Carbocupration-functionalization of arynes: Rapid access to variably ortho-substituted ((E)-3-phenylprop-1-enyl)silanes

Article abstract of DOI:10.1021/ol8021885

(Chemical Equation Presented) A consecutive three-component coupling reaction involving a lithium di[3-(prop-1-enyltrimethylsilyl)]cuprate, variably substituted ortho-arynes, and a selection of common electrophiles is described. The method affords readily functionalized homobenzylic vinylsilanes with exceptional E-diastereoselectivity and allows for in situ incorporation of carbon- or heteroatom-based electrophiles into the arene.

Full text of DOI:10.1021/ol8021885

ORGANIC
LETTERS
2008
Vol. 10, No. 22
5103-5106
Carbocupration-Functionalization of
Arynes: Rapid Access to Variably
Ortho-Substituted
((E)-3-Phenylprop-1-enyl)silanes
Ashok Ganta and Timothy S. Snowden*
Department of Chemistry, The UniVersity of Alabama, Box 870336, Tuscaloosa,
Alabama 35487-0336
snowden@bama.ua.edu
Received August 9, 2008
ABSTRACT
A consecutive three-component coupling reaction involving a lithium di[3-(prop-1-enyltrimethylsilyl)]cuprate, variably substituted ortho-arynes,
and a selection of common electrophiles is described. The method affords readily functionalized homobenzylic vinylsilanes with exceptional
E-diastereoselectivity and allows for in situ incorporation of carbon- or heteroatom-based electrophiles into the arene.
Homobenzylic alkenes are components of biologically active
natural products including the salicylihalamides,1 lobota-
mides,2 and radulanin A3 to name a few. The most common
approaches for installing homobenzylic alkenes include olefin
metathesis and transition metal-catalyzed coupling ap-
proaches. Although such routes have led to elegant syntheses
of targets bearing the moiety, these efforts have also revealed
limitations including unexpectedly poor diastereoselectivities
during olefin metathesis4 or lengthy routes, from com-
mercially available materials, to the requisite vinyl halides
for cross-coupling reactions.5 As such, we were compelled
to explore an alternative approach to homobenzylic olefin
preparation that would compliment existing routes. We also
wished to devise a method by which the substituted arenes
could serve as precursors for diversity-oriented or target-
directed synthetic endeavors where the alkene functions as
an appealing synthetic handle.
We considered an approach involving aryne allylmetalation
followed by trapping of the intermediate metalated arene with
one of many possible heteroatom- or carbon-based electro-
philes (Figure 1).6 Ideally, the allyl group would feature a
synthetic handle, aside from an unfunctionalized alkene, that
could lead to multiple derivatives, thereby broadening the
utility of the envisioned products. Also, the allylmetalation
(4) For an interesting example, see: (a) Yang, K. L.; Blackman, B.;
Diederich, W.; Flaherty, P. T.; Mossman, C. J.; Roy, S.; Ahn, Y. M.; Georg,
G. I. J. Org. Chem. 2003, 68, 10030–10039. (b) Lebreton, S.; Xie, X. S.;
Ferguson, D.; De Brabander, J. K. Tetrahedron 2004, 60, 9635–9647. For
a related discussion see: (c) Gradillas, A.; Pe´rez-Castells, J. Angew. Chem.,
Int. Ed. Engl. 2006, 45, 6086–6101.
(1) (a) Erickson, K. L.; Beutler, J. A.; Cardellina, J. H., II; Boyd, M. R.
J. Org. Chem. 1997, 62, 8188–8192. (b) Yet, L. Chem. ReV. 2003, 103,
4283–4306. (c) Beutler, J. A.; McKee, T. C. Curr. Med. Chem. 2003, 10,
787–796.
(2) Galinis, D. L.; McKee, T. C.; Pannell, L. K.; Cardellina, J. H., II;
Boyd, M. R. J. Org. Chem. 1997, 62, 8968–8969, and references 1a,c.
(3) Mac´ıas, F. A.; Molinillo, J. M. G.; Varela, R. M.; Torres, A. J. Org.
Chem. 1994, 59, 8261–8266.
(5) (a) Herb, C.; Maier, M. J. Org. Chem. 2003, 68, 8129–8135. (b)
Yadav, J. S.; Srihari, P. Tetrahedron: Asymmetry 2004, 15, 81–89. (c) Su,
Q.; Panek, J. S. J. Am. Chem. Soc. 2004, 126, 2425–2430.
10.1021/ol8021885 CCC: $40.75
Published on Web 10/18/2008
2008 American Chemical Society

conjugation with the arene, following possible deprotonation
at the benzylic position, was a concern throughout. Despite
their inherent stability under a variety of reaction conditions,
vinylsilanes are remarkably versatile synthetic handles. A
variety of functionalities are directly attainable from vinyl-
silanes or R,ꢀ-epoxysilanes.9 Hence, our planned route to
compounds of type 4 seemed amenable to functionalizing
the arene in situ and the propenylsilane postpreparation with
minimal synthetic operations.
Figure 1. Conceptualized one-pot synthesis of substituted ho-
mobenzylic alkenes.
We needed to consider two other variables before explor-
ing the planned allylmetalation-arene functionalization pro-
tocol. The aryne would play the key role in the tandem
reaction, as the yield of the overall process could be no
greater than that of the aryne formed. It was necessary to
generate the aryne efficiently under conditions compatible
with the carbometalation step. Given the conditions outlined
to prepare and employ the metalated allyltrimethysilane, the
aryne would need to be generated in ethereal solvent at or
below ambient temperature for use with 2. We recently
reported a comparative study of common aryne precursors
formed under such conditions and found 2-iodophenyl
triflates as the superior candidates.10
would need to feature high diastereoselectivity and predict-
able regioselectivity (i.e., γ- versus R-substitution) from a
substituted allyl anion intermediate (Figure 1).
Research by the Corriu and Magnus groups highlighted
an intriguing possibility for satisfying our outlined criteria.
Corriu treated a lower-order cyanocuprate, prepared from
lithiated allyltrimethylsilane and CuCN, with a variety of
electrophiles. Products were formed in 15-80% yields but
proved regioselective for the γ-substitution product.7 Magnus
established that lithiated allyltrimethylsilane, or the corre-
sponding zinc chloride species, efficiently added to carbonyl
compounds with high γ-regioselectivity and complete (E)-
alkene diastereoselectivity.8
We also needed to establish which metalated allyltrim-
ethylsilane would furnish both efficient aryne allylmetalation
and subsequent functionalization of 3. Due to the potential
for the newly installed homobenzylic alkene to migrate to
the thermodynamically preferred benzylic position under
highly basic reaction conditions, we immediately disregarded
lithium and magnesium halide as possible counterions for
2. Organocuprates and diorganozinc species seemed to offer
the best potential, although the latter would necessitate an
added step, such as inclusion of a nickel or palladium source,
to effect functionalization of 3 in many cases.11
Scheme 1. Generalized Method for One-Pot Preparation of
Ortho-Substituted ((E)-3-Phenylprop-1-enyl)silanes
Attempts at generating an aryne from 5 (Table 1) with
3.0 equiv of lithium di[3-(prop-1-enyltrimethylsilyl)]cuprate
at 0 °C in THF in the presence of 10 equiv of furan resulted
in a 44% isolated yield of the Diels-Alder cycloadduct.
However, three other byproducts were generated under these
conditions, as well as during analogous aryne trapping
experiments at lower temperatures. As a result, we attempted
to preform the aryne by adding a commercial alkyl lithium
reagent (i.e., t-BuLi, s-BuLi, or n-BuLi) to 5 at low
temperatures (ranging from -110 to -63 °C), then rapidly
transferring a 0 °C THF solution of 3.0 equiv of lithium di[3-
(prop-1-enyltrimethylsilyl)]cuprate. This afforded a complex
mixture of products and marginal yields of 8.
Prompted by the precedented high levels of γ-regio- and
(E)-alkene diastereoselectivity furnished by metalated allyl-
trimethylsilane (Scheme 1), we next considered the stability
of 3 and 4 and the synthetic versatility of the products. The
vinylsilane in putative intermediate 3 was expected to be
resistant to common electrophiles employed for installation
into the arene, although avoiding alkene migration into
(6) For an inspiring example, see: (a) Pansegrau, P. D.; Riecker, W. F.;
Meyers, A. I. J. Am. Chem. Soc. 1988, 110, 7178–7184. For a recent catalytic
alkynylcupration-alkynylation of symmetrical arynes, see: (b) Xie, C.; Liu,
L.; Zhang, Y.; Xu, P. Org. Lett. 2008, 12, 2393–2396.
(9) For reviews see: (a) Oshima, K. Sci. Synth. 2002, 4, 713–756. (b)
Whitham, G. H. Sci. Synth. 2002, 4, 633–646, and references therein.
(10) Ganta, A.; Snowden, T. S. Synlett 2007, 222, 7–2231.
(11) (a) Negishi, E.-I. Palladium-catalysed carbon-carbon cross-coupling.
Overview of the Negishi protocol with Zn, Al, Zr, and related metals. In
Handbook of Organopalladium Chemistry for Organic Synthesis; Negishi,
E.-I., Ed; John Wiley & Sons: New York, 2002; Vol. 1, pp 229-247. (b)
Negishi, E.-I., Dumond, Y. Palladium-catalyzed cross-coupling substitution.
In Handbook of Organopalladium Chemistry for Organic Synthesis; Negishi,
E.-I., Ed.; John Wiley & Sons: New York, 2002; Vol. 1, pp 767-789, and
references therein.
(7) Corriu, R. J. P.; Guerin, C.; M’Boula, J. Tetrahedron Lett. 1981,
22, 2985–2986.
(8) (a) Ayalon-Chass, D.; Ehlinger, E.; Magnus, P. J. Chem. Soc., Chem.
Commun. 1977, 772–773. (b) Ehlinger, E.; Magnus, P. J. Am. Chem. Soc.
1980, 102, 5004–5011. For theoretical consideration of the high diastereo-
selectivity, see: (c) Fraenkel, G.; Chow, A.; Winchester, W. R. J. Am. Chem.
Soc. 1990, 112, 2582–2585.
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Org. Lett., Vol. 10, No. 22, 2008

Table 1. Metal Sources for Carbometalation of 7
Table 2. Trimethysilylpropenylation-Functionalization of
Arynes
a 3.0 equiv was added, and the solution was warmed from -48 to 0 °C
over 30 min. b Prepared by treating 1 with an equimolar portion of titrated
s-BuLi at -48 °C for 30 min. c 2.0 equiv of CuI was added. d Yield of
purified product; average of two runs.
Recognizing that lithiated allyltrimethylsilane could effect
rapid lithium-halogen exchange with 512 and that the
metalated species serves as the direct precursor to the
requisite lithium diorganocuprate, we elected to include 1.0
equiv of lithiated allyltrimethylsilane beyond that needed to
prepare 2 in order to promote aryne formation. Employment
of lithiated allyltrimethylsilane circumvented possible forma-
tion of mixed diorganocuprates that could arise by introduc-
tion of 1 equiv of a commercial alkyllithium followed by
ligand exchange with lithium di[3-(prop-1-enyltrimethylsi-
lyl)]cuprate. In the described milieu, the lithiated allyl
trimethylsilane and Gilman-type cuprate may be in equilib-
rium with a homoleptic “higher order” R3CuLi2 species.
However, it is unclear what species actually promotes
metal-halogen exchange, and therewith, subsequent aryne
formation. What is clear is that the inclusion of 1.0 equiv of
lithiated allytrimethylsilane with the lithium diorganocuprate
envisioned for aryne carbometalation is required to form 8
in satisfactory yields.
a Yield of purified material. b The 2-fluorophenyl regioisomer was also
obtained in 9% yield.
metal-halogen exchange upon addition of 5 (Table 1).13
After being stirred for 15 min at 0 °C to effect aryne
carbometalation,14 the reaction mixture was cooled to -48
°C, and degassed MeOH was added to afford 8.15 Investiga-
tion of several metal sources revealed that CuI offered a
significantly higher yield than any other. As noted in entry
6, employment of 2.0 equiv of CuI (creating 2.0 equiv of
diorganocopper lithium species and 1.0 equiv of lithiated
allyltrimethylsilane) was also effective, albeit slightly less
than with 3.0 equiv. A minimum of 2.0 equiv is required, as
Given our results concerning efficient aryne formation,
reactions were conducted by preparing 7.0 equiv of lithiated
allyltrimethylsilane at -48 °C and then treating this solution
with 3.0 equiv of a metal source at 0 °C for 30 min. This
provided 3.0 equiv of the corresponding lithium diorgano-
cuprate, or di(trimethylsilylpropenyl)zinc in entry 5, and the
mandatory 1.0 equiv of lithiated 2 to promote efficient
(13) When the reaction is conducted with 3.0 equiv of lithium di[3-
(prop-1-enyltrimethylsilyl)]cuprate, in the absence of the extra equivalent
of lithiated allyltrimethylsilane under otherwise identical conditions, 8 is
generated in 39% yield.
(12) 2-Iodophenyl triflate 5 is converted to the corresponding aryne in
the presence of 1.0 equiv of lithiated allyltrimethylsilane and 10 equiv of
furan at -78 °C, affording 88% of the Diels-Alder cycloadduct.
(14) Longer reaction times or lower temperatures have insignificant
impact on yield.
(15) Acetic acid could be added with comparable results.
Org. Lett., Vol. 10, No. 22, 2008
5105

at least 1.0 equiv must be available to react with the aryne
and another to consume the 1.0 equiv of 6 generated by the
metal-halogen exchange so that it does not compete with
the intended electrophile in the terminal step.
Scheme 2. Example Derivatization of Vinylsilane 8a
With optimal conditions established, we explored the
preparation of several ortho-substituted ((E)-3-phenylprop-
1-enyl)silanes (Table 2). Electron-rich and unsubstituted
2-iodophenyl triflates (8a-d) behaved as planned during the
carbocupration-functionalization sequence when treated with
a variety of electrophiles. Protonation and alkylations offered
uniformingly high yields. Phenols were created by replacing
the argon blanket with an O2 balloon after carbocupration,16
and anilines were produced in good yields after addition of
O-benzoyl hydroxylamines.17 Meanwhile, treatment of the
arylcuprate with excess ethyl chloroformate afforded sub-
stituted salicylates in moderate yields. Numerous attempts
were made to enhance this outcome through varied reaction
modifications, without melioration. Unfortunately, treatment
of the carbometalated intermediate derived from 5a with
methyl vinyl ketone (MVK, entry 7) offered disappointing
results, in part, due to competitive 1,2- and 1,4-addition.
We found that deactivated 2-iodophenyl triflates, including
6-fluoro-derivative 5e and 2-iodo-3-trifluoromethylphenyl
triflate (not shown) are not suitable substrates for the method.
This is presumably due to the extreme instability of the
destabilized aryne intermediates that rapidly suffer side
reactions upon formation.18
of 8a using m-CPBA in buffered dichloromethane furnished
11,19 while halodesilylation garnered 12 with outstanding
diastereoselectivity (Scheme 2).20
We have established a consecutive three-component
coupling reaction involving carbocupration of substituted
o-arynes with the possibility of incorporating diverse sub-
stituents into the arene. The products feature an E-homoben-
zylic vinylsilane as a versatile synthetic handle. The approach
has potential for diversity-oriented synthesis applications and
for syntheses featuring the preparation or functionalization
of homobenzylic alkenes.
Acknowledgment is made to the Donors of the American
Chemical Society Petroleum Research Fund for support of
this research. We also thank Professor Gary A. Molander,
University of Pennsylvania Department of Chemistry, for
helpful preliminary discussions.
As expected, the installed vinylsilanes are readily trans-
formed to useful functionalities. For instance, epoxidation
Supporting Information Available: Full experimental
procedures, characterization data, and NMR spectra for all
products. This material is available free of charge via the
Internet at http://pubs.acs.org.
(16) Mo¨ller, M.; Husemann, M.; Boche, G. J. Organomet. Chem. 2001,
624, 47–52.
(17) (a) Oguri, T.; Shioiri, T.; Yamada, S. Chem. Pharm. Bull. 1975,
23, 167–172. (b) Berman, A. M.; Johnson, J. S. J. Am. Chem. Soc. 2004,
126, 5680–5681. (c) Campbell, M. J.; Johnson, J. S. Org. Lett. 2007, 9,
1521–1524.
OL8021885
(18) For a theoretical evaluation of relative energies of monosubstituted
arynes, see: Maurin, P.; Ibrahim-Ouali, M.; Parrain, J.-L.; Santelli, M.
THEOCHEM 2003, 637, 91–100.
(19) Alexakis, A.; Jachiet, D. Tetrahedron 1989, 45, 381–389.
(20) Staamos, D. P.; Taylor, A. G.; Kishi, Y. Tetrahedron Lett. 1996,
37, 8647–8650.
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