Photo-Mediated Decarboxylative Giese-Type Reaction Using Organic Pyrimidopteridine Photoredox Catalysts

Article abstract of DOI:10.1021/acs.joc.0c01955

The decarboxylative Giese-type reaction offers a versatile methodology for the radical alkylation of electron-deficient alkenes. Photo-mediated variants often require a pre-activation of carboxylic acids and/or employment of costly transition-metal photocatalysts. Herein, we present a metal-free photocatalyzed decarboxylative Giese-type addition to electron-deficient alkenes using pyrimidopteridine N-oxides as organic photoredox-active catalysts. This protocol comprises mono-, di-, and trisubstituted aliphatic, α-amino, and α-oxy acids as well as a variety of electron-deficient alkenes. Moreover, post-synthetic derivatization and applications are presented.

Full text of DOI:10.1021/acs.joc.0c01955

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Article
Photo-mediated Decarboxylative Giese-Type Reaction
using Organic Pyrimidopteridine Photoredox Catalysts
Firas El-Hage, Christopher Schöll, and Jola Pospech
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01955 • Publication Date (Web): 25 Sep 2020
Downloaded from pubs.acs.org on September 27, 2020
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Page 1 of 15
The Journal of Organic Chemistry
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Photo-mediated Decarboxylative Giese-Type Reaction using
Organic Pyrimidopteridine Photoredox Catalysts
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Firas El-Hage, Christopher Schöll and Jola Pospech*
Leibniz Institute for Catalysis, Albert-Einstein-Straße 29a, 18057 Rostock, Germany.
Decarboxylative Coupling - Organic Photoredox Catalysis – Giese Reaction - Heteroarenes
ABSTRACT: The decarboxylative Giese-type reaction offers a versatile method for the radical alkylation of electron-deficient
alkenes. Photo-mediated variants often require a pre-activation of carboxylic acids and/or employment of costly transition-
metal photocatalysts. Herein, we present a metal-free photocatalyzed decarboxylative Giese-type addition to electron-
deficient alkenes using pyrimidopteridine N-oxides as organic photoredox-active catalysts. This protocol comprises mono-,
di-, and trisubstituted aliphatic-, -amino- and -oxy acids as well as a variety of electron-deficient alkenes. Moreover, post
synthetic diversifications and applications are presented.
퐸red
catalyst
INTRODUCTION
(
1/2  0.83 V vs. SCE in MeCN-H2O, 1:1) as a photoredox
in
conjunction
with
redox-active
N-
Decarboxylative transformations present an important
tool for the construction of complex organic motifs.1-4
Carboxylic acids serve as abundant, bench stable, and
inexpensive starting materials.5-10 Particularly, the
formation of carbon dioxide as a traceless, volatile, and inert
byproduct constitute one of the appealing advantages of
this methodology. Based on seminal contributions in the
field of decarboxylative chemistry by Hunsdieker,11
Barton12 and Okada,13 transition-metal catalyzed examples
evolved as a convenient means to induce decarboxylative
modifications.14, 15 Till date, a wide repertoire of oxidative
and reductive decarboxylation reactions have been
reported. Yet, there is still a striving effort to overcome
restrictive boundaries such as the requirement of highly
pre-functionalized, toxic and expensive substrates and
additives as well as harsh reaction conditions.16, 17 Among
other decarboxylative coupling reactions, the addition of
carbon-centered radicals generated from carboxylic acids
to electron-deficient olefins, also called decarboxylative
Giese addition, depicts a multifaceted procedure to forge
new CC bonds.18, 19
hydroxyphthalimide (NHPI) esters (Fig. 1.A).30
A. Previous works
2014
(i) MacMillan et al.
:
1.0 mol%
Ir[dF(CF3)ppy]2(dtbbpy)+
(1)
R2
R2
+
X
CO2H
X
EWG
EWG
26 W CFL
K2HPO4 (1.2 equiv.)
DMF
R1
R1
X = C, N, O
r.t., 36 h
2016
(ii) König et al.
:
Eosin Y (2)
DIPEA (2 equiv.)
10 mol%
R2
R5 R2
R5
R4
R3 CO2-
R4
R3
+
EWG
EWG
Green LEDs
DCM (dry)
r.t., 18 h
air
N-Phth
R1
R1
2017
(iii) Gonzalez-Gomez et al.
:
[Acr-Mes]+ (3)
2.5 mol%
R2
R5 R2
R5
Na2CO3 (20 mol%)
R4
R3
R4
R3
+
EWG
EWG
Blue LED
MeCN:H2O or MeOH
r.t., 15 - 96 h
air
CO2H
R1
R1
B. This work
Pr
Pr
N
O
N
N
O
Recently, visible-light-promoted transformations gained
N
N
R2
R5 R2
21
tremendous attention in the chemical community.20,
Pr
N+
O-
Pr
R5
R4
R4
R3
+
O
O
R3
Decarboxylative photomediated trnsforamations emerged
as a valuable tool to access new CC and Cheteroatom
bond forming strategies.21-28 One of the earliest reported
photo-mediated protocols for the decarboxylative
conjugate addition to electron-deficient olefins was
reported by MacMillan and co-workers.29 In this work, an
EWG
EWG
CO2H
R1
R1
8
PrPPTNO
5.0 mol%
K3PO4 (20 mol%)
MeCN:H2O (9:1)
396 nm
6
7
R3, R4, R5 = H, C, N, O
organic photoredox-catalyst
25-32 °C, 16 h
catalytic amount of base
up to 99% yield
Figure 1. A. (i) Iridium-catalyzed, oxidative-, (ii) metal-
free, reductive and (iii) metal-free, oxidative photo-
mediated decarboxylative radical addition. B. This work:
Organic photoredox-catalyzed decarboxylative C−C bond
formation.
iridium photoredox catalyst Ir[dF(CF3)ppy]2(dtbbpy)+ (1) (
∗ III/II
퐸
 1.21 V vs SCE in MeCN) proved to be suitable for
1/2
the oxidative decarboxylation and subsequent addition of a
wide variety of acyclic- and cyclic alkyl- as well as
heteroatom- carboxylic acids across different Michael
acceptors (Fig. 1.A). Two years later, König and co-worker
established a metal free reductive variant using eosin y (2)
In 2017, Gonzalez-Gomez et al. reported a metal-free,
photocatalyzed, oxidative variant utilizing Fukuzumi's
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acridinium-based photocatalyst [Acr-Mes]+ (3) (Fig. 1.A).31
that the tetrapropyl-substituted, deoxygenated PrPPT
1
2
3
4
5
6
7
8
In all cases, a pre-activation of the carboxylic acids by
deprotonation to reduce the oxidation potential of the
carboxylic acid or conversion into a redox-active ester to
access a reductive decarboxylation pathway in conjunction
with stoichiometric amounts of a sacrificial reductant was
necessary. Furthermore, prolonged reaction times (up to 96
hours) restrict the applicability of this reaction type. The
deprotonation step is conducted either by addition of an
external base or by using reactants with dual functionalities.
In this context, riboflavin tetraacetate, structurally similar
to pyrimidopteridines, can simultaneously act as a base and
photocatalyst in decarboxylative transformations.9,10
facilitated the quantitative conversion of -amino acid 6o to
the desired product (Table 1, entry 9).36
Table 1. Reaction Optimization.
Pr
N
Pr
N
O
N
O
N
N
Pr
N+
O
Pr
+
O
O
CO2Me
CO2Me
CO2Me
CO2Me
CO2H
N
N
PrPPTNO
5.0 mol%
K3PO4 (1.0 equiv.)
Boc
9
Boc
MeCN:H2O (9:1), 0.1 M
396 nm
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
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58
59
60
6o
7a
8oa
(1.0 equiv.)
(2.0 equiv.)
25-32 °C, 16 h
entry deviation from reaction conditions yield [%][a]
In the mid 1980’s, Maki et al. reported the synthesis and
application of n-butyl pyrimidopteridine N-oxide (4c) as a
photochemical stoichiometric oxidant.32 In 2019, our group
started to investigate these intriguing heterocycles with
respect to their applicability as organic photoredox
catalysts.33 Photo- and electrochemical analysis revealed
that these compounds have high excited state reduction
potentials (E*[PrPPTNO*/PrPPTNO•−] = +2.29 V vs. SCE in
MeCN). The deoxygenated tetrapropylpyrimidopteridine
PrPPT (E*[PrPPT*/PrPPT•−] = +2.08 V vs. SCE in MeCN)
possess an equally high reduction potential in its excited
state.34 Thus, both heteroarenes qualify to oxidize
carboxylic acids with oxidation potentials exceeding +2.0 V.
1
2
3
4
5
6
7
8
none
96 (88)
no photocatalyst
no light
-
-
no base
10
in MeCN
73
in DCM
61
20 mol-% of K3PO4
Na2CO3 instead of K3PO4
94 (87)
(83)
PrPPT (5b) instead of PrPPTNO quant.
(4b) (quant.)
9
We herein report
a redox neutral photocatalyzed
[a] Yield determined by calibrated GC using biphenyl as internal
standard. Yield in parentheses represents isolated yield.
decarboxylative Giese-type reaction using tetrapropyl-
pyrimidopteridine N-oxide (4b) (Fig. 1.B). This example
utilized
a metal-free, easily accessible photocatalysts.
With the optimized reaction conditions (Table 1, entry 7)
in hand, the scope and limitations of carboxylic acids were
evaluated using dimethyl maleate (7a) and diethyl
ethylidenmalonate (7b) as representative radical acceptors
(Scheme 1). Tertiary cyclic- and acyclic- hydrocarbon
carboxylic acids (6a-f) furnished the corresponding
conjugate addition products in good to excellent yields
(8ab-8fa, 6692%). The structure of product (8fa) was
confirmed by X-ray crystallography (see supporting
information, Fig. S55). Notably, carboxylic acids bearing
unprotected alcohol moieties did not diminish the yields of
the corresponding products (8bb and 8ib). In contrast, non-
Moreover, mild reaction conditions using catalytic amounts
of base and a comparatively short reaction time, lead to
satisfactory decarboxylative C−C bond formation of a wide-
range of carboxylic acids and various radical acceptors.
RESULTS AND DISCUSSION
The optimization of reaction conditions for the
decarboxylative Giese-type reaction was conducted using
N-Boc proline (6o) and dimethyl maleate (7a) as model
substrates (Table 1). Initially, the best reaction outcome
was observed, using 5.0 mol-% of the tetrapropyl-
substituted pyrimidopteridine-N-oxide PrPPTNO in a 0.1 M
solution in MeCN/H2O (9:1) in the presence of
stoichiometric amounts of K3PO4. The desired coupling
product was obtained in 96% GC- and 88% isolated yield
(Table 1, entry 1). Control experiments, omitting the
heteroarene catalyst or in the absence of light did not yield
any coupling product (Table 1, entries 2-3). In the absence
of the base, only marginal 10% conversion was detected
according to calibrated GC (Table 1, entry 4). Deprotonation
of N-Boc proline results in a significant decrease of the
reduction potential from Boc-Pro-OH to Boc-Pro-O-.35
Thus, the radical decarboxylation is significantly facilitated
in the presence of a base. In the absence of water, using neat
MeCN or DCM (entries 5 and 6), a diminished product yield
was observed. Decreasing the amount of base to 20 mol-%
or substitution of the phosphate base with Na2CO3 allowed
to obtain the coupling product 8oa in excellent isolated
yields of 87% and 83%, respectively (entries 7 and 8).
Interestingly, a catalyst screening of various PPTNOs (4a-
d) and their deoxygenated analogous PPT (5a-d) revealed
proteinogenic
-amino
acids
such
as
N-Boc-
Aminoisobutyric acid (6h) as well as the tertiary -oxy acid
(6g) resulted in lower good to moderate yields (8gb-8ha,
2945%). Noteworthy, natural product-derived pentacyclic
triterpenoid enoxolone (6i) bearing a free hydroxy group
and
a potentially reactive ,- unsaturated carbonyl
subunit, proved to be an excellent coupling partner (8ia).
Yet, it is noteworthy that carboxylic acid frameworks
comprising electron-rich phenol-ethers resulted in lower
yields of alkylated products (8ja-8la). This deterioration in
yield can be attributed to the antioxidant effect of electron-
rich phenols which likely quench the excited state of the
photoredox-catalyst.37 As a result, an interruption of the
catalytic cycle due to increased radical stabilization of the
phenoxy radical (RSE = 149.8 kJ/mol) is anticipated.38 The
decarboxylative coupling of bezafibrate
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Scheme 1. Scope and limitations of carboxylic acids.[a]
1
2
Pr
N
Pr
N
O
N
O
CO2Me
3
4
5
6
7
8
9
7a
7b
N
N
R3
R3
N+
O
Pr
CO2Me
Pr
R1
R1
+
O
O
CO2R4
CO2R4
CO2H
CO2Et
CO2Et
R2
R2
PrPPTNO
5.0 mol%
K3PO4 (0.2 equiv.)
MeCN:H2O (9:1), 0.1 M
396 nm
6a z
(1.0 equiv.)
7a 7b
(2.0 equiv.)
8
-
or
Me
25-32 °C, 16 h
disubstituted carboxylic acids:
EtO2C
CO2Me
Me
CO2Me
NHCbz
trisubstituted carboxylic acids:
CO2Me
CO2Me
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
EtO2C
Me
EtO2C
Me
EtO2C
Me
EtO2C
Me
EtO2C
Me
EtO2C
CO2Et
R4
CO2Et
Me
CO2Et
Bn
CO2Et
CO2Et
O
CO2Et
Me
CO2Et
Me
Me
Me
Me
BocHN
BocN
Me Me
Me
Me
O
MeO2C
R
4 = H, 92%
8cb,
8db,
8eb,
8fa,
82%
87%
78%
66%
8ab,
[c]
8mb,
8na,
8ob,
8pb,
30%
70%
68%
45%
N
MeO2C
R
4 = OH, 84%
8bb,
Me
Me
CO2Me
Me
O
MeO2C
CO2Me
EtO2C
EtO2C
Me
EtO2C
Me
MeO2C
MeO2C
EtO2C
Me
HN
CO2Et
CO2Et
Me
CO2Et
O
CO2Me
CO2Et
Me
CO2Me
Me
O
Me
O
O
CO2Me
Me
O
Me
Me
BocHN
Me Me
O
n
Me
O
MeO
Me
HO
8tb,
n = 1
n = 3
35%
from enoxolone
Me
Me Me
Cl
[e,f]
[e,f]
[d,e]
[d]
[b]
8rb,
8sa,
8ub,
8vb,
8qa,
75%
34%
52%
37%
29%
8gb,
8ha,
8ia,
8ja,
26%
29%
45%
78%
monosubstituted carboxylic acids:
unsuccessfull acids:
Me
Me Me
H
EtO2C
CO2Et
Me
N
O
CO2Me
CO2Me
CO2Me
MeO2C
MeO2C
Me
Me
EtO2C
BocHN
CO2Et
Me
O
H
N
O
CO2Me
CO2Me
F
O
Me
CO2Me
Me
from Gemfibrozil
from Bezafibrate
[b]
[b]
8ka,
17%
8la,
31%
8wb,
8xb,
8yb,
8za,
<5%
18%
21%
0%
[a] isolated yields of purified products are shown. [b] 48 h instead of 16 h. [c] reaction was performed with 1.0 equiv. base. [d] reaction
was performed on a 0.15 mmol scale. [e] 2.0 equiv. acid, 1 equiv. alkene, 0.4 equiv. of base was used. [f] 24 h instead of 16 h.
(6l) resulted in a concomitant dehydration to the
corresponding enamine. Secondary N-protected natural -
amino acids were also suitable substrates for this protocol.
Different amine protecting groups (e.g., Cbz and Boc) as well
as -amino acids were well tolerated during the reaction,
giving access to -amino acid esters in moderate to very
good yields (8oa, 8na-8qa, 4587%). N-Boc-phenylalanine
(6p) represented an exception, leading to a diminished
yield of the corresponding product (8pb, 30%). Cyclic
disubstituted -oxy acids furnished the corresponding
alkylated products (8mb, 8rb-8sa, 3470%) in slightly
higher yields as compared to cyclic disubstituted
hydrocarbon acids (8tb-8vb, 2937%). The higher yields of
substrates bearing an -heteroatom can be attributed to the
increased radical stability in vicinity of electron lone-
pairs.38 On the same note, dipeptide 6q consisting of Boc-L-
proline and N-protected L-valine afforded the
corresponding product 8qa in a good yield of 75%. A similar
trend becomes apparent when comparing monosubstituted
(1°), disubstituted (2°), and trisubstituted (3°) carboxylic
acids. Higher product yields correlate with an increased
stability of the corresponding radical (1°<2°<3°).39 This was
especially evident when using monosubstituted carboxylic
acids (6w and 6x). Despite the positive radical stabilizing
effect of -heteroatoms in both cases, low yields of (8wb-
8xb, 1821%) were obtained. Furthermore, primary alkyl
lauric acid failed to generate the desired product. Difficult
decarboxylation and highly unstable primary alkyl radical
impaired the product formation.
Scheme 2. Hydrodecarboxylation of benzylic carboxylic
acid Flurbiprofen (6y).
Pr
N
Pr
N
O
N
O
N
N
N+
O
Pr
CO2H
Me
H
Pr
CO2Me
CO2Me
O
O
+
Me
PrPPTNO
5.0 mol%
K3PO4 (0.2 equiv.)
MeCN:H2O (9:1), 0.1 M
396 nm
Ph
Ph
F
F
6y
(1.0 equiv.)
7a
9
, 17%
25-30 °C, 16 h
(2.0 equiv.)
Unfortunately, benzylic acid derivatives, e.g. Flurbiprofen
(6y), did not lead to any product formation. In these cases,
hydrodecarboxylation constituted the major reaction
pathway (Scheme 2).40, 41 Also, N-phenylglycine (6z) rapidly
decomposed under the reaction conditions.
Next, the scope of several cyclic and acyclic electron-
deficient alkenes 7a-p was explored, using adamantane-1-
carboxylic acid (6a) as a model substrate (Scheme 3). Cyclic
,-unsaturated carbonyls (7a-d) were competent coupling
partners. Cyclopentenone (7a) and cyclohexenone (7b)
furnished the desired C−C coupling products 10 and 11 in
89% and 81%, respectively. The presence of a -methyl
group in 5-methylcyclopent-2-en-1-one (7d) was tolerated,
furnishing product 13 in a moderate yield of 57%. On the
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contrary, the expansion of the carbocycle to a seven- product 8ab was detected. A radical adduct 26 consisting of
1
2
3
4
5
6
7
8
membered ring impaired the yield of 12. Considerable ring
strain as well as the lack of ideal bond angles putatively
reduces the stability of the corresponding radical
intermediate, leading to a ring opening.38 Alkylated product
8ab was obtained from 1,1'-disubstituted olefin 7b in an
excellent yield of 92%. Likewise, dimethyl- as well as
diethyl-maleate participated efficiently in the reaction,
generating the corresponding products 8fa and 14 in
satisfying yields of 82% and 83%, respectively. Notably, (E)-
di-tert-butyl-fumarate (7f) delivered conjugated product
15 in a moderate yield of only 53%. This deterioration in
yield could be attributed to a simultaneously occurring
contra-thermodynamic (E→Z) alkene isomerization,
impairing the productive quenching of the excited state
photocatalyst. To our delight, vinyl sulfone (7i) was also
compatible under the reaction conditions and furnished the
radical addition product 16 in a synthetically useful yield of
69%. Other acrylates (7j-l), acrylonitrile (7m) and
acrylaldehyde (7n) delivered the corresponding alkylated
products (17-21) in comparably lower yields (2640%).
Next, we investigated the photo-mediated radical addition
to differently substituted chromones (7o-r). The desired
products (22-25) were obtained in yields varying between
2955%.
an adamantyl radical scaffold and TEMPO was detected by
LC-MS (see SI for further information). Next, we
investigated the role of the solvent mixture. Deuterium
incorporation experiments (entry b) revealed a high
deuterium content (93% D) in product 8ab when
MeCN/D2O (9:1) was used. In contrast, only 4% D were
detected in product 8ab when using D3CN/H2O (9:1).
Scheme 4. Mechanistic Experiments.
9
(a) Radical trapping experiment.
8ab
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
not detected
+
Me
Me
Me
Me
Me
Me
N
O
N
CO2H
O
Me
EtO2C
Me
CO2Et
Me
TEMPO
(1.2 equiv.)
+
standard conditions
6a
7b
26
detected by LC-MS
(b) Deuterium incorporation experiment.
EtO2C
H/D
Me
CO2H
CO2Et
EtO2C
Me
CO2Et
standard
+
conditions
Scheme 3. Scope of electron-deficient alkenes.
6a
7b
8ab
D3CN/H2O (9:1)
MeCN/D2O (9:1)
H/D = 96:4
H/D = 7:93
Pr
N
Pr
N
O
N
O
R2
EWG
R1
N
N
Pr
N+
O
Pr
Based on the reaction optimization and control
experiments, a potential mechanism is proposed as shown
in Scheme 5. We surmise that an early deoxygenation of the
PrPPTNO (4b) leads to the active form of the photocatalyst
5b. The catalytic cycle starts with an excitation of 5b upon
irradiation with UV-light at 396 nm. Following base-
promoted deprotonation of carboxylic acid 6, the
CO2H
R2
EWG
R1
7a r
O
O
+
PrPPTNO
5.0 mol%
K3PO4 (0.2 equiv.)
MeCN:H2O (9:1), 0.1 M
396 nm
6a
(1.0 equiv.)
10-25
-
(2.0 equiv.)
25-32 °C, 16 h
alkene scope:
O
O
corresponding carboxylate anion int-1 (e.g. Boc-Pro-O,
RO2C
RO2C
EtO2C
Me
PhO2S
Me
CO2Et
red
 0.95 V vs SCE in MeCN)35 acts as a reductive
퐸
1/2
n
quencher of the strongly oxidizing excited-state of the
photocatalyst 5b* (E*[PrPPT*/PrPPT•−] = +2.08 V vs. SCE
in MeCN).26 Single-electron transfer (SET) from anion int-1
to 2b* generates a carboxylate radical intermediate which,
upon rapid decarboxylation, gives access to a carbon-
centered radical int-2. Subsequent conjugate addition of the
highly nucleophilic neutral radical int-2 across an electron-
10
11
12
13,
8fa
8ab,
16,
69%
n = 1
, 89%
, 81%
, 19%
57%
NC
R = Me
Et
, 82%
92%
2
3
14
, 83%
[b]
15
t-Bu , 53%
O
RO2C
OHC
R
Me
deficient alkene
7 would furnish conjugate radical
O
intermediate int-3.
Scheme 5. Proposed catalytic cycle.
[c]
20,
21,
22,
23,
24,
25,
40%
32%
R = H
39%
29%
55%
44%
17
R = Et
, 28%
F
Br
Cl
18
Bn , 27%
19
Ph , 26%
[a]
Reactions were performed on 0.5 mmol scale. Isolated
yields of products are shown. [b] from di-tert-butyl fumarate. [c]
K2CO3 (1.0 equiv.) was used.
To get a better understanding of the reaction trajectory,
multiple mechanistic experiments were conducted (Scheme
4, entries a-b). Since a radical mechanism is anticipated, a
radical trapping experiment with TEMPO ((2,2,6,6-
Tetramethylpiperidin-1-yl)oxyl) was conducted (entry a).
Indeed, the coupling reaction of 1-adamantanecarboxylic
acid (6a) and alkene 7b was entirely inhibited. Thus, no
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The Journal of Organic Chemistry
LiAlH4 readily generated diole 27 in 93% yield.43 Moreover,
the concerted alkylation and lactonization of 8fa with
methyl magnesium bromide gave access to 5,5'
disubstituted lactone 28 in 87% yield. The tri-substituted
barbiturate 29, class of molecules with high

base
CO2H
CO2
R
R
R
EWG
1
2
3
4
baseH+
6
int-1
int-2
7
a
SET
a
pharmaceutical value, was directly obtained from diester
8ab and N,N’-dimethyl urea.44 Furthermore, we performed
a six-time scale-up (3.0 mmol) of the parent photo-
mediated coupling using 1-adamantanecarboxylic acid (6a)
and dimethyl maleate (7a). The corresponding product 8fa
was isolated in 45% yield after irradiation for 24 hours.
This significant decline in yield from 82% to 45% is likely
attributed to the inferior penetration of light caused by an
increased path length of light in the big-scale setup. This
technical problem could be overcome by using flow
techniques.
5
6
7
8
PrPPT*
PrPPT
R
R
EWG
int-3
9
SET
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
h.v
396 nm
EWG
int-4
PrPPT
baseH+
R
- "O"
PrPPTNO
H
CONCLUSIONS
EWG
In summary, an efficient metal-free decarboxylative
photoredox Giese-type reaction has been developed using
pyrimdopteridines as photocatalysts. The decarboxylative
alkylation of a variety of electron-deficient olefins was
amenable using catalytic amounts of base, low
photocatalyst loadings, irradiated with low intensity (30 W)
LED lamps at 396 nm. The presented protocol is especially
suitable for tri- and disubstituted carboxylic acids. Good
functional group tolerance, including unprotected alcohols
as well as substrates bearing halogen- and -unsaturated
carbonyl moieties, was shown. In addition, scale-up- and
synthetically useful derivatization-reactions of the seminal
products were demonstrated.
8
The corresponding radical intermediate int-3 (potential
퐸red
of alkyl radicals are in the range of 1/2 = 0.6 - (0.8 V) vs
SCE in MeCN)42 is sufficient to turn over the reduced form
ퟓ퐛. ― 퐸red
of the photocatalyst
( 1/2  1.22 V vs SCE in MeCN),
thus regenerating 5b and furnishing the anionic
intermediate int-4. Protonation of int-4 gives access to the
desired products (8 and 10-25) and regenerates the base.
Scheme 6. Derivatization and Reaction Scale-up.
Reduction:
CO2Me
OH
MeO2C
HO
LiAlH4
EXPERIMENTAL SECTION
THF, r.t., 23 h
General Remarks. Unless otherwise noted, all reactions
were carried out under an inert atmosphere. All chemicals
were purchased from commercial suppliers and used as
received. liquid olefins were freshly distilled prior to use.
Pyrimidopteridinetetraone N-oxides (PPTNO) according to
procedures previously reported by our group. Dry
dichloromethane (CH2Cl2), Acetonitrile (MeCN), hexanes and
THF were obtained by passing commercially available
anhydrous, oxygen-free HPLC-grade solvents through
activated alumina columns using an MBRAUN solvent
purification system. Degassed water was obtained by bubbling
argon through demineralized water for 30 minutes. Analytical
thin-layer chromatography was performed on MERCK silica gel
60 F254 aluminum plates. Visualization was accomplished with
UV light and/or potassium permanganate (KMnO4) or cerium
ammonium molybdate stain (CAM). Retention factor (Rf)
values reported were measured using a 5 × 2 cm2 TLC plate in
a developing chamber containing the solvent system described.
Flash column chromatography was performed using Silicycle
SiliaFlash® P60 (SiO2, 40-63 μm particle size, 230-400 mesh).
1H and 13C NMR spectra were recorded on Bruker 400 (400
8fa
27
, 93%
O
Alkylation/lactonization:
CO2Me
MeO2C
O
Me
Me
MeMgBr
THF
0 °Cr.t., 24 h
8fa
28
, 87%
Condensation/cyclization:
Na
O
Me
N
CO2Et
O
O
Me
Me
Me
N
N
CO2Et
Me
N
H
H
Me
O
EtOH
r.t.reflux, 23 h
8ab
29
, 33%
Scale-up:
CO2Me
CO2H
standard reaction
conditions
1
MHz, H; 100 MHz, 13C) or Varian Unity Inova 500 (500 MHz,
MeO2C
1H) MHz spectrometers. Spectra are referenced to residual
+
7a
24 h
chloroform (δ = 7.26 ppm, 1H; 77.16 ppm, 13C), residual
1
dimethyl sulfoxide (δ = 2.50 ppm, H; 39.5 ppm, 13C), residual
(3.0 mmol)
methanol (δ = 3.31 ppm, 1H; 49.0 ppm, 13C), or residual benzene
(δ = 7.16 ppm, 1H; 128.06 ppm, 13C). Chemical shifts are
reported in parts per million (ppm). Multiplicities are indicated
by s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet),
and br (broad). Coupling constants J are reported in hertz (Hz).
6a
8fa,
45%
Eventually, the synthetic utility of the product formed from
the photo-mediated decarboxylative coupling was
evaluated (Scheme 6). The reduction of 1,2-diester 8fa with
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The Journal of Organic Chemistry
Page 6 of 15
Mass spectrometry (MS) was performed by the LIKAT analytic
(100), 115 (5), 107 (12), 93 (20), 79 (21), 69 (8). HRMS (ESI-
department. Electron impact (EI+) spectra were recorded at 70
eV using methane as the carrier gas, with time-of-flight (TOF)
mass analyzer. Electrospray ionization (ESI+) spectra were
recorded using a time-of-flight (TOF) mass analyzer. Data are
reported in the form of m/z (intensity relative to the base peak
= 100). High-resolution mass spectra were recorded by using
WATERS Q-TOF Ultima ESI and Agilent 6230 ESI TOF LC/MS
spectrometers. Infrared spectra were measured neat on a
Perkin-Elmer spectrum BX FT-IR spectrometer. X-ray data
were collected on a Bruker Kappa APEX II Duo and a Bruker D8
QUEST diffractometer. Peaks are reported in cm−1 with
indicated relative intensities: s (strong, 0–33%); m (medium,
34–66%), w (weak, 67–100%), and br (broad). Melting points
of solids, compounds that solidified after chromatography,
were measured on a Buchi B-540 melting point apparatus and
are uncorrected.
TOF) m/z: [M]+ Calcd for C19H30O4 345.2041; Found 345.2033.
IR (ATR, neat, cm-1): 2980 (w), 2901 (m), 2848 (w), 1752 (m),
1728 (m), 1448 (w), 1218 (m), 1138 (m), 1031 (m). 864 (w).
The analytic data is in correspondence with that reported in
literature.45
1
2
3
4
5
6
7
8
Diethyl
2-(1-((1r,3s,5R,7S)-3-hydroxyadamantan-1-
yl)ethyl)malonate (8bb). Compound 8bb was prepared
following general procedure A. 3-Hydroxyadamantane-1-
carboxylic acid (98 mg, 0.5 mmol, 1.0 equiv) was used.
Purification
(CH2Cl2:MeOH = 100:1) yielded the title compound 8bb
(142 mg, 0.42 mmol, 84%) as colorless oil. Rf = 0.31
by
column
chromatography
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
a
1
(CH2Cl2:MeOH = 100:2, KMnO4); H NMR (300 MHz, CDCl3) δ
4.13 (m, 4H), 3.49 (d, J = 5.1 Hz, 1H), 2.09 (m, 3H), 1.86 (m, 1H),
1.57 (m, 4H), 1.36 (m, 8H), 1.21 (td, J = 7.1, 4.5 Hz, 6H), 0.94 (d,
J = 7.3 Hz, 3H). 13C {1H} NMR (75 MHz, CDCl3) δ 170.1, 169.5,
68.9, 61.4, 61.0, 52.0, 47.3, 44.7, 44.6, 42.9, 39.2, 38.2, 37.9,
35.5, 30.6, 30.5, 14.1, 14.0, 10.7; MS (EI): m/z (relative
intensity) 338 (1) [M], 292 (18), 206 (42), 188 (86), 179 (27),
161 (18), 151 (72), 142 (100), 133 (16), 121 (10), 115 (69), 109
(13), 107 (27), 95 (58), 93 (59); HRMS (ESI-TOF) m/z: [M+Na]+
Calcd for C19H30O5Na 361.1990; Found 361.1990; IR (ATR,
neat, cm-1): 3399 (w, br.), 2980 (w), 2906 (w), 2852 (w), 1726
(m), 1448 (w), 1297 (w), 1210 (m), 1138 (m), 1027 (m), 939
(w). The analytic data is in correspondence with that reported
in literature.46
General Procedure A: Photocatalytic C−C Bond
Formation. Unless otherwise noted, the reactions were
performed under Schlenk conditions using a 5 mL process vial
equipped with a NS 14.5 rubber septum. The appropriate
carboxylic acid (0.50 mmol, 1.0 equiv.), photocatalyst
PrPPTNO (5.0 mol%) and K3PO4 (20 mol-%) was added. Next,
the vial was evacuated and purged with argon 3 times. The
corresponding olefin (1.0 mmol, 2.0 equiv.) was then added.
Acetonitrile (4.5 mL) and degassed water (0.5 mL) were added
and the reaction mixture was stirred for 2 minutes in the dark.
The reaction mixture was then irradiated for the indicated time
and quenched upon exposure to air and bubbling air through
the solution with a pipette. Next, the reaction was concentrated
under reduced pressure and the crude mixture was purified by
column chromatography.
Diethyl
2-(1-(1-methylcyclohexyl)ethyl)malonate
(8cb).
Compound 8cb was prepared following general procedure A.
1-Methyl-1-cyclohexanecarboxylic acid (71 mg, 0.5 mmol,
1.0 equiv) was used. Purification by column chromatography
(n-pentane:EtOAc = 100:2) yielded the title compound 8cb
(123 mg, 0.43 mmol, 87%) as a colorless oil. Rf = 0.67 (n-
pentane:EtOAc = 10:1, KMnO4); 1H NMR (300 MHz, CDCl3) δ
4.12 (m, 4H), 3.52 (d, J = 4.7 Hz, 1H), 2.29 (qd, J = 7.2, 4.7 Hz,
1H), 1.31 (m, 17H), 0.96 (d, J = 7.2 Hz, 3H), 0.78 (s, J = 5.8 Hz,
3H); 13C {1H} NMR (75 MHz, CDCl3) δ 170.4, 169.8, 61.4, 60.9,
52.3, 42.0, 36.3, 35.9, 35.9, 26.3, 22.0, 21.9, 19.4, 14.1, 11.0; MS
(EI): m/z (relative intensity) 285 (1), 239 (13), 188 (48), 173
(9), 142 (100), 125 (20), 115 (87), 109 (6), 97 (71), 87 (27), 81
(25), 69 (53); HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for
C13H28O4Na 307.1885; Found 307.1886. IR (ATR, neat, cm-1):
2979 (w), 2926 (w), 2851 (w), 1729 (s), 1462 (w), 1389 (w),
1296 (m), 1216 (m), 1143 (m), 1059 (m), 1029 (w), 864 (w).
The analytic data is in correspondence with that reported in
literature.47
Dimethyl 2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)succinate
(8oa). Compound 8oa was prepared following general
procedure A. N-Boc-proline (108 mg, 0.5 mmol, 1.0 equiv.) and
dimethyl maleate (144 mg, 1.0 mmol, 2.0 equiv.) were used.
Purification
by
column
chromatography
(n-
pentane:acetone = 40:1 → 20:1) yielded the title compound
8oa (140 mg, 0.4 mmol, 88 %) as a yellow oil. Analytical data
are stated for a mixture of two diastereomers (d.r. = 1:1). Rf =
0.20 (n-pentane:acetone = 10:1, KMnO4); 1H NMR (300 MHz,
CDCl3) δ 4.28–3.86 (m, 1H), 3.72–3.65 (s, 3H), 3.64 (s, 3H),
3.62–3.06 (m, 3H), 2.73 (m, 1H), 2.55 – 2.22 (m, 1H), 1.97 – 1.61
(m, 4H), 1.45 (s, 9H); 13C {1H} NMR (75 MHz, CDCl3) δ 173.8,
173.4, 172.6, 58.5, 57.6, 52.1, 51.9, 47.3, 44.5, 44.1, 33.8, 28.5,
27.9, 23.6, 22.9; MS (EI, m/z, relative Intensity): 315 (0.1) [M],
154 (15), 128 (19), 114 (57), 70 (100), 57 (57), 41 (19). HRMS
(ESI-TOF) m/z: [M]+ Calcd for C15H25NO6 338.1676; Found
338.1678. IR (ATR, neat, cm-1): 2974 (w), 2955 (w), 2885 (w),
1733 (s), 1689 (s), 1557 (w), 1478 (w), 1436 (m), 1388 (s),
1366 (s), 1314 (m), 1255 (m), 1157 (s), 1116 (s), 1009 (m), 942
(w), 913 (m), 873 (m), 846 (m), 772 (m), 675 (w), 544 (w), 509
(w), 462 (w).
Diethyl 2-(1-((3r,5r,7r)-adamantan-1-yl)ethyl)malonate (8ab).
Compound 8ab was prepared following general procedure A.
Diethyl ethylidenmalonate (186 mg, 1.0 mmol, 2.0 equiv) was
used. Purification by column chromatography (n-
pentane:EtOAc = 20:1) yielded the title compound 8ab
(148 mg, 0.46 mmol, 92%) as a colorless oil. Rf = 0.60 (n-
pentane:EtOAc = 10:1, KMnO4); 1H NMR (300 MHz, CDCl3) δ
4.14 (m, 4H), 3.53 (d, J = 5.2 Hz, 1H), 2.03 (qd, J = 7.3, 5.5 Hz,
1H), 1.93 (s, 3H), 1.54 (m, 12H), 1.23 (m, 6H), 0.94 (d, J = 7.3 Hz,
3H); 13C {1H} NMR (75 MHz, CDCl3) δ 170.4, 169.8, 61.4, 60.9,
51.9, 43.1, 39.4, 37.1, 35.3, 28.7, 14.1, 14.1, 10.4; MS (EI): m/z
(relative intensity) 276 (11), 208 (11), 187 (11), 163 (12), 135
Diethyl 2-(3,3-dimethylpentan-2-yl)malonate (8db). Compound
8db was prepared following general procedure A. 2,2-
Dimethylbutyric acid (58 mg, 0.5 mmol, 1.0 equiv) was used.
Purification
by
column
chromatography
(n-
pentane:EtOAc = 100:2) yielded the title compound 8db
(104 mg, 0.40 mmol, 78%) as a colorless oil. Rf = 0.38 (n-
pentane:EtOAc = 20:1, KMnO4); 1H NMR (300 MHz, CDCl3) δ
4.15 (m, 4H), 3.49 (d, J = 4.9 Hz, 1H), 2.31 (qd, J = 7.2, 4.9 Hz,
1H), 1.26 (m, 8H), 0.97 (d, J = 7.2 Hz, 3H), 0.80 (m, 9H); 13C {1H}
NMR (75 MHz, CDCl3) δ 170.3, 169.8, 61.4, 61.0, 52.9, 40.4, 36.0,
32.9, 24.2, 24.1, 14.1, 11.7, 8.2; MS (EI): m/z (relative intensity)
229 (25), 213 (27), 188 (35), 173 (9), 169 (8), 155 (46), 142
(88), 127 (11), 115 (100), 99 (26), 87 (31), 71 (26); HRMS (ESI-
TOF) m/z: [M+Na]+ Calcd for C14H26O4Na 281.1728; Found
281.1729. IR (ATR, neat, cm-1): 2968 (w), 2881 (w), 1752 (w),
1729 (m), 1464 (w), 1369 (w), 1284 (m), 1143 (m), 1029 (m),
864 (w).
Diethyl 2-(3,3-dimethylbutan-2-yl)malonate (8eb). Compound
8eb was prepared following general procedure A. Diethyl
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The Journal of Organic Chemistry
ethylidenmalonate (186 mg, 1.0 mmol, 2.0 equiv) was used.
Purification by column chromatography (n-
intensity) 301 (90), 271 (5), 231 (12), 213 (33), 185 (14), 167
1
2
3
4
5
6
7
8
(19), 161 (24), 155 (100), 136 (18), 127 (18), 109 (18), 99 (11),
69 (21); HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C16H28O6Na
339.1783; Found 339.1789. IR (ATR, neat, cm-1): 2984 (w),
2940 (w), 2874 (w), 1728 (s), 1461 (w), 1371 (m), 1202 (m),
1148 (m), 1085 (m), 1028 (m), 831 (m).
pentane:EtOAc = 40:1) yielded the title compound 8eb (80 mg,
0.327 mmol, 66%) as colorless oil. Rf = 0.74 (n-pentane:EtOAc
1
= 10:1, KMnO4); H NMR (300 MHz, CDCl3) δ 4.14 (qd, J = 7.1,
3.1 Hz, 4H), 3.48 (d, J = 5.4 Hz, 1H), 2.20 (m, 1H), 1.22 (ddd, J =
7.1, 5.8, 3.2 Hz, 6H), 0.97 (d, J = 7.2 Hz, 3H), 0.86 (s, 9H); 13C {1H}
NMR (75 MHz, CDCl3) δ 170.3, 169.6, 61.4, 61.0, 53.4, 42.7, 33.7,
27.6, 14.1, 14.1, 12.1; MS (EI): m/z (relative intensity) 245 (1)
[M], 229 (9), 199 (28), 188 (26), 173 (7), 155 (39), 142 (72),
127 (12), 115 (100), 109 (13), 99 (24), 87 (41), 69 (45); HRMS
(ESI-TOF) m/z: [M]+ Calcd for C13H24O4 245.1753; Found
245.1753. IR (ATR, neat, cm-1): 2967 (w), 2907 (w), 1729 (s),
1466 (w), 1368 (m), 1296 (m), 1239 (m), 1144 (m), 1030 (m),
865 (w), 775 (w). The analytic data is in correspondence with
that reported in literature.46
Dimethyl
2-(2-((tert-butoxycarbonyl)amino)propan-2-
yl)succinate (8ha). Compound 8ha was prepared following
general procedure A. α-(Boc-amino)isobutyric acid (102 mg,
0.5 mmol, 1.0 equiv.) and dimethyl maleate (144 mg, 1.0 mmol,
2.0 equiv.) used. Purification by column chromatography (n-
pentane:EtOAc = 9:1) yielded the title compound 8ha (69 mg,
0.22 mmol, 45%) as a colorless oil. The products give multiple
sets of NMR signals, owing to the presence of rotamers of the
amide. Rf = 0.47 (n-pentane:EtOAc = 9:2, KMnO4); 1H NMR (300
MHz, CDCl3) δ 4.72 (br. s, 1H), 3.69 (s, 3H), 3.63 (s, 3H), 3.41 (m,
1H), 2.61 (m, 2H), 1.42 (m, 9H), 1.32 (s, 3H), 1.26 (s, 3H); 13C
{1H} NMR (75 MHz, CDCl3) δ 174.2, 172.5, 154.4, 154.4, 79.4,
79.4, 79.3, 53.5, 53.4, 52.0, 52.0, 51.8, 48.8, 48.8, 32.7, 28.5,
28.3, 25.6, 25.3, 17.5; MS (EI): m/z (relative intensity) 230 (4),
216 (6), 198 (5), 172 (7), 155 (21), 128 (19), 114 (21), 102
(57), 96 (7), 84 (10), 69 (6), 57 (100); HRMS (ESI-TOF) m/z:
[M+Na]+ Calcd for C14H25NO6Na 326.1579; found 326.1575. IR
(ATR, neat, cm-1): 3379 (w), 2977 (w), 2953 (w), 1714 (m),
1510 (m), 1439 (m), 1366 (m), 1243 (m), 1160 (s), 1074 (m),
1021 (w).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Dimethyl
2-((3r,5r,7r)-adamantan-1-yl)succinate
(8fa).
Compound 8fa was prepared following general procedure A.
Dimethyl maleate (144 mg, 1.0 mmol, 2.0 equiv). was used.
Purification
by
column
chromatography
(n-
pentane:EtOAc = 15:1) yielded the title compound 8fa
(115 mg, 0.41 mmol, 82%) as a colorless solid. m.p.  51 °C;
Rf = 0.58 (n-pentane:EtOAc = 10:1, KMnO4); 1H NMR (400 MHz,
CDCl3) δ 3.64 (s, 3H), 3.60 (s, 3H), 2.70 (m, 1H), 2.45 (m, 2H),
1.96 (m, 3H), 1.61 (q, J = 12.2 Hz, 9H), 1.42 (m, 3H); 13C {1H}
NMR (75 MHz, CDCl3) δ 174.3, 173.4, 52.3, 51.8, 51.3, 40,0, 36.8,
34.4, 31.0, 28.5; MS (EI): m/z (relative intensity) 280 (1), 248
(13), 145 (7), 135 (100), 107 (6), 93 (12), 79 (14); HRMS (ESI-
TOF) m/z: [M]+ Calcd for C16H24O4 280.1669; Found 280.1664.
IR (ATR, neat, cm-1): 2900 (s), 2847 (m), 1725 (s), 1438 (s),
1413 (w), 1366 (m), 1340 (m), 1304 (m), 1285 (w), 1229 (s),
1208 (s), 1194 (s), 1161 (s), 1119 (m), 1097 (m), 1081 (w),
1011 (w), 987 (m), 964 (m), 887 (w), 845 (m), 819 (w), 798
(w), 773 (w), 720 (w), 681 (w), 590 (w), 525 (w), 454 (w). The
analytic data is in correspondence with that reported in
literature.45
dimethyl
2-((4aR,6aS,6bR,10S,12aS,12bR)-10-hydroxy-
2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-
1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-
icosahydropicen-2-yl)succinate (8ia). Compound 8ia was
prepared following general procedure A for 48 h. 18β-
Glycyrrhetinic acid (enoxolone) (235.4 mg, 0.5 mmol, 1.0
equiv.) was used. Purification by column chromatography (n-
pentane:EtOAc = 10:1 → 5:2) yielded the title compound 8ia
(223 mg, 0.391 mmol, 78%) as a colorless thick oil. (mixture of
diastereomeres). Rf = 0.2 (n-pentane:EtOAc = 5:2, UV, KMnO4);
1H NMR (300 MHz, CDCl3) δ 5.55 (m, 1H), 3.65 (m, 6H), 3.21
(dd, J = 10.5, 5.8 Hz, 1H), 2.76 (m, 2H), 2.58 (m, 1H), 2.46 (ddd,
J = 16.4, 7.1, 2.8 Hz, 1H), 2.31 (d, J = 7.3 Hz, 1H), 2.11 (m, 1H),
1.90 (m, 3H), 1.60 (m, 5H), 1.38 (m, 10H), 1.15 (m, 8H), 0.96 (m,
9H), 0.81 (d, J = 16.2 Hz, 6H); 13C {1H } NMR (75 MHz, CDCl3) δ
200.4, 200.2, 174.4, 174.3, 173.2, 173.1, 169.7, 169.5, 128.6,
128.5, 78.8, 61.9, 61.9, 55.0, 53.3, 53.2, 52.0, 51.7, 51.6, 46.9,
45.6, 43.4, 41.8, 40.5, 39.2, 37.2, 36.1, 35.7, 32.8, 32.4, 32.4,
31.8, 31.8, 31.2, 30.1, 28.7, 28.6, 28.2, 27.4, 26.4, 26.3, 23.6,
23.5, 18.8, 18.5, 18.5, 17.6, 16.5, 16.4, 15.7; MS (EI): m/z
(relative intensity) 570 (56) [M], 539 (7), 403 (100), 362 (84),
339 (18), 302 (12), 235 (15), 217 (15), 193 (16), 188 (11), 175
(71), 161 (10), 135 (46), 121 (17), 95 (19); HRMS (ESI-TOF)
m/z: [M+H] Calcd for C35H55O6 571.3998; Found 571.4002. IR
(ATR, neat, cm-1): 3433 (w, br.), 2946 (w), 2926 (w), 2865 (w),
1730 (w), 1655 (w), 1436 (w), 1195 (w), 1162 (w), 1037 (w),
729 (w).
Big scale synthesis of dimethyl 2-((3r,5r,7r)-adamantan-1-
yl)succinate (8fa)
To a 100 ml flame dried Schlenk flask equipped with a stir bar
was added 1-adamantanecarboxylic acid (541 mg, 3.0 mmol,
1.0 equiv.), n-propyl PPTNO (64.9 mg, 150.0 µmol, 0.05 equiv.)
and K3PO4 (127.4 mg, 600.0 µmol, 0.2 equiv.). The flask was
evacuated and flushed with argon
3 times. Afterwards,
dimethyl maleate (865 mg, 6.0 mmol, 2.0 equiv.) was added,
followed by MeCN (27 ml) and degassed water (3 ml) under
argon. The reaction mixture was stirred in the dark for 5
minutes, then it was irradiated for 24 hours. The reaction was
quenched by bubbling air through the reaction mixture using a
pipette. Drying the mixture under vacuum afforded an oil
which was purified by column chromatography (n-
pentane:EtOAc = 15:1). The title compound 8fa (375 mg,
1.34 mmol, 45%) was obtained as a colorless solid.
Diethyl
2-(1-(2,2,5-trimethyl-1,3-dioxan-5-yl)ethyl)malonate
Dimethyl 2-(2-phenoxypropan-2-yl)succinate (8ja). Compound
8ja was prepared following general procedure A. Dimethyl
maleate (144 mg, 1.0 mmol, 2.0 equiv). Purification by column
chromatography (n-pentane:EtOAc = 9:1) yielded the title
compound 8ja (37 mg, 0.13 mmol, 26%) as colorless oil.
(8gb). Compound 8gb was prepared following general
procedure A. 2,2,5-trimethyl-1,3-dioxane-5-carboxylic acid
(87 mg, 0.5 mmol, 1.0 equiv.) was used. Purification by column
chromatography (n-pentane:EtOAc = 20:1) yielded the title
compound 8gb (46 mg, 0.145 mmol, 29%) as a colorless oil.
Rf = 0.31 (n-pentane:EtOAc = 10:1, KMnO4); 1H NMR (300 MHz,
CDCl3) δ 4.17 (m, 4H), 3.74 (dd, J = 21.1, 11.5 Hz, 2H), 3.58 (d, J
= 5.0 Hz, 1H), 3.46 (ddd, J = 11.8, 6.0, 1.1 Hz, 2H), 2.56 (qd, J =
7.2, 5.1 Hz, 1H), 1.38 (d, J = 3.7 Hz, 6H), 1.26 (td, J = 7.1, 3.5 Hz,
6H), 1.01 (d, J = 7.2 Hz, 3H), 0.91 (s, 3H); 13C {1H} NMR (75 MHz,
CDCl3) δ 169.7, 169.3, 98.1, 68.7, 68.0, 61.7, 61.2, 52.3, 36.5,
35.5, 24.5, 23.2, 16.4, 14.1, 11.1; MS (EI): m/z (relative
1
Rf = 0.45 (n-pentane:EtOAc = 9:1, KMnO4); H NMR (300 MHz,
CDCl3) δ 7.31 (m, 2H), 7.19 (m, 1H), 6.88 (m, 2H), 4.24 (m, 1H),
3.80 (s, 3H), 3.77 (s, 3H), 3.71 (m, 1H), 3.29 (dd, J = 17.5, 11.0
Hz, 1H), 1.55 (s, 3H), 1.26 (s, 3H); 13C {1H} NMR (75 MHz, CDCl3)
δ 172.7, 172.4, 152.5, 129.0, 127.6, 120.9, 118.0, 117.4, 108.5,
75.0, 52.6, 52.3, 50.8, 42.8, 28.6, 20.9; MS (EI): m/z (relative
intensity) 280 (6), 249(4), 220 (14), 188 (16), 166 (23), 161
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Page 8 of 15
(17), 145 (25), 134 (100), 127 (15), 119 (10), 106 (46), 95 (39),
1252 (m), 1175 (w), 1029 (m), 859 (w). The analytic data is in
correspondence with that reported in literature.31
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2
3
4
5
6
7
8
83 (21), 77 (44); HRMS (ESI-TOF) m/z: [M]+ Calcd for C15H20O5
281.1389; Found 281.1393. IR (ATR, neat, cm-1): 2986 (w),
2955 (w), 1729 (s), 1583 (w), 1436 (w), 1333 (w), 1254 (m),
1162 (m), 1114 (m), 1018 (w), 943 (w), 765 (m).
Dimethyl
2-(1-(((benzyloxy)carbonyl)amino)-2-
methylpropyl)succinate (8na). Compound 8na was prepared
following general procedure A. Dimethyl maleate (144 mg,
1.0 mmol, 2.0 equiv) and K3PO4 (0.5 mmol, 1,0 equiv.) were
used. Purification by column chromatography (n-
pentane:acetone = 20:1) yielded the title compound 8na
(120 mg, 0.34 mmol, 68 %) as a light yellow oil. Analytical data
are stated for a mixture of two diastereomers (dr 1:1). Rf = 0.28
(n-pentane:acetone = 20:1, KMnO4);1H NMR (300 MHz, CDCl3)
δ 7.33 (m, 5H), 5.28 (m, 1H), 5.10 (m, 2H), 3.67 (d, J = 6.6 Hz,
5H), 3.55 (m, 1H), 3.21 (m, 1H), 2.66 (m, 2H), 1.64 (m, 1H), 0.94
(m, 6H); 13C {1H } NMR (75 MHz, CDCl3) δ 174.1, 172.0, 156.7,
136.6, 128.8, 128.6, 128.6, 128.1, 128.0, 127.9, 66.8, 58.1, 52.0,
52.0, 42.4, 34.9, 32.0, 19.9, 19.4; MS (EI): m/z (relative
intensity) 308 (6), 204 (23), 114 (6), 91 (100), 79 (4), 65 (6),
55 (6); HRMS (ESI-TOF) m/z: [M]+ Calcd for C18H25NO6
351.1676; Found 351,1671. IR (ATR, neat, cm-1): 3350 (w),
2957 (w), 1719 (s), 1587 (w), 1527 (m), 1455 (w), 1436 (m),
1409 (w), 1390 (w), 1343 (m), 1232 (s), 1168 (s), 1116 (m),
1093 (m), 1027 (m), 999 (m), 912 (w), 889 (w), 844 (w), 772
(w), 739(m), 697 (s), 597 (w), 523 (w), 457 (w).
Dimethyl
2-(5-(2,5-dimethylphenoxy)-2-methylpentan-2-
yl)succinate (8ka). Compound 8ka was prepared following
general procedure A for 48 h instead of 16 h. Dimethyl maleate
(144 mg, 1.0 mmol, 2.0 equiv) was used. Purification by column
chromatography (n-pentane:EtOAc = 10:1) yielded the title
compound 8ka (30 mg, 0.09 mmol, 17%) as colorless oil.
Rf = 0.42 (n-pentane:EtOAc = 10:1, KMnO4); 1H NMR (300 MHz,
CDCl3) δ 7.00 (d, J = 7.5 Hz, 1H), 6.66 (d, J = 7.5 Hz, 1H), 6.61 (s,
1H), 3.91 (m, 2H), 3.69 (s, 3H), 3.66 (s, 3H), 2.82 (m, 2H), 2.48
(m, 1H), 2.31 (s, 3H), 2.17 (s, 3H), 1.82 (m, 2H), 1.45 (m, 2H),
0.97 (d, J = 2.0 Hz, 6H); 13C {1H} NMR (75 MHz, CDCl3) δ 174.8,
173.3, 157.1, 136.6, 130.4, 123.7, 120.8, 112.1, 68.2, 51.9, 51.6,
49.5, 37.3, 35.1, 32.4, 25.2, 25.0, 24.1, 21.5, 15.9; MS (EI): m/z
(relative intensity) 350 (37) [M], 229 (100), 197 (10), 179 (11),
169 (15), 165 (57), 137 (35), 122 (80), 109 (24), 95 (18), 83
(51); HRMS (ESI-TOF) m/z: [M]+ Calcd for C20H30O5 351.2171;
Found 351.2171. IR (ATR, neat, cm-1): 2951 (w), 2873 (w),
1732 (s), 1614 (w), 1509 (w), 1261 (m), 1191 (w), 1156 (s),
1129 (m), 1008 (w), 504 (w).
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Diethyl
2-(1-(1-(tert-butoxycarbonyl)pyrrolidin-2-
yl)ethyl)malonate (8ob). Compound 8ob was prepared
following general procedure A. Diethyl ethylidenmalonate
(186 mg, 1.0 mmol, 2.0 equiv) was used. Purification by column
chromatography (n-pentane:EtOAc = 20:1 → 20:3) yielded the
title compound 8ob (80 mg, 0.23 mmol, 45%) as translucent
oil. The products give multiple sets of NMR signals, owing to the
presence of rotamers around the amide. Analytical data states
for the diastereomeric mixture (1:1). Rf = 0.23 (n-
pentane:EtOAc = 10:1, KMnO4); 1H NMR (300 MHz, CDCl3) δ
4.14 (m, 4H), 3.84 (m, 1H), 3.38 (m, 2H), 3.06 (m, 1H), 2.58 (m,
1H), 1.81 (m, 4H), 1.46 (d, J = 23.9 Hz, 9H), 1.24 (m, 6H), 0.89
(d, J = 6.6 Hz, 3H); 13C {1H }NMR (75 MHz, CDCl3) δ 169.0, 168.4,
155.3, 154.9, 79.8, 79.2, 61.3, 61.2, 60.6, 60.4, 55.6, 54.8, 54.1,
47.2, 46.9, 37.1, 36.9, 29.3, 28.5, 28.5, 28.3, 28.2, 23.6, 23.4,
14.2, 14.1, 13.8, 13.6; MS (EI): m/z (relative intensity) 301(13),
255 (16), 227 (4), 187 (65), 181 (8), 160 (19), 141 (100), 133
(12), 115 (15), 113 (21), 99 (8), 87 (13), 69 (32); HRMS (ESI-
TOF) m/z: [M+Na]+ Calcd for C18H31NO6Na 380.2043; Found
380.2060. IR (ATR, neat, cm-1): 2975 (w), 2936 (w), 1751 (w),
1729 (m), 1689 (m), 1455 (w), 1381 (m), 1365 (m), 1161 (m),
1105 (m), 1030 (m), 916 (w), 861 (w), 773 (w). The analytic
data is in correspondence with that reported in literature.46
Dimethyl
(E)-2-(2-(4-(2-(4-
chlorobenzamido)vinyl)phenoxy)propan-2-yl)succinate (8la).
Compound 8la was prepared following general procedure A for
48 hours. 2-(4-(2-(4-chlorobenzamido)ethyl)phenoxy)-2-
methylpropanoic acid (Bezafibrate) (181 mg, 0.5 mmol, 1.0
equiv.) was used. Purification by column chromatography (n-
pentane:acetone = 10:1) yielded the title compound 8la
(72 mg, 0.16 mmol, 31%) as a white solid. m.p.= 172173 °C;
Rf = 0.17 (n-pentane:acetone = 20:3, UV, KMnO4); 1H NMR (300
MHz, CDCl3) δ 7.63 (m, 2H), 7.36 (m, 2H), 7.08 (m, 1H), 7.02 (m,
1H), 6.78 (d, J = 8.3 Hz, 1H), 6.26 (t, J = 5.5 Hz, 1H), 4.17 (d, J =
11.8 Hz, 1H), 3.71 (m, 7H), 3.53 (m, 1H), 3.24 (d, J = 11.7 Hz,
1H), 2.81 (m, 2H), 1.50 (s, 3H), 1.22 (s, 3H); 13C {1H} NMR (75
MHz, CDCl3) δ 172.8, 172.3, 166.5, 151.3, 137.7, 133.0, 131.2,
129.4, 128.9, 128.4, 127.9, 118.3, 117.6, 75.0, 52.6, 52.4, 50.8,
42.7, 41.4, 35.0, 28.5, 21.0; MS (EI): m/z (relative intensity) 459
(3) [M], 400 (9), 304 (100), 272 (37), 244 (64), 229 (52), 199
(24), 171 (22), 159 (10), 139 (45), 128 8), 111 (16); HRMS (ESI-
TOF) m/z: [M+H]+ Calcd for C24H27O6NCl 460.1527; Found
460.1521. IR (ATR, neat, cm-1): 3233 (w), 3083 (w), 2952 (w),
1731 (m), 1630 (w), 1303 (w), 1193 (m), 847 (w), 737 (w).
Diethyl
2-(1-(2,3-dihydrobenzo[b][1,4]dioxin-2-
Diethyl
2-(3-((tert-butoxycarbonyl)amino)-4-phenylbutan-2-
yl)ethyl)malonate (8mb). Compound 8mb was prepared
following general procedure A. 1,4-Benzodioxane-6-carboxylic
acid (90 mg, 0.50 mmol, 1.0 equiv) was used. Purification by
column chromatography (n-pentane:EtOAc = 100:2) yielded
the title compound 8mb (112 mg, 0.35 mmol, 70%) as a
colorless oil (mixture of diastereomeres 1:1). Rf = 0.31 (n-
pentane:EtOAc = 10:1, KMnO4); 1H NMR (300 MHz, CDCl3) δ
6.83 (m, 4H), 4.23 (m, 6H), 4.01 (m, 1H), 3.75 (dd, J = 51.8, 7.1
Hz, 1H), 2.57 (m, 1H), 1.27 (m, 6H), 1.12 (dd, J = 19.9, 7.0 Hz,
3H); 13C {1H} NMR (75 MHz, CDCl3) δ 169.0, 168.5, 168.4, 168.3,
143.7, 143.4, 143.3, 143.0, 121.6, 121.5, 121.4, 117.3, 117.1,
117.1, 74.6, 73.7, 66.4, 66.2, 61.7, 61.6, 61.5, 61.3, 54.4, 52.2,
34.6, 34.4, 14.2, 14.2, 14.2, 14.1, 13.1, 11.9; MS (EI): m/z
(relative intensity) 322 (34) [M], 277 (17), 231 (10), 162 (100),
147 (19), 139 (16), 135 (48), 121 (28), 111 (13), 95 (7), 69
(11); HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C17H22O6Na
345.1313; Found 345.1314. IR (ATR, neat, cm-1): 2981 (w),
2938 (w), 1727 (m), 1594 (w), 1493 (m), 1369 (w), 1265 (m),
yl)malonate (8pb). Compound 8pb was prepared following
general procedure A. Boc-L-Phenylalanine (133 mg, 0.5 mmol,
1.0 equiv.) and diethyl ethylidenmalonate (186 mg, 1.0 mmol,
2.0 equiv) was used. Purification by column chromatography
(n-pentane:EtOAc = 8:1) yielded the title compound 8pb
(61 mg, 0.15 mmol, 30%) as a pale yellow oil (mixture of
1
diastereomers). Rf = 0.44 (n-pentane:EtOAc = 8:2, KMnO4); H
NMR (300 MHz, CDCl3) δ 7.26 (m, 2H), 7.15 (m, 3H), 4.51 (d, J =
9.4 Hz, 0.39H), 4.21 (m, 5.88H), 3.77 (m, 0.53H), 3.48 (d, J = 6.8
Hz, 0.52H), 3.34 (m, 0.48H), 2.99 (m, 0.53H), 2.76 (d, J = 6.7 Hz,
0.76H), 2.62 (m, 0.54H), 2.45 (m, 1.08H), 1.28 (m, 15.88H), 1.11
(m, 1.77H), 0.92 (t, J = 7.2 Hz, 1.41H); 13C {1H } NMR (75 MHz,
CDCl3) δ 169.6, 169.0, 168.4, 155.6, 155.3, 138.0, 129.4, 129.2,
128.5, 128.5, 126.5, 79.3, 79.1, 61.6, 61.4, 61.3, 61.2, 55.6, 55.4,
55.2, 54.3, 52.8, 39.9, 39.1, 37.2, 35.8, 28.3, 28.0, 15.1, 14.2,
14.1, 11.1; MS (EI): m/z (relative intensity) 334 (2), 316 (18),
288 (4), 262 (17), 216 (100), 198 (16), 170 (32), 142 (27), 131
(16), 124 (49), 96 (17), 91 (33), 69 (10), 57 (52); HRMS (ESI-
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The Journal of Organic Chemistry
TOF) m/z: [M+Na]+ Calcd for C13H24O4Na 430.2205; Found
pentane:EtOAc = 3:1, KMnO4); 1H NMR (300 MHz, CDCl3) δ 4.00
1
2
3
4
5
6
7
8
430.2217. IR (ATR, neat, cm-1): 2978 (w), 2936 (w), 1726 (w),
1700 (w), 1497 (w), 1455 (w), 1389 (w), 1366 (w), 1168 (w),
1028 (w), 700 (w). The analytic data is in correspondence with
that reported in literature.29
(dd, J = 14.1, 6.8 Hz, 1H), 3.76 (m, 5H), 3.67 (s, 3H), 2.82 (m, 3H),
1.92 (m, 3H), 1.71 (m, 1H); 13C {1H} NMR (75 MHz, CDCl3) δ
173.5, 172.8, 78.8, 68.2, 52.2, 51.9, 46.8, 33.3, 29.8, 25.7; MS
(EI): m/z (relative intensity) 185 (3), 153 (3), 143 (15), 111
(11), 87 (3), 71 (100), 59 (13); HRMS (ESI-TOF) m/z: [M+Na]+
Calcd for C10H16O5Na 239.0895; Found 239.0899. IR (ATR, neat,
cm-1): 2953 (w), 2874 (w), 1731 (s), 1436 (m), 1358 (m), 1260
(m), 1195 (m), 1159 (s), 1063 (m), 1030 (m), 922 (w), 890 (w),
849 (m). Data for 8sa(b): Rf = 0.35 (n-pentane:EtOAc = 3:1,
KMnO4); 1H NMR (300 MHz, CDCl3) δ 4.05 (m, 1H), 3.85 (m, 1H),
3.73 (m, 4H), 3.67 (s, 3H), 3.08 (m, 1H), 2.76 (m, 1H), 2.47 (dd,
J = 16.6, 4.5 Hz, 1H), 1.90 (m, 3H), 1.63 (m, 1H); 13C {1H} NMR
(75 MHz, CDCl3) δ 173.4, 172.4, 79.0, 68.6, 52.2, 52.0, 46.2, 32.6,
28.8, 25.8; MS (EI): m/z (relative intensity) 185 (4), 153 (2),
143 (14), 111 (10), 87 (2), 71 (100), 59 (13) ; HRMS (ESI-TOF)
m/z: [M+Na]+ Calcd for C10H16O5Na 239.0895; Found
239.0894. IR (ATR, neat, cm-1): 2953 (w), 2874 (w), 1731 (s),
1436 (m), 1361 (w), 1260 (m), 1194 (m), 1160 (s), 1065 (m),
1004 (m), 925 (w), 890 (w), 849 (w). The analytic data is in
correspondence with that reported in literature.49
Dimethyl-2-(1-((4-methoxybenzoyl)-L-valyl)pyrrolidin-2-
yl)succinate (8qa). Compound 8qa was prepared following
general procedure A on a 0.2 mmol scale. (4-methoxybenzoyl)-
L-valylproline (52 mg, 0.15 mmol, 1.0 equiv), dimethyl maleate
(45 mg, 0.3 mmol, 2.0 equiv), PrPPTNO (3.2 mg, 0.01 mmol,
0.05 equiv.) and K3PO4 (31.8 mg, 0.2 mmol, 1,0 equiv.) were
used in 2 mL of MeCN:H2O (9:1). Purification by column
chromatography (n-pentane:EtOAc = 2:1) yielded the title
compound 8qa (51 mg, 0.11 mmol, 75 %) as a light yellow oil.
Analytical data are stated for a mixture of two diastereomers
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1
(dr 1:1). Rf = 0.17 (n-pentane:acetone = 1:1, KMnO4); H NMR
(300 MHz, CDCl3) δ 7.77 (dd, J = 8.8, 6.8 Hz, 4H), 6.85 (m, 6H),
4.79 (m, 2H), 4.34 (m, 2H), 3.82 (d, J = 3.2 Hz, 6H), 3.67 (d, J =
4.0 Hz, 3H), 3.65 (s, 3H), 3.60 (s, 3H), 3.57 (s, 3H), 3.52 (d, J =
4.4 Hz, 3H), 2.41 (m, 8H), 1.89 (m, 8H), 0.99 (m, 12H); 13C {1H}
NMR (75 MHz, CDCl3) δ 173.3, 173.0, 172.2, 172.1, 172.0, 171.9,
171.8, 171.4, 171.1, 171.1, 166.8, 166.8, 166.6, 162.3, 128.9,
126.5, 126.4, 126.3, 113.8, 113.7, 113.7, 77.5, 77.1, 76.6, 58.8,
58.3, 58.0, 57.7, 56.3, 56.2, 55.9, 55.9, 55.4, 52.1, 52.1, 52.1,
52.0, 52.0, 51.8, 51.7, 48.1, 47.6, 47.2, 43.3, 42.7, 42.6, 42.3,
42.0, 33.7, 33.4, 31.8, 31.6, 31.5, 31.3, 31.1, 31.0, 29.7, 27.3,
27.1, 27.0, 26.4, 25.0, 24.5, 24.3, 24.2, 23.7, 19.8, 19.8, 19.7,
19.6, 18.0, 18.0, 17.4, 17.3, 17.3, 17.2; LCMS (ESI, m/z): 471.2
[M+Na]+; HRMS (ESI-TOF) m/z: [M] Calcd for C23H32N2O7
448.2215; Found 448.2216. IR (ATR, neat, cm-1): 3323 (w),
2957 w), 1732 (s), 1623 (s), 1606 (s), 1576 (w), 1536 (w), 1500
(m), 1433 (s), 1308 (m), 1251 (s), 1170 (s), 1121 (m), 1027
(m), 896 (w), 845 (m), 767 (m), 732 (w), 606 (m), 563 (m), 523
(m).
Diethyl 2-(1-cyclobutylethyl)malonate (8tb). Compound 8tb
was prepared following general procedure A. Cyclobutane
carboxylic acid (50.1 mg, 0.5 mmol, 1.0 equiv) was used.
Purification
by
column
chromatography
(n-
pentane:EtOAc = 100:2) yielded the title compound 8tb
(43 mg, 0.177 mmol, 35%) as a colorless oil. Rf = 0.45 (n-
pentane:EtOAc = 20:1, KMnO4); 1H NMR (300 MHz, CDCl3) δ
4.15 (qt, J = 13.7, 6.8 Hz, 4H), 3.20 (d, J = 6.3 Hz, 1H), 2.19 (m,
2H), 1.93 (m, 2H), 1.71 (m, 4H), 1.25 (t, J = 7.1 Hz, 6H), 0.90 (d,
J = 6.5 Hz, 3H); 13C {1H} NMR (75 MHz, CDCl3) δ 169.4, 168.8,
61.3, 61.1, 55.1, 40.2, 40.1, 27.4, 27.2, 17.6, 14.2, 14.2, 14.1; MS
(EI): m/z (relative intensity) 227 (27), 199 (10), 197 (41), 169
(48), 160 (100), 150 (22), 141 (92), 133 (38), 122 (22), 115
(57), 105 (9), 95 (34), 87 (25), 83 (21), 69 (30); HRMS (ESI-
TOF) m/z: [M+Na]+ Calcd for C13H22O4Na 265.1415; Found
265.1418. IR (ATR, neat, cm-1): 2974 (w), 2938 (w), 1729 (s)
1463 (w), 1369 (w), 1242 (m), 1174 (m), 1148 (m), 1031 (m),
862 (w). The analytic data is in correspondence with that
reported in literature.29
Diethyl
2-(1-(tetrahydrofuran-2-yl)ethyl)malonate
(8rb).
Compound 8rb was prepared following general procedure A
for 24 h. Tetrahydro-2-furoic acid (116 mg, 1.0 mmol,
2.0 equiv) and diethyl ethylidenmalonate (93, 0.5 mmol, 1.0
equiv.) were used. Purification by column chromatography (n-
pentane:EtOAc = 20:1) yielded the title compound 8rb (44 mg,
0.17 mmol, 34%) as a colorless oil (mixture of diastereomeres
1:1.3). Rf = 0.14 (n-pentane:EtOAc = 20:1, KMnO4); 1H NMR
(300 MHz, CDCl3) δ 4.17 (qdd, J = 7.1, 2.6, 2.0 Hz, 4H), 3.75 (m,
3H), 3.59 (d, J = 6.4 Hz, 0.52H), 3.40 (d, J = 8.6 Hz, 0.43H), 2.47
(m, 0.43H), 2.27 (m, 0.56H), 1.90 (m, 3H), 1.53 (m, 1H), 1.25 (m,
6H), 0.96 (dd, J = 6.9, 4.0 Hz, 3H); 13C {1H } NMR (75 MHz, CDCl3)
δ 169.4, 169.0, 168.9, 168.9, 81.4, 80.5, 68.4, 67.9, 61.3, 61.3,
61.2, 61.1, 55.1, 54.5, 39.2, 37.5, 30.1, 28.6, 26.1, 26.0, 14.2,
14.2, 14.2, 13.6, 12.4; MS (EI): m/z (relative intensity) 257 (1)
[M], 213 (17), 189 (11), 167 (16), 139 (11), 115 (7), 98 (76), 71
(100); HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C13H22O5Na
281.1364; Found 281.1369. IR (ATR, neat, cm-1): 2977 (w),
2940 (w), 2875 (w), 1728 (s), 1464 (w), 1265 (m), 1174 (m),
1153 (m), 1065 (m), 1030 (m), 863 (w). The analytic data is in
correspondence with that reported in literature.48
Dimethyl 2-(tetrahydrofuran-2-yl)succinate (8sa). Compound
8sa was prepared following general procedure A for 24 h.
Tetrahydro-2-furoic acid (1.0 mmol, 2.0 equiv.), dimethyl
maleate (144 mg, 0.5 mmol, 1.0 equiv) and K3PO4 (0.2 mmol,
0.4 equiv.) were used. Purification by column chromatography
(n-pentane:EtOAc = 3:1) yielded the title compound 8sa
(57 mg, 0.26 mmol, 52%) as colorless oil (mixture of
diastereomeres: 1:1). Diastereomeres 8sa(a) and 8sa(b) were
Diethyl 2-(1-cyclohexylethyl)malonate (8ub). Compound 8ub
was prepared following general procedure A for 24 h. Diethyl
ethylidenmalonate
(93 mg,
0.5 mmol,
1.0 equiv),
cyclohexanecarboxylic acid (128 mg, 1.0 mmol, 2.0 equiv) and
K3PO4 (42.5 mg, 0.2 mmol, 0.4 equiv) were used. Purification by
column chromatography (n-pentane:EtOAc = 40:1) yielded the
title compound 8ub (50 mg, 0.19 mmol, 37%) as colorless oil.
Rf = 0.34 (n-pentane:EtOAc = 40:1, KMnO4); 1H NMR (300 MHz,
CDCl3) δ 4.17 (m, 4H), 3.37 (d, J = 9.1 Hz, 1H), 2.32 – 2.06 (m,
1H), 1.80 – 1.51 (m, 5H), 1.38 – 1.00 (m, 12H), 0.88 (d, J = 7.0
Hz, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 169.4, 169.2, 61.2,
61.2, 55.9, 40.4, 38.7, 31.6, 27.5, 26.9, 26.7, 26.6, 14.2, 13.0; MS
(EI): m/z (relative intensity) 271 (1) [M+H], 225 (11), 187 (42),
160 (100), 141 (31), 133 (50), 115 (54), 105 (13), 88 (18), 81
(33), 69 (60); HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for
C15H26O4Na 293.1728; Found 293.1727. IR (ATR, neat, cm-1):
2979 (w), 2925 (m), 2853 (w), 1153 (w), 1730 (m), 1463 (w),
1448 (w), 1149 (w), 1032 (w). The analytic data is in
correspondence with that reported in literature.31
Diethyl 2-(3-methylpentan-2-yl)malonate (8vb). Compound
8vb was prepared following general procedure A. 2,2-
Dimethylbutyric acid (51 mg, 0.5 mmol, 1.0 equiv) was used.
Purification
by
column
chromatography
(n-
then
separated
by
column
chromatography
(n-
pentane:EtOAc = 100:2) yielded the title compound 8vb
(35 mg, 0.14 mmol, 29%) as a colorless oil. Rf = 0.43 (n-
pentane:EtOAc = 3:1). Data for 8sa(a): Rf = 0.59 (n-
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pentane:EtOAc = 20:1, KMnO4); 1H NMR (300 MHz, CDCl3) δ
15.4; 19F NMR (282 MHz, CDCl3) δ -118.81 (dd, J = 11.5 Hz, 8.3
1
2
3
4
5
6
7
8
4.17 (m, 4H), 3.33 (dd, J = 21.7, 9.9 Hz, 1H), 2.28 (m, 1H), 1.30
(m, 9H), 0.92 (m, 10H); 13C {1H} NMR (75 MHz, CDCl3) δ 169.4,
169.2, 169.1, 61.3, 61.2, 57.0, 56.2, 38.9, 37.0, 36.6, 36.2, 28.1,
23.8, 17.5, 14.2, 13.5, 12.6, 12.2, 12.1, 11.2; MS (EI): m/z
(relative intensity) 199 (17), 187 (10), 160 (100), 141 (14), 133
(39), 115 (41), 105 (8), 87 (24), 69 (28), 55 (10); HRMS (ESI-
TOF) m/z: [M+Na]+ Calcd for C13H24O4Na 267.1572; Found
267.1570. IR (ATR, neat, cm-1): 2964 (w), 2936 (w), 1754 (m),
1730 (s), 1463 (w), 1368 (w), 1274 (w), 1191 (m), 1129 (m),
1096 (w), 1031 (m), 860 (w). The analytic data is in
correspondence with that reported in literature.46
Hz); MS (EI): m/z (relative intensity) 200 (50) [M], 185 (100),
165 (17), 157 (4), 133 (9), 92 (5), 63 (5); HRMS (ESI-TOF) m/z:
[M]+ Calcd for C14H13F1 200.0996; Found 200.0996; IR (ATR,
neat, cm-1): 2996 (w), 2873 (w), 1625 (w), 1483 (m), 1416 (m).
1266 (w), 1128 (w), 1011 (w), 911 (m), 763 (m), 695 (s). The
analytic data is in correspondence with that reported in
literature.50
3-((3r,5r,7r)-adamantan-1-yl)cyclopentan-1-one
(10).
Compound 10 was prepared following general procedure A. 2-
Cyclopentenon (82.1 mg, 1.0 mmol, 2.0 equiv) was used.
9
Purification
by
column
chromatography
(n-
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Diethyl
2-(1-((tert-butoxycarbonyl)amino)propan-2-
pentane:EtOAc = 20:1) yielded the title compound 10 (97 mg,
0.444 mmol, 89%) as a colorless oil. Rf = 0.5 (n-pentane:EtOAc
= 10:1, KMnO4); 1H NMR (400 MHz, CDCl3) δ 2.28 (m, 1H), 2.11
(m, 2H), 1.93 (m, 5H), 1.81 (m, 1H), 1.70 (m, 3H), 1.61 (m, 4H),
1.49 (m, 6H); 13C {1H} NMR (101 MHz, CDCl3) δ 220.1, 48.9,
40.1, 39.2, 38.9, 37.3, 33.5, 28.5, 22.5; MS (EI): m/z (relative
intensity) 218 (6) [M], 135 (100), 105 (3), 93 (14), 79 (15), 53
(3); HRMS (ESI-TOF) m/z: [M]+ Calcd for C15H22O1 218.1665;
Found 218.1672. IR (ATR, neat, cm-1): 2898 (m), 2845 (m),
1739 (s), 1449 (w), 1404 (w), 1171 (w), 1131 (w), 1099 (w),
499 (w). The analytic data is in correspondence with that
reported in literature.51
yl)malonate (8wb). Compound 8wb was prepared following
general procedure A. Boc-glycine (87 mg, 0.5 mmol, 1.0 equiv)
and diethyl ethylidenmalonate (186 mg, 1.0 mmol, 2.0 equiv.)
were used. Purification by column chromatography (n-
pentane:EtOAc = 8:1) yielded the title compound 8wb (29 mg,
0.09 mmol, 18%) as a colorless oil. Rf = 0.26 (n-pentane:EtOAc
= 8:1, KMnO4); 1H NMR (300 MHz, CDCl3) δ 4.72 (br. s, 1H), 4.19
(qd, J = 7.1, 1.3 Hz, 4H), 3.30 (d, J = 7.4 Hz, 1H), 3.15 (m, 2H),
2.44 (dt, J = 13.5, 6.7 Hz, 1H), 1.42 (s, J = 6.3 Hz, 9H), 1.27 (m,
6H), 1.00 (d, J = 6.9 Hz, 3H); 13C {1H } NMR (75 MHz, CDCl3) δ
168.9, 168.7, 156.1, 79.4, 61.6, 61.5, 55.2, 34.2, 28.5, 15.7, 14.2,
14.2; MS (EI): m/z (relative intensity) 260 (3), 244 (13), 216
(36), 198 (19), 172 (22), 160 (34), 152 (12), 142 (28), 126 (29),
115 (32), 101 (27), 87 (23), 69 (22), 57 (100); HRMS (ESI-TOF)
m/z: [M+Na]+ Calcd for C15H27NO6Na 340.1735; Found
340.1736. IR (ATR, neat, cm-1): 3399 (w), 2978 (w), 2936 (w),
1715 (m), 1513 (w), 1366 (m), 1254 (m), 1162 (s), 1114 (m),
1029 (m), 994 (w), 861 (w). The analytic data is in
correspondence with that reported in literature.29
3-((3r,5r,7r)-adamantan-1-yl)cyclohexan-1-one
Compound 11 was prepared following general procedure A.
Purification by column chromatography (n-
(11).
pentane:EtOAc = 15:1) yielded the title compound 11 (94 mg,
0.405 mmol, 81%) as a white solid. m.p. = 6465 °C; Rf = 0.61
(n-pentane:EtOAc = 10:1, KMnO4); 1H NMR (300 MHz, CDCl3) δ
2.36 (m, 2H), 2.20 (m, 1H), 2.06 (m, 2H), 1.92 (m, 4H), 1.61 (m,
6H), 1.48 (m, 7H), 1.27 (m, 2H); 13C {1H} NMR (75 MHz, CDCl3)
δ 213.5, 49.8, 42.2, 41.7, 37.3, 34.6, 28.7, 25.8, 24.7; MS (EI):
m/z (relative intensity) 232 (3), 135 (100), 107 (10), 93 (19),
Diethyl
2-(1-(cyclohexyloxy)propan-2-yl)malonate
(8xb).
Compound 8xb was prepared following general procedure A.
2-(cyclohexyloxy)acetic acid (79 mg, 0.5 mmol, 1.0 equiv) and
diethyl ethylidenmalonate (186 mg, 1.0 mmol, 2.0 equiv.) were
used. Purification by column chromatography (n-
pentane:EtOAc = 20:1) yielded the title compound 8xb (32 mg,
0.11 mmol, 21%) as a colorless oil. Rf = 0.65 (n-pentane:EtOAc
79 (23), 69 (4); HRMS (ESI-TOF) m/z: [M]+ Calcd for C16H24
O
232.1822; Found 232.1821. IR (ATR, neat, cm-1): 2964 (s),
2843 (s), 1708 (m), 1448 (w), 1346 (w), 1316 (w), 1228 (w),
1167 (w), 1034 (w), 923 (w). The analytic data is in
correspondence with that reported in literature.51
1
= 10:1, KMnO4); H NMR (300 MHz, CDCl3) δ 4.17 (qd, J = 7.1,
3-((3r,5r,7r)-adamantan-1-yl)cycloheptan-1-one
(12).
1.6 Hz, 4H), 3.48 (d, J = 7.4 Hz, 1H), 3.37 (m, 2H), 3.16 (dt, J =
8.6, 4.0 Hz, 1H), 2.47 (m, 1H), 1.76 (m, 4H), 1.47 (m, 1H), 1.23
(m, 11H), 1.01 (d, J = 6.9 Hz, 3H); 13C {1H } NMR (75 MHz, CDCl3)
δ 169.2, 169.0, 77.6, 70.4, 61.2, 61.1, 54.3, 34.3, 32.1, 26.0, 24.1,
14.8, 14.2, 14.2; MS (EI): m/z (relative intensity) 217 (3), 201
(14), 173 (100), 161 (38), 145 (35), 140 (78), 133 (16), 127
(64), 115 (38), 109 (5), 82 (61), 69 (17); HRMS (ESI-TOF) m/z:
[M+Na]+ Calcd for C16H28O5Na 323.1833; Found 323.1835. IR
(ATR, neat, cm-1): 2980 (w), 2932 (w), 2856 (w), 1730 (s),
1450 (w), 1367 (w), 1258 (m), 1176 (m), 1094 (s), 1029 (m),
947 (w).
4-ethyl-2-fluoro-1,1'-biphenyl (9). Compound 9 was prepared
following general procedure A. 2-(2-fluoro-[1,1'-biphenyl]-4-
yl)propanoic acid (flurbiprofen) (122.1 mg, 500.0 µmol, 1.0
equiv.) and Diethyl maleate (172 mg, 1.0 mmol, 2.0 equiv.)
were used. The reaction mixture of two vials with the same
content was combined, dried under reduced pressure and
purified by column chromatography (n-pentane:EtOAc = 50:1)
which yielded the title compound 9 (33 mg, 165 µmol, 17%) as
a colorless oil. Rf = 0.70 (n-pentane:EtOAc = 50:1, UV, KMnO4);
1H NMR (300 MHz, CDCl3) δ 7.64 – 7.52 (m, 2H), 7.48 – 7.41 (m,
2H), 7.40 – 7.31 (m, 2H), 7.10 – 6.71 (m, 2H), 2.95 – 2.31 (m,
2H), 1.40 – 0.85 (t, J = 7.6, 7.6 Hz, 3H); 13C{1H} NMR (75 MHz,
CDCl3) δ 161.5, 158.2, 146.1, 146.0, 130.6, 130.6, 129.1, 129.1,
128.5, 127.5, 126.4, 126.3, 124.0, 124.0, 115.7, 115.6, 28.5, 28.5,
Compound 12 was prepared following general procedure A. 2-
Cyclohepten-1-one (110 mg, 1.0 mmol, 2.0 equiv) was used.
Purification
by
column
chromatography
(n-
pentane:EtOAc = 97:3) yielded the title compound 12 (23 mg,
0.09 mmol, 19 %) as a white solid. m.p.= 7173 °C; Rf = 0.23 (n-
pentane:EtOAc = 20:1, KMnO4); 1H NMR (400 MHz, CDCl3) δ
2.46 (m, 3H), 2.30 (dd, J = 14.2, 11.5 Hz, 1H), 1.98 (m, 5H), 1.89
(m, 1H), 1.57 (m, 13H), 1.27 (m, 2H), 1.01 (m, 1H); 13C {1H} NMR
(101 MHz, CDCl3) δ 216.1, 46.5, 44.5, 43.4, 39.2, 37.3, 35.4, 29.7,
29.6, 28.8, 25.4; MS (EI): m/z (relative intensity) 246 (11) [M],
228 (10), 135 (100), 107 (7), 93 (13), 79 (13), 67 (5), 54 (1);
HRMS (ESI-TOF) m/z: [M]+ Calcd for C17H26O1 246.1978;
Found 246.1984. IR (ATR, neat, cm-1): 2897 (m), 2846 (m),
1697 (m), 1446 (w), 1346 (w), 1131 (w), 1005 (w).
3-((3r,5r,7r)-adamantan-1-yl)-2-methylcyclopentan-1-one (13).
Compound 13 was prepared following general procedure A. 2-
Methyl-2-cyclopenten-1-one (96 mg, 1.0 mmol, 2.0 equiv.) was
used. Purification by column chromatography (n-
pentane:EtOAc = 40:1) yielded the title compound 13 (66 mg,
0.28 mmol, 57%) as a colorless oil (mixture of diastereomeres
1:2.3). Rf = 0.70 (n-pentane:EtOAc = 10:1, KMnO4); 1H NMR
(300 MHz, CDCl3) δ 2.42 – 2.19 (m, 1H), 2.10 (m, 1H), 2.00 (m,
4H), 1.84 (m, 1H), 1.57 (m, 14H), 1.07 (dd, J = 8.6, 6.3 Hz, 3H);
13C {1H } NMR (75 MHz, CDCl3) δ 222.8, 222.6, 55.5, 52.7, 45.8,
44.1, 41.3, 40.4, 37.5, 37.4, 37.3, 37.3, 34.5, 28.7, 28.7, 20.9,
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The Journal of Organic Chemistry
19.8, 17.7, 13.2; MS (EI): m/z (relative intensity) 232 (9) [M],
MS (EI): m/z (relative intensity) 236 (7) [M], 191 (9), 135
1
2
3
4
5
6
7
8
135 (100), 119 (1), 107 (10), 93 (17), 79 (19), 67 (7), 55 (7), 41
(9); HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C16H24ONa
255.1724; Found 255.1725. IR (ATR, neat, cm-1): 2963 (w),
2892 (s), 2845 (m), 1729 (s), 1445 (w), 1404 (w), 1268 (w),
1132 (w), 981 (w), 824 (w).
(100), 119 (1), 107 (6), 93 (11), 79 (12), 67 (4); HRMS (ESI-
TOF) m/z: [M+H]+ Calcd for C15H25O2 237.1854; Found
237.1852. IR (ATR, neat, cm-1): 2949 (w), 2898 (m), 2846 (m),
1734 (m), 1450 (w), 1376 (w), 1301 (w), 1188 (m), 1150 (m),
1103 (w). The analytic data is in correspondence with that
reported in literature.52
Diethyl
2-((3r,5r,7r)-adamantan-1-yl)succinate
(14).
Compound 14 was prepared following general procedure A.
Diethyl maleate (172 mg, 1.0 mmol, 2.0 equiv) was used.
Benzyl
3-((3r,5r,7r)-adamantan-1-yl)propanoate
(18).
Compound 18 was prepared following general procedure A.
Benzylacrylat (162 mg, 1.0 mmol, 2.0 equiv) was used.
Purification
by
column
chromatography
(n-
pentane:EtOAc = 100:3) yielded the title compound 14
(128 mg, 0.42 mmol, 83%) as a colorless oil. Rf = 0.58 (n-
pentane:EtOAc = 10:1, KMnO4); 1H NMR (300 MHz, CDCl3) δ
4.12 (m, 4H), 2.72 (dd, J = 16.9, 12.2 Hz, 1H), 2.46 (dt, J = 11.7,
3.1 Hz, 2H), 1.96 (s, 3H), 1.64 (m, 9H), 1.44 (m, 3H), 1.24 (m,
6H); 13C {1H } NMR (75 MHz, CDCl3) δ 173.9, 173.0, 60.6, 60.2,
52.4, 40.1, 36.9, 34.5, 31.4, 28.6, 14.4, 14.3; MS (EI): m/z
(relative intensity) 308 (1) [M], 263 (16), 235 (11), 193 (3),
173 (17), 135 (100), 119 (2), 107 (6), 93 (11), 79 (12); HRMS
(ESI-TOF) m/z: [M+Na]+ Calcd for C18H28O4Na 331.1885;
Found 331.1883. IR (ATR, neat, cm-1): 2980 (w), 2902 (m),
2849 (w), 1726 (s), 1447 (w), 1369 (w), 1188 (m), 1156 (s),
1028 (m).
9
Purification
pentane:toluene = 5:2) yielded the title compound 18 (41 mg,
0.14 mmol, 27%) as colorless oil. Rf = 0.32 (n-
by
column
chromatography
(n-
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
a
1
pentane:Toluene = 1:1, KMnO4); H NMR (400 MHz, CDCl3) δ
7.35 (m, 5H), 5.11 (s, 2H), 2.32 (m, 2H), 1.95 (s, 3H), 1.63 (m,
6H), 1.45 (m, 8H); 13C{1H} NMR (101 MHz, CDCl3) δ 174.7,
136.3, 128.7, 128.4, 128.3, 66.3, 42.2, 39.0, 37.2, 32.0, 28.7,
28.3; MS (EI): m/z (relative intensity) 298 (4), 207 (66), 189
(16), 161 (6), 147 (16), 135 (74), 107 (18), 91 (100), 81 (8), 79
(35), 65 (17); HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for
C20H26O2Na 321.1830; Found 321.1828. IR (ATR, neat, cm-1):
2898 (m), 2845 (M), 1734 (m), 1451 (w), 1140 (m), 979 (w),
696 (m). The analytic data is in correspondence with that
reported in literature.53
Di-tert-butyl 2-((3r,5r,7r)-adamantan-1-yl)succinate (15).
Compound 15 was prepared following general procedure A. Di-
tert-butyl fumarate (228 mg, 1.0 mmol, 2.0 equiv) was used.
Phenyl
3-((3r,5r,7r)-adamantan-1-yl)propanoate
(19).
Compound 19 was prepared following general procedure A.
Phenylacrylat (148 mg, 1.0 mmol, 2.0 equiv) was used.
Purification
by
column
chromatography
(n-
pentane:EtOAc = 100:2) yielded the title compound 15 (97 mg,
Purification
by
column
chromatography
(n-
0.27 mmol, 53%) as a white solid. m.p.= 6466 °C; Rf = 0.12 (n-
pentane:EtOAc = 100:2→100:5) yielded the title compound 19
(37 mg, 0.13 mmol, 26%) as a white solid. m.p.= 4546 °C;
Rf = 0.41 (n-pentane:EtOAc = 100:2, KMnO4); 1H NMR (400
MHz, CDCl3) δ 7.55 (m, 2H), 7.39 (m, 1H), 7.25 (m, 2H), 2.69 (m,
2H), 2.16 (s, 3H), 1.84 (m, 6H), 1.73 (m, 8H); 13C{1H} NMR (101
MHz, CDCl3) δ 173.3, 150.9, 129.5, 125.8, 121.7, 42.2, 39.0, 37.2,
32.2, 28.7, 28.5; MS (EI): m/z (relative intensity) 284 (2) [M],
191 (100), 173 (18), 163 (9), 147 (5), 135 (61), 121 (3), 94
(19), 79 (19); HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for
C19H24O2Na 307.1674; Found 307.1675. IR (ATR, neat, cm-1):
2897 (m), 2843 (m), 1753 (m), 1591 (w), 1492 (w), 1452 (w),
1381 (w), 1195 (m), 1124 (m), 1103 (m), 930 (m). The analytic
data is in correspondence with that reported in literature.54
3-((3r,5r,7r)-adamantan-1-yl)propanenitrile (20). Compound
20 was prepared following general procedure A. Acrylonitrile
(53.1 mg, 1.0 mmol, 2.0 equiv) was used. Purification by
column chromatography (n-pentane:EtOAc = 10:1) yielded the
title compound 20 (38 mg, 0.201 mmol, 40%) as a white solid.
m.p. = 4344 °C; Rf = 0.55 (n-pentane:EtOAc = 10:1, KMnO4); 1H
NMR (300 MHz, CDCl3) δ 2.26 (m, 2H), 1.97 (s, 3H), 1.62 (m,
6H), 1.47 (m, 8H); 13C{1H} NMR (75 MHz, CDCl3) δ 121.0, 41.7,
39.6, 36.9, 32.2, 28.5, 11.1; MS (EI): m/z (relative intensity) 189
(4) [M], 135 (100), 107 (7), 93 (12), 79 (12), 67 (4); HRMS (ESI-
TOF) m/z: [M]+ Calcd for C13H19N 190.1595; Found 190.1597.
IR (ATR, neat, cm-1): 2896 (m), 2846 (m), 2242 (w), 1448 (w),
1360 (w), 1345 (w), 1100 (w), 973 (w), 812 (w). The analytic
data is in correspondence with that reported in literature.55
3-((3r,5r,7r)-adamantan-1-yl)butanal (21). Compound 21 was
prepared following general procedure A. Crotonaldehyde
(70 mg, 1.0 mmol, 2.0 equiv) was used. Purification by column
chromatography (n-pentane:EtOAc = 100:2) yielded the title
compound 21 (33 mg, 0.16 mmol, 32%) as a white solid. m.p. =
101103 °C; Rf = 0.29 (n-pentane:EtOAc = 100:2, KMnO4); 1H
NMR (300 MHz, CDCl3) δ 9.73 (dd, J = 3.4, 1.3 Hz, 1H), 2.57 (m,
1H), 2.02 (m, 4H), 1.65 (m, 7H), 1.48 (m, 6H), 0.86 (m, 3H);
13C{1H} NMR (75 MHz, CDCl3) δ 204.1, 45.7, 39.5, 37.9, 37.3,
34.4, 28.7, 14.0; MS (EI): m/z (relative intensity) 188 (2), 135
1
pentane:EtOAc = 100:2, KMnO4); H NMR (300 MHz, CDCl3) δ
2.42 (m, 3H), 1.94 (m, 3H), 1.62 (m, 9H), 1.48 (m, 3H), 1.43 (s,
9H), 1.40 (s, 9H); 13C {1H} NMR (75 MHz, CDCl3) δ 172.9, 172.4,
80.4, 80.3, 53.4, 40.2, 37.0, 34.4, 32.6, 28.7, 28.2, 28.2; MS (EI):
m/z (relative intensity) 308 (1), 252 (26), 234 (10), 207 (15),
165 (2), 135 (100), 107 (3), 93 (6), 79 (6), 57 (24); HRMS (ESI-
TOF) m/z: [M+Na]+ Calcd for C22H36O4Na 387.2510; Found
387.2507. IR (ATR, neat, cm-1): 2976 (w), 2903 (m), 2849 (w),
1720 (m), 1365 (m), 1247 (w), 1141 (s), 1119 (m), 849 (m).
(3r,5r,7r)-1-(2-(phenylsulfonyl)ethyl)adamantane
(16).
Compound 16 was prepared following general procedure A.
Phenyl vinyl sulfone (168 mg, 1.0 mmol, 2.0 equiv) was used.
Purification
hexane:EtOAc = 30:1) yielded the title compound 16 (105 mg,
0.35 mmol, 69%) as colorless thick oil. Rf = 0.10 (n-
by
column
chromatography
(n-
a
hexane:EtOAc = 97:3, KMnO4); 1H NMR (300 MHz, CDCl3) δ 7.89
(m, 2H), 7.64 (m, 1H), 7.55 (m, 2H), 3.04 (m, 2H), 1.91 (s, 3H),
1.58 (m, 6H), 1.45 (m, 2H), 1.38 (d, J = 2.6 Hz, 6H); 13C{1H} NMR
(75 MHz, CDCl3) δ 139.3, 133.7, 129.3, 128.1, 51.3, 42.0, 36.9,
35.9, 31.9, 28.5; MS (EI): m/z (relative intensity) 304 (1) [M],
276 (2), 239 (2), 163 (2), 135 (100), 107 (5), 93 (9), 77 (15), 67
(3); HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C18H25O2S
305.1575; Found 305.1574. IR (ATR, neat, cm-1): 2898 (m),
2845 (m), 1584 (w), 1447 (m), 1322 (m), 1150 (s), 1099 (m),
995 (w) 778 (m), 730 (m), 532 (s). The analytic data is in
correspondence with that reported in literature.31
Ethyl
3-((3r,5r,7r)-adamantan-1-yl)propanoate
(17).
Compound 17 was prepared following general procedure A.
Ethylacrylat (100 mg, 1.0 mmol, 2.0 equiv) and K2CO3 (0.5
mmol, 1.0 equiv.) were used. Purification by column
chromatography (n-pentane:diethylether = 200:1) yielded the
title compound 17 (32 mg, 0.14 mmol, 28%) as a colorless oil.
Rf = 0.61 (n-pentane:EtOAc = 20:1, KMnO4); 1H NMR (300 MHz,
CDCl3) δ 4.11 (q, J = 7.1 Hz, 2H), 2.24 (m, 2H), 1.94 (s, 3H), 1.62
(m, 6H), 1.42 (m, 8H), 1.25 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (75
MHz, CDCl3) δ 174.9, 60.4, 42.2, 39.1, 37.2, 32.1, 28.7, 28.4, 14.4;
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(100), 107 (8), 93 (13), 91 (6), 79 (13), 67 (4). 53 (2); HRMS
(ESI-TOF) m/z: [M]+ Calcd for C14H21O1 205.1587; Found
205.1590. IR (ATR, neat, cm-1): 2901 (m), 2885 (m), 2849 (m),
1699 (m), 1448 (w), 1352 (w), 1305 (m), 1208 (w), 967 (w).
The analytic data is in correspondence with that reported in
literature.31
0.22 mmol, 44%) as a light yellow solid. m.p.= 152154 °C;
Rf = 0.63 (n-pentane:EtOAc = 10:1, UV, KMnO4); H NMR (300
1
1
2
3
4
5
6
7
8
MHz, CDCl3) δ 7.81 (m, 1H), 7.39 (dd, J = 8.8, 2.7 Hz, 1H), 6.96
(m, 1H), 3.88 (dt, J = 21.8, 10.9 Hz, 1H), 2.67 (qd, J = 16.6, 8.4
Hz, 2H), 2.08 (m, 3H), 1.71 (m, 12H); 13C{1H} NMR (75 MHz,
CDCl3) δ 192.7, 160.8, 135.7, 126.5, 126.2, 121.7, 119.7, 85.9,
37.8, 37.1, 36.9, 36.0, 28.2; MS (EI): m/z (relative intensity) 316
(25) [M], 183 (21), 181 (65), 154 (17), 135 (100), 126 (19), 107
(13), 98 (5), 93 (27), 79 (38), 67 (14); HRMS (ESI-TOF) m/z:
[M+H]+ Calcd for C19H22O2Cl 317.1308; Found 317.1303. IR
(ATR, neat, cm-1): 2899 (w), 2848 (w), 1694 (w), 1602 (w),
1469 (w), 1270 (m), 1222 (w), 997 (w), 819 (w), 797 (w).
2-((3r,5r,7r)-adamantan-1-yl)butane-1,4-diol (27). Compound
27 was prepared in a similar fashion to the procedure
described in literature.43 A solution of diester 8fa (100 mg,
0.357 mmol, 1.0 equiv.) in THF (0.5 mL) was added dropwise
under argon to a stirred suspension of LiAlH4 (27 mg,
0.71 mmol, 2 equiv.) in THF (1.15 mL) at 0 °C over a period of
5 minutes. The cooling bath was removed, and the mixture was
stirred at room temperature for 24 h. Then, the reaction
mixture was quenched with water (0.5 mL) and 10% aqueous
NaOH (0.1 mL) at 0 °C and stirred for further 15 minutes.
Afterwards, the reaction mixture was extracted with 3 x 10 mL
of CH2Cl2 and the combined organic fractions were dried over
Na2SO4 and filtered. The filtrate was dried under reduced
pressure and purified by column chromatography
(CH2Cl2:EtOAc = 1:1) to give diol 27 (74 mg, 0.33 mmol, 93%)
as a colorless oil. Rf = 0.36 (CH2Cl2EtOAc = 1:2, KMnO4); 1H NMR
(300 MHz, CDCl3) δ 3.82 (m, 4H), 3.53 (ddd, J = 10.5, 8.8, 4.1 Hz,
1H), 3.41 (dd, J = 10.3, 8.7 Hz, 1H), 1.88 (m, 4H), 1.60 (m, 12H),
1.40 (m, 1H), 1.15 (m, 1H); 13C{1H} NMR (75 MHz, CDCl3) δ 62.9,
62.8, 50.0, 34.0, 37.3, 34.9, 30.4, 28.7; MS (EI): m/z (relative
intensity) 224 (1) [M], 176 (3), 165 (4), 152 (34), 135 (100),
119 (2), 107 (9), 93 (18), 81 (5), 79 (19), 67 (7); HRMS (ESI-
TOF) m/z: [M+Na]+ Calcd for C14H24O2Na 247.1673; Found
247.1677. IR (ATR, neat, cm-1): 3261 (br., w.), 2902 (w), 2844
(w), 1443 (w), 1347 (w), 1192 (w), 1103 (w), 1021 (w), 879
(w).
4-((3r,5r,7r)-adamantan-1-yl)-5,5-dimethyldihydrofuran-
2(3H)-one (28). Diester 8fa (100 mg, 0.357 mmol, 1 equiv.) was
dissolved in dry THF (4.0 mL) under argon. the reaction
mixture was then cooled to 0 °C and MeMgBr (490 µl, 1.46
mmol, 4.1 equiv., 3.0 M in diethylether) was added dropwise
over 5 minutes. Subsequently, the cooling bath was removed,
and the mixture was stirred at room temperature for 24 h.
Then, the reaction mixture was quenched at 0 °C with a sat.
ammonium chloride solution and diluted with diethylether (10
mL). The aqueous phase was extracted with diethylether (2 x
10 mL). Afterwards, combined organic phases were washed
with brine, dried over Na2SO4, and concentrated under vacuum.
Purification by column chromatography (n-pentane:EtOAc =
100:2) afforded product 28 (77 mg, 0.31 mmol, 87%) as a
white solid. m.p.= 110113 °C; Rf = 0.10 (n-pentane:EtOAc =
100:2, KMnO4); 1H NMR (300 MHz, CDCl3) δ 2.43 (dd, J = 12.2,
9.2 Hz, 1H), 1.91 (m, 8H), 1.67 (m, 6H), 1.48 (m, 3H), 1.41 (s,
3H), 1.32 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 176.4, 80.6,
50.7, 39.3, 36.9, 36.2, 33.9, 28.9, 28.4, 27.2; MS (EI): m/z
(relative intensity) 248 (5) [M], 192 (9), 147 (4), 135 (100), 105
(8), 91 (16), 79 (20), 67 (9), 55 (11); HRMS (ESI-TOF) m/z:
[M+H]+ Calcd for C16H25O2 249.1854; Found 249.1847. IR
(ATR, neat, cm-1): 2978 (w), 2909 (m), 2847 (w), 1747 (m),
1451 (w), 1385 (w), 1286 (w), 1197 (w), 1114 (m), 954 (m).
5-(1-((3r,5r,7r)-adamantan-1-yl)ethyl)-1,3-dimethylpyrimidine-
2,4,6(1H,3H,5H)-trione (29). Compound 29 was prepared in a
similar fashion to the procedure described in literature.56
2-((1S,3s)-adamantan-1-yl)chroman-4-one (22). Compound 22
was prepared following general procedure A. 4H-chromen-4-
one (146 mg, 1.0 mmol, 2.0 equiv.) was used. Purification by
column chromatography (n-pentane:EtOAc = 90:5) yielded the
title compound 22 (54 mg, 0.19 mmol, 39%) as a colorless
solid. m.p.= 103105 °C; Rf = 0.26 (n-pentane:EtOAc = 90:3,
KMnO4); 1H NMR (300 MHz, CDCl3) δ 7.85 (m, 1H), 7.45 (m, 1H),
6.97 (m, 2H), 3.90 (dd, J = 13.5, 3.1 Hz, 1H), 2.66 (qd, J = 16.5,
8.3 Hz, 2H), 2.05 (m, 3H), 1.67 (m, 12H); 13C{1H} NMR (75 MHz,
CDCl3) δ 193.9, 162.4, 135.9, 127.0, 121.0, 118.0, 85.6, 37.9,
37.2, 37.2, 36.0, 28.3; MS (EI): m/z (relative intensity) 282 (68)
[M], 164 (3), 147 (49), 135 (100), 121 (13), 93 (17), 79 (16), 67
(6); HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C19H23O2
283.1698; Found 283.1693. IR (ATR, neat, cm-1): 2897 (m),
2848 (m), 1689 (m), 1604 (m), 1472 (m), 1462 (m), 1306 (m),
1233 (m), 1147 (w), 753 (m). The analytic data is in
correspondence with that reported in literature.31
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2-((1S,3s)-adamantan-1-yl)-6-fluorochroman-4-one
(23).
Compound 23 was prepared following general procedure A. 6-
fluoro-4H-chromen-4-one (164 mg, 1.0 mmol, 2.0 equiv.) was
used. Purification by column chromatography (n-
pentane:EtOAc = 90:5) yielded the title compound 23 (43 mg,
0.14 mmol, 29%) as a white solid. m.p.= 120122 °C; Rf = 0.61
(n-pentane:EtOAc = 10:1, UV, KMnO4); 1H NMR (300 MHz,
CDCl3) δ 7.49 (m, 1H), 7.17 (ddd, J = 9.0, 7.8, 3.2 Hz, 1H), 6.95
(m, 1H), 3.88 (dd, J = 12.9, 3.8 Hz, 1H), 2.65 (m, 2H), 2.06 (m,
3H), 1.68 (m, 12H); 13C{1H} NMR (75 MHz, CDCl3) δ 193.1,
193.1, 158.7, 158.7, 158.6, 155.5, 123.6, 123.3, 121.4, 121.3,
119.7, 119.6, 112.0, 111.7, 86.0, 37.8, 37.1, 37.0, 36.0, 28.2; 19
F
NMR (282 MHz, CDCl3) δ -122.04, -122.06, -122.07, -122.09, -
122.10, -122.11; MS (EI): m/z (relative intensity) 300 (36) [M],
191 (1), 165 (74), 139 (15), 135 (100), 119 (3), 110 (20), 93
(28), 82 (10), 79 (40), 67 (13), 41 (19); HRMS (ESI-TOF) m/z:
[M+H]+ Calcd for C19H22O2F 301.1604; Found 301.1605. IR
(ATR, neat, cm-1): 2893 (m), 2851 (w), 1686 (m), 1618 (w),
1478 (m), 1450 (w), 1292 (w), 1273 (w), 1164 (w), 1001 (w),
881 (w).
2-((1S,3s)-adamantan-1-yl)-6-bromochroman-4-one
(24).
Compound 24 was prepared following general procedure A. 6-
bromo-4H-chromen-4-one (225 mg, 1.0 mmol, 2.0 equiv.) was
used. Purification by column chromatography (n-
pentane:EtOAc = 95:5) yielded the title compound 24 (100 mg,
0.28 mmol, 55%) as a white solid. m.p.= 195196 °C; Rf = 0.91
(n-pentane:EtOAc = 9:1, UV, KMnO4); 1H NMR (300 MHz, CDCl3)
δ 7.93 (m, 1H), 7.50 (dd, J = 8.8, 2.6 Hz, 1H), 6.87 (m, 1H), 3.87
(dd, J = 12.9, 3.8 Hz, 1H), 2.64 (qd, J = 16.6, 8.3 Hz, 2H), 2.05 (m,
3H), 1.69 (m, 12H); 13C{1H} NMR (75 MHz, CDCl3) δ 192.5,
161.2, 138.5, 129.4, 122.2, 120.1, 113.7, 85.9, 37.8, 37.1, 36.9,
36.0, 28.4, 28.2, 28.0; MS (EI): m/z (relative intensity) 361 (11)
[M], 281 (2), 227 (53), 2100 (10), 172 (6), 146 (2), 135 (100),
118 (8), 93 (16), 79 (20), 63 (8); HRMS (ESI-TOF) m/z: [M+H]+
Calcd for C19H22O2Br 359.0647; Found 359.0648. IR (ATR, neat,
cm-1): 2898 (w), 2847 (w), 1693 (m), 1597 (w), 1465 (w),
1414 (w), 1267 (m), 1221 (w), 989 (w), 818 (m).
2-((1S,3s)-adamantan-1-yl)-6-chlorochroman-4-one
(25).
Compound 25 was prepared following general procedure A. 6-
chloro-4H-chromen-4-one (181 mg, 1.0 mmol, 2.0 equiv.) was
used. Purification by column chromatography (n-
pentane:EtOAc = 90:5) yielded the title compound 25 (70 mg,
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3.
Rodríguez, N.; Goossen, L. J., Decarboxylative coupling
Sodium (54 mg, 2.36 mmol, 3.1 equiv.) was dissolved in
reactions: a modern strategy for C–C-bond formation. Chem. Soc.
Rev. Chem Soc Rev 2011, 40, 5030-5048.
4.
T.; Yoshimi, Y., Sequential Intermolecular Radical Addition and
Reductive Radical Cyclization of Tyrosine and Phenylalanine
Derivatives with Alkenes via Photoinduced Decarboxylation:
Access to Ring-Constrained γ-Amino Acids. J. Org. Chem. 2019, 84,
9480-9488.
1
2
3
4
5
6
7
8
absolute ethanol (1 mL) in a 25 mL flame-dried flask equipped
with a reflux condenser. A solution of diester 8ab (245 mg, 760
µmol, 1.0 equiv.) in 1 mL of absolute ethanol was added
followed by a solution of dimethyl urea (34.7 mg, 752 µmol,
1.0 equiv.) in 0.7 mL of absolute ethanol. The reaction mixture
was then refluxed for 23 hours in an oil bath and cooled to
room temperature. Afterwards, the reaction was quenched
with water (2 mL) and the reaction solution was acidified by
adding conc. HCl (0.3 mL). The aqueous phase was extracted
with 3 x CH2Cl2 (15 mL) and the combined organic phases were
dried over Na2SO4 and filtered. Afterwards, the filtrate was
dried under vacuum and the crude material was purified by
column chromatography (n-pentane:EtOAc = 15:1) which
afforded desired product 29 (81 mg, 0.25 mmol, 33%) as a
white solid. m.p.= 195198 °C, Rf = 0.44 (n-pentane:EtOAc =
5:1, UV, KMnO4); 1H NMR (300 MHz, CDCl3) δ 3.71 (d, J = 2.0 Hz,
1H), 3.28 (d, J = 5.6 Hz, 6H), 2.04 (m, 4H), 1.64 (m, 12H), 0.90
(d, J = 7.4 Hz, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 170.6, 168.9,
151.9, 50.0, 49.9, 40.1, 37.0, 36.1, 28.8, 28.8, 28.4, 11.0; MS (EI):
m/z (relative intensity) 318 (1) [M], 182 (6), 135 (100), 119
(1), 107 (6), 93 (10), 79 (11), 69 (4), 55 (2); HRMS (ESI-TOF)
m/z: [M+H]+ Calcd for C18H27O3N2 319.2021; Found 319.2016.
IR (ATR, neat, cm-1): 2965 (w), 2896 (w), 2848 (w), 1668 (w),
1416 (w), 1368 (w), 1122 (w), 1086 (w), 755 (w).
Osaka, K.; Usami, A.; Iwasaki, T.; Yamawaki, M.; Morita,
5.
Gooßen, L. J.; Rodríguez, N.; Gooßen, K., Carboxylic Acids
as Substrates in Homogeneous Catalysis. Angew. Chem. Int. Ed.
Engl. 2008, 47, 3100-3120.
6.
Decarboxylative Conjunctive Cross-coupling of Vinyl Boronic
Esters using Metallaphotoredox Catalysis. Angew. Chem. Int. Ed.
Engl. 2020, 59, 4375-4379.
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25
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27
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Mega, R. S.; Duong, V. K.; Noble, A.; Aggarwal, V. K.,
7.
Fawcett, A.; Pradeilles, J.; Wang, Y.; Mutsuga, T.; Myers, E.
L.; Aggarwal, V. K., Photoinduced decarboxylative borylation of
carboxylic acids. Science 2017, 357, 283-286.
8.
Aggarwal, V. K., Visible-Light-Mediated Decarboxylative Radical
Additions to Vinyl Boronic Esters: Rapid Access to γ-Amino
Boronic Esters. Angew. Chem. Int. Ed. Engl. 2018, 57, 2155-2159.
Noble, A.; Mega, R. S.; Pflästerer, D.; Myers, E. L.;
9.
Ramirez, N. P.; König, B.; Gonzalez-Gomez, J. C.,
Decarboxylative Cyanation of Aliphatic Carboxylic Acids via
Visible-Light Flavin Photocatalysis. Org. Lett. 2019, 21, 1368-1373.
10.
Ramirez, N. P.; Lana-Villarreal, T.; Gonzalez-Gomez, J. C.,
Direct Decarboxylative Allylation and Arylation of Aliphatic
Carboxylic Acids Using Flavin-Mediated Photoredox Catalysis. Eur.
J. Org. Chem. 2020, 2020, 1539-1550.
ASSOCIATED CONTENT
Supporting Information.
Crystal structure of 8fa (ccdc2020928), experimental
procedures, spectroscopic data, optimization reactions,
description of mechanistic experiments.
11.
Hunsdiecker, H.; Hunsdiecker, C., Über den Abbau der
Salze aliphatischer Säuren durch Brom. Ber. Dtsch. Chem. Ges 1942,
75, 291-297.
12.
Barton, D. H. R.; Crich, D.; Motherwell, W. B., New and
improved methods for the radical decarboxylation of acids. J. Chem.
Soc., Chem. Commun. 1983, 939-941.
AUTHOR INFORMATION
Corresponding Author
13.
Okada, K.; Okamoto, K.; Oda, M., A new and practical
method of decarboxylation: photosensitized decarboxylation of N-
acyloxyphthalimides via electron-transfer mechanism. J. Am. Chem.
Soc. 1988, 110, 8736-8738.
Jola Pospech - Leibniz institute for Catalysis, Albert-Einstein-
Straße 29a, 18057 Rostock, Germany. Orcid.org/0000-0001-
7794-2600. E-mail: Jola.Pospech@catalysis.de
14.
Gooßen, L. J.; Lange, P. P.; Rodríguez, N.; Linder, C., Low-
Temperature Ag/Pd-Catalyzed Decarboxylative Cross-Coupling of
Aryl Triflates with Aromatic Carboxylate Salts. Chem. Eur. J. 2010,
16, 3906-3909.
Authors
Firas El-Hage - Leibniz institute for Catalysis, Albert-Einstein-
Straße 29a, 18057 Rostock, Germany.
15.
Weaver, J. D.; Recio, A.; Grenning, A. J.; Tunge, J. A.,
Transition Metal-Catalyzed Decarboxylative Allylation and
Benzylation Reactions. Chem. Rev. 2011, 111, 1846-1913.
Christopher Schöll - Universität Regensburg, Institut für
Organische Chemie, Universitätsstr. 31, 93053 Regensburg,
Germany.
16.
without light – a comparison. Green Chemistry 2018, 20, 323-361.
17. Shang, R.; Liu, L., Transition metal-catalyzed
Schwarz, J.; König, B., Decarboxylative reactions with and
decarboxylative cross-coupling reactions. Sci China Chem 2011, 54,
Author Contributions
1670-1687.
All authors have given approval to the final version of the
manuscript.
18.
Radicals to Alkenes. Angew. Chem. Int. Ed. Engl. 1983, 22, 753-764.
19. Giese, B., Syntheses with Radicals—CC Bond Formation
Giese, B., Formation of CC Bonds by Addition of Free
ACKNOWLEDGMENT
via Organotin and Organomercury Compounds [New Synthetic
Methods (52)]. Angew. Chem. Int. Ed. Engl. 1985, 24, 553-565.
We thank Dr. A. Spannenberg for X-ray measurements and the
staff of the analytic department of LIKAT for assistance with the
data acquisition. Financial support was provided by the
European Union (ESF/14-BM-A55-0049/16).
20.
Catalysis in Organic Chemistry. J. Org. Chem. 2016, 81, 6898-6926.
21. Wang, G.-Z.; Shang, R.; Cheng, W.-M.; Fu, Y.,
Shaw, M. H.; Twilton, J.; MacMillan, D. W. C., Photoredox
Decarboxylative 1,4-Addition of α-Oxocarboxylic Acids with
Michael Acceptors Enabled by Photoredox Catalysis. Org. Lett.
2015, 17, 4830-4833.
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Petzold, D.; Giedyk, M.; Chatterjee, A.; König, B., A
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2. Arshadi, S.; Ebrahimiasl, S.; Hosseinian, A.; Monfared, A.;
Patra, T.; Maiti, D., Decarboxylation as the Key Step in
Retrosynthetic Approach for Photocatalysis. Eur. J. Org. Chem.
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Zheng, C.; Wang, G.-Z.; Shang, R., Catalyst-free
Vessally, E., Recent developments in decarboxylative cross-
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RSC Advances 2019, 9, 8964-8976.
Decarboxylation and Decarboxylative Giese Additions of Alkyl
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Carboxylates through Photoactivation of Electron Donor-Acceptor
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Insert Table of Contents artwork here
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Pr
N
Pr
N
O
N
O
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N
N
Pr
N+
O
Pr
R1
R1
+
O
O
EWG
EWG
CO2H
PrPPTNO PPT
or
cat.
Base (20 mol-%)
MeCN:H2O (9:1)
396 nm
40 examples
up to 99% yield
r.t., 16 h
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organic photoredox-catalysis
high-functional group tolerance
catalytic amount of base
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