Uniting Anion Relay Chemistry with Pd-mediated Cross Coupling: Design, synthesis and evaluation of bifunctional aryl and vinyl silane linchpins

Article abstract of DOI:10.1021/ol902784q

[Chemical equation presented] Union of type II Anion Relay Chemistry (ARC) with Pd-induced Cross Coupling Reactions (CCR) has been achieved, In conjunction with the design, synthesis, and evaluation of a new class of bifunctional linchpins, comprising a series of vinyl silanes bearing - or γ-electrophilic sites. The synthetic tactic permits both alkylation and Pd-mediated CCR of the anions derived via 1,4-silyl C(sp²) -O Brook Rearrangements.

Full text of DOI:10.1021/ol902784q

ORGANIC
LETTERS
2010
Vol. 12, No. 3
588-591
Uniting Anion Relay Chemistry with
Pd-Mediated Cross Coupling: Design,
Synthesis and Evaluation of Bifunctional
Aryl and Vinyl Silane Linchpins
Amos B. Smith III,* Won-Suk Kim, and Rongbiao Tong
Department of Chemistry, UniVersity of PennsylVania, Philadelphia, PennsylVania 19104
smithab@sas.upenn.edu
Received December 2, 2009
ABSTRACT
Union of type II Anion Relay Chemistry (ARC) with Pd-induced Cross Coupling Reactions (CCR) has been achieved, in conjunction with
the design, synthesis, and evaluation of a new class of bifunctional linchpins, comprising a series of vinyl silanes bearing ꢀ- or
γ-electrophilic sites. The synthetic tactic permits both alkylation and Pd-mediated CCR of the anions derived via 1,4-silyl C(sp2)fO
Brook Rearrangements.
Type I and II Anion Relay Chemistry (ARC),1 exploiting
Brook Rearrangements (Scheme 1A and B),2 comprises a
powerful linchpin tactic for the rapid assembly of high levels
of molecular complexity, as demanded by natural product
total synthesis. Extension of the Type II ARC process
(Scheme 1B) to include transition metal promoted Cross-
Coupling Reactions (CCR), as the culminating event in the
Type II ARC process (cf. 8f9), would, if general, greatly
extend the scope of this evolving synthetic tactic. Recently,
we recorded a single example (Table 1, Entry 1) employing
ortho-TMS benzaldehyde 10 as linchpin that demonstrated
the feasibility of uniting ARC with Pd-mediated cross
coupling.3 Convinced that this “one-flask” multicomponent
protocol would hold considerable potential, if general, we
initiated a program to unite ARC with the cross coupling
tactic. We quickly recognized, as reported by Takeda et
al.4 for ortho-TMS benzyl alcohol, that the use of CuI,
Scheme 1. Type I and II Anion Relay Chemistry (ARC)
(1) For reviews see: (a) Smith, A. B., III; Adams, C. M. Acc. Chem.
Res. 2004, 37, 365. (b) Smith, A. B., III; Wuest, W. M. Chem. Commun.
2008, 5883. (c) Moser, W. H. Tetrahedron 2001, 57, 2065.
(2) Brook, A. G. Acc. Chem. Res. 1974, 7, 77.
and in our case a mixture of HMPA and THF (1:1), is
required to trigger the 1,4-Brook rearrangement. Toward this
(3) Smith, A. B., III; Kim, W.-S.; Wuest, W. M. Angew. Chem., Int.
Ed. 2008, 47, 7082.
10.1021/ol902784q  2010 American Chemical Society
Published on Web 12/22/2009

end, addition of n-BuLi to 10, followed by CuI/HMPA:THF
induced silyl migration. Subsequent addition of diverse vinyl
and aryl halides in the presence of 3 mol % Pd(PPh3)4 in THF
at room temperature led to a series of cross coupled adducts
(10a-10h) with yields ranging from 50-67% (Table 1).
To explore the ARC tactic with 11, we selected conditions
that proved effective with 10.3 As illustrated in Table 2,
Table 2. Three-Component Coupling of Linchpin 11 with
Various Electrophilesa
Table 1. Pd-Mediated Cross-Coupling Reactions via Type II ARCa
a Conditions: 1.2 equiv n-BuLi, 1.2 equiv CuI. (a) 3 mol % Pd(PPh3)4,
THF, rt, 6 h.
a Conditions: 1.2 equiv n-BuLi, 1.2 equiv CuI.
addition of n-BuLi in Et2O, followed by CuI (1.2 equiv) in
a mixture of HMPA/THF (1:1), and then a variety of carbon-
and heteroatom-based electrophiles furnished adducts
21a-21d in 63-68% yield. Under these conditions, the 1,4
silyl migration proceeded rapidly (ca. 30 min). Equally
important, palladium-mediated cross coupling reactions,
initiated via the ARC Type II process, proved feasible. For
example, addition of 3 mol % Pd(PPh3)4 and a series of vinyl
and aryl halides after the HMPA/THF induced Brook
rearrangement furnished cross coupled adducts 21e-22h in
52-61% yield. Other common nucleophiles proved effective
as initiators of both the Type II ARC and the combined ARC-
II/Pd-mediated CCR tactics (Table 3). Use of TBAF to
remove the TMS group proved critical to avoid partial allylic
rearrangements of 22a-22f; use of 1 N HCl led to facile
allylic rearrangement (cf. 22h-22j). Neither allylic rear-
rangement nor cross-coupling was observed upon use of
anion derived from methyl dithiane, the latter due to catalyst
poisoning by the dithiane.7
Encouraged by the viability of the Type II ARC process
employing 11, we turned next to 12 as the bifunctional
linchpin (Table 4). Initially, silyl migration proved
problematic, furnishing only trace amounts of the desired
product when employing the conditions which proved
effective at triggering silyl migration with 11. However,
when two equivalents of both n-BuLi as the nucleophile
and CuI were employed in a mixture of HMPA and THF
(1:1), complete 1,4-silyl C(sp2)fO migration occurred
albeit more slowly over the course of 2 h. Addition of a
Having established the initial scope of the combined ARC-II/
Pd-mediated CCR protocol, we turned to the design, synthesis, and
evaluation of a new class of bifunctional vinyl silanes, with
electrophilic sites ꢀ or γ to the silane (Figure 1), first to explore
Figure 1. Vinyl silane bifunctional linchpins.
their utility as linchpins for the Type II ARC tactic and then as
linchpins in the combined ARC-II/Pd-mediated CCR process.
Linchpin 11 was readily available via oxidation of known
alcohol 17,5 whereas 12 was prepared from epoxide 186 and
commercial vinyl bromide 19 (Scheme 2).
Scheme 2. Preparation of Linchpins 11 and 12
(4) Taguchi, H.; Takami, K.; Tsubouchi, A.; Takeda, T. Tetrahedron
Lett. 2004, 45, 429.
(5) Han, S.; Kass, R. S. Tetrahderon Lett. 1997, 38, 7503.
(6) Kamal, A.; Ramesh, G. B. K.; Krishnaji, T.; Ramu, R. Tetrahderon:
Asymmetry 2006, 17, 1281.
Org. Lett., Vol. 12, No. 3, 2010
589

From the perspective of complex molecule synthesis, a
drawback of employing non-R-substituted linchpin alde-
hydes 11 and 12 entails the lack of stereochemical control
upon initial nucleophilic addition and the lack of the
ubiquitous methyl substituents found in polyketides. We
therefore turned to R-methyl-substituted linchpins (+)-
13 and (-)-14.10 We reasoned that addition of alkyllithi-
ums to (+)-13 and (-)-14 would produce, with good
diastereoselectivity, the corresponding syn alkoxides.
Confirmation of this scenario would further increase the
utility of both the Type II ARC and ARC-II/Pd-induced
CCR tactics, not only for natural product total synthesis
but also for polyketide diversity synthesis.11
Table 3. Three-Component Coupling of Linchpin 11 with
Various Nucleophiles and CCR with Phenyl Iodidea
Pleasingly, addition of n-BuLi to either (+)-13 or (-)-
14 (Table 5), followed in turn by silyl migration induced
Table 5. Three-Component Coupling of Linchpin (+)-13 or
(-)-14 with Various Electrophilesa
a Conditions: (a) 1 N HCl, rt, 10 min (b) TBAF, rt, 1 h. (c) R ) Allyl,
Allyl bromide, rt, 2 h. (d) R ) Ph, 3 mol % Pd(PPh3)4, Phenyl iodide THF,
rt, 6 h. (e) No cross-coupling product was obtained due to catalyst poisoning
by dithiane.
series of electrophiles (2.0 equiv) furnished alkylation
adducts 23a-23d (Table 4, Entries 1-4) in ca. 50% yield,
while modest yields of cross-coupling products 23e-23f
were obtained upon addition of 3 mol % Pd(PPh3)4
followed by aryl iodides (Entries 5-6).
Table 4. Three-Component Coupling of Linchpin 12 with
Various Electrophilesa
a Conditions: 2.0 equiv n-BuLi, 2.0 equiv CuI. (a) 3 mol % Pd(PPh3)4,
THF, rt, 12 h.
by CuI in a mixture of HMPA and THF (1:1) and reaction
with a series of electrophiles furnished multicomponent
adducts 24a-25h in yields ranging from 56 to 75% (Table
5).12 Effective cross coupling unions also occurred after
1,4-Brook rearrangement, upon addition of 3 mol %
Pd(PPh3)4, followed by vinyl or aryl halides. Importantly,
no epimerization of the R-methyl substituent was observed
during this process.
a Conditions: 2.0 equiv n-BuLi, 2.0 equiv CuI. (a) 3 mol % Pd(PPh3)4,
THF, rt, 12 h.
As with linchpin 11, other nucleophiles derived from furan,
phenyl bromide and 2-methyl-1,3-dithiane prove to be
The variable time course between 11 and 12 for 1,4-
silyl group migration is understandable in terms of the
mechanism of the Brook rearrangement.8 In the case of
linchpin 12, the 1,4-silyl C(sp2)fO migration is slow, due
to a combination of the distance between the silicon and
oxygen atoms and the multiple bond rotations required to
arrive at the cyclic transition state.9
(7) Main, C. A.; Petersson, H. M.; Rahman, S. S.; Hartley, R. C.
Tetrahderon 2008, 64, 901.
(8) (a) Jiang, X.; Bailey, W. F. Organometallics 1995, 14, 5704. (b)
Kawashima, T.; Naganuma, K.; Okazaki, R. Organometallics 1998, 17, 367.
(c) Naganuma, K.; Kawashima, T.; Okazaki, R. Chem. Lett. 1999, 1139.
(9) The results on silyl migration are in accord with Takeda and
coworkers. Tsubouchi, A.; Itoh, M.; Onishi, K.; Takeda, T. Synthesis 2004,
9, 1504.
590
Org. Lett., Vol. 12, No. 3, 2010

effective at initiating the Type II ARC tactic to furnish, in a
single flask, both three-component alkylation and cross-
coupled adducts 26a-27e (Table 6).
Scheme 4
.
Three-Component Coupling of Linchpins (-)-15 or
(+)-16 with Various Electrophilesa
Table 6. Three-Component Coupling of Linchpin (+)-13 or
(-)-14 with Various Nucleophiles and CCR with Phenyl Iodidea
a Conditions: 1.2 equiv dibutylcuprate, 1.2 equiv CuI. (a) R ) Allyl,
Allyl bromide, rt, 12 h. (b) R ) Ph, 3 mol % Pd(PPh3)4, Phenyl iodide,
THF, rt, 12 h.
by reaction with phenyl iodide to furnish (+)-33 and (+)-
35, respectively.
In summary, the union of Type II Anion Relay
Chemistry with Pd-mediated Cross Coupling has been
achieved, thereby greatly expanding the scope of this
multicomponent “one-flask” linchpin protocol. Equally
important, a new class of three and four carbon, bifunc-
tional linchpins comprising aryl and vinyl silanes bearing
ꢀ- or γ-electrophilic sites, have been designed, synthesized
and demonstrated to be competent in both Type II ARC
and combined ARC-II/Pd-induced CCR processes. Studies
to improve the efficiency of this tactic continue in our
laboratory.
a Conditions: (a) R ) Allyl, Allyl bromide, rt, 12 h. (b) R ) Ph, 3 mol
% Pd(PPh3)4, Phenyl iodide, THF, rt, 12 h.
We next explored the possibility of extending the Type II
ARC and ARC-II/Pd-induced CCR tactics to epoxide-based
linchpins possessing an electrophilic site γ to the vinyl silane.
This design led to linchpins (-)-15 and (+)-16, constructed
as illustrated in Scheme 3.13,14
Acknowledgment. Support was provide by the National
Institutes of Health (GM-29028 and GM-081253). We
gratefully acknowledge Cephalon, Inc. for a Dr. Horst
Witzel Fellowship awarded to Won-Suk Kim.
Scheme 3. Preparation of Linchpins (-)-15 and (+)-16
Supporting Information Available: Procedures and
characterization data. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL902784Q
(10) Sato and co-workers demonstrated (+)-13 and (-)-14 underwent
Grignard reactions with high syn diastereoselectivity, the result of a Cram
product-like transition state.10b,e (a) Sato, F.; Kusakabe, M.; Kobayashi, Y.
J. Chem. Soc., Chem. Commun 1984, 1130. (b) Sato, F.; Takeda, Y.;
Uchiyama, H.; Kobayashi, Y. J. Chem. Soc., Chem. Commun. 1984, 1132.
(c) Kobayashi, Y.; Kitano, Y.; Sato, F. J. Chem. Soc., Chem. Commun.
1984, 1329. (d) Sato, F.; Kusakabe, M.; Kato, Y. J. Chem. Soc., Chem.
Commun. 1984, 1331. (e) Samaddar, A. K.; Chiba, T.; Kobayashi, Y.; Sato,
F. J. Chem. Soc., Chem. Commun. 1985, 329.
With the four-carbon bifunctional linchpins in hand, we
employed lithium dibutylcuprate 31, known both to add
to epoxides15 and to initiate 1,4-silyl C(sp3)fO migration
in Anion Relay Chemistry.1b Capture of allyl bromide after
Brook rearrangement led respectively to adducts (+)-32
and (+)-34 (Scheme 4). Cross coupling reactions also
proceeded upon addition of 3 mol % Pd(PPh3)4, followed
(11) Schreiber, S. L. Science 2000, 287, 1964.
(12) Absolute configuration was confirmed by Mosher ester analysis.
(13) (a) Hicks, D. R.; Fraser-Reid, B. Synthesis 1974, 203. (b) Cink,
R. D.; Forsyth, C. J. J. Org. Chem. 1995, 60, 8122.
(14) Kobayashi, Y.; Kitano, Y.; Takeda, Y.; Sato, F. Tetrahedron 1986,
42, 2937.
(15) Herr, R. W.; Wieland, D. M.; Johnson, C. R. J. Am. Chem. Soc.
1970, 92, 3813.
Org. Lett., Vol. 12, No. 3, 2010
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