Long-range Anion Relay Chemistry (LR-ARC): A validated ARC tactic

Article abstract of DOI:10.1021/ol303080h

The design, synthesis, and validation of linchpins for Anion Relay Chemistry (ARC) capable of iterative silyl group migrations have been achieved. This tactic permits long-range relocation of negative charge across space, to generate reactive distal nucleophilic centers for both alkylation and palladium-catalyzed coupling reactions.

Full text of DOI:10.1021/ol303080h

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Long-Range Anion Relay Chemistry
(LR-ARC): A Validated ARC Tactic
Luis Sanchez and Amos B. Smith III*
Department of Chemistry, University of Pennsylvania,
Philadelphia, Pennsylvania 19104, United States
smithab@sas.upenn.edu
Received November 8, 2012
ABSTRACT
The design, synthesis, and validation of linchpins for Anion Relay Chemistry (ARC) capable of iterative silyl group migrations have been achieved.
This tactic permits “long-range” relocation of negative charge across space, to generate reactive distal nucleophilic centers for both alkylation
and palladium-catalyzed coupling reactions.
Anion Relay Chemistry (ARC Types I and II)1 com-
prises an effective strategy to construct architecturally
complex structures2 via the union of diverse building blocks
Scheme 1. Type I and Type II Anion Relay Chemistrya
(Scheme 1).3 The Type II version of the ARC protocol, in
particular, holds considerable promise for the rapid assem-
bly of the diverse scaffolds4 often found in natural products,
many of which display significant bioregulatory properties.
The Type II ARC protocol entails three components: (a)
an initiating nucleophile; (b) 1,4- and/or 1,5-bifunctional
linchpins deployed in a single or iterative fashion that
undergo facile intramolecular Brook rearrangements trig-
gered either by a change in solvent polarity, tempera-
ture, and/or gegenion;5 and (c) a terminating electrophile.
The controlled iterative union of such building blocks, a
process not dissimilar to “living polymerization”,6 is fea-
sible due to the latent nucleophilicity of the various ARC
linchpins, generated upon carefully timed Brook rearran-
gements. Of further significance, the ARC tactic yields
terminal anions amenable to either alkylation or Pd-catalyzed
(1) Smith, A. B., III; Wuest, W. M. Chem. Commun. 2008, 5883.
(2) (a) Smith, A. B., III; Tomioka, T.; Risatti, C. A.; Sperry, J. B.;
Sfouggatakis, C. Org. Lett. 2008, 10, 4359. (b) Smith, A. B., III; Kim,
a ASG = anion stabilizing group.
D.-S. Org. Lett. 2007, 9, 3311.
(3) For reviews on multicomponent reactions, see: (a) Zhu, J.;
cross-coupling reactions (CCR).7 Having demonstrated the
synthetic utility of 1,4- and 1,5-Brook5 rearrangements in
Anion Relay Chemistry (ARC), we recently integrated the
ꢀ
Bienayme, H. Multicomponent reactions; Wiley-VCH: Weinheim, 2005.
(b) Tietze, L. F. Chem. Rev. 1996, 96, 115.
(4) (a) Smith, A. B., III; Kim, W.-S. Proc. Natl. Acad. Sci. U.S.A.
2011, 108, 6787. (b) Smith, A. B., III; Han, H.; Kim, W.-S. Org. Lett.
2011, 13, 3328.
(5) Smith, A. B., III; Xian, M.; Kim, W.-S.; Kim, D.-S. J. Am. Chem.
Soc. 2006, 128, 12368.
(7) Smith, A. B., III; Kim, W. S.; Tong, R. B. A. Org. Lett. 2010, 12,
(6) Hirao, A.; Nakahama, S. Acta Polym. 1998, 49, 133.
588.
r
10.1021/ol303080h
XXXX American Chemical Society

ARC reaction manifold with Takeda and Hiyama cross-
coupling reactions,8 which in turn led to the identification
of an effective recoverable silicon-based transfer agent for
cross-coupling reactions.9 Higher order 1,n-Brook rear-
rangements (n = 6 or higher) are not particularly effective
in the ARC protocol, presumably due to the larger ring
transition states required for intramolecular silyl group
migration. Thus, these results set 1,4- and 1,5-charge
relocation as the current optimal migration distance for
the Type II ARC process.
Well aware that oxygen-bound silyl groups are known
to migrate under anionic conditions,10 especially when an
alkoxy anion is within 1,4- or 1,5-proximity,11 we reasoned
that an appropriately placed12 silyl ether might provide a
vehicletoaugmentchargerelocationandtherebyovercome
the current distance constraints of Brook rearrangements.
For example, transfer of a silyl group (i.e., TBS), present on
the benzylic oxygen in intermediate 6 (Scheme 2A), could
be envisioned to occur upon nucleophile-initiated epoxide
ring opening of 7; a 1,4-Brook rearrangement could then
generate a reactive ion, in a manner equivalent to an elongated
or long-range version of our validated Type II ARC protocol
with linchpin 8.13
To explore this scenario, we constructed the prospective
linchpin 7 from o-TMS-benzaldehyde 8 (Scheme 2B).
Namely, addition of allylmagnesium bromide to 8, fol-
lowed by Boc protection, furnished 9, which in turn was
subjected to an N-iodosuccinimide (NIS)-promoted stereo-
selective iodocyclization/methanolysis sequence.14 The re-
sulting syn-epoxyalcohol, obtained as a single diastereomer,
was then protected with TBS chloride to provide the pro-
spective linchpin 7 in good overall yield.
As envisioned, 7 performed effectively as a long-range
Type II ARC linchpin employing allyl bromide as the elec-
trophile (Scheme 3). A series of experiments were carried
out to track the formation of each intermediate during the
three-step LR-ARC sequence.15 Importantly, the overall
efficiency of this process could be adjusted by modulating
both the equivalents of CuI and concentration of the
reaction mixture during the silyl group migration steps.
Optimization afforded the three-component adduct 16
in 69% isolated yield. Monoprotected diols 14 and 15
(protonated forms of 11 and 12) could be isolated as the
main components after steps i and ii respectively; each was
characterized to define the structures of the epoxide open-
ing and migration intermediates. These studies verify that
the 1,5-OfO silyl migration takes place only after applica-
tion of the conditions required to trigger the 1,4-CfO
Brook rearrangement (step ii: Cu(I) salt, THF/HMPA).
Moreover, Ley oxidation16 of 14, 15, and 16 provided
ketone 17 and benzophenones 18 and 19, respectively,
confirming the location of the migrating TBS group during
the course of the LR-ARC transformation.
Scheme 2. (A) Design of LR-ARC Linchpin7 Based on Validated
Linchpin 8; (B) Preparation of 7
Having established that the silyl group migrations oc-
curred as predicted, the nature of the ARC anionic species
12 was evaluated in a series of alkylation experiments
(Table 1). With reactive electrophiles, three-component
ARC adducts were produced in good yields as the free
benzylic alcohols (16, 20aꢀc) upon aqueous workup. Iso-
lation of TMS-ether adducts (13 and 21) was also feasible
by carefully maintaining the amount of nucleophile to near
1.0 equiv (entries 4 and 13), indicating possible involvement
of the excess cuprate in TMS removal. Interestingly, use of
propargyl bromide as an electrophile (entries 8ꢀ10) furn-
ished exclusively the SN20 allene product 20b, which suggests
that, upon 1,5-OfO silyl migration and subsequent 1,4-
Brook rearrangement, the resultant aryl anion undergoes
conversion to a heterocuprate species [ArCu(X)M].17 Of
special note, use of CuBr SMe2 in place of CuI in some
cases led to equal or superior results (entries 2, 6, and 9);
however, the use of this Cu(I) source often resulted in
3
(8) (a) Hatanaka, Y.; Hiyama, T. Synlett 1991, 845. (b) Hiyama, T.;
Hatanaka, Y. Pure Appl. Chem. 1994, 66, 1471. (c) Hiyama, T. J.
Organomet. Chem. 2002, 653, 58. (d) Nakao, Y.; Imanaka, H.; Sahoo,
A. K.; Yada, A.; Hiyama, T. J. Am. Chem. Soc. 2005, 127, 6952. (e)
Chen, J.; Tanaka, M.; Sahoo, A. K.; Takeda, M.; Yada, A.; Nakao, Y.;
Hiyama, T. Bull. Chem. Soc. Jpn. 2010, 83, 554. (f) Nakao, Y.; Takeda,
M.; Matsumoto, T.; Hiyama, T. Angew. Chem., Int. Ed. 2010, 49, 4447.
(9) Smith, A. B., III; Hoye, A. T.; Martinez-Solorio, D.; Kim, W.-S.;
Tong, R. J. Am. Chem. Soc. 2012, 134, 4533.
(12) For examples of silyl group migrations followed by a subsequent
reaction, see: (a) Hillier, M. C.; Meyers, A. I. Tetrahedron Lett. 2001, 42,
5145. (b) Hunter, T. J.; O’Doherty, G. A. Org. Lett. 2001, 3, 1049.
(13) Smith, A. B., III; Kim, W.-S.; Wuest, W. M. Angew. Chem., Int.
Ed. 2008, 47, 7082.
(14) Stereochemical assignments of 7, 26, and 28 are based on
previously reported iodocyclizations; see: (a) Taylor, R. E.; Jin, M.
Org. Lett. 2003, 5, 4959. (b) Duan, J. J. W.; Smith, A. B., III. J. Org.
Chem. 1993, 58, 3703.
(10) Wuts, P. G. M.;Greene, T. W. Greene’s Protective Groups in Organic
Synthesis, 4th ed.; Wiley-Interscience: Hoboken, NJ, 2007; pp 166ꢀ169.
(11) (a) For a report on 1,4 OfO migrations of TBDPS groups in
(15) See Supporting Information for details.
(16) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis
1994, 639.
€
polyols under basic conditions, see: Mulzer, J.; Schollhorn, B. Angew.
Chem., Int. Ed. Engl. 1990, 29, 431. (b) For an interesting 1,11-OfO silyl
group migration, see: Evans, D. A.; Kaldor, S. W.; Jones, T. K.; Clardy,
J.; Stout, T. J. J. Am. Chem. Soc. 1990, 112, 7001.
(17) Yoshikai, N.; Nakamura, E. Chem. Rev. 2011, 112, 2339.
B
Org. Lett., Vol. XX, No. XX, XXXX

Scheme 3. Analysis of the Reactive Species at Each Stage of the Long-Range ARC Protocol
variable outcomes that appeared to be CuBr SMe2 batch-
3
dependent.18 Importantly, overall yields could be notably
Table 1. Three-Component ARC Union of Cuprate or Dithiane
Nucleophiles, Linchpin 7, and a Series of Electrophiles
improved by concentrating the reaction mixture prior to the
alkylation step (compare entries 5 and 7, also 11 and 12).
Operationally, concentration was achieved by evaporating
the volatiles using a nitrogen gas stream or in vacuo.15 When
the bulky dithiane anion was employed as a nucleophile for
epoxide opening in place of methylcuprate, the LR-ARC
Type-II protocol proved equally effective furnishing pro-
duct 22 in 70% yield (entry 14).
We next turned to exploring the viability of exploiting
the derived LR-ARC anions in cross-coupling reactions
(Table 2). After some experimentation, effective conditions
were found using Pd(OAc)2 (5 mol %) and dppf ligand
(10 mol %) to furnish cross-coupled products 23aꢀb and
24aꢀb in good yields. Both higher concentration and tem-
perature were required during the cross-coupling step, and
use of more complex aryl halides as coupling partners
resulted in low conversions. Currently we are evaluating
conditions that may overcome the presumed steric hin-
drance that appears to play a role.
Given the viability of the sequential 1,4- and 1,5-silyl
group migrations (Scheme 3), we were intrigued by the
potential use of the LR-ARC concept in the design of
building blocks containing oxygenated centers in moi-
eties other than syn-1,3-diols. We thus constructed and
tested linchpin 26, the anti-congener of 7 (Scheme 4).14
Effective LR-ARC formation of the three-component
alkylation adduct 27 was again achieved.
The observation that the intermediate after 1,5-OfO
silyl group migration pre-(1,4-OfSi) Brook was not ob-
served in significant, if any, quantity in reactions with
either linchpin 7 or 26 suggests that formation of the critical
aryl heterocuprate, upon Brook rearrangement, provides
a strong driving force for the consecutive silyl group
a CuBr SMe2 was used as additive instead of CuI in step ii. b 1.05 equiv of
3
Me2CuLi was used in step i. c A K2CO3/MeOH TMS-deprotection step was
used. d A pH 7 aqueous workup was used. e The reaction mixture was
concentrated prior to the alkylation step. f A pH 4 aqueous workup was used.
(18) Lipshutz, B. H.; Whitney, S.; Kozlowski, J. A.; Breneman, C. M.
Tetrahedron Lett. 1986, 27, 4273.
Org. Lett., Vol. XX, No. XX, XXXX
C

Table 2. Three-Component ARC Union of Nucleophiles,
Linchpin 7, and Electrophiles under Coupling Conditions
Scheme 4. Preparation of Linchpin 26, the anti Isomer of
Linchpin 7, and Validation of the LR-ARC Protocol
Scheme 5. Synthesis of Extended Linchpin 28 and Validation of
the LR-ARC Protocol
a Entries 1,3: 55 °C, 2 h. Entry 2: 85 °C, 6 h. Entry 4: 55 °C, 6 h.
migrations. With this in mind, we explored the possibility of
further charge migration (i.e., a longer-range ARC process).
To this end, we constructed 28 (Scheme 5) following
a sequence similar to that employed for the preparation
of 7.14,15 Gratifyingly, under the same LR-ARC condi-
tions, linchpin 28 furnished the corresponding three-
component alkylation adduct 29 in 50% yield. The structure
of the final product was again confirmed by derivatization,15
thereby validating that the silyl group migrations occur in
sequential fashion to transfer the negative charge to a
position now eight atoms removed from the origin!
In summary, long-range relocation of negative charges
to sites positioned six and eight atoms distal to their
origin, well beyond the known distance limitation ofclassic
Brook rearrangements,5 can be achieved under carefully
controlled conditions by the combination of 1,4-Brook
rearrangements with 1,5-OfO silyl group migrations.
Importantly, the multiple transfer of the silyl group,
orchestrated by 1,5-OfO and 1,4-CfO migrations, pro-
ceeds in a sequential manner to furnish nucleophiles
capable of both alkylations and, in several cases, cross-
coupling reactions. To the best of our knowledge, there
are no previous reports of controlled, consecutive silyl
group migrations. Taken together, the successful design,
validation, and application of long-range Anion Relay
Chemistry (LR-ARC) hold the promise for even greater
structural diversity and synthetic efficiency to emanate
from Type II Anion Relay Chemistry.
Acknowledgment. Financial support was provided by
the National Institutes of Health (Institute of General
Medical Sciences) through Grant GM-29028. Optimiza-
tion experiments were performed at the Penn-Merck High
Throughput Experimentation Laboratory (NSF Grant
CHE-0848460). We thank Drs. G. Furst and R. Kohli at
the University of Pennsylvania for assistance in obtaining
the NMR and HRMS, respectively.
Supporting Information Available. Experimental pro-
cedures and spectroscopic and analytical data for all new
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX