Base-Promoted C-C Bond Activation Enables Radical Allylation with Homoallylic Alcohols

Article abstract of DOI:10.1021/jacs.9b12343

The C_α-C_β bond in homoallylic alcohols can be activated under basic conditions, qualifying these nonstrained acyclic systems as radical allylation reagents. This reactivity is exemplified by photoinitiated (with visible light and/or

Full text of DOI:10.1021/jacs.9b12343

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Article
Base-promoted C-C bond activation enables
radical allylation with homoallylic alcohols
Maximilian Lübbesmeyer, Emily G. Mackay, Mark A. R.
Raycroft, Jonas Elfert, Derek A. Pratt, and Armido Studer
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 15 Jan 2020
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Journal of the American Chemical Society
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Base-promoted CC bond activation enables radical allylation with
homoallylic alcohols
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Maximilian Lübbesmeyer†, Emily G. Mackay†, Mark A. R. Raycroft‡, Jonas Elfert†, Derek A. Pratt‡,*,
Armido Studer†,*
†Westfälische Wilhelms Universität, Organisch-Chemisches Institut, Corrensstraße 40, 48149 Münster, Germany.
‡Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, Ontario, K1N 6N5, Canada.
KEYWORDS Radical chemistry, allylation, fluoroalkylation, electron catalysis, C-C bond activation
ABSTRACT: The CαCβ bond in homoallylic alcohols can be activated under basic conditions, qualifying these non-strained acyclic
systems as radical allylation reagents. This reactivity is exemplified by photoinitiated (with visible light and/or blue LEDs) allylation
of perfluoroalkyl and alkyl radicals generated from perfluoroalkyl iodides and alkyl pyridinium salts, respectively, with homoallylic
alcohols. C-radical addition to the double bond of the title reagents and subsequent base-promoted homolytic CαCβ cleavage leads
to the formation of the corresponding allylated products along with ketyl radicals that act as single electron reductants to sustain the
chain reactions. Substrate scope is documented and the role of base in the CC bond activation is studied by computation.
suggested mechanism for the allylation using homoallylic
alcohols
1. INTRODUCTION
The difficult activation of CC bonds precludes its routine
implementation as a strategic disconnection in retrosynthetic
analyses.1–3 Along these lines, efficient CC bond cleavage is
generally achieved only in strained cyclic systems where relief
of ring-strain drives the fragmentation process. Indeed, -bond
cleavage in non-strained compounds remains a significant and
largely unmet challenge.2–5 Among developments in the context
of the reactivity reported below, retroallylation of acyclic
homoallylic alcohols by various metals, e.g. Li,6,7 Mg,7 Zn,8,9
Ru,10 Ga,11 Rh,12 Pd,13–16 Ni,17 and Cu18 is particularly relevant
(Scheme 1a). The resultant organometallic species can then be
added to various electrophiles. Since allyl groups are attractive
structural entities that can be readily converted into a range of
functional groups, we sought to develop homoallylic alcohols
as radical allylation reagents (Scheme 1b).
a) Retroallylation by CC bond activation
M
O
M
O
M = e.g. Li, Mg, Zn, Ru, Zr, Ga, Pd, Ni, Cu
b) Homoallylic alcohols in radical allylations and established reagents
prior work
X
R
R
+
+
X
(X = Sn, Si, S, Br, Cl, P, O)
this work
R1 R2
OH
O
R
- e
, - H
R
+
+
Current methods for radical allylation rely on the homolytic
cleavage of CSn,19,20 CS,21–24 CSi,25,26 CCl/Br,27–29 CP,30
or CO31–33 carbon-heteroatom bonds. To the best of our
knowledge, the only radical allylations proceeding via CC
bond cleavage were achieved by Nishikata et al. using copper
catalysis34 and Zard et al. who discovered in the course of their
studies on allylic alcohols and ethers as allylating reagents that α-
substituted allylic alcohols can undergo carbon radical induced C-
C-bond homolysis leading to functionalized ketones (after
tautomerization).35 Current methods typically require high
temperatures and many involve the use of toxic reagents.
Addressing these critical aspects, Weaver et al. recently
developed a mild photocatalytic prenylation of perfluorinated
aryl radicals with allylic ethers.33 Herein, we disclose our results
on the use of homoallylic alcohols as radical allylation reagents.
R1
R2
1
c) Base-promoted radical allylation - suggested mechanism
O
R-X
2
R1
R2
M
O
O
Hbase
R2
or
R1
R
R1
R2
R1
R2
R1
R2
or
R
O
O
M
R1 R2
3
H
base
R
H
base
O
Scheme 1. Metal catalyzed retroallylation, complementary
base-promoted radical allylation, existing methodology and
or
R1 R2
R
O
M
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that the CC bond cleavage can also be promoted by LiOH or
DABCO. In the absence of any base, the product was not
formed. For both protocols, DABCO significantly increased the
yield, likely due to more efficient radical initiation.64,65
We were motivated by recent studies by Zhu and co-workers as
1
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4
5
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8
well as some of our own successful radical alkene
difunctionalizations, which proceed via intramolecular alkynyl
and alkenyl migrations involving a σ-CC bond homolysis
step.36–40 We envisioned that either deprotonation of, or
hydrogen-bond donation from, a homoallylic alcohol 1 would
activate the CαCβ bond, enabling radical-mediated
fragmentation as part of an overall allylation reaction. This
activation mode, reminiscent of the “oxy-anionic substituent
effect” in the oxy-Cope reaction,41,42 has been leveraged for the
activation of α-CH bonds,43–45 in selective CH
Scheme 2. Radical allylation of perfluorobutyl iodide with
1a
Method A
Ph
Ph
1) nBuLi (3.0 equiv), DME
2) DABCO (2.0 equiv),
Me Ph
OH
C4F9
9
3aa
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functionalization
reactions46
and
efficient
H-atom
3.0 equiv
2a
LiOH (0.5 equiv), C4F9-I ( ),
h 50 C, 18 h, 61%
abstractions.47,48 Such -bond activation relies on the
1a
휎 ∗
휎 ∗
Method B
Ph
interaction of the oxygen lone pair with the 퐶퐶 or 퐶퐻 orbital,
but perhaps more importantly, by destabilizing the substrate
(when involving ions in apolar solvents) while stabilizing the
products resulting from -bond cleavage.
Ph
1) K3PO4 (3.0 equiv), DCE
2) DABCO (2.0 equiv),
Me Ph
C4F9
OH
3.0 equiv
2a
LiOH (1.5 equiv), C4F9-I ( ),
3aa
With regard to homolytic CC bond cleavage, this effect is also
known,49,50 albeit less intensively explored, and applied in
reverse pinacol coupling reactions,51–54 cleavage of α,β-
dihydroxyketones,55 and the aforementioned intramolecular
alkynyl and alkenyl migrations.37,39 As a working model, we
envisioned that alkyl radical addition to a compound of general
structure 1 would afford the allylation product 3 along with a
ketyl radical anion that could be used to generate a new alkyl
radical by dissociative electron transfer to a suitable precursor
2, making possible a radical chain reaction as in Scheme 1c.
Hence, this sequence qualifies as an electron-catalyzed
process.56,57 Due to the intrinsically strong CC -bond, an
SH2’-type concerted addition/fragmentation was expected to be
less likely.58 The homoallylic alcohol could, in principle, be pre-
activated to C-C fragmentation either by deprotonation by a
strong base or by an H-bonding interaction with a weak base.
h 50 C, 24 h, 63%
1a
The reactions were performed with 1 (3.0 equiv), C4F9I (1.0
equiv), nBuLi (1.6 M in hexane, 3.0 equiv) or K3PO4 (3.0 equiv),
DABCO (2.0 equiv), LiOH (0.50 equiv or 1.5 equiv), DME or DCE
(0.10 M). For visible-light irradiation a Philips Master HPI-T Plus
(400 W) bulb was used. Isolated yields are reported.
Since the stability of the ketyl radical leaving group should have
an impact on the fragmentation step and on the reduction of the
radical precursor, we tested different homoallylic alcohols in
the reaction with 2a, varying the substituents R1 and R2 (Table
1). Little to no product formation was observed for the -
unsubstituted, monomethyl, or dimethyl substituted
homoallylic alcohols (Table 1, entries 1-3). A stabilizing
aromatic substituent appears to be required, as the mono-phenyl
congener provided 3aa in 62% yield using method A (Table 1,
entry 4). Notably, when this homoallylic alcohol and all other
secondary benzylic alcohols were tested as acceptors, method
B afforded significantly lower yields (Table 1, entries 4-8). The
electronics of the -aryl substituent were found to be relatively
unimportant; although slightly higher yields could be obtained
with -conjugating or electron-withdrawing substituents (e.g.
85% and 75% for para-biphenyl and para-cyanophenyl
alcohols, respectively), electron-rich aryl substituents were still
reasonable substrates (e.g. -para-methoxyphenyl gave 68%
yield). The highest yields using either method were obtained
when tertiary homoallylic benzylic alcohols were used as the
allylating reagent (Table 1, entries 9-11).
Given the acidity of the resultant α–hydroxyalkyl radical,59,60
a
ketyl radical is expected after/during fragmentation even in the
presence of a weak base.
2. RESULTS AND DISCUSSION
To test our hypothesis, we chose perfluoroalkyl iodides 2 as
radical precursors since their single electron reductive cleavage
is well established and the corresponding perfluoroalkyl
radicals are known to efficiently add to unactivated terminal
alkenes.37,39 Initiation with such radical precursors can be
readily achieved by simple visible light irradiation. Moreover,
fluoroalkyl substituents are privileged motifs in agricultural61
and medicinal chemistry,62,63 due primarily to their lipophilicity
and metabolic stability, which enhance bioavailability.
Table 1. Reaction of 2a with various homoallylic alcohols –
variation of the substituents R1 and R2
The optimized reaction conditions are presented in Scheme 2
(see the Supporting Information for details on the optimization).
Following an extensive screen of basic reagents, we found that
the Li-alcoholate Li-1a generated by deprotonation of 1a with
nBuLi in DME reacts with perfluorobutyl iodide (2a) in the
presence of DABCO and LiOH under visible light irradiation at
50 °C to yield the target compound 3aa (61%, Method A).
While deprotonation with nBuLi was not necessary for the
activation of 1a (omission of nBuLi gave a similar yield), the
addition of nBuLi was strictly necessary for the activation of
several other substrates (e.g. 1ab, vide infra). Alternatively,
allylation with 1a could be achieved under milder conditions
using potassium phosphate to provide 3aa (63% yield, Method
B). Without potassium phosphate, the desired product 3aa was
also formed, albeit in lower yield of 44%. These results indicate
R1 R2
Method A or
Method B
Ph
Ph
C4F9I
+
C4F9
OH
1
2a
3aa
Entry R1
R2
Yield
Yield
(Method A)
(Method B)
1
2
3
4
H
H
n. d.
n. d.
<5%
62%
n. d.
15%
35%
22%
H
Me
Me
Ph
Me
H
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surmised that iodine atom transfer to the intermediate alkyl
5
H
4-F-C6H4
4-NC-C6H4
4-Ph-C6H4
4-MeO-C6H4
Ph
68%
75%
85%
61%
65%
59%
71%
27%
13%
26%
36%
68%
35%
77%
1
2
3
4
5
6
7
8
radical is faster than the desired fragmentation. Subsequent
elimination of HI would lead to the corresponding alkene,
which was observed by GC-MS. Alkyl groups in the β- and γ-
positions of the homoallylic alcohol are tolerated and the
allylated products 3ac, 3ad, 3af and 3ah were obtained in 52-
80% yield. Also, prenylation proved to be feasible (3ae, 68%
yield). Starting with a homopropargylic alcohol, the allene 3ag
could be prepared, albeit in moderate yield (36%). The
dialkylmalonyl moiety is compatible with method B (3ai, 48%
yield). Aryl groups are tolerated in the γ- as well as the β-
position of the homoallylic alcohol (3aa, 3ak-3ap, 50-77%
yield). Also, -biphenyl-substituted homoallylic alcohols were
successfully alkylated with 2a (3ar-3at, 34-76% yield). The
functionalized indene 3aq and the alkylidenecyclobutane 3au
were obtained in excellent yields (93% and 95%, respectively).
6
H
7
H
8
H
9
Me
10
11
CF3 Ph
Ph Ph
Yields determined by H- and/or 19F-NMR of the crude reaction mixture.
1,3,5-Trimethoxybenzene and benzotrifluoride were used as internal
standards. n. d.: not detected.
1
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We next focused on the scope of the reaction and tested
different homoallylic alcohols as substrates in combination with
various perfluoroalkyl iodides (Scheme 3). Most of the
acceptors were readily prepared from the corresponding allyl
bromides by the Barbier reaction (see Supporting Information).
Since tertiary alcohols generally gave higher yields, we focused
on -methyl--phenyl and -phenyl--trifluoromethyl
homoallylic alcohols. While the former usually resulted in
slightly higher allylation yields, the Barbier reaction providing
the latter was more efficient. The promising -diphenyl
congeners were not considered in the scope study, since the
Barbier reaction to form them was presumably less efficient. In
selected cases (3ab, 3ae and 3az), the corresponding secondary
p-phenylbenzyl alcohols were tested; however, lower yields
were observed compared to those obtained with the tertiary
homoallylic alcohols.
The perfluorobutyl iodide (2a) could be replaced with other
perfluoroalkyl radical precursors, as demonstrated by the
successful preparation of 3ad-3af, 3aj, and 3ax-3az.
ICF2CF2Br and ICF2CF2Cl reacted chemoselectively to give
3ba and 3bb, respectively, albeit in low yield. Surprisingly,
even homoallylic alcohols bearing an electron deficient double
bond reacted with electrophilic perfluoroalkyl radicals to give
the allylated products 3av and 3aw, albeit in modest yields
(41% and 37%, respectively). We also tested
a
cyanomethylation, which proceeds via radical addition to vinyl
azide 1ax, loss of dinitrogen and subsequent fragmentation of
the iminyl radical.66 The primary allylation product was found
to be unstable and underwent HF elimination under the reaction
conditions to provide compound 3ax in 56% isolated yield.
Homoallylic alcohol 1ab was used to allylate perfluoroalkyl
iodide 2a to yield 3ab in 60% yield using Method A. Notably,
we did not observe product formation with Method B. We
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Scheme 3. Reaction of perfluoroalkyl iodides with various homoallylic alcohols
1
2
3
4
5
6
7
8
R3
OH
R3
R2
R1
Rf
R5
Method A or
Method B
RfI
+
R4 R5
R4
Substrate
Substrate
R1 OH
Product
Product
R1 OH
R2
C4F9
R2
R
9
, R1 = Ph, R2 = CH3
, with
with
: 60%
: 55%
a
a
1ab
3ab
1ab
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C4F9
, R1 = 4-Ph-C4H6, R2 = H
1ab'
1ab'
OH
R
C4F9
Ph
, R1 = Ph, R2 = CH3, R = H
, R1 = Ph, R2 = CH3, R = Cl
, R1 = Ph, R2 = CH3, R = OMe
, R = H, 62% , 72%
b
c
1an
3an
3ao
3ap
b
c
1ao
1ap
, R = Cl, 73% , 77%
, 53%a (E:Z = 7:1)
1ac
3ac
c
, R = OMe, 58%
OH
C10F21
3ad
OH
C4F9
Ph
CF3
a
1ad
, 52%
R1 OH
R2
C10F21
c
1aq
3aq
, 93%
, R1 = Ph, R2 = Me
, R1 = 4-Ph-C4H6, R2 = H
b
c
1ae
3ae
1ae
, with : 62% , 68%
C4F9
b
1ae'
1ae'
with
: 62%
OH
R2
Ph
CF3 OH
Ph
C10F21
R
R
b
1af
3af
C4F9
3ag
, 54%
, R2 = CH3, R = H
, R = H, 69% , 76%
b
c
OH
1ar
3ar
C
, R2 = CH3, R = CN
, R = CN, 65%
c
1as
1at
3as
3at
Ph
c
, R2 = CF3, R = OBn
. R = OBn, 34%
a
1ag
, 36%
Ph
Ph OH
Ph
CF3 OH
Ph
Ph
C4F9
C4F9
c
1au
O
3au
, 95%
RO
b
c
OH
1ah
O
OR
3ah
, 54% , 80%
OH
C10F21
C4F9
CO2iPr
CO2iPr
Ph
c,d
iPrO2C
1av
3av
, R = Et, 41%
, R = Et
1aw
c,d
, R = tBu
3aw
, R = tBu, 37%
CO2iPr
N3
F
c
1ai
3ai
, 48%
CN
C9F19
3ax
R
OH
Ph OH
R2
c,d
, 56%
1ax
C10F21
R
C6F21
C10F21
3az
C4F9
R1 OH
R2
, R1 = Ph, R2 = CH3
, R1 = 4-Ph-C4H6, R2 = H
1ab'
a
a
3ay
1ab
: 64%
, 63%
, with
, R2 = CH3, R = H
1a'
, 49%
with 1ab': 55%b
b
b
c
1a
3aj
3aa
3ak
1a
, R = H, with : 61% , 63%
a
, R2 = CF3, R = H
with
1ab
1a'
: 59%
XF2CF2C
b
, R2 = CF3, R = CH3
1ak
1al
, R = CH3, 73%
a
b
, R2 = CF3, R = F
3ba
3bb
, X = Br, 20%
3al
, R = F, 50%
a
b
c
, R2 = CF3, R = Br
, X = Cl, 30%
3am
1am
, R = Br, 56% , 46%
aYields were determined by 19F-NMR with benzotrifluoride as an internal standard. Method A was applied. bIsolated yields. Method A was
applied. cIsolated yields. Method B was applied. dNo LiOH was added.
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To demonstrate the general applicability of our allylation 4a could be allylated with 1aw in 67% yield upon irradiation
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8
approach, we next focused on Katritzky salts as radical
precursors that can be readily obtained from primary amines
and are known to efficiently generate C-radicals upon single
electron reduction.67–74 In contrast to the perfluoroalkyl radicals
that are electrophilic, the Katritzky salts enable generation of
nucleophilic C-radicals, thereby expanding the scope with
respect to the electronics of the homoallyl alcohol acceptors.
with blue LEDs at 80 °C in DMA using iPr2NEt as the base
(Scheme 4). Irradiation was essential for this transformation. At
lower temperatures, the desired CC bond homolysis was less
efficient, and in the absence of iPr2NEt the yield dropped to
44%. Notably, addition of nBuLi as the base led to
decomposition of the starting homoallylic alcohol and
potassium phosphate promoted its lactonization. With the
optimized conditions in hand, we explored the reaction scope
by first varying the electrophilic homoallylic alcohol
component. Along with alkyl acrylates (see 5a and 5b),
acrylamides (see 5c and 5d) and also a styrene derivative (see
5e) engaged in the reaction with salt 4a (36-67% yield).
Keeping acceptor 1aw, we next varied the Katritzky salt. For
the more challenging generation of unactivated primary alkyl
radicals from pyridinium salts 4f and 4g, the temperature had to
be increased to 120 °C and the respective allylated products 5f
and 5g were obtained in moderate 38% and 46% yields.
However, primary benzylic pyridinium salts turned out to be
good substrates to afford the desired products in synthetically
useful yields (54-67%). In these systems, methyl (5i), chloro
(5j), bromo (5l), and cyano (5k) substitution at the phenyl
moiety was tolerated. Also, naphthyl and pyridine moieties
were compatible with the conditions and the corresponding
products 5m and 5n were obtained in 39% and 71% yield,
respectively. Secondary alkyl radicals could be allylated with
1aw via our novel method to afford the products 5o – 5r in 57-
72% yield. Of note, a free hydroxy group (5p) was also
tolerated. Moreover, the pyridinium salt 4s, which was derived
from phenylalanine methyl ester, could be used as a precursor,
and the respective allylated products 5s and 5t were obtained in
60% and 57% yield, respectively.
Scheme 4. Radical allylation of various Katritzky salts with
homoallylic alcohols
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Ph
R1
Ph
DMA
iPr2NEt
R2
R2
HO
Ph
R1
+
N
blue LEDs
80 °C, 20 h
BF4
Ph
4
1
5
O
OtBu
O
OEt
5a
5b
, 67%
N
, 49%
O
O
N
O
5c
5d
, 36%
5e
, 37%
, 41%
Variation of the C-radical precursor
OtBu
O
To provide insight on the mechanism of the base-promoted C–
C
bond cleavage reaction, we turned to CBS-QB3
a
5f
, 38%
computations.75 Specifically, we explored how deprotonation or
H-bonding of the homoallylic alcohol promotes C–C bond
fragmentation following radical addition to the terminal double
bond. Model intermediates arising from radical addition to
homoallylic tertiary alcohols with either two methyl groups (R1
= R2 = Me) or one methyl (R1 = Me) and one phenyl (R2 = Ph)
group were selected to facilitate comparison to the foregoing
experimental results. For each of these two models, transition
state structures for C–C bond fragmentation were readily
located for each of the alcohol, alkoxide and lithium alcoholate,
as well as the alcohol H-bonded to either ammonia or
monobasic phosphate anion. Calculations were carried out in
the gas phase as well as a self-consistent reaction field76
parameterized to account for the effects of the 1,2-
dichloroethane solvent employed in the experiments. Free
energy barriers are shown for R1 = Me, R2 = Ph in Figure 1A.
a
5g
, 46%
5h
, R = H, 66%
5i
5j
, R = Me, 54%
, R = Cl, 67%
Br
R
5k
, R = CN, 64%
5l
, 67%
HO
N
5m
5n
5p
5o
, 72% (dr = 1:1)
, 39%
, 71%
, 57%
Ph
Ph
Ph
O
O
O
O
O
5q
5r
5s
5t
, 57%
, 57%
, 67%
, 60%
The reactions were performed with 4 (1.0 equiv), 1 (3.0 equiv),
iPr2NEt (1.5 equiv), and DMA (0.10 M). The reaction tubes were
heated in a beaker filled with paraffin oil and irradiated with two
blue LEDs (5 W each, 465 nm). Isolated yields. aReaction
performed at 120 °C instead of 80 °C.
We therefore chose the electrophilic tert-butyl acrylate 1aw as
a reaction partner. After careful reaction optimization (see
Supporting Information for full details), we found that 1-
cyclododecyl-2,4,6-triphenylpyridin-1-ium tetrafluoroborate
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Figure 1. A) Computed (CBS-QB3) free energy barriers for C–C bond fragmentation in model intermediates featuring different electronics
–
about the oxygen atom of the incipient ketyl radical. B) A comparison of the reactivity involving H-bond assistance (with H2PO4 ) and
lithium alcoholate formation to that of the unassisted alcohol using the computed free energies for C–C bond fragmentation when R1 = R2 =
Me and R1 = Me, R2 = Ph. C) Reaction pathway and corresponding free energy diagram depicting H-bond-assisted C–C bond fragmentation
–
(black, no H-bond assistance; red, B = H2PO4 ; blue, B = NH3) where R1 = Me, R2 = Ph. All computed values shown employ a CPCM
solvation model for 1,2-dichloroethane.
Several trends are notable in the data. As the electron density
on the alcohol(ate) increases (OH → OLi → O–), the
exergonicity of the reaction increases and the magnitude of the
barrier decreases. The progressively earlier nature of the TSs
can be seen in the C–C bond lengths at the TS as well as in the
degree of rehybridization of the carbon atoms shown in the TS
structures (see Supporting Information). This trend is
presumably driven by SM destabilization, which is accentuated
in the low polarity medium (DCE, used in method B above).
Reactions of model substrates with R1 = R2 = Me were
computed to be endergonic, consistent with the lesser stability
of alkyl ketyl radicals relative to their aryl counterparts (Figure
1B). Nevertheless, deprotonation and formation of the lithium
alcoholate yields a barrier for fragmentation that is only slightly
higher than that in the highly exergonic reaction when R1 = Me,
R2 = Ph.
larger in the solvent continuum. No transition states
corresponding to a concerted proton-coupled C–C bond
fragmentation were identified, presumably because the
resultant ketyl radical is less acidic than the conjugate acid of
the H-bond acceptor.78 It is likely, however, that subsequent
oxidation of the ketyl radical by the alkyl iodide or the Katritzky
salt is facilitated by the coupled movement of the proton within
the H-bond, turning over the catalytic cycle and producing the
ketone along with the iodide of the conjugate acid of the H-bond
acceptor or triphenylpyridine, respectively.
3. SUMMARY
We have explored the activation of Cα–Cβ bonds in alcohols
under basic conditions. In this context, we presented a carbon-
radical induced C–C bond fragmentation in homoallylic
alcohols, which is facilitated by the formation of an alkoxide
anion or by hydrogen-bonding, reducing the energy barrier to
the fragmentation and enabling propagation of a chain reaction.
This rare example of a C–C bond fragmentation in a non-
strained acyclic system was exploited for the radical allylation
of fluoroalkyl and alkyl radicals. We are convinced that this
mode of activation will serve as inspiration for the development
of new useful synthetic methods.
The electron density on the incipient ketyl radical is more subtly
manipulated by H-bonding, which also reduces the barrier to C–
C bond fragmentation, but to a lesser extent than deprotonation.
The calculations suggest that stronger H-bonding interactions
lead to larger reductions in barrier height (Figure 1C). The
stronger H-bonds found for H2PO4– compared to NH3 reflect the
higher H-bond basicity of phosphates than amines,77 and the
progressive increase in the strength of the H-bond on going
from SM to TS to P (see bottom of Figure 1C) reflects the
greater H-bond acidity of the ketyl radical compared to the
alcohol.60 It is interesting to note that the strengthening of the
H-bond on going from the SM to TS to P is predicted to be
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Alcohols to Aldehydes via Retro-Allylation Followed by
Isomerization into Ketones. Org. Lett. 2006, 8 (12), 2515–
2517.
ASSOCIATED CONTENT
Supporting Information. Experimental procedures, optimization
tables, analytical data, and computational data. This material is
available free of charge via the Internet at http://pubs.acs.org.
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Hayashi, S.; Hirano, K.; Yorimitsu, H.; Oshima, K.
Palladium-Catalyzed Stereo- and Regiospecific Allylation of
Aryl Halides with Homoallyl Alcohols via Retro-Allylation:ꢀ
Selective Generation and Use of σ-Allylpalladium. J. Am.
Chem. Soc. 2006, 128 (7), 2210–2211.
Iwasaki, M.; Hayashi, S.; Hirano, K.; Yorimitsu, H.; Oshima,
K. Pd(OAc)2/P(CC6H11)3-Catalyzed Allylation of Aryl
Halides with Homoallyl Alcohols via Retro-Allylation. J. Am.
Chem. Soc. 2007, 129 (14), 4463–4469.
AUTHOR INFORMATION
(14)
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Corresponding Author
studer@uni-muenster.de, dpratt@uottawa.ca
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Hayashi, S.; Hirano, K.; Yorimitsu, H.; Oshima, K. Synthesis
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ACKNOWLEDGMENT
of
(Arylalkenyl)Silanes
by
Palladium-Catalyzed
Regiospecific and Stereoselective Allyl Transfer from Silyl-
Substituted Homoallyl Alcohols to Aryl Halides. J. Am.
Chem. Soc. 2007, 129 (42), 12650–12651.
Waibel, M.; Cramer, N. Palladium-Catalyzed Arylative Ring-
Opening Reactions of Norbornenols: Entry to Highly
We thank the WWU Münster, the European Research Council
(advanced grant agreement no. 692640), the Fonds der Chemischen
Industrie (fellowship to M.L.), and the Alexander von Humboldt
Foundation (fellowship to E.G.M. and Bessel award to D.A.P.) for
financial support. We thank Catharina Erbacher and Max
Schwenzer for experimental support.
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Substituted
Cyclohexenes,
Quinolines,
and
Tetrahydroquinolines. Angew. Chem. Int. Ed. 2010, 49 (26),
4455–4458.
ABBREVIATIONS
DABCO, 1,4-diazabicyclo[2.2.2]octane; DCE, 1,2-dichloroethane;
DMA, N,N-dimethylacetamide; DME, 1,2-dimethoxyethane; SI,
supporting information; TS, transition state.
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Sumida, Y.; Hayashi, S.; Hirano, K.; Yorimitsu, H.; Oshima,
K. Nickel-Catalyzed Allylation of Allyl Carbonates with
Homoallyl Alcohols via Retro-Allylation Providing 1,5-
Hexadienes. Org. Lett. 2008, 10 (8), 1629–1632.
Sai, M.; Yorimitsu, H.; Oshima, K. Allyl-, Allenyl-, and
Propargyl-Transfer Reactions through Cleavage of C−C
Bonds Catalyzed by an N-Heterocyclic Carbene/Copper
Complex: Synthesis of Multisubstituted Pyrroles. Angew.
Chem. Int. Ed. 2011, 50 (14), 3294–3298.
Keck, G. E.; Yates, J. B. A Novel Synthesis of (±)-
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Montgomery, J. A.; Frisch, M. J.; Ochterski, J. W.; Petersson,
G. A. A Complete Basis Set Model Chemistry. VI. Use of
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(77)
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To evaluate the feasibility of this mechanism we explored
several privileged substrates in a variety of dielectric
environments. We were able to find a substrate (R1 = CF3, R2
= C6F5) in an aqueous reaction field where, upon optimization
of the starting materials, the proton remained on the alcoholic
substrate, and, upon optimization of the products, the proton
remained on the amine base. Despite employing these
conditions in our TS optimizations, no concerted TS was
found.
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5
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Ar
R'
via
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base
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H
visible light or
blue LEDs
base
O
R
I
(with R = Rf)
R
or
or
R' Ar
Ph
O
BF4
R
O
M
R'
Ar
R
N+
Ph
Ph
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