Cyclization reactions involving palladium-catalyzed carbene insertion into aryl halides

Article abstract of DOI:10.1021/jo800109d

(Chemical Equation Presented) Palladium is shown to catalyze the insertion of trimethylsilylmethylene into aryl halides, leading to benzylpalladium intermediates that cyclize to give indenylsilanes through carbopalladation of pendant alkenes or allenes. A

Full text of DOI:10.1021/jo800109d

SCHEME 1. Insertion of Carbenes versus Insertion of CO
Cyclization Reactions Involving
Palladium-Catalyzed Carbene Insertion into Aryl
Halides
Romas Kudirka and David L. Van Vranken*
Chemistry Department, 1102 Natural Sciences 2, UniVersity
of California, IrVine, California 92697-2025
daVid.VV@uci.edu
produce indane ring systems.5 In these reactions, the indanone
ring is generated through CO insertion followed by insertion
of a pendant olefin. The resulting intermediate can then
efficiently proceed to product through either ꢀ-hydride elimina-
tion (5) or a second CO insertion (6), depending on the
conditions (Scheme 2). Indanes are present in the drug Aricept6
and a wide range of natural products7 and bioactive compounds.8
ReceiVed January 30, 2008
SCHEME 2. Single and Double Insertion of CO
Palladium is shown to catalyze the insertion of trimethylsi-
lylmethylene into aryl halides, leading to benzylpalladium
intermediates that cyclize to give indenylsilanes through
carbopalladation of pendant alkenes or allenes. Allylsilanes
generated through these processes are susceptible to pro-
todesilylation in situ.
There is growing interest in palladium-catalyzed reactions
that insert carbene fragments derived from diazo compounds.1
Diazo compounds like trimethylsilyldiazomethane (TMSD) are
convenient precursors to metal carbenes.2 Using TMSD, Sole
and co-workers showed that trimethylsilylmethylene inserts
readily into palladium-carbon bonds in analogy to insertion
of CO (Scheme 1).3
The insertion of trimethylsilylmethylene into a palladium-
carbon bond can be envisioned to occur through migration of
the arene to the empty orbital of the carbene. Insertion of
trimethylsilylmethylene is particularly exciting because it
introduces the new carbon atom as a stereogenic center, whereas
CO insertion does not. A particular advantage of inserting
trimethylsilylmethylenes into arene-palladium bonds is that it
generates a benzyltrimethylsilyl functional group, which can be
nucleophilically activated by catalytic fluoride.4
We sought to explore a version of the Negishi carbonylative
cyclization reaction in which trimethylsilylmethylene takes the
place of CO (Scheme 3). Little is known about the ability of
carbene insertion to compete with other important processes like
olefin insertion (carbopalladation) or ꢀ-hydride elimination.9 To
increase the utility of TMSD in palladium-catalyzed reactions
we set out to study the competition between carbene insertion
and other processes like carbopalladation and ꢀ-hydride elimi-
nation in the context of a palladium-catalyzed indane formation
reaction.
(5) (a) Negishi, E.-I.; Coperet, C.; Ma, S.; Mita, T.; Sugihara, T.; Tour, J. M.
J. Am. Chem. Soc. 1996, 118, 5904–5918. (b) Wu, G.-Z.; Lamaty, F.; Negishi,
E.-I. J. Org. Chem. 1989, 54, 2507–2508.
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Negishi and co-workers have shown that palladium can
catalyze the carbonylative Heck cyclization of 2-iodoarenes to
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2001, 57, 5219–5225. (b) Ihara, E.; Haida, N.; Iio, M.; Inoue, K. Macromolecules
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2047–2049. (d) Ihara, E.; Kida, M.; Fujioka, M.; Haida, N.; Itoh, T.; Inoue, K.
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Yoshinaga, K.; Kobayashi, N.; Ikeda, Y.; Arai, H. J. Med. Chem. 1994, 37,
2071–2078. (b) Reiter, L. A.; Melvin, L. S., Jr.; Crean, G. L.; Showell, H. J.;
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Organometallics 2004, 23, 1438–1447.
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10.1021/jo800109d CCC: $40.75
Published on Web 03/28/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 3585–3588 3585

SCHEME 3. Single and Double Insertion of
Trimethylsilylmethylene
(Z)-12 was established through an nOE between the olefinic
proton He and the ring protons Hb, Hc, and Hd (Scheme 6). The
coupling constants observed for (Z)-12 were consistent only with
the anti-isomer in a diaxial conformation and were within 1
Hz of the calculated coupling constants (MM2).
1
SCHEME 6. Diagnostic H NMR Data for Isomers of 12
Initially, we examined the reaction of 2-allylbromobenzene
with 4 equiv TMSD in the presence of a palladium catalyst,
but low mass balance was observed, along with low yields of
insertion products, which proved difficult to separate. When an
extra methyl group was incorporated into the substrate, aryl
halide 7a afforded small amounts of the desired indanes as part
of an inseparable mixture. When the reaction was carried out
on R,ꢀ-unsaturated ester 7b, the primary product was the
styrylsilane 10, as a 1:1 mixture of E and Z isomers, arising
from two sequential carbene insertions and loss of Me3Si-Br
(Scheme 4). Clearly, the desired carbopalladation of the
trisubstituted olefin is significantly slower than a second carbene
insertion. Indeed, when a large excess of TMSD was added,
styrylsilane 10 was formed in 68% yield. The choice of base is
crucial for this reaction because soluble bases like triethylamine
isomerize the R,ꢀ-unsaturated ester to a ꢀ,γ-unsaturated ester.
The double bond configuration of (E)-12 was readily assigned
on the basis of a strong nOE between the allylic proton Hc and
the vinylic trimethylsilyl and the absence of an nOE between
1
the allylic proton Hc and the olefinic proton He. The H NMR
data for (E)-12 were not consistent with a rigid conformation,
making it more difficult to establish the relative configuration
of the substituents on the five-membered ring. For example,
the benzylic protons Ha and Hb of (E)-12 exhibited overlapping
signals, even at 800 MHz. In contrast, the same protons were
well-resolved for the anti-diaxial isomer (Z)-12 at 500 MHz.
Both the benzylic trimethylsilyl group and Hd exhibited cross-
ring nOEs to the Ha/Hb system. It is not possible for Hd to exhibit
a cross-ring nOE to the Ha/Hb system unless it spends time in
an axial conformation; in fact, the coupling constants seem to
have values midway between those predicted for the diaxial
and diequatorial isomers of (E)-12. All evidence points to an
anti-relationship between the ring substituents in the (E)-12
isomer where steric congestion leads to conformers that
SCHEME 4. Double Insertion without Carbopalladation
1
equilibrate on the H NMR time scale.
The formation of indane 12 is accounted for by the mecha-
nism depicted in Scheme 7. Arylpalladium bromide, a, can
undergo carbene insertion to generate benzylpalladium inter-
mediate, b. Intramolecular carbopalladation leads to indane, c.
Indane, c, has two choices: ꢀ-hydride elimination or carbene
insertion. Apparently, ꢀ-hydride elimination is slow because it
would place both the HPdBrL moiety and the benzylic trime-
thylsilyl group on the R-face of the indanestoo close for
comfort. Instead, intermediate c inserts another trimethylsilyl-
methylene to generate intermediate d, which undergoes ꢀ-hy-
dride elimination. Dissociation of the HPdBrL from the
vinylsilane generates the indane product 12.
When the reaction was carried out on R,ꢀ-unsaturated ester
11,10 the carbopalladative cyclization was more facile and three
indane products were isolated: indane 12 (1:1 mixture of
isomers) and indenes 13 and 14 (Scheme 5).
SCHEME 5. Formation of Indanes and Indenes
Why is the syn-isomer of indane 12 not observed? Carbo-
palladation of intermediate b is clearly the focal point for this
question, but we could not find a rationale for stereoselective
cyclization. Instead, we began to speculate that the carbopal-
ladative cyclization of intermediate b generates both anti- and
syn-isomers (Scheme 8). Anti-c has a significant steric barrier
toward ꢀ-hydride elimination, but syn-c does not. ꢀ-Hydride
elimination of syn-c would place the HPdBrL moiety on the
face of the allylsilane that is opposite the trimethylsilyl group.
In this orientation, the allylsilane of intermediate f is stereo-
electronically predisposed to transmetallate onto the Pd(II),
The two isomers of indane 12 were separated by HPLC, and
we then set out to assign the relative configuration of each
isomer with respect to the indane substituents and the config-
uration of the double bond. The double bond configuration of
(10) Huang, Q.; Larock, R. Org. Lett. 2002, 4, 1291–1294.
3586 J. Org. Chem. Vol. 73, No. 9, 2008

SCHEME 7. Proposed Catalytic Cycle
nate to form 13. Based on the ratio of indane 12 to indenes 13
and 14, the cyclization of intermediate b generates a 1:1 mixture
of anti- and syn-disubstituted indanes. Sterics and stereoelec-
tronics then conspire to force them down different reaction
pathways.
We sought to improve the yield of the indene products 13
and 14 relative to indane 12 by changing the ligands. To achieve
this we needed to control the diastereoselection in the carbo-
palladative cyclization of intermediate b. Ligands offer one
element of control in diastereoselective Heck cyclizations.13
Recall that when triphenylphosphine was used as the ligand,
the protodesilylated product 13 was isolated in only 20% yield
(Scheme 9). Bulkier ligands gave more of the indene 14 and
less of the indane 12. Surprisingly, bulky ligands led to
negligible amounts of indene 13. With tris-(o-anisyl)phosphine,
the yield of indene 14 was improved to 49%, and the yield of
indane 12 was diminished to 4%; thus, the stereoselection could
be forced to over 11:1 in favor of syn-c over anti-c. Unfortu-
nately, the overall mass balance was lower than the reaction in
the presence of triphenylphosphine.
SCHEME 9. Bulky Ligands Favor Indene 11
SCHEME 8. Different Fates of anti- and syn-Indane
Intermediates
Isolation of achiral indene 14, without the benzylic trimeth-
ylsilyl group, is a disappointment. In theory, halting halodesi-
lylation of intermediate f (Scheme 8) would allow us to isolate
an allylsilane like 8. Silver salts have been shown to prevent
the Pd-catalyzed protodesilylation of vinylsilanes during Heck
reactions.14 However, when silver triflate was added to the
reaction of 11, no turnover was observed and starting material
remained unreacted. The halide may indeed be important for
oxidative addition,15 but the full role of halide in our reaction
remains to be fully defined.
Carbopalladation of allenes generates η3-allylpalladium in-
termediates, which are well-behaved in the presence of diazo
compounds. However, Pd(0) is well-known to catalyze the
addition of secondary amines to phenylallene in the presence
of ammonium halide catalysts in refluxing THF, nearly identical
to the conditions we used for carbenylative cyclizations.16
Undaunted, we subjected the allene 15 to the carbenylative
cyclization conditions using 1.1 equiv of TMSD and 2 equivs
of piperidine (Scheme 10). Cyclized indene 17 was isolated in
generating allyl-hydridopalladium intermediate g. Allylsilanes
are known to react readily with Pd(II) at room temperature or
below.11 For example, allyltrimethylsilane reacts with PdCl2 at
room temperature to produce the µ-bridged dimer [C3H5PdCl]2
in high yield.12 The hydridopalladium intermediate g can
reductively eliminate to form indene 14 or undergo insertion
of another trimethylsilylmethylene and then reductively elimi-
(11) (a) Kliegman, J. M. J. Organomet. Chem. 1971, 29, 73–77. (b) Hayashi,
T.; Konishi, M.; Kumada, M. J. Chem. Soc., Chem. Commun. 1983, 736–739.
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12, 578–579.
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(14) Karabelas, K.; Hallberg, A. J. Org. Chem. 1986, 51, 5286–5290.
(15) Amatore, C.; Jutand, A. Acc. Chem. Res. 2000, 33, 314–321.
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J. Org. Chem. Vol. 73, No. 9, 2008 3587

51% yield, presumably formed by way of the sensitive inde-
nylsilane 16.
intermediates is different. Substrates with pendant alkenes
regenerate the palladium(0) catalyst through ꢀ-hydride elimina-
tion, whereas substrates with pendant allenes regenerate pal-
ladium(0) through attack of a nucleophile on an η3-allylpalla-
dium intermediate. Protodesilylation reactions can be facile
under the conditions of the reaction. Thus, the TMSD can serve
as either a trimethylsilylmethylene equivalent or a methine
equivalent.
The mechanism for protodesilylation of indenylsilane 16 is
unclear but may be due to simple acid-catalyzed protodesily-
lation. Indenyltrimethylsilane is 108 more reactive toward
nucleophilic protodesilylation than benzyltrimethylsilane.17
Indeed, when an authentic sample of indenyltrimethylsilane was
stirred with 1 equiv of piperidinium iodide at 66 °C, it underwent
quantitative protodesilylation in a few hours. Ironically, inde-
nylsilanes are more reactive toward η3-allylpalladium intermedi-
ates than other allylsilanes,18 however, dimeric indene products
were not observed.
Experimental Section
Representative Procedure. A round-bottomed flask fitted with
a reflux condenser was charged with Pd2dba3 ·CHCl3 (0.0069 mmol,
7.1 mg), (o-MeOPh)3P (0.041 mmol), K2CO3 (0.55 mmol, 76 mg),
and arene 7b (0.27 mmol, 72 mg) under argon. The contents were
dissolved in 3.0 mL of THF, and the mixture was stirred for several
minutes until a colorless yellow solution was obtained. The reaction
vessel was heated to 66 °C and a solution of TMSD (1.1 mmol in
1 mL THF) was then added via syringe pump over 10 h. The
reaction was allowed to cool to 23 °C, and the mixture was filtered
through a plug of silica gel to remove the palladium salts. The
filtrate was concentrated in vacuo to afford a yellow residue that
was purified by HPLC (silica 5 µ, 250 mm × 22 mm, step gradient
1–15% EtOAc/Hex) to give indene 14 as a colorless oil. 1H NMR
(CDCl3, 500 MHz) δ 7.40 (d, J ) 7.4 Hz, 1 H), 7.31 (d, J ) 7.7,
1 H), 7.23 (dd, J ) 7.7, 7.5, 1 H), 7.15 (dd, J ) 7.5, 7.4, 1 H),
6.70 (s, 1 H), 4.17 (q, J ) 7.1, 2 H), 3.52 (s, 2 H), 3.46 (s, 2 H),
1.28 (t, J ) 7.1, 3 H); 13C NMR (CDCl3, 125 MHz) δ 171.2 C,
145.0 C, 143.7 C, 141.4 C, 130.2 CH, 126.5 CH, 124.6 CH, 123.7
CH, 120.8 CH, 61.1 CH2, 41.5 CH2, 37.4 CH3, 14.4 CH3. IR (thin
film) 3054, 1986, 1725 cm-1; HRMS (ESI) m/z calcd for for
C13H14O2Na [M + Na]+, 225.0892; found, 225.0893.
SCHEME 10. Allenes Generate Allylamines through
Insertion
In conclusion, we have shown that TMSD can serve as a
carbene equivalent in carbenylative cyclization reactions leading
to indenes. Two types of aryl halide substrates were examined:
aryl halides with pendant alkenes and aryl halides with pendant
allenes. Both types of substrates generate benzylpalladium
intermediates through carbene insertion, and these benzylpal-
ladium intermediates undergo intramolecular carbopalladation
to produce indenes. However, the fate of these indenyl
Acknowledgment. This work was supported by ACS PRF
42780-AC1. We appreciate the help of Evgeny Fadeev with
our NMR experiments.
Supporting Information Available: Procedures and char-
acterization data for 7a, 7b, 10-14, and 17. This material is
available free of charge via the Internet at http://pubs.acs.org.
(17) Eaborn, C.; Walton, D. R. M. J. Chem. Soc., Chem. Commun. 1975,
937–939.
(18) Trost, B. M.; Keinan, E. Tetrahedron Lett. 1980, 21, 2595–2598.
JO800109D
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