Potassium Alkylpentafluorosilicates, Primary Alkyl Radical Precursors in the C-1 Alkylation of Tetrahydroisoquinolines

Article abstract of DOI:10.1021/acs.orglett.9b01124

In this study, we demonstrate that potassium alkylpentafluorosilicates (RSiF₅K₂) are efficient primary alkyl radical precursors for selective C(sp³)-C(sp³) bond-forming reactions. RSiF₅K₂ reagents are white, free-flowing solids and are moisture and air stable. This class of reagents enables the direct C-1 alkylation of tetrahydroisoquinolines under mild conditions via single-electron transfer. The broad substrate scope of both alkylpentafluorosilicates and tetrahydroisoquinolines is tolerated in this transformation. Both radical scavenger and EPR capture experiments show that the primary radical is generated by the oxidation of RSiF₅K₂. A mechanism involving alkyl radical addition to an iminium salt followed by reduction by an amine is proposed.

Full text of DOI:10.1021/acs.orglett.9b01124

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Potassium Alkylpentafluorosilicates, Primary Alkyl Radical
Precursors in the C‑1 Alkylation of Tetrahydroisoquinolines
Teng Wang and Dong-Hui Wang*
CAS Key Laboratory of Synthetic and Self-Assembly Chemistry for Organic Functional Molecules, Center for Excellence in
Molecular Synthesis, University of Chinese Academy of Sciences, Shanghai Institute of Organic Chemistry, CAS, 345 Lingling Road,
Shanghai 200032, China
S
* Supporting Information
ABSTRACT: In this study, we demonstrate that potassium
alkylpentafluorosilicates (RSiF5K2) are efficient primary alkyl
radical precursors for selective C(sp3)−C(sp3) bond-forming
reactions. RSiF5K2 reagents are white, free-flowing solids and
are moisture and air stable. This class of reagents enables the
direct C-1 alkylation of tetrahydroisoquinolines under mild
conditions via single-electron transfer. The broad substrate
scope of both alkylpentafluorosilicates and tetrahydroisoquinolines is tolerated in this transformation. Both radical scavenger
and EPR capture experiments show that the primary radical is generated by the oxidation of RSiF5K2. A mechanism involving
alkyl radical addition to an iminium salt followed by reduction by an amine is proposed.
ree radical couplings that proceed via single-electron
transfer (SET) under metal-mediated redox conditions1
Scheme 1. Hypervalent silicates as radical precursors
F
or photoredox catalysis2 have emerged as a uniquely effective
mode of reactivity for selective C(sp2)−C(sp3) bond formation
in synthetic chemistry. However, the radical intermediates in
such processes and their corresponding precursors are limited
mainly to secondary and tertiary C-centered alkyl variants. This
is due to the fact that the precursors have lower disassociation
energy and the radical intermediates have inherently higher
stability than in the case of primary variants. Though some
classical organometallic compounds, such as organotins and
organolithiums, and more recently developed progenitors,
including organoborons,3 peroxides,4 carboxylic acids and their
derivatives,5 alkyl halides,6 and others,7 can be readily converted
into primary alkyl radicals, some of them require special
substitution patterns to stabilize the corresponding radical, and
some of these approaches also lack functional group tolerance.
There is high demand for developing practical precursors for
primary C-centered radicals. In parallel, achieving controllable
transformations with primary alkyl radicals, such as C(sp3)−
C(sp3) coupling, is also a pertinent challenge.
To this end, the Molander and Fensterbank laboratories have
recently reported that primary alkyl hypervalent silicates are
efficient C-based radical precursors.8 In their preliminary
reports, primary alkyl radicals were successfully generated from
the stabilized bis(catecholato)silicates under photoredox
conditions with Ir or Ru catalysts (Scheme. 1a). The resulting
primary alkyl radicals were then demonstrated to be competent
in C(sp2)−C(sp3) bond-forming reactions, such as addition to
alkenes, and cross-coupling with vinyl halides or aryl bromides,
as well as viable initiators for the cross-coupling of thiols and aryl
bromides.
environmentally friendly, nontoxic, simple to prepare, and
convenient to handle would broaden the utility of such reagents
in the synthesis of C−C bonds, especially in the construction of
C(sp3)−C(sp3) bonds. To achieve this goal, we focused on
potassium alkylpentafluorosilicates (RSiF5K2). Though Kumada
and others have previously observed the generation of carbon-
centered radicals from RSiF5K2 upon treatment with stoichio-
metric quantities of CuIIX2, halogens, or NBS, these primary
Inspired by these reports, we envisioned that alternative
hypervalent silicate radical precursor that are atom-economic,
Received: March 30, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01124
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization of the Reaction Conditions
b
entry
[Cu]
CuBr
CuBr
CuBr
oxidant
PTC
additive
base
solvent
yield (%)
1
2
3
4
5
6
7
8
TBHP (aq)
TBHP (aq)
DTBP
DTBP
DTBP
DCE
DCE
CCl4
CCl4
CCl4
CCl4
CCl4
CCl4
CCl4
CCl4
CCl4
CCl4
CCl4
CCl4
0
>5 ( 2)
39
67
66
0
63
46
65
52
52
69
72 (67)
88 (82)
TBAI
TBAF
TBAF
TBAF
TBAF
TBAF
TBAF
TBAF
TBAF
TBAF
TBAF
CuBr
Cu(OTf)2
Cu(OTf)2
CuCl2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Et3N
Et3N
Et2NH
tBuNH2
Et2NH
Et2NH
Et2NH
Et2NH, H2O
9
10
11
12
13
NaOAc
NaOAc·3H2O
KHCO3
c
14
KHCO3
a
Reaction conditions: 1a (0.3 mmol), 2a (1.2 mmol), oxidant (2.2 equiv), TBAF (10 mol %), base (2 equiv), additive (3 equiv), CCl4 (2 mL), 80
b
°C, N2. Yields were determined by 1H NMR spectra of crude reaction mixtures with Ph3CH as internal standard. Isolated yields are in
parentheses. H2O (3 equiv) was added.
c
radicals could only be trapped by a few select reaction partners,
including the counteranions of the CuII salts, alcoholic solvents,
or actived alkenes, in reasonable yields (Scheme 1b).9 Methods
that utilize primary alkyl radicals generated from RSiF5K2
precursors in selective C(sp3)−C(sp3) bond formation are
rare.10
We further envisioned that such species would be well-suited
for traditionally challenging C(sp3)−H functionalization for
C(sp3)−C(sp3) bond formation11 in a catalytic cycle in which a
tertiary amine is oxidized to the corresponding iminium salts
followed by primary radical addition.12 Herein, we report a
Cu(II)-mediated coupling of N-aryl tetrahydroisoquinolines at
the C−1 position with RSiF5K2, forming C(sp3)−C(sp3) bonds
under mild conditions via SET (Scheme. 1c). In this reaction,
alkyl pentafluorosilicates (RSiF5K2) are demonstrated to be
efficient primary C-centered radical precursors.
We initiated our study by investigating the reaction of N-
phenyl tetrahydroisoquinoline (1a) with potassium phenethyl-
pentafluorosilicate (2a). Encouragingly, the desired product 3a
was obtained in the presence of 30 mol % CuBr and 2 equiv of
TBHP (5.5 M in decane) in anhydrous dichloromethane under
N2 atmosphere for 11 h, albeit only in 2% isolated yield (Table 1,
entry 2). When we switched to CCl4 as solvent and DTBP as
oxidant, 39% conversion was observed (entry 3). Increasing
CuBr to 50 mol % catalyst loading and using 3 equiv of oxidant
further improved the conversion (entry 4). Phosphine- or
pyridine-type ligands, which are generally used to promote Cu-
catalyzed reactions, inhibited this transformation. When a phase-
transfer reagent was introduced to the reaction mixture, the yield
increased. TBAF afforded 66% yield of 3a after 8 h at 80 °C
(entry 5); however, the reaction was contaminated with trace
quantities of a byproduct that resulted from the coupling of the
tert-butoxyl radical (from oxidant DTBP, di-tert-butyl peroxide)
with 1a at the C-1 position. This observation prompted us to
consider the use of stoichiometric Cu(II) as oxidant. Use of 2.2
equiv of Cu(OTf)2 alone did not afford any desired product
(Table 1, entry 6). After considering the mechanistic features of
the reaction (vide infra), we realized that single-electron
reductants, such as amines, were necessary for reducing the
intermediate to the final product.13 Thus, diethylamine was
identified as a suitable additive, and the desired product was
achieved in 69% yield (Table 1, entry 12). Various copper salts
were screened, among which Cu(OTf)2 was found to be the
most efficient. Interestingly, we found that the addition of
inorganic base and H2O could further improve the trans-
formation; thus, KHCO3 and 3 equiv of H2O together provided
82% isolated yield (Table 1, entries 11−13). A plausible
explanation is that water might promote the transformation or
simply increase the solubility of the silicate salts in the reaction,
and a similar water effect has also observed for potassium
organotrifluoroborates (RBF3K).14
Having identified the optimal conditions, we next examined
the substrate scope of organopentafluorosilicate reagents as
primary radical precursors using N-phenyl tetrahydroisoquino-
line (1a) (Table 2) as a model substrate. First, the reactivity of
various phenethyl pentafluorosilicates was tested (2a−2h). We
found that these pentafluorosilicates reacted smoothly with 1a to
provide the desired alkylation products in moderate to good
yields (3a−3h, respectively). In all of these cases, the products
resulted exclusively from 2-phenethyl radical addition to 1a, with
no evidence of formation of the corresponding 1-phenethyl (i.e.,
benzyl)-substituted products.15 Multiple functional groups on
the aryl ring of the phenethylsilicates, such as Me (3b), OMe (3c,
and 3d), halogens F, Cl, Br, (3e−3g), and ester (3h), were
compatible with the mild reaction conditions and afforded the
C(sp3)−C(sp3)-coupled products in good yields. These func-
tional groups provide an additional handle for further synthetic
elaboration. Additionally, benzyl pentafluorosilicates (2i−2k)
that contain substituents are also compatible for this C(sp3)−
C(sp3) bond-forming reaction, providing the desired products in
moderate yields (3i−3k). Furthermore, 3-phenylpropyl silicate
(2l) reacted readily with 1a to provide the desired product (3l)
in moderate yield. At last, we examined the compatibility of
purely aliphatic pentafluorosilicates in this transformation. It
turned out that ethyl, 2-carbonylhexyl, ethoxymethyl, and
glycomethyl petafluorosilicates reacted successfully with the
B
DOI: 10.1021/acs.orglett.9b01124
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Table 2. Scope of Organopentafluorosilicates
Table 3. Scope of N-Phenyl Tetrahydroisoquinolines
a
Reaction conditions: 1a (0.3 mmol), 2 (1.2 mmol), Cu(OTf)2 (0.66
mmol), TBAF (0.03 mmol), Et2NH (0.9 mmol), KHCO3 (0.6
b
mmol), H2O (0.9 mmol), CCl4 (2 mL), N2, 80 °C, 8 h. Air, 60 °C,
c
d
36 h. 60 °C, 36 h. Air, 60 °C, 12 h.
isoquinonline substrate and delivered the desired C(sp3)−
C(sp3) cross-coupled products in moderate togood yields (3m−
3p). These examples show that organopentafluorosilicate
reagents are reliable precursors for generating the corresponding
C-centered primary radicals.
a
Reaction conditions: 1a (0.3 mmol), 2 (1.2 mmol), Cu(OTf)2 (0.66
mmol), TBAF (0.03 mmol), Et2NH (0.9 mmol), KHCO3 (0.6
mmol), H2O (0.9 mmol), CCl4 (2 mL), N2, 80 °C, 8 h. The
organopentafluorosilicate was added in two batches.
b
We next probed the scope of tetrahydroisoquinolines (1) with
potassium phenethylpentafluorosilicates (2a) (Table 3). A
variety of N-aryl tetrahydroisoquinoline substrates (1b−1p)
reacted smoothly with 2a to afford C(sp3)−C(sp3) cross-
coupled products in moderate to good yields. Substrates bearing
substituents on the N-aryl ring, including methyl (4a−4c),
trifluoromethoxyl (4d), halogens such as fluoro (4e, and 4f),
chloro (4g), and bromo (4h), carbonyl (4i), and esters (4j),
afforded the desired products in good yields. A strongly electron-
withdrawing group, namely CF3, is also tolerated (4k), albeit in
low yield. Substituents on the tetrahydroisoquinoline ring, such
as chloro (4l), methoxyl (4m), phenyl (4n), and alkynyl (4o),
were well tolerated in the reaction, providing moderate to good
yields (4l−4o).
This protocol is good for gram-scale uses. For example, the
reaction of 1.2 g of 1a (6 mmol) with 2a affords 1.48 g of 3a in
79% yield (eq 1). Similarly, the reaction between 1.37 g of 1e and
2a affords 1.62 g of the desired product, 4e, in 82% isolated yield
(eq 2).
To understand the reaction mechanism, a radical scavenger
test was conducted. When pentafluorosilicate 2a was stirred with
2,2,6,6-tetramethylpiperidine N-oxide (TEMPO) in the pres-
ence of catalytic CuBr2 and 3 equiv of di-tert-butyl peroxide
(DTBP) in THF at 80 °C, we isolated 55% yield of 2,2,6,6-
tetramethyl-1-phenethoxypiperidine 5 (eq 3). Moreover, under
analogous conditions, 2a was found to undergo Minisci-type C2-
alkylation of a representative pyridine substrate (eq 4). These
results are consistent with a mechanism in which the alkyl
pentafluorosilicate serves as a C-centered radical precursor in the
coupling reaction.
To gain more insight into the redox chemistry involved in this
reaction, we next performed EPR capture experiments. When 2a,
Cu(OTf)2, and phenyl tert-butyl nitrone (PBN, a spin-trapping
C
DOI: 10.1021/acs.orglett.9b01124
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
g = 2.00636, αN = 13.90G, and αH = 1.78G. Taking these results
together, we can conclude that a C-centered primary free radical
is involved in the reaction. This radical then plays an important
role in C-1-selective C(sp3)−C(sp3) bond formation.17
Though elucidating the full mechanistic details remains the
goal of ongoing investigations, based on the preliminary
observations above, we propose a radical SET pathway for this
transformation (Figure 2). Tetrahydroisoquinoline is oxidized
reagent) were stirred in CCl4 at 80 °C for 2 h, the EPR signal
clearly indicated formation of a PBN adduct, R(Ph)CHN-
(•OC)tBu (Figure 1a, red line), in which g = 2.00632, αN =
Figure 2. Proposed reaction mechanism.
by Cu(II) to provide radical cation A,18 which then affords
iminium salt B through homolytic hydrogen-atom abstraction.19
The organopentafluorosilicate is oxidized by Cu(II) via SET to
provide silicon-centered radical C,20 which affords carbon-
−
centered alkyl radical D by releasing SiF5 or SiF4; attack of
carbon-centered radical D on to the iminium ion B provides
radical cation E, which is then reduced with an electron from
diethyl amine to provide the final product.
In conclusion, we show that potassium alkylpentafluorosili-
cates (RSiF5K2) are an effective class of precursors for generating
carbon-centered primary alkyl free radicals under mild oxidative
conditions using stoichiometric copper(II). The resultant
primary alkyl radical can be effectively trapped by an imium
ion generated from N-phenyl tetrahydroisoquinoline at the C−1
position to afford a C(sp3)−C(sp3) cross-coupled product in
moderate to good yields. We also trapped the primary radicals
with a radical scavenger and performed EPR experiment to
support the involvement of a radical intermediate. Organo-
pentafluorosilicates are easily prepared on large scale, and they
are generally air- and moisture-stable, nontoxic, free-flowing
white solids, making them a valuable addition to the toolkit of
primary alkyl radical precursors in synthetic chemistry.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.9b01124.
Experimental procedures, and characterization data and
spectra of new compounds (PDF)
Figure 1. EPR capture tests. (a) EPR test for the alkyl pentafluor-
osilicate. (b) EPR test for the C-1 alkylation reaction mixture.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: dhwang@sioc.ac.cn.
ORCID
13.98G, and αH = 1.69G. However, in the control experiment
(i.e., in the absence of 2a), no radical adduct was observed
(Figure 1a, black line). It should be noted that the R group in the
spin-adduct product, R(Ph)CHN(•OC)tBu, may be two
different groups. One possibility is the phenethyl moiety, as
would be expected from radical generation via oxidation of
RSiF5K2 by CuII. The other possibility would result from
addition of •CCl3 radical that is generated from the Cl
abstraction of CCl4 by the phenethyl radical.16 Next, we added
PBN under the standard reaction conditions, and in this case, we
observed a similar alkyl radical spin adduct (Figure 1b) for which
Dong-Hui Wang: 0000-0002-4318-5450
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We acknowledge support from the National Key R&D Program
of China (2016YFA0202900), the Strategic Priority Research
■
D
DOI: 10.1021/acs.orglett.9b01124
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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DOI: 10.1021/acs.orglett.9b01124
Org. Lett. XXXX, XXX, XXX−XXX