Anion relay chemistry: Access to the type II ARC reaction manifold through a fundamentally different reaction pathway exploiting 1-oxa-2-silacyclopentanes and related congeners

Article abstract of DOI:10.1002/anie.201103886

Distinctly different: Two 1-oxa-2-silacyclopentenes and a saturated congener have been synthesized and demonstrated to provide access to type II anion relay chemistry (ARC) through a fundamentally new mechanistic pathway. Similar to previous studies, but contrary to initial hypothesis, Brook rearrangement additives (hexamethylphosphoramide and CuI) are necessary to promote Si migration and anion capture.

Full text of DOI:10.1002/anie.201103886

Communications
DOI: 10.1002/anie.201103886
Synthetic Methods
Anion Relay Chemistry: Access to the Type II ARC Reaction Manifold
through a Fundamentally Different Reaction Pathway Exploiting
1-Oxa-2-silacyclopentanes and Related Congeners**
Amos B. Smith III,* Rongbiao Tong, Won-Suk Kim, and William A. Maio
Type I and II anion relay chemistry (ARC)[1] exploiting [1,n]-
Brook rearrangements[2] (Scheme 1A and B, respectively),
comprise an effective set of synthetic tactics that unite
multiple components, in a single reaction flask, that permits
rapid access to architecturally diverse polyketide and alkaloid
molecular arrays.[2]
Scheme 2. Type I and II anion relay chemistry (ARC).
metal ion additive was required to trigger the [1,4]-Brook
rearrangement after initial addition of a nucleophile. The
presumed silicon ate intermediate[7] then furnishes the
reactive anion 5, capable of alkylation,[3d] or in the presence
of a palladium catalyst, cross-coupling.[3d,f,8] By arriving at the
silicon ate intermediate through a different pathway (cf. 2!
Scheme 1. Type I and II anion relay chemistry (ARC).
4), we anticipated that the use of such “triggers” might not be
required to arrive at 5. That is, access to the pentacoordinate
To extend the ARC concept, we recently designed,
synthesized and evaluated a number of new bifunctional
linchpins for the type II process,[3] and then demonstrated
their utility both in natural product[4] and diversity oriented
synthesis (DOS).[5] During the development of the type II
multicomponent process, we became intrigued with the
possibility of accessing the type II ARC reaction manifold
through a fundamentally different pathway employing 1-oxa-
2-silacyclopentanes and related congeners (cf. 2, Scheme 2).
Based on the structural resemblance of 1-oxa-2-silacyclo-
pentene 2 to the proposed ARC silicon ate intermediate 4, we
envisioned that addition of a nucleophile (MeLi) might
provide access to the type II reaction products. We were of
course cognizant of the elegant observation of Mosher and
Brook,[6] that in the [1,2]-Brook rearrangement, charge
transfer from the initially derived oxyanion to carbon
proceeds through a silicon ate intermediate.[7] However to
achieve success with the type II ARC protocol, we learned
early on that a change in temperature, solvent polarity, and/or
silicon ate species 4, followed by conversion and capture of
the resultant anion 5 might only require addition of methyl-
lithium in a compatible solvent (Scheme 2).
The synthetic utility of 1-oxa-2-silacyclopentanes and
related congeners has been widely recognized by other
laboratories. Ito[9] and Woerpel[10] exploited the Tamao–
Fleming oxidation to furnish 1,3-diols; Hiyama,[11a]
Tamao,[11b] and Denmark[11c,d] achieved Hiyama-type palla-
dium-catalyzed cross-coupling reactions induced by fluoride;
and both Roush[12] and Schreiber[13] employed 1-oxa-2-sila-
cyclopentanes as templates for intramolecular Diels–Alder
reactions. More recently, Trost[14] and Lee[15] exploited
1-oxa-2-silacyclopentanes respectively both to access aldol-
type products and to achieve anionic desilylation followed by
C-alkylation, the latter induced by fluoride ion.
We began our study with the recognition that o-trime-
thylsilylbenzaldehyde 1 is a competent linchpin in a variety of
type II ARC processes.[3d] For example, addition of a nucle-
ophile (i.e., nBuLi) to 1 (Scheme 2), followed by a solvent/
metal-mediated [1,4]-Brook rearrangement, employing
HMPA (hexamethylphosphoramide) and CuI as the trigger-
ing conditions, leads to charge migration “across space” from
oxygen to carbon with subsequent anion capture. Based on
the structural resemblance of the pentacoordinate silicon ate
complex envisioned to arise during validated ARC type II
protocols,[3f,g] 1-oxa-2-silacyclopentenes 2 and 10, and the
saturated congener 1-oxa-2-silacyclopentane 12, a diastereo-
meric mixture (4:1, syn: anti),[16] were synthesized (Scheme 3)
and evaluated as progenitors of the respective silyl ate
complexes (see Supporting Information).
[*] Prof. Dr. A. B. Smith III, Dr. R. Tong, Dr. W.-S. Kim, Dr. W. A. Maio
Department of Chemistry, University of Pennsylvania
Philadelphia, PA 19104 (USA)
E-mail: smithab@sas.upenn.edu
[**] Financial support was provided by the NIH through Grant GM-
29028. We thank Drs P. J. Carroll and R. Kohli at the University of
Pennsylvania for assistance in obtaining X-ray diffraction and high
resolution mass spectra, respectively.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201103886.
8904
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Angew. Chem. Int. Ed. 2011, 50, 8904 –8907

Scheme 5. MeLi addition to 1-oxa-2-silacyclopentanes and -pentenes.
HMPA=hexamethylphosphoramide.
desilylated alcohol 6b and o-methylbenzyl alcohol 6c. At
first, we envisioned that the unexpected o-methylbenzyl
alcohol was the result of the excess methyllithium
(1.5 equiv) employed for complete consumption of the
starting 1-oxa-2-silacyclopentane. However, when alcohol 14
was treated with only one equivalent of nBuLi, we again
observed a minor amount of product 6c. Similar products
were observed employing 1-oxa-2-silacyclopentene 10 (ca. 2–
8%), although not with the saturated oxasilane congener 12,
where, as in the type II ARC protocol, CuI is not required.[3g]
While protodesilylation events (e.g., 6b) are known to occur
in polar aprotic solvents,[19] the mechanism for the formation
of 6c remains unclear.
To demonstrate that addition of nucleophiles to 1-oxa-2-
silacyclopentenes 2 and 10 and to the saturated congener 12
can in general serve as surrogates to access the corresponding
ARC type II three-component adducts, we explored nBuLi,
PhLi, and the cuprate (nBu)2CuLi, exploiting the conditions
optimized for methyllithium-mediated formation of 6a,
employing allyl bromide as the electrophile (Scheme 6).
Yields of the allylation products were comparable, if not
better than those obtained employing MeLi. To the best of
our knowledge, this is the first documented example of a
cuprate leading to cleavage of a silicon–oxygen bond. The
ability to exploit different carbon nucleophiles to access ate
intermediates holds the promise of orchestrating the steric
and electronic features at silicon, that once generated, would
furnish a variety of silyl protected alcohols (i.e., TMS, TBS
ethers, etc).
Scheme 3. Synthesis of 1-oxa-2-silacyclopentanes and -pentenes.
TsOH=p-toluenesulfonic acid.
With 2, 10 and 12 in hand, we quickly recognized that
addition of methyllithium to 2 led only to rupture of the
silicon–oxygen bond to produce trimethylsilyl alcohol 14
(Scheme 4A).[17] Even in the presence of excess allyl bromide,
no C-alkylation or protodesilylation could be detected.
Similar results were observed for 10 and 12. Thus, our initial
hypothesis that direct access to the pentacoordinate silicon
ate intermediate through addition of a nucleophile that would
lead directly to 5 through the silicon ate intermediate without
additives was not correct. We also discovered that treatment
of aryl bromide 13 with nBuLi at ꢀ788C led only to
trimethylsilyl alcohol 14 through a retro-Brook rearrange-
ment process.[18] From these experiments we conclude that the
oxyanion 3, and the corresponding oxyanions derived from 10
and 12 (Scheme 4A and C), comprise the more stable
intermediate resulting from anion equilibrium (cf. 3Ð5),
presumably through intermediacy of the pentacoordinate
silicon ate species.
We next attempted to shift the equilibrium (3Ð5) to be in
favor of anion 5, exploiting the previously documented
triggering conditions of HMPA and CuI addition required
in the type II ARC protocol for conversion of 1 to 5.
Pleasingly, treatment of 2 with MeLi, followed by addition
of a mixture of HMPA/CuI, and in turn allyl bromide,
furnished alcohol 6a (68%), the tricomponent type II ARC
adduct (Scheme 5). Also of interest was isolation of proto-
Scheme 6. Scope of nucleophile initiation for 1-oxa-2-silacyclopentanes
and -pentenes. Conditions: THF, NuLi (1.5 equiv), CuI (1.2 equiv for 2
and 10), allyl bromide (3 equiv). TBAF=tetra-n-butylammonium fluo-
ride.
Scheme 4. MeLi addition to 1-oxa-2-silacyclopentanes and -pentenes.
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Communications
Scheme 8. Catalytic CuI-promoted Brook rearrangement/cross-
coupling.
(ARC) reaction manifold through a fundamentally different
pathway. By exploring the scope of this transformation with a
number of nucleophiles and electrophiles, these studies offer
insight into the mechanistic details of the [1,4]-Brook
rearrangement, namely that charge migration from oxygen
to carbon is not the immediate result of direct access to the
pentacoordinate silicon ate species. Even when the silicon ate
intermediate is accessed through a distinctly different route, a
change of solvent polarity and/or the use of metal additives is
required to complete either the observed alkylation or cross-
coupling reactions.
Scheme 7. Scope of electrophile termination for 1-oxa-2-silacyclopen-
tanes and -pentenes. Conditions: THF, MeLi (1.5 equiv), Cul (1.2 equiv
for 2 and 10), electrophile (3.0 equiv). For cross-coupling: [Pd(PPh3)4]
(0.05 equiv), Ar-I (2.0 equiv).
We also explored the use of different reactive electro-
philes (Scheme 7). With 1-oxa-2-silacyclopentenes 2 and 10,
both C-alkylation and palladium-catalyzed cross-coupling
reactions were achieved, the latter when a catalytic amount Experimental Section
General procedure for the alkylation of 2 and 10: To a solution of 1-
of [Pd(PPh3)4] was employed with iodobenzene in THF.
Pleasingly, the cross-coupling reactions proceed at room
temperature. Although the literature provides many exam-
ples of 1-oxa-2-silacyclopentanes reacting to yield products of
protodesilylation,[19] oxidative desilylation[9,10] and cross-cou-
pling,[11] few reports of C-alkylation have been described.[15]
The saturated oxasilane congener 12 also furnished
alkylation products analogous to the type II ARC counterpart
with electrophiles 19a, b, and e; however in these examples, as
with the corresponding type II ARC reaction, CuI was not
required. Here, use of the diastereomeric mixture of 12 (4:1)
led to 18a and b, wherein the diastereomeric ratio degraded
to 1:1. This result is in accord with our observations employ-
ing b-TMS-hydrocinnamaldehyde as an ARC linchpin.[3g] We
attribute the lack of stereoretention to anion equilibration via
resonance stabilization with the p-system of the aromatic
ring.[3g,20]
oxa-2-silacyclopentene (0.2 mmol) in dry THF (1 mL) was added
MeLi (1.6m in Et2O, 0.14 mL, 0.22 mmol) at ꢀ788C. After stirring for
30 min, the solution was transferred through cannula to a pre-mixed
homogeneous solution of HMPA (0.5 mL) and copper iodide
(45.6 mg, 0.24 mmol) at room temperature. The resulting black
solution was stirred for 30 min at room temperature and the
electrophile (0.4 mmol) was added. The resulting solution was stirred
at room temperature overnight (ca. 16 h), then diluted with Et2O
(2 mL) and quenched by addition of aqueous HCl (1n, 2 mL), and
was vigorously stirred for 20 min. The organic layer was collected and
the aqueous layer was extracted with Et2O (3 ꢀ 2 mL). The combined
organic layers were washed with brine, dried with MgSO4, and
concentrated in vacuo. The crude product was purified by flash
chromatography on silica gel (1:10, EtOAc/Hexane) to afford the
desired alkylated products with yields indicated in Scheme 6 and 7.
Received: June 8, 2011
Published online: August 10, 2011
Having achieved room temperature cross-coupling pro-
tocols upon addition of MeLi to 2 and 10 employing
stoichiometric copper iodide, HMPA and a catalytic amount
of [Pd(PPh3)4] (Scheme 7, 6d and 17d), we initiated a search
for a version of this process that would also prove catalytic in
CuI. After considerable experimentation, we found that
cross-coupling adducts 20a and b could be obtained in
unoptimized yields of 36% and 44%, respectively
(Scheme 8), when 10 mol% CuI and 3 mol% PdCl2 were
employed in the presence of 4 mol% of the iminophosphine
ligand dpca.[21] Although preliminary, these results suggest
that a version of the type II ARC cross-coupling tactic
catatlytic in both palladium and copper is viable in a “single
flask.” Studies to explore this and other aspects of the type II
ARC reaction manifold continue in our laboratory.
Keywords: alkylating desilylation · anion relay chemistry ·
Brook rearrangement · cross coupling · siloxanes
.
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