Decarboxylative Giese-Type Reaction of Carboxylic Acids Promoted by Visible Light: A Sustainable and Photoredox-Neutral Protocol

Article abstract of DOI:10.1002/ejoc.201601478

We describe herein a transition-metal-free method for the decarboxylative generation of radicals from carboxylic acids and their 1,4-addition to Michael acceptors. The Fukuzumi catalyst (9-mesitylene-10-methylacridinium perchlorate, [Acr-Mes]ClO₄) enabled this transformation under visible-light irradiation at room temperature with CO₂ as the only byproduct. The scope and limitations of this protocol were examined by using a range of Michael acceptors (15 examples) and carboxylic acids (18 examples). The use of 3-hydroxypivalic acid in this protocol allowed the straightforward formation of a diastereomerically pure δ-lactone. Moreover, when a homoallylic acid was used, a radical cascade reaction took place with the formation of three C–C bonds.

Full text of DOI:10.1002/ejoc.201601478

A Journal of
Accepted Article
Title: Decarboxylative Giese-type reaction of carboxylic acids promoted
by visible-light: a sustainable and photoredox neutral protocol.
Authors: Jose Carlos Gonzalez-Gomez and Nieves P. Ramirez
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
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to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
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content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201601478
Link to VoR: http://dx.doi.org/10.1002/ejoc.201601478
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10.1002/ejoc.201601478
European Journal of Organic Chemistry
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Decarboxylative Giese-type reaction of carboxylic acids
promoted by visible-light: a sustainable and photoredox neutral
protocol.
Nieves P. Ramirez,[a] and Jose C. Gonzalez-Gomez*[a]
Dedication ((optional))
Abstract: This work describes a transition-metal free method for
decarboxylative generation of radicals from carboxylic acids and their
1,4-addition to Michael acceptors. The Fukuzumi catalyst ([Acr+-Mes])
enabled this transformation under visible light irradiation, at room
temperature and with CO2 as the only byproduct. Scope and
limitations of this protocol were examined using a range of Michael
acceptors (15 examples) and a diverse array of carboxylic acids (18
examples). The use of 3-hydroxypivalic acid in this protocol allowed
the straighforward formation of a diastereomerically pure -lactone.
Moreover, when a homoallylic acid was used, a radical cascade took
place with the formation of three C-C bonds.
Very recently, visible-light-promoted photoredox catalysis has
emerged as a powerful and sustainable tool for the generation of
radicals from carboxylic acids at room temperature.6 Interestingly,
if a photoexcited catalyst is oxidant enough to remove an electron
from a carboxylate anion [E(RCOO•/RCOO‾)  +1.1 to +1.5 V vs
SCE],7 after rapid decarboxylation of aliphatic acyloxy radicals,8
this radical can be added to electron-poor alkenes and the new -
acyl radical could be reduced [E(R•/R‾)  −0.7 to -0.6 V vs SCE]9
and protonated. In this last step, the 1,4-adduct is delivered, while
regenerating the photocatalyst and also the base (Scheme 1a).
Since the process is redox-neutral, stoichiometric amounts of
chemicals and wastes (except CO2) are avoided, being a valuable
strategy to increase molecular complexity within the principles of
“Green-Chemistry”.10 This strategy was first put into practice by
Yoshimi’s group, using 10 mol % of 1,4-dicyanonaphthalene and
phenanthrene as a catalytic system, but still using UV light and
very dilute conditions.11 Almost at the same time, Nishibayashi
and coworkers found an iridium photocatalyst [Ir(ppy)2bpy]+
competent for the visible-light-promoted decarboxylative addition
of arylacetic acids to Michael acceptors.12 Soon after, fine tuning
of the iridium photocatalyst structure and reaction conditions
Introduction
The addition of radicals to ,β-unsaturated carbonyl compounds
takes place selectively at the  position without any 1,2-addition.
This selectivity in the formation of a C-C bond was first discovered
by Giese and has found several applications in organic
synthesis.1 The reaction is very efficient when alkyl radicals (high-
lying SOMO) are added to electron-deficient olefins (low-lying
LUMO), becoming a good alternative to the Michael reaction.2
This strategy benefits from some issues associated to radical
processes, such as: (a) carbonyl, hydroxyl and free amino groups
are generally tolerated; (b) since free-radicals are neutral species,
they are poorly solvated and tertiary radicals can be used to
generate quaternary centers.
Carboxylic acids have gathered much attention as radical sources
since they are abundant, non-toxic and renewable feedstocks,
which make them ideal starting materials in organic synthesis.3
Moreover, radicals are produced upon decarboxylation and the
elimination of CO2, as a traceless by-product, does not impact on
their reactivity. Decarboxylative radical generation dated back to
the classical works of Kolbe, Hunsdiecker and Barton, among
others.4 In the last two decades, the use of transition-metal
catalysts has expanded the scope of this strategy, but still high
allowed to MacMillan’s group to find
a protocol for this
transformation amenable to a wide range of carboxylic acids and
electron-deficient olefins.13 Very recently, iridium-based
photocatalysts have also been successful in the decarboxylative
Giese-type reaction of -aminoacids.14 Given the low abundance
of iridium in earth, iridium catalysts are expensive. Consequently,
cheaper and more sustainable catalysts are desired for this
transformation. In this context, the group of Koike and Akita has
reported that organic [Acr-Mes]ClO4 (Fukuzumi catalyst)15 is also
a competent photocatalyst in this neutral photoredox process.
However, only four acids were examined with the same Michael
acceptor and the efficiency of the reaction was rather low for
secondary acids (Scheme 1b).16 Encouraged by these results, we
decided to reexamine the reaction conditions in order to improve
the applicability of this organic photoredox catalyst in the
decarboxylative alkylation of carboxylic acids.17
temperatures are required and only scarce examples of Csp3
-
CO2H decarboxylation were reported for cross-coupling
reactions.5
Results and Discussion
Giving the strong oxidant capacity of the Fukuzumi catalyst,15 it is
not surprising that carboxylic acids, or more efficiently the
corresponding carboxylates, can act as reductive quenchers of
this photocatalyst. Following the general mechanism for
decarboxylative alkylation depicted in Scheme 1a, the turnover of
[Acr+-Mes] is proposed to occur by ET from the [Acr•-Mes] to the
[a]
Departamento de Química Orgánica, Facultad de Ciencias and
Instituto de Síntesis Orgánica (ISO), Universidad de Alicante, Apdo.
99, 03080 Alicante, Spain.
E-mail: josecarlos.gonzalez@ua.es.
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201601478
European Journal of Organic Chemistry
FULL PAPER
-acyl radical. Since the acridinyl radical is a fairly weak reductant
[E1/2 (PC+/PC•)= -0.57 V vs SCE],15 it was not clear at the outset
of this work that a range of -substituted alkyl radicals could
efficiently regenerate the photocatalyst. For example, according
to the reported reduction potential of CH3CH•−CO2Me (E1/2 = -0.66
V vs SCE),9 the reaction with the acridinyl radical would operate
against a moderate potential gradient (about 100 mV). We
furnished the expected products (3ah-3am) in very good isolated
yields after reasonable reaction times (12 – 36 h). Vinylsulfone 2n
was also a suitable substrate under the reaction conditions to
obtain 3an in good yield and, more importantly, compound 3ao
was obtained in very good yield after only 14
h when
crotonaldehyde (2o) was used as acceptor. On the contrary,
sterically demanding acceptor 2p failed to add the bulky
adamantane moiety. In addition, substrates substituted at -
position by a single ester group (2q, 2r and 2s) also failed to react,
probably because the -acyl radical is unable to reoxidize [Acr•-
Mes]. Moreover, (E)-chalcone (2t) failed to give any product under
the same reaction conditions, likely due to the competitive
generation of a stable benzylic radical that is not capable to
recycle the catalyst.
reasoned that
a final fast and thermodynamically favor
protonation would compensate this issue for some acceptors.
Scheme 1. (a) Plausible mechanism for a photoredox neutral decarboxylative
Giese-type reaction catalyzed by [Acr+-Mes] and base. (b) Previous work.
With the precedents above mentioned, we decided to screen
different Michael acceptors with adamantane-1-carboxylic acid
(1a). The results of this study are shown in Scheme 2. It is worth
mentioning that due to the steric bulkiness of adamantane, radical
chemistry is very convenient for its derivatization and this moiety
has been quintessential for the development of new drugs and
catalysts.18. With apparently minor modifications from Akita’s
conditions (Scheme 1b), we [0.2 equiv of Na2CO3, under air
atmosphere and using one bulb of 12 x 1 W blue leds and 0.3 M
of 2] were able to isolate compound 3aa in similar excellent yields
but in a significant shorter time (19 h vs 60 h). Importantly, careful
deoxygenation and the use of inert atmosphere were not
necessary to achieve this goal, simplifying this procedure even
more. Under these conditions, other double activated Michael
acceptors gave the corresponding products (3ab-3ae) in very
good yields after only 15 to 21 h of irradiation. Notably, 4-
chromenone (2f) and butyl methacrylate (2g) afforded
compounds 3af and 3ag in good yields, although longer reaction
times were necessary. Apparently, the push-pull effect in 4-
chromenone and the increased stability of the -Me--acyl radical
(or its higher nucleophilicity) with methacrylate acceptor, had a
positive impact on the reactivity. We were pleased to find that
acyclic (2h2k) and cyclic (2l, 2m) ,-unsaturated ketones
Scheme 2 Scope of electron-deficient alkenes. aIsolated pure product. b1.7:1
MeOH/EtOAc (0.185 M) was used as solvent mixture to improve the solubility
of substrates. c3 equiv of volatile MVK were used.
Regarding the carboxylic acid partners, it was reported that the
reaction of secondary substrates examined (1e and 1f) under the
conditions disclosed by Koike and Akita never went to completion
(Scheme 1b).16 Consequently, we decided to examine this issue
in more detail using cyclohexane carboxylic acid (1e) and diethyl
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10.1002/ejoc.201601478
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2-ethylidene malonate (2a) as acceptor in a model reaction. The
results of this study are summarized in Table 1.
LED bulbs, but the yield of the reaction was similar (entry 13 vs
1).20 Control experiments revealed that the reaction absolutely
requires the photocatalyst (entry 20). In addition, while full
conversion is achieved after only 10 h using 5 mol % of catalyst
(entry 18), similar results are obtained with 2.5 mol % after 17 h
and the reaction is significantly slower when the load of
photocatalyst is reduced even further (entry 19). It was also found
that the reaction progress poorly without base (entry 23). The use
of 20 mol % of Cs2CO3 leads to similar results than with Na2CO3,
while lower yields were achieved with DBU (entries 21 and 22).
Table 1. Optimization of reaction conditions.
Entry
1
2
3
4
5
6
7
8
Modification from standard conditions
none
Yield (%)a
92
77
0
in MeOH (0.3 M)
in CF3CH2OH (0.3 M)
in t-BuOH (0.3 M)
in [CH2Cl]2/MeOH (2:1)
in Me2CO/H2O (2:1)
in MeCN/H2O (1:1)
12
72
32
20
50
59
71
57
58
89
77
70b
0
in MeCN/H2O (3:1)
9
under argon atmosphere
under oxygen atmosphere (1 atm)
1e (1 equiv) : 2a (1 equiv)
1e (1 equiv) : 2a (1.5 equiv)
blue LED 2 bulbs (12 W)
white LED bulb (13.5 W)
Sunlight (10 h)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
CFL light bulb (18 W)
in the dark
0
5 mol % of photocatalyst (10 h)
1 mol % photocatalyst
without photocatalyst
with 20 mol % of Cs2CO3
with 20 mol % of DBU
without base
100
25
0
90
55
23
[a] aYield determined by GC using adamantane as internal standard. [b] See SI
for details. DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene.
After some experimentation, we have found that the solvent
system has a significant impact on the reaction (entries 1-9),
obtaining the best results in 2:1 MeCN/H2O and observing some
competitive Michael addition of MeOH when it is used as solvent.
To our delight, when the reaction was run under air atmosphere,
it was completed after only 17 h (entry 1). Surprisingly, an argon
atmosphere (entry 9) had an even more deleterious effect on the
yield than an oxygen atmosphere (entry 10).19 Regarding the
stoichiometry, a slight excess of acid (1.5 equiv.) was found
beneficial (entries 1, 11 and 12) and it was also helpful to work
under concentrated conditions (0.2 − 0.3 M). It was clearly
demonstrated that the reaction progress depends highly on the
source of light (entries 1, 13-17), obtaining optimal results with
intense blue LEDs (12 x 1W). This could also explain the
difference in the reaction rate observed under Akita’s conditions
(3W blue LEDs, Scheme 1b) and ours. Since it has been recently
reported that the reductive quenching of [Acr+-Mes]* by
carboxylates has low efficiency, we examined the use of two blue
Scheme 3. Scope of acids. aIsolated pure product. b2 equivalents of acid 1 were
d
used. cAnother portion of photocatalyst (2.5 mol %) was added after 48 h.
Another portion of acid 1 (1.5 equiv.) was added after 48 h. eSee SI for details.
Having found these new optimized conditions, we examined the
scope of acids with this protocol, using acceptor 2a (Scheme 3).
Tertiary carboxylic acids, including natural clofibric acid (1d),
participate efficiently in the reaction (products 3ba-3da) to
generate quaternary centers. Secondary cyclic and acyclic acids
were also suitable substrates with this protocol (1e-1k). Notably,
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10.1002/ejoc.201601478
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secondary -oxyacids 1h and 1i furnished the corresponding
conjugate adducts (3ha and 3ia) in good to excellent yields. Since
ethers are formed, this protocol represents a good alternative to
the classic Williamson ether synthesis. In addition, natural N-Boc
protected secondary -aminoacids provide the corresponding -
alkylamines (3ja and 3ka) in synthetically useful yields. Primary
-amino (from glycine derivative 1l) and -oxyacids (from
phenoxyacetic derivatives 1m and 1n) are also suitable
substrates. This procedure allowed the formation of aminomethyl
derivative 3la and aryloximethyl derivative 3ma and 3na in good
to excellent yields. Importantly, for phenoxyacetic derivatives,
electron-donating groups in the aromatic ring accelerate the
reaction (1m vs 1n). Remarkably, -ketoacids were well tolerated,
not only aromatic 2-oxophenylacetic acid (1o), but also the
aliphatic 2-oxoethyl acetic acid (1p), gave the corresponding
products (3oa and 3pa) in reasonable good yields. This method
to build 1,4-dicarbonyl compounds is complementary to the
classic Stetter reaction.21 Very recently, the visible-light mediated
decarboxylative 1,4-addition of a range of aromatic -ketoacids to
different Michael acceptors was successfully accomplished using
an iridium photocatalyst.22 Although our protocol furnished
compound 3pa in a moderate yield, we have not found in the
literature other examples for the decarboxylative coupling of
aliphatic -ketoacids with Michael acceptors. It is worth
mentioning that (S)-lactic acid (1q) failed in this protocol, most
likely due to formation of acetaldehyde after oxidative
decarboxylation. Electron-poor phenoxyacetic derivatives (such
as 1r), as well as common primary aliphatic acids (1s) and
arylacetic acids (e.g. 1t) failed to provide the conjugate adduct in
synthetically useful yields.23
In contrast, high content of deuterium was observed for the
product when D2O was used as co-solvent. This result is in
accordance with a single electron reduction of the -acyl radical
and final deuteration with D2O and, in a minor extend, protonation
with the in-situ formed small amount of H2O to regenerate the
base (Scheme 1).
Scheme 5. Synthetic applications.
Some synthetic applications accomplished with the developed
protocol are depicted in Scheme 5. When hydroxypivalic acid (1r)
was used under standard conditions, the free hydroxyl group was
well tolerated and after conjugated addition, the lactonization took
Scheme 4. Mechanistic studies
place smoothly to afford compound 3ra as
a
single
To gain insight into the reaction pathway, we confirmed that the
reaction of 1e and 2a was completely inhibited in the presence of
TEMPO (Scheme 4a) and cyclohexyl radical was trapped to form
compound 4 (detected by LC-MS, see SI). Moreover, when the
reaction was conducted in CD3CN/H2O, incorporation of
deuterium was not observed in product 3ea, excluding the
possibility of hydrogen abstraction from the solvent (Scheme 4b).
diastereoisomer (according to 1H- and 13C-NMR). Since poor
diastereoselection was observed for other studied examples, we
think that this should be the result of
a thermodynamic
equilibration by deprotonation-protonation at C3. In addition, when
acid 1q was used in our decarboxylative alkylation protocol with
acceptor 2a, compound 5 was isolated in very good yield, as well
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10.1002/ejoc.201601478
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General procedure A (GPA) for the preparation of adamantane
derivatives (Scheme 3): In a microwave tube, equipped with a stirring bar,
were introduced adamantane-1-carboxylic acid (1a, 99 mg, 0.55 mmol,
1.10 equiv.), Na2CO3 (4.06 mg, 0.10 mmol, 20 mol %) and [Acr-Mes]ClO4
(5.2 mg, 2.5 mol %), followed by a solution of the desired Michael acceptor
(0.50 mmol) in MeOH (1.7 mL). The yellow solution was irradiated using
blue LED’s and stirred at room temperature, without any inert atmosphere,
until complete conversion was observed (monitored by TLC and/or GC).
The reaction mixture was concentrated under reduced pressure and the
residue was purified by column chromatography.
as minor amounts of disulfide 6 (Scheme 5b). Based on the
radical nature of this process, we presume that after
decarboxylation, -fragmentation takes place efficiently to release
isobutene and the aromatic thiyl radical, which is quickly trapped
by acceptor 2a.24 Finally, we took advantage of our protocol to
develop a radical cascade where two molecules of acceptor 2a
are incorporated in the product and three new σ C-C bonds are
formed (Scheme 5c). For this transformation, homoallylic acid 1s
was put into react with acceptor 2a (2.5 equiv.) under standard
conditions, after decarboxylation and radical addition, fast 5-exo-
trig cyclization took place to generate a primary nucleophilic
radical that was trapped by another molecule of Michael acceptor.
Upon formation of the new electrophilic radical, electron transfer
to [Acr•-Mes] could occurs, regenerating the photocatalyst, and
final protonation allowed formation of compound 7 in good yield.
Remarkably, only two diastereoisomers out of four are formed
(GC-MS, 1H, 13C-NMR). It seems reasonable that the
diastereocontrol is achieved in the cyclization step, following a
chairlike transition state akin to the Beckwith stereoelectronic
model.25
Diethyl 2-(1-((3r, 5r, 7r)-adamantan-1-yl)ethyl)malonate (3aa, Scheme
2):13 Prepared according to GPA, after 19 h. It was purified by FC
(Hexane/EtOAc 97:3 to 90:10) and obtained as a colorless oil (128 mg,
0.40 mmol, 80%): TLC Rf 0.12 (Hexane/EtOAc 97:3); IR ν 2908, 2848,
1756, 1727, 1447, 1147, 1032, 733 cm-1; 1H-NMR (300 MHz, CDCl3) δ
4.19 (q, J = 7.1Hz, 2H), 4.18 (q, J = 7.1 Hz, 2H), 3.57 (d, J = 5.2 Hz, 1H),
2.08 (dd, J = 7.4, 5.5 Hz, 1H), 1.97 (br s, 3H), 1.71 - 1.59 (m, 7H), 1.52 (br
s, 5H), 1.28 (t, J = 7.1 Hz, 3H), 1.27 (t, J = 7.1 Hz, 3H), 0.99 (d, J = 7.3 Hz,
3H); 13C-NMR (75 MHz, CDCl3) δ 170.5 (C), 169.9 (C), 61.4 (CH2), 61.0
(CH2), 52.0 (CH), 43.2 (CH), 39.5 (3 × CH2), 37.1 (3 × CH2), 35.3 (C), 28.7
(3 × CH), 14.19 (CH3), 14.15 (CH3), 10.5 (CH3); GC RT 19.896 min; LRMS
(EI) m/z (%) =277 (M+-C2H5O, 4), 276 (8), 136 (11), 135 (100), 93 (10).
(Diethyl 2 - ((3r, 5r, 7r)-adamantan-1-yl(phenyl)methyl)malonate (3ab,
Scheme 2): Prepared according to GPA, after 21 h. It was purified by FC
(Hexane/EtOAc 99:1 to 85:15) and obtained as a pale yellow oil (166 mg,
0.43 mmol, 86%): TLC Rf 0.19 (Hexane/EtOAc 97:3); IR ν 2905, 2847,
1752, 1724, 1257, 729, 684 cm-1; 1H-NMR (300 MHz, CDCl3) δ 7.26 - 7.07
(m, 5H), 4.32 - 4.14 (m, 2H), 4.00 (d, J = 10.8 Hz, 1H), 3.77 - 3.61 (m,
2H),3.34 (d, J = 10.8 Hz, 1H), 1.91 (br s, 3H), 1.66 - 1.46 (m, 12H), 1.30 (t,
J = 7.1 Hz, 3H), 0.78 (t, J = 7.1 Hz, 3H); 13C-NMR (75 MHz, CDCl3) δ 169.7
(C), 168.5 (C), 138.9 (C), 127.3 (2 × CH), 126.6 (3 × CH), 61.8 (CH2), 61.3
(CH2), 56.2 (CH), 53.7 (CH) 40.0 (3 × CH2), 36.8 (3 × CH2), 36.2 (C), 28.7
(3 × CH), 14.1 (CH3), 13.5 (CH3); GC RT 25.638 min; LRMS (EI) m/z (%) =
384 (M+, 2), 136 (11), 135 (100), 93 (6); HRMS (EI) Calcd.for C24H32O4
384.2301, found 384.2302.
Conclusions
In conclusion, we have demonstrated the applicability of visible-
light induced decarboxylative Giese-type reaction, catalysed by
[Acr+-Mes], for a range of substrates. The transformation is redox
neutral and the only residue is CO2. Regarding the acceptor, not
only alkylidene malonates/malonitriles were suitable substrates,
but also -substituted acrylates, conjugated ketones/aldehydes
and conjugated sulfones. The scope of carboxylic acids includes
mainly tertiary and secondary substrates diversely substituted, as
well as -ketoacids and primary -amino and -oxy acids.
Compare to other existing methods, some salient features of this
protocol are: (a) is free of nobel-metal catalysts; (b) only 20 mol %
of cheap Na2CO3 is used; (c) an aqueous solvent mixture is used
and neither deoxygenation nor inert atmosphere is required. We
hope that this work contributes to the transformation of carboxylic
acids renewable feedstocks into pharmaceuticals or fine
chemicals using Green Chemistry.
Diethyl 2-((3r, 5r, 7r)-adamantan-1-yl(4-methoxyphenyl)methyl)-
malonate (3ac, Scheme 2): Prepared according to GPA, after 15 h. It was
purified by FC (Hexane/EtOAc 95:5 to 85:15) and obtained as a white solid
(141 mg, 0.34 mmol, 68%): TLC Rf 0.15 (Hexane/EtOAc 97:3); IR ν 2971,
2888, 2300, 1767, 1716, 1457, 1309, 1194, 1047, 1033, 761 cm-1; 1H-NMR
(300 MHz, CDCl3) δ 7.04 (d, J = 8.1 Hz, 2H), 6.76 (d, J = 8.8 Hz, 2H), 4.31
- 4.13 (m, 2H), 3.96 (d, J = 10.7 Hz, 1H), 3.77 (s, 3H), 3.76 - 3.68 (m, 2H),
3.29 (d, J = 10.7 Hz, 1H), 1.91 (s, 3H), 1.70 - 1.42 (m, 12H), 1.29 (t, J =
7.1 Hz, 3H), 0.84 (t, J = 7.1 Hz, 3H); 13C-NMR (75 MHz, CDCl3) δ 169.8
(C), 168.6 (C), 158.2 (C), 130.9 (C), 112.7 (4 × CH), 61.8 (CH3), 61.2 (CH2),
55.4 (CH2), 55.2 (CH), 53.7 (CH), 40.0 (3 × CH2), 36.9 (3 × CH2), 36.3 (C),
28.7 (3 × CH3), 14.1 (CH3), 13.7 (CH3); GC RT 16.558 min; LRMS (EI) m/z
(%) = 414 (M+, 18), 279 (16), 278 (18), 255 (13), 136 (11), 135 (100);
HRMS (EI) Calcd.for C25H34O5 414.2406, found 414.2414.
Experimental Section
General Remarks: TLCs were performed on silica gel 60 F254, using
aluminium plates and visualized by exposure to ultraviolet light or using
different stains (PMA, KMnO4 or Ninhydrin). Flash chromatographies (FC)
were carried out on handpacked columns of silica gel 60 (230 – 400 mesh).
Infrared (IR) analysis was performed with a spectrophotometer equipped
with an ATR component; wavenumbers are given in cm-1. LRMS were
performed in a mass spectrometer coupled with a gas chromatographer
(GC); the mobile phase was helium (2 mL/min); HP-1 column of 12 m was
used; temperature program starts at 80 ºC for 3 min, then up to 270 ºC
with a rate of 20 ºC/min, and 17.5 min at 270 ºC. HRMS analyses were
carried out using the Electron Impact (EI) mode at 70 eV by Q-TOF. 1 H
NMR spectra were recorded at 300 or 400 MHz for 1H-NMR and 75 or 100
MHz for 13C-NMR, using CDCl3 as solvent and TMS as an internal
standard (0.00 ppm). 13C-NMR spectra were recorded with 1H-decoupling
at 100 MHz and referenced to CDCl3 at 77.16 ppm.
2-((3r, 5r, 7r)-adamantan-1-yl(phenyl)methyl)malononitrile (3ad,
Scheme 2): Prepared according to GPA, after 21 h, but in this case
MeOH/EtOAc (1.7 mL/1 mL) was the solvent mixture to improve the
solubility of benzylidenemalonitrile. It was purified by FC (Hexane/EtOAc
97:3 to 85:15) and obtained as a white solid (93 mg, 0.32 mmol, 64%):
TLC Rf 0.08 (Hexane/EtOAc 97:3); IR ν 2937, 2900, 1713, 1048, 703 cm-
1;1H-NMR (300 MHz, CDCl3) δ 7.38 (s, 5H), 4.25 (d, J = 5.4 Hz, 1H), 2.80
(d, J = 5.4 Hz, 1H), 2.02 (s, 3H), 1.78 - 1.48 (m, 12H); 13C-NMR (75 MHz,
CDCl3) δ 135.4 (CH), 129.8 (C), 128.68 (2 × CH), 128.6 (2 × CH), 113.6
(C), 113.4 (C), 58.1 (CH), 40.5 (3 × CH2), 36.6 (C), 36.4 (3 × CH2), 28.5 (3
× CH3), 23.9 (CH); GC RT 22.913 min; LRMS (EI) m/z (%) = 290 (M+,1),
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10.1002/ejoc.201601478
European Journal of Organic Chemistry
FULL PAPER
136 (11), 135 (100), 93 (10); HRMS (EI) Calcd.for C20H22N2 290.1783,
found 290.1782.
(Hexane/EtOAc 97:3 to 90:10) and obtained as a pale yellow oil (70.2 mg,
0.30 mmoles, 60%, >98:2 dr according to NMR and GC experiments): TLC
Rf 0.22 (Hexane/EtOAc 97:3); IR ν 2908, 2849, 1702, 1442, 1342, 1087,
1048, 871 cm-1; 1H-NMR (400 MHz, CDCl3) δ 2.18 (qd, J = 7.1, 3.4 Hz,
1H), 2.17 (s, 3 H), 1.97 (br s, 3H), 1.73 - 1.47 (m , 12H), 1.32 - 1.23 (m,
1H), 1.13 (d, J = 7.1 Hz, 3H), 0.95 (d, J = 7.4 Hz, 3H); 13C-NMR (101 MHz,
CDCl3) δ 213.9 (C), 48.7 (CH), 46.3 (CH), 40.3 (3 × CH2), 37.3 (3 × CH2),
36.1 (C), 30.1 (CH3), 28.8 (3 × CH), 18.3 (CH3), 10.4 (CH3); GC RT 16.223
min; LRMS (EI) m/z (%) = 216 (M+ - H2O, 11), 136 (11), 135 (100), 93 (10),
79 (10); HRMS (EI) Calcd.for C16H26O 234.1984, found 234.1983.
Ethyl 4-((3r, 5r, 7r)-adamantan-1-yl)-2-oxochroman-3-carboxylate
(3ae, Scheme 2): Prepared according to GPA, after 16 h, but in this case
the solvent mixture was MeOH/EtOAc (1.7 mL/1 mL) to improve the
solubility of ethyl 2-oxo-2H-chromene-3-carboxylate. It was purified by FC
(Hexane/EtOAc 95:5 to 90:10) and obtained as a white solid (124 mg, 0.35
mmol, 70%, >98:2 dr according to 1H-NMR): TLC Rf 0.06 (Hexane/EtOAc
97:3); IR ν 2971, 2888, 2300, 1767, 1716, 1457, 1309, 1194, 1033, 761
cm-1;1H-NMR (300 MHz, CDCl3) δ 7.34 -7.25 (m, 1H), 7.15 - 7.05 (m, 3H),
4.12 - 4.04 (m, 1H), 4.02 (d, J = 1.3 Hz, 1H), 4.00 - 3.91 (m, 1H), 2.96 (d,
J= 0.7 Hz, 1H), 1.98 (br s, 3H), 1.70 - 1.52 (m, 12H), 0.98 (t, J = 7.1 Hz,
3H); 13C-NMR (75 MHz, CDCl3) δ 168.3 (C), 166.2 (C), 151.8 (C), 131.4
(CH), 129.0 (CH), 124.0 (CH), 120.6 (C), 117.0 (CH), 62.3 (CH2), 51.7 (CH),
47.2 (CH), 39.5 (3 × CH2), 36.6 (3 × CH2), 36.2 (C), 28.4 (3 × CH), 13.9
(CH3); GC RT 23.503 min; LRMS (EI) m/z (%) = 282 (M++1-C3H5O2, 4), 281
(M+-C3H5O2, 1), 136 (12), 135 (100), 93 (12), 91 (10), 79 (10); HRMS (EI)
Calcd.for C22H26O4 354.1831, found 354.1812.
4-((3r, 5r, 7r)-adamantan-1-yl)butan-2-one (3aj, Scheme 2):27 Prepared
according to GPA, after 36 h, but in this case the reaction was performed
using 1-adamantanecarboxylic acid (90 mg,0.50 mmol) and methyl vinyl
ketone (125 µl, 1.5 mmol, 3 equiv.). It was purified by FC (Hexane/EtOAc
97:3 to 90:10) and obtained as a colorless oil (83 mg, 0.40 mmol, 80%):
TLC Rf 0.24 (Hexane/EtOAc 97:3); IR ν 2902, 2844, 1713, 1269, 737, 700
cm-1; 1H-NMR (300 MHz, CDCl3) δ 2.44 - 2.31 (m, 2H), 2.15 (s, 3H), 1.95
(br s, 3H), 1.76 - 1.54 (m, 6H), 1.46 - 1.45 (m, 6H), 1.40 - 1.30 (m, 2H); 13
C
-NMR (101 MHz, CDCl3) δ 210.2 (C), 42.3 (3 х CH2), 37.9 (CH2), 37.6
(CH2), 37.2 (3 х CH2), 31.9 (C), 30.0 (CH3), 28.8 (3 х CH); GC RT 15.479
min; LRMS (EI) m/z (%) = 206 (M+, 1), 189 (5), 188 (33), 136 (11), 135
(100), 93 (13), 79 (13).
2-((3r, 5r, 7r)-adamantan-1-yl)chroman-4-one (3af, Scheme 2):26
Prepared according to GPA, after 67 h. It was purified by FC
(Hexane/EtOAc 97:3 to 95:5) and obtained as a colorless oil (105 mg, 0.37
mmol, 74%): TLC Rf 0.27 (Hexane/EtOAc 97:3); IR ν 2908, 2859, 1678,
1601, 1461, 1313, 1229, 1038, 752 cm-1; 1H-NMR (300 MHz, CDCl3) δ
7.86 (dd, J = 8.1, 1.8 Hz, 1H), 7.46 (ddd, J = 8.5, 7.2, 1.8 Hz, 1H), 7.02 -
6.94 (m, 2H), 3.91 (dd, J = 13.6, 3.1 Hz, 1H), 2.67 (qd, J = 16.5, 8.3 Hz,
2H), 2.06 (br s, 3H), 1.94 - 1.40 (m, 12H); 13C-NMR (75 MHz, CDCl3) δ
193.9 (C), 162.4 (C), 135.9 (CH), 127.0 (CH), 121.0 (C + CH), 118.0 (CH),
85.6 (CH), 37.9 (3 × CH2), 37.24 (CH2), 37.17 (3 × CH2), 36.0 (C), 28.3 (3
× CH); GC RT 23.746 min; LRMS (EI) m/z (%) = 283 (M++1, 19), 282 (M+,
94), 281 (M+-1, 15), 147 (50), 136 (11), 135 (100), 121 (12), 120 (10), 93
(14), 92 (10), 91 (12), 79 (12).
3-((3r, 5r, 7r)-adamantan-1-yl)-1-phenylbutan-1-one (3ak, Scheme 2):
Prepared according to GPA, after 17 h. It was purified by FC
(Hexane/EtOAc 97:3 to 85:15) and obtained as a pale yellow oil (90 mg,
0.32 mmol, 64%): TLC Rf 0.44 (Hexane/EtOAc 97:3); IR ν 2898, 2849,
1678, 1442, 1205, 999, 743, 674 cm-1; 1H-NMR (300 MHz, CDCl3) δ 8.05
- 7.88 (m, 2H), 1H), 7.58 - 7.51 (m, 1H), 7.50 - 7.41 (m, 2H), 3.16 (dd, J =
15.4, 2.9 Hz, 1H), 2.57 (dd, J = 15.4, 10.4 Hz, 1H), 2.00 (br s, 3H), 1.89 -
1.78 (m, 1H), 1.76 - 1.59 (m, 6H), 1.57 - 1.56 (m, 6H), 0.83 (d, J = 6.8 Hz,
3H); 13C-NMR (101 MHz, CDCl3) δ 201.7 (C), 137.6 (C), 132.9 (CH), 128.6
(2 х CH), 128.3 (2 х CH), 40.2 (CH2), 39.6 (3 х CH2), 37.4 (3 х CH2) , 34.8
(C + CH), 28.8 (3 х CH), 13.7 (CH3); GC RT 22.617 min; LRMS (EI) m/z
(%) = 282 (M+, 10), 162 (18), 147 (22), 146 (13), 136 (11), 135 (100), 105
(19), 93 (11), 79 (11), 77 (17); HRMS (EI) Calcd. for C20H26O 282.1984,
found 282.1999.
Butyl 3-((3r, 5r, 7r)-adamantan-1-yl)-2-methylpropanoate (3ag,
Scheme 2): Prepared according to GPA, after 70 h. It was purified by FC
(Hexane/EtOAc 97:3 to 95:5)and obtained as a colorless oil (68 mg, 0.25
mmol, 50%): TLC Rf 0.43 (Hexane/EtOAc 97:3); IR ν 2957, 2898, 2846,
1
1727, 1451, 1181, 1121, 1095 cm-1; H-NMR (300 MHz, CDCl3) δ 4.12 -
3.98 (m, 2H), 2.54 (dqd, J = 14.1, 7.1, 3.1 Hz, 1H), 1.92 (brs, 3H), 1.79 -
1.55 (m, 9H), 1.54 - 1.33 (m, 8H), 1.13 (d, J = 7.1 Hz, 3H), 1.01 (dd, J =
14.2, 3.1 Hz, 1H), 0.94 (t, J = 7.3 Hz, 3H); 13C-NMR (75 MHz, CDCl3) δ
178.3 (C), 64.2 (CH2), 48.7 (CH2), 42.4 (3 × CH2), 37.1 (3 × CH2), 34.5
(CH), 32.8 (C), 30.8 (CH2), 28.8 (3 × CH), 20.7 (CH2), 19.3 (CH3), 13.9
(CH3); GC RT 17.869 min; LRMS (EI) m/z (%) = 278 (M+, 5), 143 (12), 136
(12), 135 (100); HRMS (EI) Calcd.for C18H30O2 - C4H9O 204.1514, found
204.1517.
3-((3r, 5r, 7r)-adamantan-1-yl)cyclohexanone (3al, Scheme 2):28
Prepared according to GPA, after 28 h. It was purified by FC
(Hexane/EtOAc 97:3 to 90:10) and obtained as a pale yellow oil (108 mg,
0.46 mmol, 92%): TLC Rf 0.31 (Hexane/EtOAc 97:3); IR ν 2898, 2848,
1701, 1451, 1231, 1058 cm-1; 1H-NMR (300 MHz, CDCl3) δ 2.50 - 2.03 (m,
5H), 1.98 (br s, 4H), 1.74 - 1.59 (m, 6H), 1.52 - 1.51 (m, 6H), 1.41 - 1.19
(m, 3H); 13C-NMR (75 MHz, CDCl3) δ 213.5 (C), 49.8 (CH), 42.2 (CH2),
41.6 (CH2), 39.5 (3 × CH2), 37.3 (3 × CH2), 34.5 (C), 28.7 (3 × CH3), 25.8
(CH2), 24.7 (CH2); GC RT 19.014 min; LRMS (EI) m/z (%) = 232 (M+, 4),
136 (11), 135 (100), 93 (10), 79 (10).
4-((3r, 5r, 7r)-adamantan-1-yl)pentan-2-one (3ah, Scheme 2): Prepared
according to GPA, after 12 h, but in this case the reaction was performed
using 1-adamantanecarboxylic acid (90 mg, 0.50 mmol) and 3-penten-2-
one (103 µL, 0.75 mmol, 1.5 equiv.). It was purified by FC (Hexane/EtOAc
95:5) and obtained as a colorless oil (88 mg, 0.40 mmol, 79%): TLC Rf
0.38 (Hexane/EtOAc 97:3); IR ν 1707, 1255, 723, 703 cm-1; 1H-NMR (400
MHz, CDCl3) δ 2.59 (dd, J = 15.7, 2.6 Hz, 1H), 2.14 (s, 3H), 2.06 (dd, J =
15.7, 10.3 Hz, 3H), 1.97 (br s, 3H), 1.74 - 1.57 (m, 6H), 1.48 (s, 5H), 0.79
(d, J = 6.9 Hz, 3H);13C-NMR (101 MHz, CDCl3) δ 210.2 (C), 45.5 (CH2),
39.4 (3 х CH2), 39.0 (CH3), 37.4 (3 х CH2), 34.4 (C), 30.5 (CH), 28.8 (3 х
CH), 13.7 (CH3); GC RT 16.080 min; LRMS (EI) m/z (%) = 220 (M+, 1), 202
(15), 136 (11), 135 (100), 93 (14), 79 (14); HRMS (EI) Calcd.for C15H24O
220.1827, found 220.1836.
3-((3r, 5r, 7r)-adamantan-1-yl)-2-pentylcyclopentan-1-one (3am,
Scheme 2): Prepared according to GPA, after 23 h. It was purified by FC
(Hexane/EtOAc 98:2 to 95:5) and obtained as a pale-yellow oil (108 mg,
0.375 mmol, 75%, 95:5 dr according GC): TLC Rf 0.32 (Hexane/EtOAc
1
97:3); IR ν 2900, 2846, 1734, 1451, 1168, 753 cm-1; H-NMR (300 MHz,
CDCl3) mixture of diastereoisomers δ 2.48 - 2.04 (m, 3H), 1.98 (brs, 3H),
1.94 - 1.85 (m, 1H), 1.84 - 1.57 (m, 9H), 1.54 - 1.53 (m, 7H), 1.38 - 1.20
(m, 7H), 0.88 (t, J = 6.9 Hz, 3H); 13C-NMR (75 MHz, CDCl3) mixture of
diastereoisomers δ 223.0 (C=O), 220.6 (C=O), 52.8, 51.4, 51.2, 48.6, 41.6,
40.2, 38.2, 37.3, 36.8, 34.9, 34.6, 32.2, 28.8, 28.6, 27.0, 26.3, 26.2, 22.7 ,
22.6, 20.6, 19.8, 14.2; GC RT 24.300 min and 24.515 min (two
diastereoisomers); LRMS (EI) m/z (%) (Diastereoisomer A) = 218 (M+-
C5H11, 31), 136 (11), 135 (100), 93 (16), 83 (28), 82 (98), 79 (16); m/z (%)
(Diastereoisomer B) = 218 (M+ - C5H11, 18), 136 (11), 135 (100), 93 (12),
4-((3r, 5r, 7r)-adamantan-1-yl)-3-methylpentan-2-one (3ai, Scheme 2):
Prepared according to GPA, after 23 h. It was purified by FC
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10.1002/ejoc.201601478
European Journal of Organic Chemistry
FULL PAPER
83 (16), 82 (63), 79 (13); HRMS (EI) Calcd. for C20H32O - C5H10 218.1671,
127 (25), 117 (11), 115 (17), 109 (30), 105 (11), 91 (68), 69 (12); HRMS
found 218.1678.
(EI) Calcd. for C19H28O4 319.1908, found 319.1909.
(3r, 5r, 7r)-1-(2-(phenylsulfonyl)ethyl)adamantane (3an, Scheme 2):29
Prepared according to GPA, after 36 h. It was purified by FC
(Hexane/EtOAc 95:5 to 80:20) and obtained as a white solid (102 mg,
0.335 mmol, 67%): TLC Rf 0.10 (Hexane/EtOAc 97:3); IR ν 1734, 1373,
1237, 1046, 914, 730 cm-1; 1H-NMR (300 MHz, CDCl3) δ 7.97 - 7.96 (m,
2H), 7.70 - 7.63 (m, 1H), 7.61 - 7.54 (m, 2H), 3.06 (d, J = 17.3 Hz, 1H),
3.06 (dd, J = 5.1, 3.8 Hz, 1H), 1.94 (br s, 3H), 1.75 - 1.53 (m, 6H), 1.52 -
1.43 (m, 2H), 1.41 - 1.40 (m, 6H); 13C-NMR (75 MHz, CDCl3) δ 139.3 (C),
133.7 (CH), 129.3 (2 × CH), 128.1 (2 × CH), 51.4 (CH2), 42.0 (3 × CH2),
36.9 (3 × CH2), 36.0 (CH2), 31.9 (C), 28.5 (3 × CH); GC RT 23.559 min;
LRMS (EI) m/z (%) = 136 (M++ 1 - C8H8O2S, 11), 135 (100).
Diethyl 2-(3-(4-chlorophenoxy)-3-methylbutan-2-yl)malonate (3da,
Scheme 3): Prepared according to GPB, after 43 h. It was purified by FC
(Hexane/EtOAc 97:3 to 95:5) and obtained as a colorless oil (107 mg, 0.3
mmol, 60%): TLC Rf 0.29 (9:1 Hexane/EtOAc); IR ν 2986, 1724, 1482,
1375, 1234, 1145, 1094, 1036, 850 cm-1; 1H-NMR (400 MHz, CDCl3) δ
7.26 - 7.14 (m, 2H), 6.98 - 6.84 (m, 2H), 4.24 - 4.16 (m, 2H), 4.12 (q, J =
7.1 Hz, 2H), 3.78 (d, J = 6.8 Hz, 1H), 2.77 (p, J = 7.1 Hz 1H), 1.28 (t, J =
7.2 Hz, 3H), 1.25 (s, 3H), 1.19 (t, J = 7.1 Hz, 3H), 1.19 (s, 3H), 1.12 (d, J
= 7.1 Hz, 3H); 13C-NMR (101 MHz, CDCl3) δ 169.6 (C), 169.3 (C), 153.3
(C), 129.0 (C + 2 × CH), 125.7 (2 × CH), 83.0 (C), 61.4 (CH2), 61.2 (CH2),
53.6 (CH), 43.7 (CH), 25.7 (CH3), 21.9 (CH3), 14.19 (CH3), 14.12 (CH3),
13.2 (CH3); GC RT 20.674 min; LRMS (EI) m/z (%) = 229 (M+ - C6H4ClO,
27), 156 (12), 155 (100), 137 (29), 136 (24), 130 (24), 128 (81), 127 (31),
111 (17), 109 (39), 108 (17), 81 (14), 69 (24), 65 (25); HRMS (EI) Calcd.
for C18H25ClO5 - C6H4ClO 229.1440, found 229.1447.
3-((3r, 5r, 7r)-adamantan-1-yl)butanal (3ao, Scheme 2: Prepared
according to GPA, after 14 h. It was purified by FC (Hexane/EtOAc 97:3 to
90:10) and obtained as a colorless oil (80.340 mg, 0.39 mmol, 78%): TLC
Rf 0.32 (Hexane/EtOAc 97:3); IR ν 2924, 2848, 1723, 1707, 1309, 1208,
967, 733 cm-1; 1H-NMR (300 MHz, CDCl3) δ 9.71 (dd, J = 3.4, 1.3 Hz, 1H),
2.56 (dd, J = 16.2, 3.3 Hz, 1H), 2.09 - 1.99 (m, 1H), 1.99 - 1.90 (m, 4H),
1.72 - 1.75 (m, 6H), 1.46 (s, 6H), 0.83 (dd, J = 6.9, 0.5 Hz, 3H); 13C-NMR
(75 MHz, CDCl3) δ 203.9 (C=O), 45.6 (CH2), 39.4 (3 × CH2), 37.8 (CH),
37.2 (3 × CH2), 34.4 (C), 28.7 (3 × CH), 14.0 (CH3); GC RT 15.605 min;
LRMS (EI) m/z (%) = 206 (M+, 1), 136 (11), 135 (100), 93 (11), 79 (11);
HRMS (EI) Calcd. for C14H22O 206.1671, found 206.1674.
Diethyl 2-(1-cyclohexylethyl)malonate (3ea, Scheme 3):16 Prepared
according to GPB, after 22 h. It was purified by FC (97:3 to 85:15
Hexane/EtOAc) and obtained as a pale yellow oil (97 mg, 0.38 mmol,
76%): TLC Rf 0.16 (Hexane/EtOAc 97:3), stained with KMnO4; IR ν 2977,
1
2926, 2848, 1730, 1451, 1147, 1032 cm-1; H-NMR (300 MHz, CDCl3) δ
4.25 - 4.14 (m, 4H), 3.39 (d, J = 9.2 Hz, 1H), 2.18 (dqd, J = 13.8, 6.9, 4.4
Hz, 1H), 1.82 - 1.49 (m, 6H), 1.27 (t, J = 7.1 Hz, 6H), 1.20 – 0.93 (m, 5H),
0.90 (d, J = 7.0 Hz, 3H); 13C-NMR (75 MHz, CDCl3) δ 169.4 (C), 169.2 (C),
61.3 (CH2), 61.2 (CH2), 55.9 (CH), 40.4 (CH), 38.7 (CH), 31.6 (CH2), 27.5
(CH2), 26.9 (CH2), 26.7 (CH2), 26.6 (CH2), 14.2 (2 × CH3), 13.0 (CH3); GC
RT 15.943 min; LRMS (EI) m/z (%) = 225 (M+ - C2H5O, 13), 187 (48), 161
(91), 160 (100), 141 (26), 133 (39), 132 (11), 115 (39), 114 (10), 110 (10),
109 (19), 90 (10), 87 (18), 81 (16), 69 (24), 67 (11), 55 (16).
General procedure B (GPB) for the decarboxylative addition of
different carboxylic acids to Michael acceptor 2a (Scheme 3): The
method is similar to GPA, but in this case a solution of the desired
carboxylic acid (0.75 mmol, 1.5 equiv.) and diethyl 2-ethylidene malonate
(2a, 92 μL, 0.50 mmol) in MeCN (1.7 mL) were charged in the microwave
tube, followed by H2O (0.85 mL).
Diethyl 2-(3-methylpentan-2-yl)malonate (3fa, Scheme 3):16 Prepared
according to GPB, after 28 h, but using 2 equiv. of volatile (±)-2-
methylbutyric acid (111 µL, 1 mmol). It was purified by FC (Hexane/EtOAc
95:5 to 85:15) and obtained as a pale yellow oil (95 mg, 0.39 mmol, 78%,
51:49 dr according to 1H-NMR): TLC Rf 0.35 (Hexane/EtOAc 97:3), stained
with KMnO4; IR ν 2972, 2939, 2880, 1747, 1725, 1463, 1035, 912, 735 cm-
Diethyl 2-((3, 3-dimethylbutan-2-yl)malonate (3ba, Scheme 3):16
Prepared according to GPB, after 22 h, but in this case 2 equiv. of pivalic
acid were used (1b, 103 mg, 1mmol). It was purified by FC (Hexane/EtOAc
97:3 to 85:15) and obtained as a pale yellow oil (103 mg, 0.42 mmol, 84%):
TLC Rf 0.27 (Hexane/EtOAc 97:3); IR ν 2962, 1757, 1731, 1466, 1370,
1289, 1147, 1024 cm-1; 1H-NMR (300 MHz, CDCl3) δ 4.19 (q, J = 7.1 Hz,
2H), 4.18 (q, J = 7.1 Hz, 2H), 3.52 (d, J = 5.4 Hz, 1H), 2.30 - 2.19 (m, 1H),
1.28 (t, J = 7.1 Hz, 3H), 1.26 (t, J = 7.1 Hz, 3H), 1.01 (d, J = 7.2 Hz, 3H),
0.90 (s, 9H); 13C-NMR (75 MHz, CDCl3) δ 170.3 (C), 169.7 (C), 61.4 (CH2),
61.0 (CH2), 53.5 (CH), 42.7 (CH), 33.7 (C), 27.6 (3 × CH3), 14.14 (CH3),
14.12 (CH3) 12.2 (CH3); GC RT 13.178 min; LRMS (EI) m/z (%) = 229 (M+
- CH3, 16), 199 (41), 189 (21), 188 (39), 173 (10), 160 (15), 155 (44), 143
(24), 142 (89), 147 (10), 127 (10), 116 (10), 115 (100), 114 (15), 109 (10),
99 (18), 87 (29), 86 (14), 85 (16), 69 (23), 57 (20), 55 (10).
1
1; H-NMR (300 MHz, CDCl3) δ 4.19 (q, J = 7.1 Hz, 5H), 3.39 (d, J = 9.4
Hz, 0.48H), 3.31 (d, J = 10.4 Hz, 0.46H), 2.44 - 2.31 (m, 0.47H), 2.25 (dqd,
J = 13.8, 7.0, 4.0 Hz, 0.52H), 1.53 - 1.31 (m, 2H), 1.27 (t, J = 7.1 Hz, 3H),
1.26 (t, J = 7.1 Hz, 3H), 0.95 - 0.86 (m, 6H), 0.82 (d, J = 6.9 Hz, 1.46Hz),
0.79 (d, J = 6.7 Hz, 1.44H); 13C-NMR (101 MHz, CDCl3) δ 169.3 (C),
169.11 (C), 169.09 (C), 169.0 (C), 61.2 (CH2), 61.1 (CH2), 56.9 (CH), 56.1
(CH), 38.8 (CH), 36.9 (CH), 36.5 (CH), 36.2 (CH), 28.1 (CH2), 23.8 (CH3),
17.5 (CH3), 14.2 (3 х CH3), 13.4 (CH3), 12.5 (CH3), 12.1 (CH3), 13.0 (CH3),
11.2 (CH3); GC RT 13.429 min; LRMS (EI) m/z (%) = 199 (M+- C2H5O, 19),
187 (11), 161 (30), 160 (100), 141 (18), 133 (37), 132 (11), 115 (39), 114
(13), 88 (12), 87 (20), 86 (12), 69 (23).
Diethyl 2-(3, 3-dimethyl-4-phenylbutan-2-yl)malonate (3ca, Scheme
4): Prepared according to GPB, after 24 h. It was purified by FC
(Hexane/EtOAc100% Hexane to 97: 3 Hexane) and obtained as a
colorless oil (120 mg, 0.375 mmol, 75%): TLC Rf 0.22 (Hexane/EtOAc
97:3); IR ν 2977, 1754, 1725, 1463, 1289, 1148, 697 cm-1;1H-NMR (300
MHz, CDCl3) δ 7.30 - 7.17 (m, 3H), 7.13 - 7.10 (m, 2H), 4.20 (q, J = 7.1 Hz,
2H), 4.18 (q, J = 7.1 Hz, 2H), 3.65 (d, J = 4.9 Hz, 1H), 2.56 (d, J = 1.6 Hz,
2H), 2.38 (qd, J = 7.2 Hz, 4.9 Hz, 1H), 1.29 (t, J = 7.1 Hz, 3H), 1.25 (t, J =
7.1 Hz, 3H), 1.13 (d, J = 7.2 Hz, 3H), 0.83 (s, 3H), 0.82 (s, 3H); 13C-NMR
(75 MHz, CDCl3) δ 170.2 (C), 169.7 (C), 138.8 (C), 130.9 (2 × CH), 127.8
(2 × CH), 126.1 (CH), 61.6 (CH2), 61.2 (CH2), 53.1 (CH), 45.7 (CH2), 42.0
(CH), 37.5 (C), 24.5 (CH3), 24.1 (CH3), 14.20 (CH3), 14.15 (CH3), 12.04
(CH3); GC RT 19.440 min; LRMS (EI) m/z (%) = 275 (M+ - C2H5, 9), 230
(19), 229 (100), 201 (12), 187 (73), 156 (15), 155 (100), 145 (11), 137 (39),
Diethyl 2-(1-(1-tert-butyl)piperidin-4-yl)ethyl)malonate (3ga, Scheme
3):16 Prepared according to GPB, after 72 h, but in this case another
portion of photocatalyst (5.2 mg, 2.5 mol %) was added after 48 h of
reaction. It was purified by FC (Hexane/EtOAc 97:3 to 85:15) and obtained
as a colorless oil (113 mg, 0.305 mmol, 61%): TLC Rf 0.10 (Hexane/EtOAc
97:3); IR ν 1746, 1720, 1681, 1426, 1364, 1263, 732, 701 cm-1; 1H-NMR
(300 MHz, CDCl3) mixture of rotamers δ 4.21 (q, J = 7.1 Hz, 2H), 4.20 (q,
J = 7.1 Hz, 2H), 3.39 (d, J = 8.6 Hz, 1H), 2.65 - 2.52 (m, 2H), 2.30 - 2.14
(m, 1H), 1.67 - 1.46 (m, 2.42H), 1.45 (s, 9.82H), 1.37 - 1.30 (m, 1H), 1.27
(t, J = 7.1 Hz, 7H), 1.22 - 1.01 (m, 2H), 0.93 (d, J = 7.0 Hz, 3H); 13C-NMR
(75 MHz, CDCl3) mixture of rotamers δ 169.2 (C), 168.8 (C), 154.9 (C),
79.5 (C), 61.4 (CH2), 61.3 (CH2), 55.5 (CH), 44.3 (CH2), 44.0 (CH2), 38.9
(CH), 37.9 (CH), 30.4 (CH2) 28.6 (3 × CH3), 27.1 (CH2) 14.2 (2 × CH3),
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201601478
European Journal of Organic Chemistry
FULL PAPER
13.1 (CH3); LRMS (DIP) m/z (%) = 314 (M+-C4H9, 11), 298 (12), 270 (31),
226 (22), 198 (39), 188 (10), 187 (100), 180 (11), 160 (15), 156 (28), 153
(11), 141 (23), 112 (18), 85 (13), 84 (10), 82 (13), 57 (72), 41 (12).
(CH), 35.8 (CH), 28.3 (CH3), 28.1 (CH3), 15.1 (CH3), 14.2 (CH3), 14.1 (CH3),
11.2 (CH3); LRMS (DIP) m/z (%) = 316 (M+-C7H7, 23), 262 (15), 260 (17),
217 (12), 216 (100), 170 (18), 142 (21), 131 (12), 124 (25), 120 (17), 91
(21), 57 (45).
Diethyl 2-(1-(2,3-dihydrobenzo[b][1,4]dioxin-2-yl)ethyl)malonate (3ha,
Scheme 3): Prepared according to GPB after 15 h. It was purified by FC
(Hexane/EtOAc 95:5 to 85:15) and obtained as a pale yellow oil (139 mg,
0.43 mmol, 86%, 54:46 dr according to 1H-NMR): TLC Rf 0.17
(Hexane/EtOAc); IR ν 2986, 1737, 1594, 1491, 1262, 1175, 743 cm-1; 1H-
NMR (300 MHz, CDCl3) mixture of diastereoisomers δ 6.89 - 6.79 (m, 4H),
4.31 (dd, J = 11.3, 2.1 Hz, 0.55H), 4.27 - 4.13 (m, 6H), 4.08 - 3.93 (m, 1H),
3.84 (d, J = 5.3 Hz, 0.53H), 3.67 (d, J = 8.9 Hz, 0.46H), 2.74 - 2.50 (m, 1H),
1.35 - 1.19 (m, 6H), 1.15 (d, J = 7.0 Hz, 1.65H), 1.15 (d, J = 7.0 Hz, 1.49H);
13C-NMR (75 MHz, CDCl3) mixture of diastereoisomers δ 169.0 (C), 168.5
(C), 168.4 (C), 168.3 (C), 143.7 (C), 143.4 (C), 143.3 (C), 143.0 (C), 121.6
(CH), 121.5 (2 × CH), 121.4 (CH), 117.3 (CH), 117.14 (2 × CH), 117.07
(CH), 74.6 (CH), 73.7 (CH), 66.4 (CH2), 66.2 (CH2), 61.7 (CH2), 61.6 (CH2),
61.5 (CH2), 61.3 (CH2), 54.5 (CH), 52.2 (CH), 34.6 (CH), 34.4 (CH), 14.21
(CH3), 14.18 (CH3), 14.16 (CH3), 14.12 (CH3), 13.1 (CH3), 11.9 (CH3); GC
RT 19.393 and 19.460 min (two diastereoisomers); LRMS (EI) m/z
(Diastereoisomer A) (%) = 322 (M+, 34), 277 (17), 231 (15), 163 (15), 162
(100), 161 (12), 149 (18), 139 (12), 135 (43), 121 (23); m/z
(Diastereoisomer B) (%) = 322 (M+, 32), 277 (18), 231 (10), 163 (15), 162
(100), 161 (15), 149 (18), 139 (15), 135 (45), 121 (26); HRMS (EI):
Calcd.for C17H22O6 – C7H11O4 163.0759, found 163.0761.
Diethyl
2-(1-(1-tert-butoxycarbonyl)pyrrolidin-2-yl)ethyl)malonate
(3ka, Scheme 3):13 Prepared according to GPB, after 72 h. It was purified
by FC (Hexane/EtOAc97:3 to 85:15) and obtained as a pale yellow oil (107
mg, 0.3 mmol, 60%, 82:18 dr according to 1H-NMR):TLC Rf 0.10
(Hexane/EtOAc); IR ν 1726, 1678, 1382, 1264, 1166, 723, 704 cm-1; H-
1
NMR (300 MHz, CDCl3) mixture of diastereoisomers and rotamers δ 4.26
- 4.10 (m, 4H), 4.01 - 3.23 (m, 3H), 3.25 - 2.99 (m, 1H), 2.81 - 2.66 (m,
0.76H), 2.62 - 2.50 (m, 0.17H), 2.09 - 1.61 (m, 4H), 1.47 (s, 9H), 1.31 -
1.22 (m, 6H), 0.94 (d, J = 6.7 Hz, 3H); 13C-NMR (101 MHz, CDCl3) mixture
of diastereoisomers and rotamers δ 169.0 (C), 168.9 (C), 168.8 (C), 155.6
(C), 155.4 (C), 155.3 (C), 80.0 (C), 79.9 (C), 61.4 (CH2), 61.3 (CH2), 60.7
(CH), 60.4 (CH), 55.7 (CH), 54.9 (CH), 54.2 (CH), 48.1 (CH2), 47.7 (CH2),
47.3 (CH2), 47.0 (CH2), 37.2 (CH), 37.0 (CH), 28.6 (CH3), 28.58 (CH3),
28.3 (CH3), 24.3 (CH2), 23.9 (CH2), 23.8 (CH2), 14.22 (CH3), 14.16 (CH3),
13.6 (CH3); LRMS (DIP) m/z (%) = 256 (M+ - C4H9, 10), 212 (26), 197 (16),
170 (18), 142 (11), 141 (19), 115 (17), 114 (100), 70 (89), 57 (47), 41 (12).
Diethyl 2-(1-((tert-butoxycarbonyl)amino)propan-2-yl)malonate (3la,
Scheme 3):13 Prepared according to GPB, after 96 h, but in this case
another portion of photocatalyst (2.5 mol %, 5.2 mg) was added after 48 h
of reaction. It was purified by FC (Hexane/EtOAc 95:5 to 75:25) and
obtained as a pale yellow oil (117 mg, 0.37 mmol, 74%): TLC Rf 0.10
(Hexane/EtOAc); IR ν 2981, 1718, 1518, 1243, 1167, 1039, 784 cm-1; 1H-
NMR (300 MHz, CDCl3) mixture of rotamers δ 4.74 (br s, 0.59H), 4.39 -
4.27 (m, 0.68H), 4.21 (q, J = 7.1 Hz, 2H), 4.20 (q, J = 7.1 Hz, 2H), 3.58 -
3.38 (m, 0.36H), 3.31 (d, J = 7.4 Hz, 1H), 3.19 - 3.17 (m, 1.78H), 2.45 (p,
J = 6.8 Hz, 1H), 1.43 (s, 9H), 1.27 (t, J = 7.1Hz, 6H), 1.02 (d, J = 6.9 Hz,
3H); 13C-NMR (75 MHz, CDCl3) mixture of rotamers δ 168.9 (C), 168.7 (C),
156.1 (C), 79.4 (C), 61.54 (CH2), 61.48 (CH2), 55.2 (CH), 44.4 (CH), 34.2
(CH2), 28.54 (CH3), 28.45 (CH3), 28.4 (CH3), 28.1 (CH3), 15.7 (CH3), 14.22
(CH3), 14.20 (CH3); LRMS (DIP) m/z (%) 244 (M+ - C2H5O, 14), 216 (40),
198 (15), 172 (20), 161 (23), 160 (32), 142 (29), 126 (19), 115 (29), 101
(26), 87 (15), 69 (13), 57 (100), 41 (14).
Diethyl 2-(3-phenoxybutan-2-yl)malonate (3ia, Scheme 3): Prepared
according to GPB, after 44 h. It was purified by FC (Hexane/EtOAc 95:5)
and obtained as a colorless oil (108 mg, 0.35 mmol, 70%, 62:38 dr
according to 1H-NMR): TLC Rf 0.14 (Hexane/EtOAc 97:3); IR ν 1717, 1599,
1
1494, 1265, 1232, 1027, 732, 727, 692 cm-1; H-NMR (300 MHz, CDCl3)
mixture of diastereoisomers δ 7.33 - 7.15 (m, 2H), 6.98 - 6.80 (m, 3H), 4.51
(qd, J = 6.3, 3.0 Hz, 0.35H), 4.40 (dq, J = 12.3, 6.1 Hz, 0.59H), 4.33 - 3.99
(m, 4H), 3.69 (d, J = 6.5 Hz, 0.51H), 3.54 (d, J = 9.2 Hz, 0.31H), 2.69 -
2.58 (m, 0.56H), 2.5 - 2.39 (m, 0.40H), 1.33 - 1.05 (m, 12H); 13C-NMR (75
MHz, CDCl3) mixture of diastereoisomers δ 169.3 (C), 169.00 (C), 168.96
(C), 168.7 (C), 158.1 (C), 157.7 (C), 129.6 (2 × CH), 121.0 (CH), 120.8
(CH), 116.2 (CH), 115.9 (CH), 75.0 (CH), 73.8 (CH), 61.4 (CH2), 61.2 (CH2),
55.2 (CH), 53.7 (CH), 38.82 (CH), 38.78 (CH), 17.0 (CH3), 16.9 (CH3), 14.2
(2 ×CH3), 14.1 (CH3), 13.9 (CH3), 12.9 (CH3), 11.6 (CH3); GC RT 17.695
and 17.796 min (two diastereoisomers); LRMS (EI) m/z (Diastereoisomer
A) (%) =216 (M+ + 1 - C6H5O, 11), 215 (88), 187 (11), 169 (24), 141 (100),
123 (24), 121 (16), 113 (49), 97 (22), 95 (16), 94 (31), 77 (20), 69 (10); m/z
(Diastereoisomer B) (%) = 216 (M++1 - C6H5O, 11), 215 (90), 187 (6), 169
(21), 141 (100), 123 (23), 121 (13) 113 (49), 97 (17), 95 (14), 94 (27), 77
(18), 69 (10); HRMS (EI) Calcd. for C17H24O5 308.1624, found 308.1624.
Diethyl 2-(1-phenoxypropan-2-yl)malonate (3ma, Scheme 3):
Prepared according to GPB, after 85 h, but in this case, after 48 h, another
portion of photocatalyst (5.2 mg, 2.5 mol %) and more of phenoxyacetic
acid (230 mg, 1.5 mmol) were added. It was purified by FC (Hexane/EtOAc
97:3 to 90:10) and obtained as a colorless oil (96 mg, 0.325 mmol, 65%):
TLC Rf 0.10 (Hexane/EtOAc 97:3); IR ν 1741, 1369, 1234, 1035, 752 cm-
1
1; H-NMR (300 MHz, CDCl3) δ 7.31 - 7.23 (m, 2H), 6.98 - 6.84 (m, 3H),
4.28 - 4.13 (m, 4H), 4.04 - 3.90 (m, 2H), 3.59 (d, J = 7.7 Hz, 1H), 2.85 -
2.69 (m, 1H), 1.26 (t, J = 7.1 Hz, 3H), 1.22 (t, J = 7.1 Hz, 3H), 1.16 (d, J =
7.0 Hz, 3H); 13C-NMR (75 MHz, CDCl3) δ 168.8 (C), 168.7 (C), 158.9 (C),
129.5 (2 × CH), 120.9 (CH), 114.7 (2 × CH), 70.2 (CH2), 61.5 (CH2), 61.4
(CH2), 54.2 (CH), 33.6 (CH), 15.0 (CH3), 14.2 (CH3), 14.1 (CH3); GC RT
17.778 min; LRMS (EI) m/z (%) = 249 (M+ - C2H5O), 203 (38), 202 (11),
201 (100), 173 (50), 145 (51), 138 (22), 127 (89), 109 (11), 99 (10), 94 (30),
83 (38), 57 (32), 69 (11), 55 (22); HRMS (EI) Calcd. for C16H22O5 294.1467,
found 294.1476.
Diethyl
2-(3-(tert-butylamino)-4-phenylbutan-2-yl)malonate
(3ja,
Scheme 3):13 Prepared according to GPB, after 72 h, but in this case
another portion of photocatalyst (5.2 mg, 2.5 mol %) was added after 48
hours of reaction. It was purified by FC (Hexane/EtOAc 95:5 to 70:30) and
obtained as a pale yellow oil (122.3 mg, 0.30 mmol, 60%, 57:43 dr
according to 1H-NMR): TLC Rf 0.10 (Hexane/EtOAc 97:3); IR ν 2975, 1708,
1502, 1239, 1167, 1028, 702 cm-1; 1H-NMR (300 MHz, CDCl3) mixture of
diastereoisomers and rotamers δ 7.36 - 7.12 (m, 5H), 4.52 (d, J = 9.7 Hz,
0.52H), 4.40 (d, J = 10.1 Hz, 0.55H), 4.25 - 4.13 (m, 4H), 3.93 - 3.72 (m,
0.44H), 3.51 (d, J = 6.8 Hz, 0.43H), 3.35 (d, J = 9.9 Hz, 0.41H), 2.97 (dd,
J = 13.9, 4.7 Hz, 0.44H), 2.77 (d, J = 6.7 Hz, 0.71H), 2.69 - 2.57 (m, 0.49H),
2.52 - 2.37 (m, 0.96H), 1.55 - 1.19 (m, 16H), 1.14 (d, J = 6.9 Hz, 1.87 H),
0.95 (d, J = 7.0 Hz, 1.41H); 13C-NMR (75 MHz, CDCl3) mixture of
diastereoisomers and rotamers δ 169.6 (C), 169.0 (C), 168.4 (C), 155.6
(C), 155.4 (C), 138.04 (C), 137.99 (C), 129.4 (CH), 129.2 (CH), 128.49
(CH), 128.47 (CH), 126.5 (CH), 79.3 (C), 79.1 (C), 61.6 (CH2), 61.4 (CH2),
55.7 (CH), 55.3 (CH), 54.3 (CH), 52.8 (CH), 39.9 (CH2), 39.1 (CH2), 37.2
Diethyl 2-(1-(p-tolyloxy)propan-2-yl)malonate (3na, Scheme 3):
Prepared according to GPB, after 50 h. It was purified by FC
(Hexane/EtOAc 97:3 to 90:10) and obtained as a colorless oil (142 mg,
0.46 mmol, 92%): TLC Rf 0.10 (Hexane/EtOAc 97:3), visualized by
exposure to UV light; IR ν 1738, 1507, 1236, 1174, 1034, 812 cm-1; 1H-
NMR (300 MHz, CDCl3) δ 7.07 - 7.04 (m, 2H), 6.79 - 6.76 (m, 2H), 4.24 -
4.13 (m, 4H), 3.98 - 3.87 (m, 2H), 3.58 (d, J = 7.7 Hz, 1H), 2.81 - 2.66 (m,
1H), 2.27 (s, 3H), 1.26 (t, J = 7.1 Hz, 3H), 1.22 (t, J = 7.1 Hz, 3H), 1.14 (d,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201601478
European Journal of Organic Chemistry
FULL PAPER
J = 6.9 Hz, 3H); 13C-NMR (75 MHz, CDCl3) δ 168.8 (C), 168.7 (C), 156.8
(C), 130.1 (C), 130.0 (2 × CH), 114.6 (2 × CH), 70.4 (CH2), 61.5 (CH2),
64.4 (CH2), 54.2 (CH), 33.7 (CH), 20.6 (CH3), 14.9 (CH3), 14.2 (CH3), 14.17
(CH3); GC RT 18.585 min; LRMS (EI) m/z (%) = 308 (M+, 4), 263 (10), 217
(28), 202 (11), 201 (100), 173 (56), 148 (11), 145 (51), 127 (82), 109 (11),
108 (35), 107 (18), 99 (11), 91 (18), 83 (30), 55 (14); HRMS (EI) Calcd. for
C17H24O5 308.1624, found 308.1634.
Diethyl 2-(1-((3,4-dichlorophenyl)thio)ethyl)malonate (5): Prepared
according the GPB, after 24 h. It was purified by FC (Hexane/EtOAc 95:5
to 90:10) and obtained as a colorless oil (135 mg, 0.37 mmol, 74%): TLC
Rf 0.28 (95:5 Hexane/EtOAc); IR ν 2989, 1730, 1456, 1258, 1219, 1133,
1
1050, 1025, 809 cm-1; H-NMR (300 MHz, CDCl3) δ 7.58 (d, J = 2.0 Hz,
1H), 7.39 (d, J = 8.3 Hz, 1H), 7.32 (dd, J = 8.3, 2.1 Hz, 1H), 4.23 (q, J =
7.2 Hz, 2H), 4.22 (q, J = 7.2 Hz, 2H), 3.75 (dq, J = 8.6, 6.9 Hz, 1H), 3.48
(d, J = 8.6 Hz, 1H), 1.39 (d, J = 6.9 Hz, 3H), 1.29 (t, J = 7.1 Hz, 3 H), 1.28
(t, J = 7.1 Hz, 3H); 13C-NMR (75 MHz, CDCl3) δ 167.5 (C), 167.2 (C), 134.9
(CH), 133.7 (C), 133.0 (C), 132.7 (CH), 132.5 (C), 130.8 (CH), 62.0 (CH2),
61.9 (CH2), 57.7 (CH), 43.5 (CH), 19.5 (CH3), 14.2 (2 х CH3); LRMS (DIP)
m/z (%) = 368 (M+37Cl, 12), 367 (10), 366 (63), 365 (16), 364 (M+ +35Cl, 87),
247 (32), 245 (42), 217 (31), 207 (49), 205 (68), 179 (48), 178 (39), 177
(64), 142 (77), 141 (100), 135 (39), 113 (46), 97 (31), 95 (32), 87 (51), 85
(67), 73 (58), 69 (97), 57 (40), 55 (38), 43 (34), 41 (46); HRMS (DIP) Calcd.
for C15H18Cl2O4S 364.0303, found 364.0301.
Diethyl 2-(1-oxo-1-phenylpropan-2-yl)malonate (3oa, Scheme 3):
Prepared according to GPB, after 38 h, but in this case 1 equiv. of ketoacid
was added and after 8 h, another 1 equiv. was added. It was purified by
FC (Hexane/EtOAc 95:5 to 90:10) and obtained as a pale yellow oil (98
mg, 0.335 mmol, 67%): TLC Rf 0.15 (Hexane/EtOAc 97:3); IR ν 2977, 1744,
1727, 1681, 1457, 1288, 1179, 1024, 981, 714 cm-1; 1H-NMR (300 MHz,
CDCl3) δ 8.04 - 7.99 (m, 2H), 7.63 - 7.55 (m, 1H), 7.53 - 7.45 (m, 2H), 4.36
- 4.05 (m, 5H), 3.99 (d, J = 10.8 Hz, 1H), 1.32 (t, J = 7.1 Hz, 3H), 1.20 (d,
J = 7.3 Hz, 3H), 1.17 (t, J = 7.1 Hz, 3H);13C-NMR (75 MHz, CDCl3) δ 201.7
(C), 168.9 (C), 168.5 (C), 135.7 (C), 133.4 (CH), 128.8 (2 х CH), 128.7 (2
х CH), 61.8 (2 ×CH2), 56.4 (CH), 40.6 (CH), 16.0 (CH3), 14.3 (CH3), 14.0
(CH3); GC RT 17.797 min; LRMS (EI) m/z (%) = 247 (M+ - C2H5O, 5), 201
(7), 106 (8), 105 (100), 77 (18).
1, 2-bis(3,4-dichlorophenyl)disulfane (6, Scheme 5b):30 Compound 6
was obtained as side-product of 5, following the procedure described
above. It was purified by FC (Hexane/EtOAc 97:3) and obtained as a white
solid (45 mg, 0.13 mmol, 17%): TLC Rf 0.65 (Hexane/EtOAc 97:3); IR ν
2913, 1563, 1454, 1362, 1143, 1117, 1084, 1030, 858, 799, 675 cm-1; 1H-
NMR (300 MHz, CDCl3) δ 7.56 (d, J = 2.1 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H),
7.29 (dd, J = 8.4, 2.2 Hz, 2H); 13C-NMR (75 MHz, CDCl3) δ 136.3 (2 х C),
133.6 (2 х C), 132.1 (2 х C), 131.1 (2 х CH), 129.3 (2 х CH), 127.0 (2 х
CH); GC RT 25.335 min; LRMS (EI) m/z (%) = 360 (M+37Cl, 11), 358 (40),
357 (11), 356 (M+35Cl, 72), 354 (54), 179 (69), 177 (100), 144 (30), 142
(76).
Diethyl 2-(3-oxopentan-2-yl)malonate (3pa, Scheme 3): Prepared
according to GPB, after 69 h, but in this case another portions of
photocatalyst (1 mol %, 2.08 mg) and Na2CO3 (1 equiv., 0.5 mmol, 53 mg)
were added after 48 h of reaction. Moreover, in this case 4 x 1 equiv. (207
mg, 2 mmol) of 2-ketobutyric acid were added every 12 h. It was purified
by FC (Hexane/EtOAc 97:3 to 85:15) and obtained as a pale yellow oil (66
mg, 0.27 mmol, 54%): TLC Rf 0.10 (Hexane/EtOAc 97:3); IR ν 1746, 1720,
1264, 1090, 1046, 916, 732 cm-1; 1H-NMR (300 MHz, CDCl3) δ 4.27 - 4.08
(m, 4H), 3.77 (d, J = 10.6 Hz, 1H), 3.28 (dq, J = 10.6 Hz, 7.2 Hz, 1H), 2.63
(qd, J = 7.3, 3.2 Hz, 2H), 1.29 (t, J = 7.1 Hz, 3H), 1.23 (t, J = 7.1 Hz, 3H),
1.11 (d, J = 7.1 Hz, 3H), 1.08 (t, J = 7.1Hz, 3H); 13C-NMR (75 MHz, CDCl3)
δ 212.3 (C), 168.8 (C), 168.7 (C), 61.8 (CH2), 61.7 (CH2), 54.7 (CH), 44.8
(CH), 34.8 (CH2), 15.0 (CH3), 14.3 (CH3), 14.1 (CH3), 7.8 (CH3); GC RT
13.745 min ; LRMS (EI) m/z (%) = 215 (M+ - C2H5, 51), 200 (76), 189 (89),
188 (17), 187 (93), 171 (11), 169 (10), 159 (11), 154 (94), 143 (25), 142
(47), 122 (21), 115 (53), 114 (11), 113 (23), 99 (14), 87 (29), 86 (14), 68
(43), 57 (89); HRMS (EI) Calcd. for C12H20O5 - C2H5 215.0919, found
215.0921.
Radical Cascade of Homoallylic Acid 1s with 2a (Scheme 5c)
Diethyl (2S,5R)-5-(4-ethoxy-3-(ethoxycarbonyl)-2-methyl-4-oxobutyl)-
2,3,3- trimethylcyclopentane- 1, 1- dicarboxylate (7): Prepared
according to GPB, after 24 h, but in this case the reaction was performed
employing 1 equiv. of homoallylic acid 1s (65 mg, 0.5 mmol) and 2.5 equiv.
of 2a (235 mg, 1.25 mmol). It was purified by FC (97:3 to 90:10
Hexane/EtOAc) and obtained as a colorless oil (148 mg, 0.33mmol, 65%,
1:1 dr according NMR and GC experiments): TLC Rf 0.2 (Hexane/EtOAc
95:5 ); IR ν 2978, 1727, 1366, 1243, 1179, 1036, 856 cm-1; 1H-NMR (300
MHz, CDCl3) mixture of diastereoisomers δ 4.30 - 4.07 (m, 8H), 3.34 (d, J
= 5.9 Hz, 0.40H), 3.16 (d, J = 8.4 Hz, 0.40H), 3.09 - 2.94 (m, 1H), 2.66 (q,
J = 7.4 Hz, 1H), 2.36 - 2.12 (m, 1H), 1.78 (p, J = 6.2 Hz, 1H), 1.71 - 1.53
(m, 1H), 1.30 - 1.21 (m, 13H), 1.07 - 0.99 m, 7H), 0.88 (d, J = 3.2 Hz,
1.50H), 0.86 (d, J = 3.2 Hz, 1.50H), 0.98 (s, 3H); 13C-NMR (75 MHz, CDCl3)
mixture of diastereoisomers δ 172.0 (C), 171.8 (2 × C), 171.7 (C), 169.3
(C), 168.8 (C), 168.7 (C), 168.6 (C), 67.7 (C), 67.6 (C), 61.32 (CH2), 61.27
(2 × CH2), 61.13 (CH2), 61.07 (CH2), 61.0 (CH2), 60.94 (CH2), 60.87 (CH2),
58.8 (CH), 56.1 (CH), 49.5 (CH), 49.2 (CH), 47.2 (CH2), 45.7 (CH2), 41.3
(CH), 40.6 (CH), 40.2 (C), 40.1 (C), 37.2 (CH), 36.5 (CH), 32.3 (CH3), 31.8
(CH3), 29.21 (CH3), 29.17 (CH3), 22.8 (CH3), 22.6 (CH3), 18.1 (CH3), 16.4
(CH3), 14.21 (5 × CH3), 14.15 (CH3), 11.62 (CH3), 11, 57 (CH3); GC RT
22.008 min and 22.224 min (two diastereoisomers); LRMS (EI) m/z
(diastereoisomer A) (%) = 411 (M+ - C2H5, 9), 337 (25), 297 (43), 222 (19),
196 (21), 187 (100), 149 (44), 141 (50), 107 (19), 69 (19); m/z
(diastereoisomer B) (%) = 411 (M+ - C2H5O, 15), 337 (38), 336 (20), 297
(45), 205 (24), 196 (19), 187 (100), 149 (45), 141 (50), 107 (19), 69 (19);
HRMS (EI) Calcd. for C24H40O8 - C2H5O 411.2383 found 411.2392.
Tandem decarboxylation-Giese reaction-lactonization (Scheme 5a).
Ethyl (3S*, 4R*)-4, 5, 5-trimethyl-2-oxotetrahydro-2H-pyran-3-
carboxylate ((±)-trans-3ra): Prepared according to GPB, after 14 h. It was
purified by FC (Hexane/EtOAc 95:5 to 80:20) and obtained as a pale
yellow oil (86 mg, 0.40 mmol, 80%, >98:2 dr according 1H and 13C-NMR):
TLC Rf 0.10 (Hexane/EtOAc 95:5); IR ν 2977, 1724, 1481, 1379, 1249,
1174, 1154, 1090, 1046 cm-1; 1H-NMR (300 MHz, CDCl3) δ 4.24 (q, J =
7.1 Hz, 2H), 4.09 (d, J = 11.1 Hz, 1H), 3.97 (d, J = 11.1 Hz, 1H), 3.18 (d, J
= 11.4 Hz, 1H), 2.17 (dq, J = 11.4, 6.8 Hz, 1H), 1.31 (t, J = 7.1 Hz, 3H),
0.98 (s, 3H), 0.97 (d, J = 6.7 Hz, 3H), 0.96 (s, 3H); 13C-NMR (101 MHz,
CDCl3) δ 169.5 (C), 167.3 (C), 79.8 (CH2), 62.0 (CH2), 53.8 (CH), 40.0
(CH), 32.5 (C), 23.5 (CH3), 17.4 (CH3), 14.2 (CH3), 14.1 (CH3); GC RT
15.882 min; LRMS (EI) m/z (%) = 214 (M+, 6), 199 (13), 169 (32), 159 (10),
155 (18), 142 (13), 141 (91), 127 (15), 125 (16), 123 (12), 115 (55), 113
(18), 109 (23), 97 (37), 96 (21), 95 (26), 87 (45), 83 (27), 82 (23), 81 (18),
70 (100), 69 (73), 67 (16), 56 (30), 55 (69); HRMS (DIP) Calcd. for
C11H18O4 – CH3 199.0970, found 199.0977.
Acknowledgements
β-Fragmentation after addition of 1q to 2a (Scheme 5b).
We thank the Ministerio de Economia
y Competitividad
(CTQ2015-66624-P) and to the University of Alicante (VIGROB-
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10.1002/ejoc.201601478
European Journal of Organic Chemistry
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T. M. Locascio, J. A. Tunge, Eur. J. Org. Chem. 2016, 3331; d) For a
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173) for financial support. N. P. R. thanks the ISO for a grant. We
also thank to Irene Bosque for preliminary investigations.
Keywords: carboxylic acids • synthetic methods • radical
reactions • photocatalysis • sustainable chemistry
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10.1002/ejoc.201601478
European Journal of Organic Chemistry
FULL PAPER
Entry for the Table of Contents
Synthetic Methods
Nieves P. Ramirez, Jose C. Gonzalez-
Gomez*
Page No. – Page No.
Decarboxylative Giese-type reaction
of carboxylic acids promoted by
visible-light: a sustainable and
photoredox neutral protocol.
Text for Table of Contents
The decarboxylative alkylation of carboxylic acids can be efficiently conducted under air atmosphere, at room temperature, using [Acr-
Mes]+ as photocatalyst and promoted by visible-light. A range of readily available starting materials has been well tolerated with this
transition-metal-free protocol.
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