of molecules that had previously
proved resistant to this process.
The initial cyclizations employing this catalyst were
explored with 1-allyl-2-vinyl-1H-pyrrole (1) as a substrate
(Table 1). In a typical reaction using this protocol,
heterocyclic diene 1 (0.5 M in cyclohexane) and 1.1 equiv
of phenylsilane were reacted in the presence of 8-10 mol
% of [CpTMS2Y(µ-Me)]2 for 6 h at room temperature.12 This
provided an essentially quantitative yield of (1R*,2R*)-
(6) (a) Zinnen, H. A.; Pluth, J . J .; Evans, W. J . J . Chem. Soc., Chem.
Commun. 1980, 810. (b) Brothers, P. J . Prog. Inorg. Chem. 1981, 28,
1. (c) Evans, W. J .; Meadow, J . H.; Wayda, A.; Hunter, W. E.; Atwood,
J . L. J . Am. Chem. Soc. 1982, 104, 2008. (d) Schumann, H.; Genthe,
W. J . Organomet. Chem. 1981, 213, C7. (e) Marks, T. J . Inorg. Chim.
Acta 1987, 140. (f) Thompsen, M. E.; Baxter, S. M.; Bulls, A. R.; Burger,
B. J .; Nolan, M. C.; Santarrisiero, B. D.; Schaefer, W. P.; Bercaw, J .
E. J . Am. Chem. Soc. 1987, 109, 203.
(7) Schumann, H.; Keitsch, M.; Demtschuk, J .; Molander, G. A. J .
Organomet. Chem. 1999, 582, 70. Although the methyl precatalyst is
a dimer, the active hydride catalyst is most likely a monomer and is
capable of a rapid olefin insertion of most 1,1-disubstituted alkenes.
Another interesting feature of the catalyst is its unusual stability.
Members of this class of precatalyst have been weighed in the air and
utilized in hydrosilylation reactions employing normal procedures for
the benchtop handling of air-sensitive materials.
(8) Brown, H. C. Hydroboration; W. A. Benjamin, Inc.: New York,
1962.
(11) Prepared by a modification of the procedure found in: Baskoboy-
nikow, A. Z.; Parshina, I. N.; Shestakova, A. K.; Butin, K. P.; Belet-
skaya, I. P.; Kuz’mina, L. G.; Howard, J . A. K. Organometallics 1997,
16, 4041. KCpTMS (6 mmol) and YCl3 (3 mmol) were heated at reflux
in THF for 4 h. The solvent was removed in vacuo and replaced with
Et2O. MeLi (2.15 mL of a 1.5 M solution in Et2O, 3.2 mmol) was added
at -78 °C, and the reaction was warmed to room temperature. After
the solution was stirred for 4 h, the solvent was removed and the solids
were extracted with hexanes to provide the desired organometallics.
(9) (a) Molander, G. A.; Hoberg, J . O. J . Am. Chem. Soc. 1992, 114,
3123. (b) Piers, W. E.; Bercaw, J . E. J . Am. Chem. Soc. 1990, 112, 9406.
(c) Piers, W. E.; Shapiro, P. J .; Bunel, E. E.; Bercaw, J . E. Synlett 1990,
74. (e) Heeres, H. J .; Teuben, J . H. Organometallics 1990, 9, 1508. (f)
Gagne´, M. R.; Marks, T. J . J . Am. Chem. Soc. 1989, 111, 4108. (g) den
Haan, K. H.; Wielstra, Y.; Teuben, J . H. Organometallics 1987, 6, 2053.
(10) Fu, P.-F.; Brard, L.; Li, Y.; Marks, T. J . J . Am. Chem. Soc. 1995,
117, 7157.

Nitrogen-Heteroaromatic Dienes
J . Org. Chem., Vol. 65, No. 12, 2000 3769
Ta ble 1. [Cp TMS2Y(µ-Me)]2-Ca ta lyzed Cycliza tion /
Silyla tion Rea ction s of Su bstitu ted Heter oa r om a tic
Dien esa
products derived from the regioisomeric organometallic
intermediate could be detected in the crude reaction
mixtures.
Remarkably, we observed that this process works
extremely well for conjugated 1,1-disubstituted alkenes,
even though the competitive rate studies had indicated
that 1-decene and 1-methyl-2-isopropenylpyrrole had
nearly the same reaction rate in the hydrosilylation
reaction.3 Thus the cyclization/silylation reaction of the
heteroaromatic diene 4 provided product 5 in excellent
yield. This reaction required 12 h to proceed to completion
(Table 1). Presumably, the increased reaction time was
necessary because the sterically more congested 1,1-
disubstituted alkene makes it much less reactive than
monosubstituted alkenes, and the creation of a tertiary
organometallic should also be extraordinarily difficult,
further retarding the reaction. Importantly, although
there are examples for the same sense of regioselection
in enantioselective catalytic hydrogenation and hydrosi-
lylation reactions of styrene derivatives,2i,10 this appears
to be the first such selectivity observed in polyunsatu-
rated systems where chemoselectivity is an issue. Fur-
thermore, it is the first example of which we are aware
in which olefin insertion takes place into a tertiary
metal-carbon bond.
As evidenced by the remainder of the results depicted
in Table 1, a variety of substrates could be efficiently
converted to cyclized organosilanes in high yield and with
excellent diastereoselectivities using this protocol. For
1,5-diene 6, the product can again be attributable to “aryl-
directed” olefin insertion of the organoyttrium hydride
catalyst at the conjugated alkene, followed by cyclization
to provide 1,2-disubstituted bicyclic product 7. To avoid
the formation of cyclized, dialkylated silanes in the slower
cyclization of 1,6-dienes, phenylmethylsilane can be
employed as a chain terminator.1c,e Utilizing this more
hindered silane slows the intermolecular σ-bond metath-
esis of the intermediate organometallic with the silane
sufficiently to allow the cyclization to take place.
The cyclization/silylation process does not work well
for substrates 8a ,b. Apparently, the intermediate tertiary
organometallic is not able to effectively cyclize onto the
more highly hindered 1,1-disubstituted alkene center,
and a complex mixture of products is generated.
a
Some phenylsilanes were immediately converted to the cor-
responding alcohols by known transformations for structural
b
characterization. All reactions were performed with 8-10 mol
% of catalyst and PhSiH3 unless otherwise noted. c Isolated by
flash chromatography. The diastereoselectivity was determined
on isolated material by spectroscopic data. All of these compounds
have been fully characterized spectroscopically (1H NMR, 13C
NMR, IR), and elemental composition has been established by
high-resolution mass spectrometry and/or combustion analysis.
The products were >98% pure by GC analysis and none of the cis
d
isomer could be observed by NMR. The reaction time indicated
is for the cyclization/silylation reaction. e Isolated yield for the two-
step process (cyclization/silylation and oxidation). f The reaction
was performed with PhMeSiH2 instead of PhSiH3.
Indole derivatives were examined, and as expected,
they worked as well as the analogous pyrroles. The
strongly Lewis acidic catalyst tolerates the Lewis basic
ether as illustrated with substrate 9b. Interestingly, this
electron-releasing group significantly accelerates the
process (compare the reaction time for 9a to that of 9b).
As in the pyrrole series, 1,1-disubstituted alkenes were
tolerated as well, and thus, 11 can be converted to 12 in
reasonable overall yield. Finally, a juxtaposition of react-
ing substituents is possible in the indole platform, with
substrate 13 leading to 14 in good yields through initial
olefin insertion of the vinyl group on the carbocycle.
In summary, [CpTMS2Y(µ-Me)]2 has been shown to be
an efficient precatalyst for the cyclization and subsequent
silylation of substituted heteroaromatic dienes. This
process has been extended to 1,1-disubstituted olefins
and provided excellent selectivities and yields in many
cases. The relatively easy preparation of the organome-
tallic catalyst and the facile oxidation of the resulting
phenylsilanes to the synthetically more versatile alcohols
provide an attractive synthetic method for the construc-
tion of functionalized five- and six-membered nitrogen
1-methyl-2-[(1-phenylsilyl)methyl]-2,3-dihydro-1H-pyr-
rolizine (2).13 Because structural characterization of the
newly generated phenylsilane 2 proved difficult, this
intermediate was converted to the corresponding alcohol
3 by facile oxidation using excess KH and t-BuOOH in
the presence of DMF according to the method developed
by Woerpel and Smitrovich.14 Analysis of the resulting
alcohol15 revealed that all of the steps proceeded in
excellent yields and with high selectivities. None of the
(12) One problem with the catalyst is that it apparently becomes
deactivated over time because of hydride dimer formation. Ideal
conditions involve the addition of smaller portions of the catalyst at
fixed intervals to maintain an active concentration of the catalyst.
(13) The general workup procedure involved filtration of the crude
mixture through a small plug of Florisil prior to concentration by rotary
evaporation and purification by flash chromatography. Many of these
reactions are so clean, in fact, that pouring the reaction mixture
through a short bed of Florisil to remove the catalyst, followed by
evaporation of the solvent and bulb-to-bulb distillation, leads to
essentially quantitative yields of analytically pure products.
(14) Smitrovich, J . H.; Woerpel, K. H. J . Org. Chem. 1996, 61, 6044.
(15) The relative stereochemistry of the major isomer of 2 was
assigned on the basis of NOE difference experiments using alcohol 3.

3770 J . Org. Chem., Vol. 65, No. 12, 2000
Molander and Schmitt
heterocycles. Many of these structural motifs are present
in diverse natural products. Most remarkable is the fact
that heteroaromatic dienes react cleanly at the conju-
gated alkene with “inverted” regioselectivity. The “aryl-
directed” insertion process allows the normal (sterically
and electronically driven) regioselectivity patterns to be
overcome even with 1,1-disubstituted alkenes, and thus,
structures complementary to those observed in nonaro-
matic systems can be accessed.
Su p p or tin g In for m a tion Ava ila ble: Text providing full
experimental details. This material is available free of charge
via the Internet at http://pubs.acs.org.
J O0000527