Tandem 1,4-addition reactions with benzene and alkylated benzenes promoted by pentaammineosmium(II)

Article abstract of DOI:10.1021/ja020279e

Electrophiles such as dimethoxymethane and 3-penten-2-one react with the complex [Os(NH₃)₅-(η²-benzene)]²⁺ in the presence of triflic acid to form metastable benzenium intermediates. These benzenium intermediates further react with carbon nucleophiles including silyl ketene acetals, (silyloxy)alkenes, and phenyllithium in an overall tandem 1,4-addition sequence. The metal fragment controls the relative stereo- and regiochemistry for both electrophilic and nucleophilic addition steps. Upon oxidative demetalation with silver triflate, cis-1,4 cyclohexadienes are formed in yields ranging from 16 to 82%. This methodology can also be used to dearomatize toluene and ortho- and meta-xylene with unexpectedly high regio- and stereocontrol.

Full text of DOI:10.1021/ja020279e

Published on Web 10/11/2002
Tandem 1,4-Addition Reactions with Benzene and Alkylated
Benzenes Promoted by Pentaammineosmium(II)
Fei Ding, Michael E. Kopach, Michal Sabat, and W. Dean Harman*
Contribution from the Department of Chemistry, UniVersity of Virginia,
CharlottesVille, Virginia 22901
Received February 22, 2002
Abstract: Electrophiles such as dimethoxymethane and 3-penten-2-one react with the complex [Os(NH
(
3 5
) -
η2-benzene)]2+ in the presence of triflic acid to form metastable benzenium intermediates. These benzenium
intermediates further react with carbon nucleophiles including silyl ketene acetals, (silyloxy)alkenes, and
phenyllithium in an overall tandem 1,4-addition sequence. The metal fragment controls the relative stereo-
and regiochemistry for both electrophilic and nucleophilic addition steps. Upon oxidative demetalation with
silver triflate, cis-1,4 cyclohexadienes are formed in yields ranging from 16 to 82%. This methodology can
also be used to dearomatize toluene and ortho- and meta-xylene with unexpectedly high regio- and
stereocontrol.
Introduction
(toluene) occurs at the ortho (9%), meta (35%), and para (35%)
positions, as well as at the methyl group (20%). By comparison,
Friedel-Crafts alkylation of toluene slightly favors ortho and
para addition but again with practically no selectivity,10 and
these reactions are further complicated by multiple alkylations
and cation rearrangements.
9
Aromatic hydrocarbons are attractive as possible reagents for
organic syntheses, having the potential to form highly substi-
tuted alicyclic and polycyclic compounds if properly activated.
Given the abundance and stability of arenes, several methodolo-
gies have been developed to convert them into cyclohexadienes.
When catalyzed by the bacterium Pseudomonas putida, benzene
and toluene can be oxidized to cis-dihydrodiols with high
1
2
The electron-rich pentaammineosmium(II) fragment is known
2
to bind anisole, aniline, and phenol in an η fashion. Once bound
they are activated toward electrophilic addition,6 and the
resulting arenium intermediates may be treated with nucleophiles
to form 1,3-diene complexes. The electrophilic addition occurs
for these reactions at C4 with excellent regio- and stereocon-
3
stereoselectivities. The Birch reduction is often used to dearo-
matize benzenes to 1,4-cyclohexadienes with good regioselec-
4
tivity. Alkylation under Birch reduction conditions has been
developed into a useful method but has been mostly limited to
arenes with electron-withdrawing substituents. Alternatively,
1
1,12
5
trol.
Benzene, toluene, and xylenes have previously been
shown to form stable complexes with the pentaammineosmium-
coordination by transition metals has been used to promote the
1
3
addition of electrophiles or nucleophiles to arenes.6
,7
(II) fragment, but owing to the lack of electron-releasing
substituents, these complexes are less thermally stable and less
nucleophilic than their heteroatom-substituted counterparts.
Consequently, the benzenium intermediates resulting from
electrophilic addition are highly acidic (the pKa of the parent
Relative to functionalized arenes such as anisoles, anilines,
phenols, and phenones, the dearomatization of benzene and
alkylbenzenes is a much greater challenge due to their higher
degrees of aromatic stability. In addition, control of the
regiochemistry is highly problematic given the relatively weak
electron-donating abilities of alkyl groups. While coordination
14
benzenium complex is -8.9) and not stable enough to isolate.
Nonetheless, we hoped that by forming these intermediates in
situ at low temperature and trapping them with a suitable
nucleophile, tandem addition reactions could be carried out.
to an electron-deficient transition metal, as in Cr(CO)3 or [Mn-
+
(
CO)3] , sufficiently activates an arene to the addition of
organometallic nucleophiles, regioselectivity is typically low,
with alkylation often occurring at both ortho and meta positions.
8
Results
Regioselective deprotonation followed by electrophilic alkylation
is also problematic. For example, the lithiation of Cr(CO)3-
Triflic acid (HOTf) and dimethoxymethane (DMM) were
combined with the [Os(NH3)5(η -benzene)] complex (A,
2
2+
*
Corresponding author. E-mail: wdh5z@virginia.edu.
(
(
(
(
(
(
(
(
1) Hendrickson, J. B. J. Am. Chem. Soc. 1977, 99, 5439.
(9) Semmelhack, M. F. Transition Metal Arene Complexes: Ring Lithiation;
Pergamon: Oxford, U.K., 1995; Vol. 12.
2) Mander, L. N. Synlett 1991, 134.
3) Carless, H. A. J. Tetrahedron: Asymmetry 1992, 3, 795.
4) Krapcho, A. P.; Bothner-By, A. A. J. Am. Chem. Soc. 1959, 81, 3658.
5) Loewenthal, H. J. E.; Gottlieb, L. J. Org. Chem. 1992, 57, 2631.
6) Harman, W. D. Chem. ReV. 1997, 97, 1953.
(10) Roberts, R. M.; Khalaf, A. A. A Century of Friedel-Crafts Alkylation
Chemistry; Marcel Dekker Inc.: New York, 1984.
(11) Kopach, M. E.; Kolis, S. P.; Liu, R.; Robertson, J. W.; Chordia, M. D.;
Harman, W. D. J. Am. Chem. Soc. 1998, 120, 6199.
(12) Winemiller, M. D.; Harman, W. D. J. Am. Chem. Soc. 1998, 120, 7835.
(13) Harman, W. D.; Sekine, M.; Taube, H. J. Am. Chem. Soc. 1988, 110, 5725.
(14) Winemiller, W. D.; Kopach, M. E.; Harman, W. D. J. Am. Chem. Soc.
1997, 119, 2096.
7) Pape, A. R.; Kaliappan, K. P.; K u¨ ndig, E. P. Chem. ReV. 2000, 100, 2917.
8) Semmelhack, M. F. Transition Metal Arene Complexes: Nucleophilic
Addition; Abel, E. W., Stone, F. G. A., Wilkinson, G., Ed.; Pergamon:
Oxford, U.K., 1995; Vol. 12, p 979.
13080
9
J. AM. CHEM. SOC. 2002, 124, 13080-13087
10.1021/ja020279e CCC: $22.00 © 2002 American Chemical Society

Tandem 1,4-Addition Reactions
A R T I C L E S
1
Scheme 1. Proposed Reaction Pathway for the Tandem Addition
to Alkylated Benzenes
diene 4 in 31% isolated yield. Careful examination of the H
NMR spectra for the crude organic products 1-4 shows no
indication of any other regio- or stereoisomer (dr > 20:1).
Although reactions with methyl vinyl ketone failed to give a
clean addition reaction, the Michael acceptor 3-penten-2-one
reacted cleanly with the benzene complex (A). Subsequent
nucleophilic addition by the acetal 1-methoxy-2-phenyl-1-
(trimethylsiloxy)ethene, followed by oxidative decomplexation,
afforded the corresponding 1,4-cyclohexadiene 5 in 27% overall
yield. For the diene 5, NMR data also suggest that a single
diastereomer is formed, but in this case the two stereocenters
are sufficiently far removed that it is likely that diastereomers
could not be resolved.
In an earlier study, the toluene complex (D) was found to
react with HOTf to form a toluenium intermediate E in which
protonation occurred exclusively ortho to the methyl group.14
This complex was stable enough to be observed at low
temperatures but again could not be isolated. However, when a
cold solution of E was treated with MMTP, followed by silver
triflate, a 1,4-cyclohexadiene was formed and isolated in 56%
yield. Given that COSY data showed no coupling between the
olefinic proton adjacent to the ring methyl group at δ 5.24 and
either of the other two olefinic protons at δ 5.85 or 5.54, the
product (8) is thought to be a 1,4 cyclohexadiene species similar
to those formed from benzene (1-5). When the methyl group
on C1 at δ1.70 was irradiated, the methylene protons on C2 at
δ 2.52 showed 1.6% NOE enhancement, confirming the
protonation occurred on the ortho position of toluene.
The tandem addition of DMM and MMTP to the toluene
complex gave two isomers (6) in a 5:1 ratio when the reaction
was carried out at -40 °C, and this ratio improved to 10:1 when
the reaction was run at -80 °C. These isomers could not be
separated by chromatography. With the aid of COSY data and
the results from the analogous reaction with triflic acid, the
major isomer (6a) was tentatively assigned as the 2,5 addition
product with respect to the methyl group of toluene (vide infra).
Surprisingly, 3-penten-2-one and MMTP reacted with the
toluene complex (D) to yield after oxidative decomplexation a
single diastereomer of 7, even though three new stereocenters
were formed. The methine proton (δ 2.50) on the methylox-
obutyl substituent showed a 10.4% NOE enhancement when
the methyl group on the ring at δ 1.68 was irradiated, indicating
that the electrophile added to the ortho position of toluene
exclusively. Attempts to assign the relative configuration of the
stereogenic centers for 7 by X-ray diffraction were frustrated
by the difficulties in growing high-quality crystals of either the
cyclohexadiene complex of pentaammineosmium(II) or the
organic product.
Scheme 1) in CD3CN at -40 °C. The light red solution was
monitored by proton NMR spectroscopy (-40 °C). Peaks at δ
6
.51, 6.14, 6.05, 5.95, and 5.13 were compared to the ring
protons found for the parent benzenium complex and found to
be similar.14 Carbon data also closely matched, indicating the
formation of the alkylbenzenium B. No other complex was
detectable in the proton or carbon NMR spectrum. Although
the benzenium complex B could not be isolated due to its
thermal instability, subsequent treatment of B with 1-methoxy-
2-methyl-1-(trimethylsiloxy)propene (MMTP) formed the puta-
tive diene complex C. Silver triflate was added to oxidize the
metal. Heating this solution resulted in liberation of the
disubstituted cyclohexadiene 1 in an isolated yield of 82%. The
assignment of a 1,4-cyclohexadiene addition product was
supported by the splitting pattern of olefinic protons at δ 5.84
and 5.58 and carbons at δ 128.6 and 126.1, indicating mirror
symmetry in the product. Following DMM addition to the
benzene complex, both 2-(trimethylsiloxy)propene and phenyl-
lithium (with cuprous cyanide) were found to react, giving 1,4
addition products with overall isolated yields of 23% (2) and
Protonation of the o-xylene complex (G) with HOTf occurred
14
at a carbon adjacent to one of the methyl groups. When this
xylenium complex is treated with MMTP, a 1,4-cyclohexadiene
again is isolated in 67% yield after demetalation. The assignment
of 9 as a 1,2,3-trialkyl-1,4-cyclohexadiene was made on the basis
of the coupling between the methylene protons at δ 2.56 and
one olefinic proton at δ 5.88. On the basis of similar coupling
patterns of the olefinic protons, similar regiochemistry was
assigned for the tandem addition of DMM and MMTP to
o-xylene to generate 10 in overall 28% yield. A CD3CN solution
of the xylene complex G was then treated with DMM and HOTf
at -40 °C. Proton signals recorded at -40 °C for the putative
1
6% (3), respectively. Less sterically hindered silyl ketene
acetals were prepared according to the procedure of Mikami et
1
5
al. The addition of DMM followed by the ketene acetal
-ethoxy-1-(trimethylsiloxy)ethene generated the 1,4-cyclohexa-
1
(
15) Mikami, K.; Matsumoto, S.; Ishida, A.; Takamuku, S.; Suenobu, T.;
Fukuzumi, S. J. Am. Chem. Soc. 1995, 117, 11134.
J. AM. CHEM. SOC.
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VOL. 124, NO. 44, 2002 13081

A R T I C L E S
Ding et al.
Table 1. Products and Yields of the Tandem Additions to Benzene, Toluene, and Xylenes
xylenium intermediate at δ 6.75, 6.51, 6.13, and 2.14 and carbon
signals at δ 187.9 (C), 166.3 (C), 130.0 (CH), 69.7 (CH), 62.9
π* transition or the conjugated diene π f π* transition.
However, a conjugated diene would be expected to have a very
5
(CH), and 50.0 (CH) corresponding to the ring carbons indicated
high extinction coefficient (∼2 × 10 ). On this basis, ꢀmax of
1
6
that the carbon electrophile added exclusively to C6 in a manner
similar to that observed for protonation.
the sample was attributed to ester absorption, and 11 was
assigned as the 1,4-cyclohexadiene shown in Table 1.
Several experiments were carried out in an attempt to extend
this methodology to para-dialkylated benzenes. In particular,
the para-xylene complex was synthesized and isolated. Several
attempts were made to add a carbon electrophile to this complex,
but none were successful.
The m-xylene complex (J) can be protonated, 1 but subse-
quent treatment with MMTP followed by silver(I) oxidation
failed to yield any of the expected diene products. However,
when triflic acid and DMM were combined with the meta-xylene
complex followed by MMTP and silver triflate, diene 11 was
isolated in 32% yield. Diene 11 had a quaternary carbon in the
ring and three alkene protons, but this situation did not
distinguish between the nucleophile adding at C1 (a 1,3-
cyclohexadiene) or at C3 (a 1,4 cyclohexadiene). Ultraviolet
absorption spectroscopy showed a λmax of 238 nm with the ꢀmax
4
Previous studies of tandem addition reactions with naphtha-
lene were shown to consistently produce cis-disubstituted
products with both the electrophile and nucleophile adding anti
to the face of metal coordination. To confirm this expectation
for benzenes, the osmium complex (N) of the diene 7 was
isolated and characterized (Figure 1). When the cis ammine
-
1
-1
of 78 M cm . Note that isolated dienes normally absorb
below 200 nm, which is out of the range of the spectrometer,
so the absorption could be attributed to either the carbonyl n f
(
16) Silverstein, R. M.; Bassler, G. C.; Morril, T. C. Spectrometric Identification
of Organic Compounds; John Wiley & Sons: New York, 1991.
13082 J. AM. CHEM. SOC.
9
VOL. 124, NO. 44, 2002

Tandem 1,4-Addition Reactions
A R T I C L E S
Discussion
The majority of dearomatization reactions that generate 1,4-
alkylated cyclohexadienes already have their carbon skeleton
18,19
intact prior to reduction.
Reductive alkylation has been used
to introduce one alkyl group; however, to our knowledge, there
is no general method available that allows a regio- and
stereoselective 1,4-dialkylation of benzenes. Although the
methodology described herein is stoichiometric with respect to
the metal fragment, it allows the addition of acetals or Michael
acceptors, two of the most important classes of carbon electro-
philes, in concert with ester- or ketone-derived silylenolates or
phenyllithium. The addition sequence is carried out on an
unactivated hydrocarbon under relatively mild conditions, with
readily predictable outcomes.
Figure 1. Assignment of regio- and stereochemistry for cyclohexadiene 7
and its complex N.
One of the most interesting features of this tandem addition
sequence is the high degree of regiocontrol expressed in the
initial dearomatization step. This is particularly remarkable for
toluene given that the only directing influence is a methyl group.
In comparison, the regioselectivity for the addition of organo-
lithium reagents for Cr(CO)3 to alkylated benzenes is generally
8
,20,21
poor unless very bulky nucleophiles are used.
Similarly,
the addition of Grignard reagents and ketone enolates to {Mn-
+
22
(
(
CO)3}
occurs with poor regiocontrol. Because the {Mn-
+
CO)3} fragment is more π-acidic than the Cr(CO)3 analogue,
double nucleophilic addition is sometimes possible, and it is
worth noting that, after methylation of the benzene complex,
hard nucleophiles can be added ortho and syn to the methyl
2
3,24
group.
The high regioselectivity observed for the addition of carbon
electrophiles to alkylated benzene complexes of pentaammin-
eosmium(II) mirrors that of protonation in all cases that we
14
investigated. Important factors include the ability of the metal
fragment to rapidly adjust to different positions in the ring, steric
interactions between the metal and alkyl groups that direct the
metal away from these substituents, and, most importantly, the
stabilization of the resulting arenium intermediate by hyper-
Figure 2. Preparation of a 3H-benzofuran-2-one ring system from
cyclohexadiene 1.
resonance of the metal fragment was irradiated, the proton (δ
2
.39) at the nucleophilic addition site (C5) showed an 8.0%
14
conjugation with an alkyl group. In an earlier study, we
NOE enhancement, indicating that nucleophilic attack was anti
to the metal. The overlap of the methyloxobutyl methine proton
and the C2 ring proton hampered the identification of the relative
stereochemistry on C2. However, the C2 and C5 protons of the
organic diene 7 show unusually strong homoallylic coupling
with each other (J ) 9.5 Hz), supporting the hypothesis that
they are in a syn relationship.17
2
determined that protonation of η -bound alkylated benzenes
occurs with high selectivity (dr > 25:1) under thermodynamic
control. In every case, protonation occurs adjacent to an alkyl
group, and as a result, the alkyl group is in a terminal position
of the arenium π system where it can stabilize the partial positive
charge while minimizing steric strain (Scheme 2). Note the
contrast with the regiochemistry typically observed with het-
6
Because both olefin and ester functional groups are present
in some of the tandem addition products to benzenes, we
considered coupling the tandem addition sequence with iodola-
ctonization as a possible new route to partially saturated
benzofuranones. Compound 1 was hydrolyzed by iodotrimeth-
ylsilane, formed in situ from chlorotrimethylsilane and NaI, and
iodolactonization proceeded in an aqueous I2 and NaHCO3
solution, concomitant with the demethylation of the methoxym-
ethyl substituent, to afford the â-iodo-δ-lactone with a 62%
overall yield (Figure 2). Note that four of the benzene’s six
carbons have been converted to stereogenic centers with high
stereoselectivity. An X-ray structure determination confirms the
structure shown in Figure 2 (30% ellipsoids) and confirms that
DMM and MMTP were added syn to each other.
eroatom-substituted benzenes such as anisole or aniline. When
the arene substituent has a good π donor (e.g., as in anisole),
3
the metal does not need to bind η to stabilize the arenium
positive charge and this relieves the steric strain between the
metal fragment and the substituent. If the heteroatom itself has
(
18) Mander, L. N. Partial Reduction of Aromatic Rings by DissolVing Metals
and Other Methods; Trost, B. M., Flemming, I., Ed.; Pergamon: Oxford,
U.K., 1991; Vol. 8, p 341.
(19) Donohoe, T. J.; Garg, R.; Stevenson, C. A. Tetrahedron: Asymmetry 1996,
7, 317.
(20) K u¨ ndig, E. P.; Desobry, V.; Simmons, D. P.; Wenger, E. J. Am. Chem.
Soc. 1989, 111, 1804.
(
21) K u¨ ndig, E. P.; Desobry, V.; Simmons, D. P.; Wenger, E. Organometallics
1993, 12, 3724.
(22) Chung, Y. K.; Willard, P. G.; Sweigart, D. A. Organometallics 1982, 1,
1053.
(23) Roell, B. C.; McDaniel, K. F.; Vanghan, W. S.; Macy, T. S. Organometallics
1993, 12, 224.
(24) Chung, Y. K.; Choi, H. S.; Sweigart, D. A.; Connelly, N. G. J. Am. Chem.
(17) Grossel, M. C. Tetrahedron Lett. 1980, 21, 1075.
Soc. 1982, 104, 4245.
J. AM. CHEM. SOC.
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A R T I C L E S
Ding et al.
Scheme 4. Formation of the Minor Diastereomer 6b from the
Scheme 2. Comparison of Reaction Mechanisms for the
Electrophilic Addition to Alkylated Benzene and
Heteroatom-Substituted Arene Complexes
Osmium(II) Toluene Complex
suggests that the actual structure of the arenium ion is slightly
3
distorted from a true η -allyl system where the metal is closer
to C6 than to C4. This distortion should predispose the allyl to
react with a nucleophile at C4 over C2. In addition, if an alkyl
electrophile was added, its steric interaction with the nucleophile
could inhibit C6 addition. Interestingly, earlier studies have
shown that the osmium forms more stable complexes with 1,3-
2
5
dienes than with isolated alkenes as ligands; thus, the
regioselectivity observed in the present study is strictly a kinetic
phenomenon. A similar observation was made with 1,4-tandem
Scheme 3. Comparison of Possible Nucleophilic Addition
Pathways
12
addition reactions with osmium naphthalene complexes.
Two products (6a,b) were observed in a 5:1 ratio for the
tandem addition of DMM and MMTP to toluene. Due to the
obscurity of the minor product in the proton spectrum, UV
spectroscopy was also used and the maximal absorption was
-
1
-1
found at 242 nm, with the ꢀmax of 63 M cm , assuming the
two isomers have similar absorption wavelengths. As mentioned
earlier, since the absorption of a typical 1,3-diene is 3 orders
of magnitude stronger than that of the ester carbonyl, the minor
product almost certainly is a 1,4-cyclohexadiene species (note
the NMR ratio). Given the proton NMR signal corresponding
to the ring methyl group has a chemical shift consistent with
being attached to an alkene carbon, we tentatively assign the
minor isomer according to Scheme 4. This would come about
by the electrophilic addition of the acetal to the meta carbon of
toluene. This side reaction becomes less significant (10%) when
the temperature is dropped to -70 °C.
In all examples of this study, both the electrophile and the
nucleophile add to the side of the ring opposite metal coordina-
tion, similar to what has been observed with other aromatic
a substituent (e.g., anisole) the ortho position is sterically
congested as a result of the requirement that R must lie in the
plane of the arene to allow for a good π interaction with the
heteroatom. The coordinated side of the arene is hence blocked
by the pentaammineosmium fragment. Thus, while oxygen and
nitrogen substituents are good para directors for osmium-
benzene complexes, an alkyl group is a good ortho director.
A second important difference between alkylated benzene and
heteroatom-substituted benzene complexes of pentaammin-
eosmium(II) is found in the regioselectivity for the addition of
6
complexes of pentaammineosmium(II). As previously dis-
14
cussed, this represents a departure from most other metal-
promoted addition sequences to arenes in that the electrophile
adds directly to the ligand without the intervention of the metal.
The tandem reactions to benzenes involving 3-penten-2-one
deserve special comment. As best as we are able to determine,
cyclohexadienes 5 and 7 are formed as single diastereomers.
The two side-chain stereocenters in 5 are far removed from each
other, making it difficult to resolve hypothetical diastereomers
in the proton or carbon NMR spectrum. However, for 7 the
high diastereoselectivity is unmistakable. The surprising feature
6
the nucleophile. In Scheme 3, three resonance contributors are
3
shown for the η -arenium intermediate resulting from electro-
philic addition. Form I could be considered to have slightly
higher weighting in that it allows the positive charge on C4 to
interact with the double bond of C2 and C3. This interpretation
(25) Harman, W. D.; Hasegawa, T.; Taube, H. Inorg. Chem. 1991, 30, 453.
13084 J. AM. CHEM. SOC.
9
VOL. 124, NO. 44, 2002

Tandem 1,4-Addition Reactions
A R T I C L E S
provides complete differentiation of otherwise similar or identi-
cal CdC bonds. Thus, one can envision subsequent chemistry
at the free alkene site while the other remains protected by metal
coordination. The reaction conditions are relatively mild,
+
requiring a Brønsted acid at -40 °C (CH3CNH ), and the metal
is easily removed by the action of either silver(I) or H2O2,
thereby exposing the coordinated double bond. Finally, by using
a silyl ketene acetal as the nucleophile, following the tandem
addition by an iodolactonization sequence, a novel route to a
functionalized benzofuranone was demonstrated in which four
contiguous stereocenters are set from benzene.
Experimental Section
General Procedure. All the tandem addition reactions were
performed under nitrogen in a Vacuum Atmospheres Co. glovebox.
1
13
H and C NMR spectra were collected on a 300 MHz Varian INOVA
spectrometer. Chemical shifts are reported in parts per million relative
to tetramethylsilane (TMS) using the deuterated solvents as the internal
reference, and coupling constants are reported in hertz. NOE, DQCOSY,
and HSQC experiments were carried out using standard parameters.
UV spectra were collected on a Hewlett-Packard 8452A diode array
spectrophotometer in a quartz cell with the path length of 1 mm using
Figure 3. Proposed transition states for the electrophilic addition of
3
-penten-2-one to the toluene complex D.
3
CDCl as the solvent and background.
3 5 2
Reagents. The precursor [Os(NH ) OTf](OTf) was synthesized as
is the control of the newly formed benzylic center. We have
seen high stereocontrol of this position in Michael additions
with other aromatic systems for both osmium and rhenium and
have attributed it to a Diels-Alder-like transition state or
intermediate similar to that depicted in Figure 3. Evans et al.
have recently invoked a similar explanation for high stereo-
chemical fidelity observed in Mukaiyama-Michael addition
described by Lay et al.27 Magnesium powder was activated by iodine
in DMA (N,N-dimethylacetamide) under nitrogen with stirring for 30
min and then washed with DMA and Et
2
O and dried in vacuo. Benzene,
toluene, xylenes, DMA, ether, CH Cl , and hexanes were purged with
2
2
nitrogen before being brought into the glovebox.
Typical Procedure for the Preparation of Complexes. To a
solution of [Os(NH
the benzene and 1.0 g of DMA was added 0.8 g of activated mag-
nesium (cleaned with I ). The reaction mixture was stirred vigorously
for 30 min and then quenched into 120 mL of 1:1 Et O/CH Cl 120
3 5 2
) OTf](OTf) (400 mg, 0.554 mmol) in 1.5 g of
(
note that regular Michael additions do not demonstrate such
26
stereoselectivity). Apparently this mechanism is operative for
2
2
unfunctionalized η -benzene complexes as well.
2
2
2
The same principles outlined above for toluene explain the
regiochemistry for ortho- and meta-xylene. The electrophilic
addition occurs adjacent to a methyl group, and the nucleophile
subsequently attacks in such a manner that a 1,4-cyclohexadiene
complex results. This holds true even in the case of 11, where
addition of DMM to form K (Scheme 1) followed by MMTP
results in the formation of adjacent quaternary carbons (M).
Noteworthy is that protonation followed by MMTP addition only
worked for toluene and o-xylene, which is consistent with the
acidity of coordinated benzenes. At -40 °C, the toluenium
mL and washed with 10 mL of CH
vacuo, giving the complex in 95% yield.
2 2
Cl . The precipitate was dried in
Typical Procedure for the Preparation of the Silyl Ketene
Acetals. Silyl ketene acetals were prepared on the basis of the procedure
in ref 15, except for MMTP, which is commercially available. A
solution of ethyl acetate (352 mg, 4.00 mmol) in 1.0 g of THF was
added into a solution of lithium bis(trimethylsilyl)amide (20% in THF,
3
.67 g, 4.40 mmol) at -40 °C. The reaction mixture stood for 0.5 h
before trimethylsilyl chloride (523 mg, 4.80 mmol) was added. After
another 0.5 h, the reaction mixture was warmed to 20 °C and allowed
to stand for 1 h. Hexanes (18 mL) and water (8 mL) were then added.
The organic layer was washed with 8 mL of brine and dried over Na2-
(-6.5) and ortho-xylene (-6.6) complexes have comparably
high pKa values, but the benzenium and para-xylene complexes
are considerably more acidic (pKa, ∼-9).
4
SO . Evaporation of the solvents yielded the crude product (481 mg,
75%), which was cooled to -40 °C for use.
Typical Procedure for the Tandem Addition to Arene Complexes
and Subsequent Oxidation. The pentaammineosmium benzene com-
plex (A, 338 mg, 0.519 mmol), DMM (60 mg, 0.77 mmol), and 2.0
Conclusion
Coordination of alkylated benzenes with the π base pentaam-
mineosmium(II) provides a means to add in a tandem sequence
a carbon electrophile and a nucleophile across the benzene ring
to form functionalized 1,4-cyclohexadienes. Addition of both
the electrophile and carbon nucleophile is highly regio- and
stereoselective, the electrophile adding ortho to an alkyl
substituent and the nucleophile adding para to it, with both
additions occurring anti to metal coordination. The conditions
for tandem addition are sufficiently mild that no isomerization
or rearomatization to the arene occurs. The metal fragment also
mL CH
3
CN were added together, and the solution was cooled to -40
CN
°
C. A solution of triflic acid (120 mg, 0.800 mmol) in 0.5 g of CH
3
was also prepared and chilled. The acid solution was then added into
the complex solution, and the mixture was allowed to stand for 1 h.
Separately, a solution of phenyllithium (1.8 M in cyclohexane and ether,
1.41 g, 3.06 mmol) and a suspension of copper(I) cyanide (320 mg,
3.55 mmol) in 1.2 g of ether were cooled to -40 °C, mixed together,
and briefly allowed to warm to 20 °C and then cooled to -40 °C. The
latter reaction mixture was then added into the former, and this mixture
was allowed to stand for 12 h. Triflic acid (309 mg, 2.06 mmol) and
silver triflate (266 mg, 1.04 mmol) were then added, and the reaction
(
26) Evans, D. A.; Scheidt, K. A.; Johnston, J. N.; Willis, M. C. J. Am. Chem.
Soc. 2001, 123, 4480.
(27) Lay, P. A.; Magnuson, R. H.; Taube, H. Inorg. Synth. 1986, 24, 269.
J. AM. CHEM. SOC.
9
VOL. 124, NO. 44, 2002 13085

A R T I C L E S
Ding et al.
mixture was then transferred to a pressure tube and put into a 70 °C
oil bath for 2 h. After cooling, the solvents were evaporated and 1 mL
water was added to dissolve the oil-like residue. The water layer was
extracted with 2 × 10 mL ether, and the combination of the two portions
Methyl [4-(1-methyl-3-oxobutyl)cyclohexa-2,5-dien-1-yl]phenyl-
1
acetate (5): R
f
) 0.52; yield ) 27%; H NMR (300 Hz, CDCl
3
) δ
7.30 (m, 5H), 5.58 (m, 4H), 3.69 (s, 3H), 3.50 (m, 1H), 3.36 (d, J )
9.8, 1H), 2.73 (m, 1H), 2.28 (dd, J ) 11.0, 7.0, 1H), 2.11 (s, 3H), 2.06
of ether layer was washed with 2 mL of brine and dried over Na
2
4
SO .
(dd, J ) 11.0, 2.2, 1H), 0.85 (d, J ) 6.6, 3H); 13C NMR (CDCl
) δ
3
Ether was then evaporated, and the residue was dissolved in chloroform
and subjected to chromatography. The elution of 10% ethyl acetate in
173.52, 136.68, 128.90, 128.78, 128.50, 128.38, 128.22, 128.11, 127.72,
58.27, 52.25, 47.57, 40.83, 39.33, 32.79, 30.77; HRMS calcd for
+
1
hexanes on silica gel yielded the product (16.3 mg, 16%) (R
visualized by iodine). For the nucleophiles other than phenyllithium,
.5 equiv of pyridine with respect to the starting complex was added
instead of triflic acid in the demetalation step.
f
) 0.52,
C
20
H
25
O
3
313.1804, found 313.1804; purity ( H NMR) >95%.
Methyl 2-[4-(methoxymethyl)-3-methylcyclohexa-2,5-dien-1-yl]-
1
1
2-methylpropanoate (6b): Rf ) 0.39; yield ) 34%; H NMR (300
Hz, CDCl ) δ 5.87 (m, 1H), 5.56 (m, 1H), 5.29 (m, 1H), 3.66 (s, 3H),
3
3
[
Os(NH
B). The benzene complex (A, 65 mg, 0.11 mmol) was dissolved in
CD CN (400 mg), dimethoxymethane (8.0 mg, 0.11 mmol) was added,
and the reaction mixture was cooled to -40°C. Cold HOTf (30 mg,
.20 mmol) was added, causing a quick reddening. After 1 h at -40
C the reaction mixture was frozen with liquid N in an NMR tube
3
)
5
(1r-methoxymethyl-2â,3â,4â-η -benzenium](OTf)
3
3.47 (m, 1H), 3.21 (m, 1H), 3.12 (m, 1H), 2.80 (m, 1H), 1.73 (br s,
1
(
3H), 1.08 (br s, 6H); purity ( H NMR) >95% (two isomers).
3
Methyl 2-methyl-2-[3-methyl-4-(1-methyl-3-oxobutyl)cyclohexa-
1
2,5-dien-1-yl]propanoate (7): R ) 0.21; yield ) 43%; H NMR (300
f
0
°
Hz, CDCl ) δ 5.77 (m, 1H), 5.61 (m, 1H), 5.34 (m, 1H), 3.71 (s, 3H),
3
2
1
3.14 (m, 1H), 2.63 (m, 1H), 2.50 (m, 1H), 2.22 (dd, J ) 15.3, 2.8,
1H), 2.00 (dd, J ) 15.3, 2.8, 1H), 1.68 (s, 3H), 1.14 (s, 3H), 1.13 (s,
and rethawed at -40 °C in the NMR spectrometer. A H NMR spectrum
then revealed exclusive η -arenium formation. H NMR (CD
3
1
13
3
CN/-40
3H), 1.02 (d, J ) 6.9, 3H); C NMR (CDCl ) δ 209.33, 178.12, 135.60,
3
°
C): δ 6.51 (dd, 1H, J ) 8.4, 3.3 Hz), 6.14 (br d, 1H, J ) 9.0 Hz),
126.89, 126.46, 122.78, 51.99, 46.41, 46.03, 45.03, 43.99, 30.71, 29.67,
+
5
.95-6.05 (m, 2H), 5.13 (t, 1H, J ) 6.0 Hz), 5.07 (br s, 3H, trans-
), 3.93 (br s, 12 H, cis-NH ), 3.34 (s, 3H), 1.27 (br s, 1H), 3.90-
.0 (m, 2H-buried in cis NH CN/-40 °C): δ 134.1
). 13C NMR (CD
CH), 128.0 (CH), 80.7 (CH), 79.4 (CH), 74.2 (CH), 68.3 (CH ), 58.1
CH ), 46.2 (CH).
Os(NH (1r-methoxymethyl-2â,3â-η -4,6-dimethylbenzen-
ium)](OTf) (H). The meta-xylene complex (G, 48 mg, 0.071 mmol)
was dissolved in CD CN (500 mg), dimethoxymethane (6.2 mg, 0.081
22.73, 22.62, 22.26, 18.26; HRMS calcd for C H O 279.1960, found
1
7
27
3
1
NH
3
3
279.1960; purity (H NMR) >95%.
Methyl 2-methyl-2-(3-methylcyclohexa-2,5-dien-1-yl)propanoate
(8): yield ) 56%; H NMR (300 Hz, CDCl ) δ 5.85 (m, 1H), 5.54 (m,
1H), 5.24 (m, 1H), 3.69 (s, 3H), 3.12 (m, 1H), 2.52 (m, 2H), 1.70 (br
4
3
3
(
(
2
1
3
3
2
13
[
3
)
5
s, 3H), 1.10 (br s, 6H); C NMR (CDCl
3
) δ 178.40, 134.36, 127.08,
3
125.12, 119.63, 51.92, 46.91, 43.80, 31.53, 23.70, 21.95, 21.82; HRMS
+
1
3
calcd for C12
H
19
O
2
195.1385, found 195.1381; purity ( H NMR)
mmol) was added, and the reaction mixture was cooled to -40 °C.
Cold HOTf (30 mg, 0.20 mmol) was then added, which imparted a
dark green appearance to the reaction mixture. After 0.25 h at -40 °C
>98%.
Methyl 2-(2,3-dimethylcyclohexa-2,5-dien-1-yl)-2-methylpro-
panoate (9): yield ) 67%; H NMR (300 Hz, CDCl ) δ 5.88 (m, 1H),
5.71 (m, 1H), 3.67 (s, 3H), 3.14 (m, 1H), 2.52 (m, 1H), 2.45 (m, 1H),
1.65 (s, 3H), 1.56 (br s, 3H), 1.15 (s, 3H), 1.00 (s, 3H); C NMR
1
3
1
2
1
a H NMR spectrum revealed exclusive η -arenium formation. H NMR
CD CN/-40 °C): δ 6.75 (d, 1H, J ) 6.0 Hz), 6.51 (s, 1H), 6.13 (t,
H, J ) 6.3 Hz), 5.08 (br s, 3H, trans-NH ), 4.01 (br s, 12 H, cis-
), 3.90-4.0 (m, 2H), 3.72 (s, 3H), 2.14 (br s, 1H), 1.78 (s, 3H).
CN/-40 °C): δ 187.9 (C), 166.3 (C), 130.0 (CH), 70.0
1
3
(
3
1
3
(CDCl ) δ 179.23, 128.87, 128.09, 126.85, 125.29, 51.83, 49.53, 48.05,
3
+
NH
C NMR (CD
3
33.86, 23.88, 20.41, 19.44, 18.81; HRMS calcd for C H O 209.1542,
found 209.1543; purity ( H NMR) >99%.
Methyl 2-[4-(methoxymethyl)-2,3-dimethylcyclohexa-2,5-dien-1-
yl]-2-methylpropanoate (10): R ) 0.36; yield 28%; H NMR (300
Hz, CDCl ) δ 5.97 (m, 1H), 5.69 (m, 1H), 3.67 (s, 3H), 3.54 (dd, J )
8.7, 4.8, 1H), 3.33 (s, 3H), 3.21 (dd, J ) 17.4, 4.2, 1H), 3.17 (d, J )
17.4, 1H), 2.80 (m, 1H), 1.67 (s, 3H), 1.51 (s, 3H), 1.15 (s, 3H), 0.98
(s, 3H); C NMR (CDCl ) δ 179.37, 130.24, 128.96, 127.47, 126.08,
77.23, 58.99, 51.91, 49.39, 45.34, 43.71, 25.07, 21.00, 18.58, 18.29;
HRMS calcd for C H O 253.1804, found 253.1803; purity ( H
15 25 3
1
3
21
2
13
1
3
(
(
CH
2
), 69.7 (CH), 62.9 (CH), 58.6 (CH
).
3 3
), 50.0 (CH), 27.7 (CH ), 22.6
CH
3
1
f
Methyl 2-[4-(methoxymethyl)cyclohexa-2,5-dien-1-yl]-2-methyl-
3
1
propanoate (1): R
f
) 0.30; yield ) 82%; H NMR (300 Hz, CDCl
3
)
δ 5.84 (m, 2H), 5.58 (m, 2H), 3.68 (s, 3H), 3.36 (s, 3H), 3.28 (d, J )
.2, 2H), 3.16 (m, 1H), 2.96 (m, 1H), 1.12 (s, 6H); 1 C NMR (CDCl
3
13
8
3
)
3
δ 178.10, 128.60, 126.13, 77.40, 59.12, 52.01, 45.59, 43.32, 37.14,
+
+
1
2
(
2.26; HRMS calcd for C13
H NMR) >99%.
H
21
O
3
225.1491, found 225.1492; purity
1
NMR) >95%.
2
-[4-(Methoxymethyl)cyclohexa-2,5-dien-1-yl]acetone (2): R
.27 (for further purification, the compounds were reloaded on silica
of 0.54);
) δ 5.71 (m, 4H), 3.35 (s, 3H),
.31 (d, J ) 6.5, 1H), 3.23 (m, 1H), 2.96 (m, 1H), 2.50 (d, J ) 6.5,
f
)
Methyl 2-[4-(methoxymethyl)-1,3-dimethylcyclohexa-2,5-dien-1-
1
0
yl]-2-methyl propanoate (11): R ) 0.50; yield 32%; H NMR (300
f
and eluted with 20% ethyl acetate in hexanes with the R
yield ) 23%; H NMR (300 Hz, CDCl
f
Hz, CDCl ) δ 5.81 (dd, J ) 10.3, 3.7, 1H), 5.60 (m, 1H), 5.31 (m,
3
1
3
1H), 3.65 (s, 3H), 3.53 (dd, J ) 8.8, 4.8, 1H), 3.34 (s, 3H), 3.22 (dd,
J ) 8.8, 7.7, 1H), 2.75 (m, 1H), 1.76 (s, 3H), 1.11 (br s, 6H), 1.04 (s,
3
1
3
1
1
3
13
H), 2.14 (s, 3H); C NMR (CDCl
6.89, 31.89, 30.81, CO not observed; HRMS calcd for C11
81.1229, found 181.1229; purity ( H NMR) 90%.
3
) δ 129.35, 126.83, 77.43, 50.87,
3H); C NMR (CDCl ) δ 177.37, 132.11, 131.15, 127.80, 126.77,
3
+
H
17
O
2
76.36, 59.06, 51.50, 48.27, 42.26, 41.00, 25.20, 22.55, 22.24, 22.17;
1
+
1
15 25 3
HRMS calcd for C H O 253.1804, found 253.1803; purity ( H
[
4-(Methoxymethyl)cyclohexa-2,5-dien-1-yl]benzene (3): R
f
)
NMR) >95%.
[Os(NH ) {methyl 2-methyl-2-[3-methyl-4-(1-methyl-3-oxobutyl)-
1
0
.52; yield ) 16%; H NMR (300 Hz, CDCl ) δ 7.27 (m, 5H), 5.80
3
3
5
(
1
7
>
)
(
2
m, 4H), 3.98 (m, 1H), 3.43 (d, J ) 6.6, 2H), 3.41 (s, 3H), 3.06 (m,
cyclohexa-2,5-dien-1-yl]propanoate}](OTf) (12). On the basis of the
2
1
3
H); C NMR (CDCl
7.55, 59.26, 42.96, 36.53; MS (FAB) m/z 201.2; purity (H NMR)
3
) δ 144.44, 129.68, 128.78, 128.30, 126.70,
typical procedure, the tandem addition of 3-penten-2-one and MMTP
to toluene complex (334 mg, 0.502 mmol) was carried out by allowing
15 min for the electrophilic addition step and 2 h for the nucleophilic
attack to optimize the yield of the product complex. The reaction
1
90%.
Ethyl [4-(methoxymethyl)cyclohexa-2,5-dien-1-yl]acetate (4): R
f
1
0.49; yield ) 31%; H NMR (300 Hz, CDCl
3
) δ 5.74 (m, 4H), 4.15
mixture was quenched into 50 mL of 1:1 Et
mL of hexanes was added to afford an ivory precipitate (382 mg, 86%),
which was filtered through a fritted funnel, washed with Et O, and
CN): δ 5.49 (m, 1H), 3.99 (br
), 3.71 (s, 3H), 3.40 (m, 1H), 3.06 (m, 1H), 2.94 (br
), 2.59 (m, 2H), 2.39 (d, J ) 5.3, 1H), 2.09 (s, 3H),
2 2 2
O/CH Cl , and then 100
q, J ) 7.1, 2H), 3.35 (s, 3H), 3.30 (d, J ) 6.4, 2H), 3.19 (m, 1H),
.96 (m, 1H), 2.35 (d, J ) 7.5, 2H), 1.26 (t, J ) 7.2, 3H); 13C NMR
2
1
(
3
CDCl
3
) δ 172.28, 128.99, 127.03, 77.32, 60.62, 59.22, 41.80, 36.92,
dried in vacuo. H NMR (300 Hz, CD
s, 3H, trans NH
s, 12H, cis NH
3
+
3.02, 14.49; HRMS calcd for C12
H O
19 3
211.1334, found 211.1333;
3
1
purity ( H NMR) >95%.
3
13086 J. AM. CHEM. SOC.
9
VOL. 124, NO. 44, 2002

Tandem 1,4-Addition Reactions
A R T I C L E S
1
1
1
1
2
.96 (m, 2H, overlapped by CD
.24 (s, 3H), 1.01 (d, J ) 7.3, 3H). C NMR (CD
39.33, 124.76, 52.97, 50.21, 49.97, 49.22, 47.40, 46.09, 33.45, 30.59,
3
CN), 1.72 (br s, 3H), 1.29 (s, 3H),
compound (212 mg, 98%). H NMR (300 Hz, CDCl
3
): δ 5.82 (m,
1
3
3
CN): δ 180.61,
2H), 4.95 (t, J ) 7.3, 1H), 4.51 (dd, J ) 7.7, 6.6, 1H), 3.81 (m, 2H),
1
3
2.96 (m, 1H), 2.82 (m, 1H), 1.33 (s, 3H), 1.19 (s, 3H). C NMR
(CDCl ): δ 180.78, 128.43, 124.34, 80.38, 65.73, 46.36, 45.33, 43.37,
6.13, 22.85, 2081, 19.01, CO not observed for the ketone substituent.
3
1
1
E
1/2 ) 0.66 V. Purity ( H NMR, CV): 73%.
26.70, 25.73, 22.61. Purity ( H NMR): >90%.
6
-(Hydroxymethyl)-7-iodo-3,3-dimethyl-3a,6,7,7a-tetrahydro-1-
benzofuran -2(3H)-one (13). To a solution of compound 1 (176 mg,
.786 mmol) in 5.0 g of CH CN were added chlorotrimethylsilane (256
mg, 2.36 mmol) and NaI (358 mg, 2.39 mmol), and the reaction was
refluxed for 18 h. After CH CN was evaporated, the reaction residue
was dissolved in 5 mL of water and extracted with 50 mL of ether.
The organic layer was dried over Na SO , and the subsequent
evaporation of ether yielded the product acid (141 mg, 85%), which
was then dissolved in a saturated NaHCO aqueous solution (0.6 g).
To the above solution, a solution of I (158 mg, 0.622 mmol) and KI
112 mg, 0.675 mmol) in water (3.0 g) was added over the course of
Acknowledgment is made to the donors of the Petroleum
Research Fund, administered by the American chemical Society,
for partial support of this research (Grant ACS-PRF#36638-
AC1). This work was also supported by the NSF (Grants
CHE0111558 and 9974875) and the NIH (Grant R01-GM49236).
High-resolution mass spectra were obtained in the Mass
Spectrometry Laboratory, School of Chemical Sciences, Uni-
versity of Illinois, supported in part by a grant from the National
Institute of General Medical Science (GM27029).
0
3
3
2
4
3
2
(
1
1
h. The reaction mixture was stirred for an additional 1 h before a
0% Na solution was added until the yellow color faded. CHCl
3
Supporting Information Available: Tables of X-ray crystal-
lographic data and an ORTEP diagram. This material is available
free of charge via the Internet at http://pubs.acs.org.
S
2 2
O
4
(
30 mL) was added for extraction and then evaporated to yield the
crude product which was redissolved in 1:1 CHCl /ether (1.0 g) and
crystallized overnight by solvent evaporation to afford a yellow
3
JA020279E
J. AM. CHEM. SOC.
9
VOL. 124, NO. 44, 2002 13087