3-Acetoxyquinuclidine as Catalyst in Electron Donor-Acceptor Complex-Mediated Reactions Triggered by Visible Light

Article abstract of DOI:10.1021/acscatal.9b01039

3-Acetoxyquinuclidine was found to act as a catalytic electron donor species in a variety of electron donor-acceptor complex-mediated reactions. Only substoichiometric amounts (10-25 mol %) were needed to trigger the desired reaction. The outcome could be tuned by selecting the nature of the formed radical to perform amino- and hydro-decarboxylation, dimerization, and cyclization reactions. Importantly, no external additives were needed in this reaction.

Full text of DOI:10.1021/acscatal.9b01039

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Article
3-Acetoxyquinuclidine as Catalyst in EDA Complex-
Mediated Reactions triggered by Visible Light
Irene Bosque Martínez, and Thorsten Bach
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b01039 • Publication Date (Web): 23 Aug 2019
Downloaded from pubs.acs.org on August 23, 2019
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3-Acetoxyquinuclidine as Catalyst in EDA
Complex-Mediated Reactions triggered by Visible
Light
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Irene Bosque †* and Thorsten Bach
Department of Chemistry and Catalysis Research Center (CRC) Technische
Universität München, 85747 Garching, Germany.
ABSTRACT: 3-Acetoxyquinuclidine was found to act as a catalytic electron donor
species in a variety of electron donor-acceptor (EDA) complex-mediated reactions.
Only substoichometric amounts (10 to 25 mol%) were needed to trigger the desired
reaction. The outcome could be tuned by selecting the nature of the formed radical to
perform amino- and hydro-decarboxylation, dimerization, and cyclization reactions.
Importantly, no external additives were needed in this reaction.
KEYWORDS:
electron
donor-acceptor
complex,
photochemistry,
3-
acetoxyquinuclidine, homogeneous catalysis, tetrachlorophthalimide.
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1. INTRODUCTION
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Harnessing the power of sunlight in a productive manner has been an aim of many
synthetic groups in the last decades. Different strategies such as direct excitation of
molecules using UV-light, or activation via energy transfer or via electron transfer from
a photocatalyst using visible light are used in order to achieve selective reactivity.1-11
However, UV-light can be harmful, and photocatalysts are non-innocent species that
might react with the product, as they are intrinsically active molecules under visible
light conditions.
Electron donor-acceptor (EDA) complexes,12 on the other hand, emerged as an
alternative to the use of photocatalysts in visible light-triggered reactions.12-16 These
complexes are formed by two species, an electron donor and an electron acceptor,
which show a change transfer band only when combined. When this band occurs in
the visible region of the spectra, visible light can be used to induce an electron transfer
from the donor to the acceptor. Thermal activation of these complexes is also
possible.17,18 Since only selected pairs of molecules form EDA complexes, there are
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only few reports in the literature for selective reactivity, even though these complexes
have been known for decades.12,19 In the vast majority of the examples, after electron
transfer (ET) the electron donor (ED) radical cation and the electron acceptor (EA)
radical anion react with each other to form the product (Scheme 1a). Elegant work
from the group of Melchiorre exploited the formation of an intramolecular EDA complex
via iminium formation (Scheme 1b).20-22 However, to the best of our knowledge, there
are no reports showing the use of an electron donor or acceptor as external catalytic
species for visible light-mediated reactions via EDA complex formation.
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Intrigued by this lack of precedent, we sought to explore new avenues of EDA
complexes, in particular, the possibility of finding a molecule easy to obtain that could
act as a donor of an EDA complex, but which, at the same time, could be regenerated
and used in catalytic amounts in different types of reactions (Scheme 1c). In this work,
we present the synthetic possibilities of using an ED catalyst in EDA complex-
mediated reactions that could greatly expand the use of this strategy in synthetic
chemistry.
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Selected examples of EDA complex formation modes
a) Classic approach for EDA complex-mediated reactions:
EDA complex
Selected examples of reductive decarboxylation of phthalimide esters
d) Use of metal-base photocatalysts
CO2Me
TBSO
h
O
H
O
D
A
P
+
D
A
Me
Me
H
H
NPhth
H
H
1.5 equiv
O
Cl
H
Cl
Ru(bpy)3(BF4)2 (1 mol%)
HE (1.5 equiv)
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O
O
Bpin
N
Cs2CO3
EtOAc, LED (400 nm)
Me
Me
Me
Me
B
+
NPhth
i-Pr2NEt (2.25 eq)
CH2Cl2, visible light
Bpin
O
Ar
O
Ar
b) Intramolecular EDA complex formation via substrate activation:
e) Use of organophotocatalysts
O
EY (10 mol%)
i-Pr2NEt (2 equiv)
O
cat.
NPhth
O
OnBu
cat.
cat.
A
CH2Cl2, rT
light (535 nm)
h
D
+
S
N
N
A
P
D
D
Boc
Boc
O
(5 equiv)
iminium formation
EDA complex
OnBu
O
O
f) C-C coupling chemistry
O
R1-TMS (1.5 equiv)
N
+
(CyCH2)2Zn (2 equiv)
NiCl2.glyme (20 mol%)
Ligand (20 mol%)
NH2
salicylic acid (40 mol%)
MeCN, H2O
R
R
R
NTClPhth
R1
R
O
LED (420 nm)
Cy
R
THF:DMF, rT
R
Idea of this work:
c)
P
h
X
O
O
absence of stoichometric reductants
redox neutral reaction
X
EDA complex
donor
=
X = H, NPhth
X = Cl, NTClPhth
D
A
R
O
N
as catalyst
D
A
X
O
donor as catalyst
X
A
Scheme 1. Selected literature precedents on EDA complex (top left) and reductive
decarboxylative phthalimide esters chemistry (top right); Idea and advantages of this
work (bottom); HE: Hantzsch ester; EY: Eosin Y.
Since phthalimide-derived esters have been largely used in borylations (Scheme
1a),15,23,24 in photoredox catalysis (Scheme 1d-e),25-27 or in coupling chemistry
(Scheme 1f)28-30 among others, we decided to use them as initial substrates. Most of
the approaches for the reductive decarboxylation of phthalimide ester substrates are
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net-reductive methods that require the use of stoichometric amounts of an external
reductant (Scheme 1d-f). In this work we propose a redox-neutral process using the
phthalimide moieties as acceptor partners of a catalytic donor to induce reactivity via
EDA complex formation.
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2. RESULTS AND DISCUSSION
2.1. Selection of 3-acetoxyquinuclidine as catalyst
Our investigations started with the synthesis of the corresponding phthalimide ester
of 2-phenylbutyric acid, 1a (Figure 1). However, no EDA complex formation was
observed when mixing 1a with a common donor such as triethylamine (Et3N). Since
the potential of the single electron reduction of phthalimide esters (E1/2 = –1.24 to –
1.38 V vs. SCE27) is lower than the potential of the corresponding
tetrachlorophthalimide esters (E1/2 = –0.70 to –0.54 V vs. SCE, see Supporting
Information) we synthetized the analogous tetrachlorophthalimide derivative. An
equimolar mixture of the tetrachlorophthalimide ester of 2-phenylbutyric acid, 2a, with
Et3N in MeCN gave a band with a maximum defined in the blue region of the spectra,
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not observed for the separate components. This band was our first indication for the
formation of an EDA complex. We then decided to explore amines more stable in their
oxidized state than Et3N, for instance triaryl amines such as dimethylaniline,
triphenylamine and 4-methoxytriphenylamine. Unfortunately, none of them gave an
observable band in the desired region. Even N-methylmorpholine, which has a higher
stability due to the orientation of the oxygen lone pairs, showed no EDA complex
formation with 2a (See Scheme S1).
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We then turned our attention to a different group of amines. In particular we focused
on quinuclidine (azabicylo[2.2.2]octane) derivatives, as we were attracted by its
peculiar tethered structure which imparts unique redox properties to this trialkylamine.
As opposed to non-cyclic trialkylamines, such as Et3N, the bicyclic structure of
quinuclidine avoids its degradation after oxidation, since the fixed orientation of the C-
H bonds in α-position to the oxidized nitrogen center avoids α-deprotonation (Scheme
2a). For this reason, quinuclidine derivatives have been used by many research
groups as reductive quenchers and hydrogen atom donors (HAT) in photo-induced
processes (Scheme 2b).31 We hypothesized that this molecule could act not only as a
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single electron donor but also as an acceptor playing the role of a SET catalyst
triggered by an EDA process (Scheme 2c). To the best of our knowledge, this is the
first study of this matter in the literature.
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Scheme 2. Unique structure of quinuclidine. PC: photocatalyst. SET: single electron
transfer. HAT: hydrogen atom transfer. R: organic moiety. ED: electron donor. A:
molecule acting as electron acceptor. D: electron donor catalyst quinuclidine. S:
organic molecule.
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2.2. Towards the aminodecarboxylation reaction
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With this hypothesis in mind, 3-acetoxyquinuclidine (q-OAc) was chosen as potential
EDA catalyst for its simplicity in handling compared to the non-substituted quinuclidine.
An equimolar mixture of 2a and q-OAc gave a bright yellow solution, indicating the
formation of an EDA complex that was observed in the UV-visible spectra recorded
for this mixture, not observed for the separate components (Figure 1a). In order to
verify the generality of the formation of an EDA complex with q-OAc in the presence
of diverse tetrachlorophthalimide acid derivatives, we synthetized the corresponding
ester of N-Boc-proline 2b which, in the presence of q-OAc, revealed a yellow solution
indicative of the formation of an EDA complex in MeCN (Figure 1b).
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Based on these promising observations, we subjected the mixture of 2b and
substoichometric amounts of q-OAc (25 mol%) in MeCN to blue LEDs irradiation (λ =
455 nm) at room temperature. A single product and complete conversion were
observed after 20 h of irradiation. The characterization of the isolated material
revealed the formation of the corresponding decarboxylated product 3b in a 69% yield
(Figure 1c, entry 1). No starting material was recovered and no apparent formation of
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any other product was detected. Control reactions in the absence of light or q-OAc
resulted in recovery of the starting material (entries 2 and 3), indicating that this is a
light-mediated reaction that proceeds via EDA-complex formation. Optimization of the
reaction conditions was performed. Change of solvent to 1,4-dioxane gave incomplete
conversion (entry 4), but the use of dimethylformamide (DMF) notably improved the
yield of this reaction, providing a 91% yield even after only 4 h of irradiation (entries 5
and 6). No conversion was observed in the absence of light but a background reaction
in the absence of catalyst gave 39% yield of 3b (entries 7 and 8) which can be
attributed to the contribution of a radical cage mechanism explained by the absorption
at 455 nm in DMF observed in the UV-visible spectra of 2b (see Supporting Information
for further details). The use of a higher wavelength, 470 nm, in order to minimize this
background reaction gave similar results (entries 9 and 10). Further optimization of the
catalyst revealed 10 mol% of q-OAc to be optimal, giving a yield of 89% of 3b (entries
11 to 13. See Scheme S2).
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Figure 1. a) UV-visible spectra of 15 mM solutions in MeCN containing 1a, 2a or an
equimolar mixture with the corresponding amines, path length 1 cm. b) Initial
observations of an EDA complex formation; picture shows a solution of 2b (left), q-
OAc (right) and a 1:1 mixture of both (center) in MeCN. c) a Isolated yields. b 12% of
2b was recovered, c 6% of 2b was recovered.
Remarkably, this reaction failed when common photocatalysts as Ru(bpy)3Cl2 or
Eosin Y were used under the same reaction conditions (Scheme 3). For comparison,
substrate 2b’ was selected since the control reaction in the absence of catalyst gave
no product formation. The reduction potentials of the excited states of these two
photocatalysts suggest that both should be capable of reducing the tetrachlorophthalimide
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moiety. On the other hand, a second SET event needs to occur for the turnover of the
photocatalyst to its ground state, which might not be the case for these catalysts. In any case,
our catalyst q-OAc fulfils both requirements and it is capable of reducing the
tetrachlorophthalimide moiety via EDA-complex formation and closing the catalytic cycle for
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a redox-neutral process without the need of any external additives. Furthermore, the
formation of this aminodecarboxylated product would not be possible by using other
EDA complex-mediated approaches due to the following reasons: (1) the use of
stoichiometric amounts of a non-tethered amine, such as Et3N, gave minimal or no
product formation when substrates 2b’ (Scheme 3) or 2b (see Scheme S6) where
used, probably due to the degradation of the oxidized amine, which avoids the second
SET from taking place; (2) there was no EDA complex formation observed between
tetrachlorophthalimide and N-Boc-pyrrolidine; nor (3) between 2b and 3b (see Scheme
S10); and (4) no concentration dependency of absorption spectrum of 2b was
observed (see Scheme S10) which excludes the possibility of intramolecular SET.
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Cl
Cl
2b'
(
)
Reaction conditions
Yield of 3b'
NTClPhth
O
O
Cl
Cl
PCn+1
or
N
Cbz
N
Cbz
O N
catalytic
EDA complex
q-OAc (10 mol%)
 = 455 nm
(0%)
72%
N
Cbz
O
SET
PCn
2b'
Control
reaction
(49%)
0%
 = 455 nm
no
turnover
*
PCn
2b'
h
Reaction
conditions
metal-based
photocatalyst
Ru(bpy)3Cl2 (1 mol%)
(78%)
(71%)
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0%
0%
 = 455 nm
NTClPhth
N
N
organo-
photocatalyst
Cl
Eosin Y (5 mol%)
 = 525 nm
O
N
Cbz
Cl
Cl
Cbz
EDA
N
stoichometric
EDA complex
complex
Et3N (1 equiv.)
 = 455 nm
N
(0%)
23%
h
O
Cbz
Cl
2b'
no
turnover
3b'
DMF, 17 - 20 h, 25 °C
N
Scheme 3: Comparison of the method described in this work using q-OAc vs the use
of other photocatalysts or stoichiometric EDA complex conditions in the synthesis of
compound 3b’ from substrate 2b’. Isolated yields given. Yields of recovered starting
material 2b’ are given in parenthesis.
These results are in agreement with the hypothesized behavior of q-OAc in its role as
reversible SET catalyst. We envisioned that the formation of the EDA complex 2b/q-
OAc and light irradiation of this complex would result in SET from the catalyst (q-OAc)
to the tetrachlorophthalimide moiety. Decarboxylation to form the corresponding α-
amino radical intermediate would be followed by its oxidation with q-OAc+•,
regenerating the initial q-OAc in this process, to presumably form an iminium ion that
would be trapped by the previously liberated tetrachlorophthalimide anion, delivering
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the observed product 3b (Scheme 4a). The quantum yield of this reaction was found
to be 0.02 (See Supporting Information), suggesting that propagative pathways can
be ruled out of the mechanism. We believe that the close proximity of the generated
q-OAc+• to the α-amino radical species after SET promotes a fast back SET and avoids
any HAT pathway from being productive. The formation of this α-amino radical
intermediate was proved when the reaction was run in the presence of 2 equiv. of
TEMPO as radical trapping agent. Starting material 2b was recovered in 66% yield
and product 3b was observed only in trace amounts. The product formed as
consequence of TEMPO trapping the α-amino radical (m/z = 327 [M+H+]) was
observed by mass-spectrometry (MS) (see Scheme S5).
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a) Proposed mechanism for the use of q-OAc as reversible SET catalyst
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Cl
Cl
O
O
O
O
Boc
2b
EDA
Cl
Cl
Cl
Cl
N
N
N
N
Boc O
3b
O
Cl
Cl
OAc
via
=
D
N
complex
SET
SET
OAc
h
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N
N
Boc
NTClPhth
CO2
Cl
Cl
O
O
Cl
Cl
N
O
N
Boc
N
Boc
O
b) Proposed mechanism for the use of q-OAc as SET/HAT catalyst
Cl
Cl
Cl
O
O
OAc
O
=
D
N
O
N
HN
- H+
Cl
Boc
2k
O
O
EDA
complex
OAc
SET
CO2
NTClPhth
H
N
h
H
Boc NH
3k
HAT
HAT
DMF
OAc
H
H
cis
Boc
5-exo-trig
Boc
DMF
O
N
O
N
N
H
H
Scheme 4. Mechanistic proposal.
A variety of tetrachlorophthalimide esters derived form α-amino acids (2b to 2f) as
well as α-hydroxy acid derivatives (2g to 2j) were synthesized and submitted to the
optimized catalytic conditions. In order to achieve full conversion of the starting
material in all cases, irradiation times were established to be 17 to 20 h. Cyclic and
acyclic amines and ethers gave stable aminals (3b – 3f) and hemiaminals (3g – 3j,
through the corresponding oxonium ion) in yields up to 89% yield using only 10 mol%
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of q-OAc. Olefinic double bonds in 3c, 3e and 3h were tolerated as well as the NH
group of products 3d and 3f. Interestingly, product 3d bearing a sensitive sulfinyl group
was obtained in a 76% yield. Aromatic ethers with substituents in meta- and para-
positions 3i and 3j were obtained in 78% and 70% respectively, with special interest
in 3j due to the formation of a quaternary hemiaminal center (Scheme 5).
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2.3. Cyclization reaction
Intrigued by the high efficiency of these reaction conditions, we wondered whether we
could tune the outcome of this reaction by selecting the molecular structure of the
starting material. As observed in examples 3c and 3h, products derived from the
corresponding 6-exo-trig or 7-exo-trig cyclization were not observed. However, the
irradiation of the tetrachlorophthalimide derivative of O-allyl-N-Boc-serine (2k) in the
presence of an optimized 25 mol% of q-OAc (see Scheme S3 for optimization
conditions) induced the 5-exo-trig cyclization to form the tetrahydrofuran derivative 3k
in 59% yield. The use of other photocatalysts as Eosin Y failed to give the product
(See Scheme S9). Importantly, control reactions in the absence of light or q-OAc gave
no product formation and led to recovery of 2k, highlighting the essential role of the q-
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OAc in the formation of the EDA complex for this reaction to proceed under blue LEDs.
Two-dimensional NMR analysis revealed the formation of a 4:1 diasteromeric cis:trans
mixture (See Supporting Information). According to the proposed mechanism, radical
cyclization would be followed by the oxidation of the primary radical to the primary
carbocation (from the q-OAc+•), which is a highly energetically uphill process, and
proton elimination to form a double bond. However, this behavior was not observed.
In order to better understand the mechanism we attempted to use DMF-d7 as solvent
which resulted in the formation of 3k in trace amounts and degradation of the starting
material 2k (See Scheme S7). These results suggest that DMF has a crucial role in
this cyclization, probably as a terminal hydrogen atom transfer (HAT) species (Scheme
4b), which is precedented in the literature32,33 (See Supporting Information for more
details). This is in agreement with the absence of product formation when the reaction
was performed in MeCN (see Scheme S3). Comparing bond dissociation energies
(BDE) of a primary alkyl radical (BDE [C1-H in propane] = 100 kcal/mol34) and DMF
(BDE [H-CH2N(Me)CHO or Me2NC(O)-H] = 89 – 90 kcal/mol32), HAT is feasible.
Furthermore, the submission of esters 2l and 2m to the reaction conditions resulted in
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the isolation of product 3l in slightly lower yield (49%), and detection of product 3m
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only in traces (Scheme 5).
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Cl
Cl
Cl
aminodecarboxylation
intramolecular cyclization
hydrodecarboxylation
dimerization
 = 455 nm
q-OAc (10 or 25 mol%)
O
OAc
O
O
D
=
N
N
OH
O
DMF
17 - 20 h, 25 °C
q-OAc
Cl
O
NTClPhth
2
accessible
catalyst
-CO2
abundant
source
activated
substrate
tuneable outcome
O
MeS
Cbz
Ph
PG
N
O
NTClPhth
O
NTClPhth
N
NTClPhth
N
PG
NTClPhth
NTClPhth
R
OH
N
Boc
Me
NH
NH
Boc
Boc
R'
3b
Boc (89%)
Cbz (72%)
 -amino acidsa
3f
3c
3d
3e
(53%)
(89%)
(42%:25%, cis:trans)
(76%)
3b'
O
R
O
NTClPhth
Ph
O
O
O
O
OH
Boc
O
NTClPhth
(30%)
R
OH
Me
Me
HN
O
R' R''
NH
NH
Boc
Boc
R'
 -hydroxy acidsa
3g
3h
(66%)
c
d
O-allyl- -amino acidsb
(59%, 4:1 dr)
(49%, 2:1 dr)
3k
3l
NTClPhth
Me
Me
O
O
O
Cl
O
NTClPhth
Me
O
Me
Me
*
Me
Me
Me
Cl
NH
Boc
NH
NH
Boc
Boc
Me
e
f
3i
3j
(78%)
(70%)
3m
3n
(51%, 9:1 dr)
3o
(traces)
(42%)
O
O
Ph
Ph
Me
R
Me
Ph
OH
Ph
Ph
Ph
H
OH
Ph
Ph
N
( )n
Ph
H
Me
PG
R
Ph
3s
Ph
N
Cbz
N
Cbz
phenylacetic acidsb
j
3a
4s
(67%, 1:1 dr)
(24%) +
(18%)
N-alkyl
g
h
3p
4p
(35%)
 -amino acidsb
(15%, > 9:1 dr)
Me
+
O
Me
Ph
H
O
H
N
Ph
N
N
R
N
N
OH
Cbz
Cbz
PG
Ph
H
O
Cbz
R'
Me
alkyl acidsb
3t
Ts (75%)
i
3r
4r
(23%)
(41%) +
3q
(26%, > 9:1 dr)
3v
3w
(62%)
(67%)
3u
Cbz (62%)
Scheme 5. Products isolated from the photocatalytic reaction. a 10 mol% of q-OAc was
used. b 25 mol% of q-OAc was used. c 8% of product 4k was also isolated. d Isolated
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e
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as an inseparable 88:12 mixture of 3l and 4l. Not isolated. 8% of product 4o was
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g
h
also isolated. 14% of product 5p was also isolated. Only the trans-configurated
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i
j
product was observed. 25% of an unidentified product was also isolated. 3% of
product 4a was also isolated. *Indicates the center to which the dr refers to. NTClPhth:
tetrachlorophthalimide moiety. PG: protecting group. For cyclic voltammograms (CVs)
and UV-visible spectra of compounds 2 see Supporting Information.
Direct comparison of the BDEs of the bonds involved in the process could explain
these results. The BDE of a C-H bond decreases with the higher substitution of the
carbon center, meaning that the strength of the C-H bond decreases in the same order:
RH2C-H > R2HC-H > R3C-H.34 In consequence, for the formation of product 3m the
reaction might not have a thermodynamically favorable HAT from DMF, giving no
product formation (See Scheme S7). On the other hand, turnover of the catalyst must
occur in a different way than indicated for the formation of aminals and hemiaminals
3b to 3j. Using the same reasoning, we can presume that HAT is also feasible from
DMF to q-OAc+• (BDE [q-OAc+-H] = 95-100 kcal/mol35) (Scheme 4b). Other
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tetrahydrofuran derivatives were synthetized, as 3n with three consecutive
stereocenters and an excellent 9:1 dr isolated in 51% yield, and product 3o with a
newly formed quaternary carbon atom obtained in 42% yield (Scheme 5).
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Further examples using N-alkylated leucine, phenylalanine, or glycine derivatives
with unsaturation at different distances from the formed radical were tested (Scheme
5). Cyclization in order to give the corresponding pyrrolidine 3q was observed from the
N-(3-butenyl) derivative of phenylalanine 2q. In the case of the leucine derivative 2p,
pyrrolidine 3p was isolated in 15% yield and with an excellent dr (>9:1) together with
the stable enamide 4p as major product (35%), presumably from overoxidation of the
formed radical, and some aminodecarboxylation product (5p, 14% yield, see
Supporting Information). Interestingly, the submission of the N-(4-butenyl) derivative
of glycine 2r to the optimized reaction conditions resulted in the formation of products
3r and 4r as the only observed products with yields of 41% and 23%, respectively.
This result is in contrast with the observed behavior of the formed radical in the case
of product 3h, where products derived from the cyclization were not observed.
Oxidation of the radical formed from 2h after SET and decarboxylation under these
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reaction conditions might be consequently faster than cyclization, giving 3h as single
product instead of products derived from 6-exo-trig or 7-endo-trig cyclization as
observed for 3r and 4r respectively. In addition, the analogue ester of 2r with an oxygen
instead of a nitrogen atom at the α-position of the formed radical gave 54% of the initial
acid (ester 2z, Supporting Information) with no decarboxylation observed. These
results suggest that both factors, the substituents (N or O) and the substitution of the
esters (primary or secondary), affect to the outcome of the reaction.
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2.4. Dimerization and hydrodecarboxylation reactions
As expected, when the tetrachlorophthalimide ester of phenylacetic acid 2a was
exposed to blue LEDs in the presence of 25 mol% of q-OAc in DMF, dimerization of
the benzylic radical was observed to form 3a in a 67% yield with a 1:1 dr, a behavior
that was also observed when the diphenylacetic acid derivative 2s was submitted to
the same reaction conditions. In the latter case, not only the dimerized product 3s was
observed in 24%, but also alkene 4s was isolated as orange needles in 18% yield
(Scheme 5).
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When purely alkyl radicals were formed in the reaction, hydrodecarboxylation
products 3t to 3w were isolated in good yields ranging 62% to 75% yield (Scheme 5)
under the optimized conditions (See Scheme S4). Replacing q-OAc by Ru(bpy)3Cl2 or
Eosin Y resulted in no product formation (See Scheme S9), highlighting the
importance of q-OAc in this reaction. Interestingly, the q-OAc tolerated the presence
of the pendant tetrahydrophthalimide (THPhth) group in product 3w, which was
obtained in 62% yield. A formation of an EDA complex between the q-OAc and this
pendant THPhth group, stronger than between the q-OAc and the active
tetrachlorophthalimide moiety, could have resulted in trapping and inactivation of the
catalyst. A control reaction in the absence of q-OAc gave no product formation.
Remarkably, this method proved to be very selective for hydrodecarboxylation of di-
substituted acids, as mono- or tri-substituted acids were unreactive (See Scheme S8).
Mechanistically, the formation of these products would occur in a similar fashion as for
compounds 3k to 3o, from decarboxylation after SET in the EDA complex to give the
corresponding secondary radical, followed by HAT presumably from DMF to deliver
the final product.
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3. CONCLUSIONS
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In summary, we have shown the potential of q-OAc as electron donor catalyst in EDA
complex-mediated reactions. Furthermore, we have demonstrated a new mode of
action of q-OAc as reversible SET catalyst. It was found that q-OAc can be
regenerated, in contrast to most traditional chemistry where the overall reaction
consumes the DA pair. Using the tetrachlorophthalimide moiety to activate a great
variety of acids and q-OAc in catalytic amounts (10 to 25 mol%) we have proved the
versatility of these unique reaction conditions. By precise selection of the nature of the
formed radical we have been able to achieve amino- and hydro-decarboxylation
reactions as well as cyclizations and dimerizations in yields up to 89%. Control
reactions have shown the necessity of light and catalytic amounts of the ED catalyst
q-OAc for the reaction to be effective. Interestingly, no incorporation of the q-OAc
catalyst to any product was detected or derivatives of the catalyst in any of the
experiments. Further investigations on the stability and versatility of q-OAc as well as
other derivatives will be performed.
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ASSOCIATED CONTENT
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Supporting Information. Experimental procedures, full characterization of all
synthesized compounds, cyclic voltammetry experiments of the starting materials and
additional experiments explained in Scheme S1 to S13 are included.
AUTHOR INFORMATION
Corresponding Author
*Email: irene.bosque@ua.es. †Present Address: Institute of Electrochemistry and
Institute of Organic Synthesis, University of Alicante, Carretera San Vicente del
Raspeig s/n, 03690, San Vicente del Raspeig, Alicante, Spain.
Author Contributions
I.B. performed the experiments. The manuscript was written through contributions of
all authors. All authors have given approval to the final version of the manuscript.
ACKNOWLEDGMENT
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I.B. gratefully thanks the Alexander von Humboldt Foundation for a postdoctoral
fellowship. The Spanish Ministerio de Economía y Competitividad (No. CTQ2017-
88171-P) is acknowledged. The authors would like to thank Michael Grübel for
assistance in the CV measurements and Jose Carlos Gonzalez-Gomez for helpful
discussions.
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