Oxidative [1,2]-Brook Rearrangements Exploiting Single-Electron Transfer: Photoredox-Catalyzed Alkylations and Arylations

Article abstract of DOI:10.1021/jacs.7b05165

Oxidative [1,2]-Brook rearrangements via hypervalent silicon intermediates induced by photoredox-catalyzed single-electron transfer have been achieved, permitting the formation of reactive radical species that can engage in alkylations and arylations.

Full text of DOI:10.1021/jacs.7b05165

Communication
pubs.acs.org/JACS
Oxidative [1,2]-Brook Rearrangements Exploiting Single-Electron
Transfer: Photoredox-Catalyzed Alkylations and Arylations
Yifan Deng, Qi Liu, and Amos B. Smith, III*
Department of Chemistry, Laboratory for Research on the Structure of Matter and Monell Chemical Senses Center, University of
Pennsylvania, Philadelphia, Pennsylvania 19104, United States
S
* Supporting Information
Scheme 2. Comparison of Hypervalent Silicon Species
ABSTRACT: Oxidative [1,2]-Brook rearrangements via
hypervalent silicon intermediates induced by photoredox-
catalyzed single-electron transfer have been achieved,
permitting the formation of reactive radical species that
can engage in alkylations and arylations.
rook rearrangements comprise the transfer of a silyl group
Bfrom a carbon to an oxygen atom with concomitant
migration of charge resulting in a carbanion from the initiating
alkoxide species.1 This rearrangement, initially introduced by
achieving the oxidative cleavage of a strong C−Si bond via single-
Brook et al.,2 has been well studied1b,3 and is now known to
proceed reversibly via a hypervalent silicon (Scheme 1a).4
electron transfer employing photoredox catalysts.10 This
chemistry might provide an alternative to the direct generation
of an α-hydroxy radical. To the best of our knowledge, such a
reaction sequence is unprecedented.
Scheme 1. Brook and Radical Brook Rearrangement
To achieve an oxidative [1,2]-Brook rearrangement, two
criteria would be required: (i) the reduction potential of the
excited-state photoredox catalysts must be sufficiently high to
cleave a strong Si−C bond; and (ii) selective cleavage of the C−Si
bond to form the alkyl radical mustbe achieved when the silicon is
tetraalkyl-substituted (i.e., TMS, TBS, or TIPS). Thus, we report
here the first visible-light-induced SET tactic to achieve an
oxidative[1,2]-Brookrearrangement. Bothphotoredox-catalyzed
alkylations and arylations have been achieved.
Based on the above hypothesis, we propose the reaction
sequence in Scheme 3. First, deprotonation of an aryl-
(trialkylsilyl)methanol to set up an equilibrium between the
alcohol and the hypervalent silicon (i.e., A) in analogy to the well-
known anionic Brook rearrangement. Intermediate A could then
serve either as aradical precursor of the α-benzyl silyl ether radical
(i.e., B), capable of alkylation with an electron-deficient olefin
(catalytic cycle in Scheme 3a), or arylation with an electron-
deficient aromatic compound (catalytic cycle in Scheme 3b).11
For alkylation (Scheme 3a), oxidation of intermediate A by the
excited state of an Ir photocatalyst must occur. The resulting
open-shell intermediate B could then engage in a conjugate
addition with an electron-deficient olefin to form an α-carbonyl
radical C. Electron transfer from the reduced photocatalyst would
then generate an enolate anion, which in turn would undergo
protonation to provide the alkylation product D, with the
photocatalyst returning to the ground state. For arylation
(Scheme 3b), a photoactivated Ir photocatalyst would first
undergo SET with an electron-deficient arene to furnish the
Brook rearrangements have been employed extensively in our
and other Laboratories in conjunction with a multicomponent
coupling tactic we now term Anion Relay Chemistry (ARC).5
Although negative charge interchange via migration of a silyl
group is now well-known, Brook rearrangements via single-
electron transfer (SET) have not been extensively explored
(Scheme 1b). Moreover, such rearrangements have not been
employed synthetically,6 presumably due to the difficulty
associated with the formation of an alkoxy radical. Organosilicon
compounds, especially alkylsilanes, are generally known to be
quiteresistant tooxidants given their high oxidation potential (for
example, Eox = +1.68 V vs SCE7 for I in Scheme 2). Recently
however a mild catalytic photoredox system has been introduced
to employ hypervalent organosilicates as alkyl radical precurors.8
In these reports, pentacoordinate silicates9 are prepared and
demonstrated to have relatively low oxidation potentials (for
example, Eox = +0.61 V8b vs SCE forII inScheme 2). As illustrated
in Scheme 1a, the Brook rearrangement builds a direct linkage
between alkylsilanes and hypervalent silicates. We therefore
hypothesized thatit might be possible toaccess apentacoordinate
alkylsilicate in situ via a Brook rearrangement, followed by
Received: May 18, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.7b05165
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Journal of the American Chemical Society
Communication
Scheme 3. Proposed Reaction Route
a
correspondingareneradicalanionE,withgenerationoftheIr(IV)
photocatalyst. We hypothesize that the Ir(IV) species would then
be able to oxidize the hypervalent silicon intermediate A to form
radical B. A bond-forming step could then occur via radical union
between intermediates B and E, followed by elimination of
cyanide to yield the arylated product (i.e., F).
Scheme 4. Arylsilylmethanol Substrate Scope
Tobegin, weselected(tert-butyldimethylsilyl)phenylmethanol
(1b) as a model substrate and methyl vinyl ketone (2a) as the
radical acceptor. After extensive screening, we found that
employing KOPiv as the base in dichloroethane (DCE) led to
alkylation product 3b in 38% yield employing 3 mol % of
Ir[dF(CF3)ppy]2(dtbpy)PF6 as the photocatalyst (entry 1 in
Table 1). Other photocatalysts led to poor results (entries 2−3).
a
Table 1. Optimization of the Alkylation Reaction
a
Reactions were run with 1a−q (1.0 equiv), methylvinylketone (2.0
equiv), photocatalyst (3 mol %), KOPiv (1.0 equiv), CsOAc (1.0
equiv) in 2 mL of DCE on 0.2 mmol scale.
a
Reactions were run with 1b (0.1 mmol, 1 equiv), 2a, photocatalyst (3
b
mol %), base (1.0 equiv), in 1 mL of solvent. 1H NMR yields.
Isolated yield is given in parentheses. 1.0 equiv of KOPiv and 1.0
equiv of CsOAc. 0.5 mmol scale of 1b in 0.2 mL of DCE for 4 days.
c
d
Groups such as TMS, TES, TBS, and TIPS delivered over 70% of
3a−3e, indicating that steric hindrance on the silicon atom does
not influence the reaction. Generally, TES and TBS substrates
proceeded in higher yield than the corresponding TMS
congeners. This result is attributed to the higher stability of the
TES- and TBS-carbon bonds. However, changing the silyl group
to the dimethylphenylsilyl (DMPS) witnessed a modest decrease
in yield (3d, 56% yield). The electron-withdrawing effect of the
phenyl group on the Si atom appears to play a negative role in this
photoredox reaction. Next, different functional groups on the
aromatic ring attached to the carbinol were explored. Electron-
donating groups were well tolerated leading in high yield to
products 3f−3k. Halogenated substrates were also well tolerated
leading to 3l−3n. However, in contrast with fluoro, the stronger
electron-withdrawing group CF3 in 3o led to diminished
reactivity. Sterically hindered systems such as ortho-methyl
substituted aryl(trimethylsilyl)methanol also reacted well to
Thespecificchoiceofbaseandsolventsignificantlyinfluencedthe
yield. Forexample, polarsolventssuchasacetoneandCH3CNled
tono product (entries 4−5). Stronger basessuch as NaOH (entry
6)ledtotheformationof(benzyloxy)trimethylsilane, whichisthe
byproduct of a base-mediated Brook rearrangement. A weaker
base such as K2CO3 (entry 7) led to low conversion. The best
combinationofbasesprovedtobe1:1equivofKOPivandCsOAc
and 1:2 equiv of 1b and 2a; the isolated yield was then 78% (entry
9). To our delight, the loading of radical acceptor 2a could be
further decreased to 1 equiv with a 72% isolated yield when the
reaction was run in high concentration (2.5 M) on 0.5 mmol scale
(entry 10).
Wenextevaluatedthescopeofthealkylationprotocol(Scheme
4). Initially, aryl(trialkylsilyl)-methanols were explored (1a−1e).
B
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Journal of the American Chemical Society
Communication
a
providea67%yieldof3j. Equallypleasingly, substratespossessing
heterocyclic substituents proved to be viable substrates leading to
3p−3q in moderate yields. We reason that the decrease in yield of
3q is mainly due to facile decomposition of the corresponding
substrate 1q. Finally, the alkylation could be scaled up for gram-
scale synthesis employing a high concentration (1.0 M) of 1f
using 2 mol % of Ir photocatalyst (Scheme 4b).
Table 2. Optimization of the Arylation Reaction
We next explored diverse radical acceptors testing both alkyl
and aryl enones (Scheme 5, 2b−2k). The presence of bulky alkyl
a
Scheme 5. Radical Acceptor Scope
a
Reactions were run with 1b, terephthalonitrile (0.1 mmol, 1 equiv),
b
photocatalyst (3 mol %), base in 0.5 mL of solvent. Yields were
determined by 1H NMR analysis, and isolated yield is given in
parentheses.
solvent selection had a significant effect on reaction performance.
Polar solvents such as DMF and DMA led to the best results
(entries 2−3). Based on the persistent radical effect, transient
radical precursor 1b self-terminates to cause a buildup of excess
persistent radicals, thus accelerating the cross-reaction.13 There-
fore, increasing the loading of the transient radical precursor 1b
provided an effective way to enhance conversion (entry 4).11,14
When we adjusted the amount of the base, we were surprised to
find that a substoichiometric amount of base furnished a similar
yield (entry 5). Finally, 83% isolated yield of 6a was achieved with
3 equiv of 1b (entry 6).
With these conditions in hand, we examined the structural
diversity of both coupling partners. As shown in Scheme 6, both
a
Reactions were run with 1c (1.0 equiv), 2b−2l (2.0 equiv), KOPiv
(1.0 equiv), CsOAc (1.0 equiv), photocatalyst (3 mol %) in 2 mL of
DCE on 0.2 mmol scale.
a
Scheme 6. Substrate Scope for the Arylation Reaction
groups did not influence the reactivity; good to high yields were
obtained (4b−4c). An alkyl enone with a remote OTBS group
(2d)was alsowell tolerated, thusproviding ascaffold amenable to
synthetic applications. Aryl enones normally gave better results
than alkyl enones. Different functional groups on the aromatic
ring were also explored (2e−2i). Neither electronic nor steric
effects reduced the reactivity. However, a 1- and 2-substituted
enone(2kand2j)revealedthatstericandelectronic effectsonthe
enonecan stronglyinfluencetheyield. Forexample, withamethyl
group as in 2j, the yield was significantly reduced, but with an
electron-withdrawingphenylgroupasin2k,anexcellentyieldwas
obtained.However, simpleacrylatesprovidedonlyatraceamount
of the alkylation product. We reasoned that this outcome is likely
due to the difficulty associated with reducing α-carbonyl radicals
in simple acrylates.12 However, when a phenyl group was
introduced at the α-position, alkylation product 4l was produced
in 86% yield.
a
With the alkylation protocol established, we next explored
whether a SET pathway could be employed to achieve arylation
(catalytic cycle in Scheme 3b). We reasoned that radical B could
enter the catalytic cycle of a photoredox-catalyzed radical−radical
union protocol.11 Thus, a formal arylation would be achieved,
whichinturnwouldincreasethesyntheticutilityofthischemistry.
To this end, we selected (tert-butyldimethylsilyl)phenyl-
methanol (1b) as a model substrate and terephthalonitrile (5a)
as the radical acceptor. Octanal was used as an additive to
sequester the cyanide anion formed in the reaction process.11
Initially, dichloroethane was employed as solvent with 1 equiv of
CsOAcas thebase. Wewerepleasedto find thatasmallamount of
desired product could be detected (entry 1, Table 2). Again,
Reactions were run with arylsilylmethanol (3.0 equiv), aryl cyanide
(1.0 equiv), Ir(ppy)3 (3 mol %), CsOAc (1.0 equiv), octanal (1.2
b
c
equiv) in 1 mL of DMA on 0.2 mmol scale. 2 equiv of 1c. CsOAc
d
(1.0 equiv) and KOPiv (1.0 equiv). CsOAc (0.5 equiv)
electron-donating and -withdrawing groups were well tolerated
on the transient radical precursor leading to high yields (6a−6e,
66−85% yield). Furan and thiophene aromatic systems also
proceeded in moderate to high yield (6f−6g). Changing the TBS
group to a TES group also led to similar reactions, although a
loweryieldwasobservedfor6hduetothedesilylation. Turningto
arene coupling partners, substituted terephthalonitriles, and
cyanopyridines readily react with the benzylic radicals to yield
C
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Journal of the American Chemical Society
Communication
similar products (7a−7c). Also of interest, benzonitriles
substituted with sulfones and esters undergo this reaction,
although lower yields were observed (7d−7e).
To gain mechanistic insights of the photochemical/oxidation
Brook rearrangement, we conducted several control experiments.
We first carried out a TEMPO radical quenching experiment with
the (tert-butyldimethylsilyl)phenylmethanol as the substrate; a
42% yield of the TEMPO adduct 9 was isolated, with the yield of
3b decreasing significantly to 16% (Scheme 7, eq 1). Also, control
AUTHOR INFORMATION
Corresponding Author
*smithab@sas.upenn.edu
ORCID
Amos B. Smith III: 0000-0002-1712-8567
Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS
■
Financial support was provided by the NIH through Grants CA-
19033 and GM-29028. We thank Yusen Qiao for collecting cyclic
voltammetry data. We also thank Prof. Tehshik P. Yoon for
discussions about mechanism.
Scheme 7. Control Experiments
REFERENCES
■
(1) (a) Brook, A. G. Acc. Chem. Res. 1974, 7, 77. (b) Moser, W. H.
Tetrahedron 2001, 57, 2065 and references therein.
(2) (a) Brook, A. G. J. Am. Chem. Soc. 1958, 80, 1886. (b) Brook, A. G.;
Warner, C. M.; McGriskin, M. E. J. Am. Chem. Soc. 1959, 81, 981.
(c) Brook, A. G.; Schwartz, N. V. J. Am. Chem. Soc. 1960, 82, 2435.
(d) Brook, A. G.; Iachia, B. J. Am. Chem. Soc. 1961, 83, 827.
(3) (a) Linderman, R. J.; Ghannam, A. J. Am. Chem. Soc. 1990, 112,
2392. (b) Jankowski, P.; Raubo, P.; Wicha, J. Synlett 1994, 1994, 985.
(c) Fleming, I.; Roberts, R. S.; Smith, S. C. J. Chem. Soc., Perkin Trans. 1
1998, 1215.
(4) (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, 28,
1139. (d) Speier, J. L. J. Am. Chem. Soc. 1952, 74, 1003. (e) West, R.;
Lowe, R.; Stewart, H. F.; Wright, A. J. Am. Chem. Soc. 1971, 93, 282.
(5)Forreviews: (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, 45,
5883.
(6) Paredes, M. D.; Alonso, R. J. Org. Chem. 2000, 65, 2292 and
references therein.
(7) Maruyama, T.; Mizuno, Y.; Shimizu, I.; Suga, S.; Yoshida, J. J. Am.
Chem. Soc. 2007, 129, 1902.
(8) (a) Matsuoka, D.; Nishigaichi, Y. Chem. Lett. 2014, 43, 559.
experiments revealed the requirement for base, light, and
photocatalyst (eq 2). Without light or a photocatalyst, almost
all starting material remained. Also, if a base is not added to the
reaction, only a trace amount of 3b could be detected with the
conversion of 1b at 55% due to over-oxidation to form
benzaldehyde.
Notwithstanding the above results, consistent with the
proposed photoredox-catalyzed mechanism in Scheme 3, there
is the possibility of proton-coupled electron transfer (PCET)15
activation of the initial stronger O−H bond16 of the silyl alcohol,
followed by a radical Brook rearrangement to generate the
benzylic radical. Kinetic studies however revealed that although
the reaction rate decreases as the basicity of the anion decreases,
employing a higher oxidizing photocatalyst does not compensate
for the lower rate of the weaker base. Moreover, cyclic
voltammetry revealed no oxidation potential for 1b within the
tested range (0−2.00 V vs SCE in MeCN). Yet, in the presence of
CsOAc,anoxidationpotentialwasobserved(Eo1/2 =0.78VvsSCE
in MeCN), indicating the necessity of the base. Finally, when
employing weaker bases such as CsOBz, the oxidation potential
remained the same (see Supporting Information). These results
indicate the PCET model is less likely.
́
(b) Corce, V.; Chamoreau, L.-M.; Derat, E.; Goddard, J.-P.; Ollivier, C.;
Fensterbank, L. Angew. Chem., Int. Ed. 2015, 54, 11414. (c) Jouffroy, M.;
Primer, D. N.; Molander, G. A. J. Am. Chem. Soc. 2016, 138, 475.
(9)Chuit, C.;Corriu, R. J. P.;Reye, C.;Young, J. C. Chem. Rev. 1993, 93,
1371 and references therein.
(10) For reviews: (a) Hopkinson, M. N.; Sahoo, B.; Li, J.-L; Glorius, F.
Chem. - Eur. J. 2014, 20, 3874. (b) Romero, N. A.; Nicewicz, D. A. Chem.
Rev. 2016, 116, 10075. (c) Skubi, K. L.; Blum, T. R.; Yoon, T. P. Chem.
Rev. 2016, 116, 10035. (d) Shaw, M. H.; Twilton, J.; MacMillan, D. W. C.
J. Org. Chem. 2016, 81, 6898 and references therein.
(11) Qvortrup, K.; Rankic, D. A.; MacMillan, D. W. C. J. Am. Chem. Soc.
2014, 136, 626.
In summary, wehave designed and validated an oxidative [1,2]-
Brook rearrangement involving visible-light-induced SET ex-
ploiting the oxidation of a hypervalent silicon species. The
resulting alkyl radical was found to engage both in conjugate
additions to achieve formal alkylation and in radical coupling
reactions to achieve arylation. Studies to extend Brook rearrange-
ments involving visible-light-induced SET continue in our
laboratory.
(12) Bortolamei, N.; Isse, A. A.; Gennaro, A. Electrochim. Acta 2010, 55,
8312.
(13) Fischer, H. Chem. Rev. 2001, 101, 3581.
(14)Forexamples:(a) Hager, D.;MacMillan, D. W. C. J. Am. Chem. Soc.
2014, 136, 16986. (b) Cuthbertson, J. D.; MacMillan, D. W. C. Nature
2015, 519, 74.
(15) Gentry, E. C.; Knowles, R. R. Acc. Chem. Res. 2016, 49, 1546 and
references therein.
(16) There is only one report about PCET activation of O−H bond via
photoredox catalysis: Yayla, H. G.; Wang, H.; Tarantino, K. T.; Orbe, H.
S.; Knowles, R. R. J. Am. Chem. Soc. 2016, 138, 10794.
ASSOCIATED CONTENT
* Supporting Information
■
S
TheSupportingInformationisavailablefreeofchargeontheACS
Publications website at DOI: 10.1021/jacs.7b05165.
Experimental procedures, NMR spectra for obtained
compounds, and mechanistic studies (PDF)
D
DOI: 10.1021/jacs.7b05165
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