Visible-Light-Mediated Oxidative Coupling of Vinylarenes with Bromocarboxylates Leading to γ-Ketoesters

Article abstract of DOI:10.1021/acs.joc.9b02310

A photocatalytic strategy for the synthesis of γ-ketoesters was reported. Using DMSO as both the solvent and terminal oxidant, oxidative coupling of vinylarenes with bromocarboxylates proceeded readily, giving a variety of γ-ketoesters in good isolated yi

Full text of DOI:10.1021/acs.joc.9b02310

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Note
Visible-light-mediated oxidative coupling of vinylarenes
with bromocarboxylates leading to #-ketoesters
Xing-Xiao Fang, Peng-Fei Wang, Wei Yi, Wei Chen, Sheng-Chun Lou, and Gong-Qing Liu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02310 • Publication Date (Web): 05 Nov 2019
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Visible-light-mediated oxidative coupling of
vinylarenes with bromocarboxylates leading to
γ-ketoesters
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Xing-Xiao Fang,§ Peng-Fei Wang,§ Wei Yi,§ Wei Chen, Sheng-Chun Lou and
Gong-Qing Liu*
School of Pharmacy, Nantong University, 19 Qixiu Road, Nantong 226001, People’s
Republic of China.
§These authors are contributed equally.
Abstract Graphics
O
1 mol% fac-Ir(ppy)3
FG
+
R
Br
FG
R
2 equiv. Na2CO3
DMSO, N2, r.t, CFL
FG: CO2R, -CN, -CF3, -NO2
Mild oxidative conditions
Redox-neutral transformation
Broad substrate scopes
Abstract
A photocatalytic strategy for the synthesis of γ-ketoesters was reported. Using
dimethyl sulfoxide (DMSO) as both the solvent and the terminal oxidant, oxidative
coupling of vinylarenes with bromocarboxylates proceeded readily, giving a variety
of γ-ketoesters in good isolated yields and with a broad functional-group tolerance.
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γ-Ketoesters are versatile building blocks in organic synthesis since ketone and
ester groups are reactive centers in many well-established transformations.1
Moreover, carbonyl moiety is a ubiquitous structural feature of many natural
products and lists among the most significant structural elements of
pharmaceuticals.2 Thus, the development of diverse synthetic approaches to
prepare these compounds has been the subject of intense research. Typically,
these compounds can be prepared through the conjugate addition of an acyl
group to a Michael acceptor (Scheme 1, eq. 1).3
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Another attractive approach toward γ-ketoesters involves intermolecular
addition of carbonyl alkyl radicals to olefins. Since inefficiency of
intermolecular radical reactions, highly efficient radical acceptors were usually
employed to solve this problem, and such preformed compounds include:
enolates4 and enamines.5 In this regard, Hosomi et al. reported the
AIBN-initiated reaction of ethyl 2-bromopropanoate with tributylstannyl
enolate to produce γ-ketoester (Scheme 1, eq. 2).4b Kim et al. reported
photoinduced radical alkylations of activated alkyl iodides using vinyl triflates
in the presence of hexadimethyltin in benzene under irradiation at 300 nm,
which gave γ-ketoesters after homolytic scission of the O-sulfone bond
(Scheme 1, eq. 3).4e However, these methodologies require organotin
compounds either as a starting material or as a radical initiator, which
negatively impact the environment. Zhang and coworkers recently reported the
visible-light-mediated radical addition of α-brominated carboxylates to
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enamines to give the corresponding γ-ketoesters (Scheme 1, eq. 4).5c Overall,
these above-mentioned methodologies require preformed radical acceptors as a
substrate, which are sometimes difficult to make and thus detract from the
practicality of these methods. Therefore, the oxidative coupling involving the
direct C–H functionalization of alkenes would be an attractive alternative to the
preparation of γ-ketoesters due to its step economy by the avoidance of the
pre-functionalization process.6 For example, the Wan group recently reported
an elegant cobalt-catalyzed oxidative coupling between vinylarenes and
α-bromoesters to construct γ-ketoesters involving a cascade organocobalt
addition/trapping/Kornblum−DeLaMare rearrangement (Scheme 1, eq. 5).7
However, this protocol suffers from high reaction temperatures as well as needs
to be carried out under strong oxidative conditions and the use of triethylamine
as solvent.
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Scheme 1 Synthesis of γ-ketoesters
O
O
O
OR'
Michael reaction
AIBN
+
L
Ar
eq. 1
Ar
OR'
O
O
O
OSnBu3
OEt
OEt
OEt
OEt
+
Br
I
eq. 2
eq. 3
Ph
Ph
C6H6, 80 o
C
Ph
Ph
O
O
O
OSO2CF3
(Me3Sn)2
+
C6H6, hv=300 nm
O
O
2 mo% Ru(bpy)3Cl2
4-methoxypyridine
OEt
OEt
eq. 4
eq. 5
N
Ph
Ph
OEt
OEt
+
+
Br
Br
Et3N, DMF, hv
O
Ph
O
O
10 mol % Co(acac)2
4 equiv. TBHP
Et3N, 100 oC, 24 h
Ph
O
O
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It is well known that α-bromocarboxylate can generate electrophilic alkyl
radicals under visible-light irradiation.8 Accordingly, we envisioned that these
electron-deficient radicals generated by the photocatalyzed reduction of the
C-Br bond in α-bromocarboxylates can be applied in the oxyalkylation of
alkenes, leading to the formation of γ-ketoesters, which may overcome the
aforementioned limitations.9 In this process, the photogenerated carbonyl alkyl
radicals are trapped by styrene, followed by single electron transfer (SET) and
Kornblum-type oxidation,10 finally furnishing γ-ketoesters (Scheme 2, path a).
From a synthetic point of view, this methodology is intriguing due to its mild
conditions and the use of readily available styrenes and α-bromocarboxylates as
starting materials. However, we need to overcome several obstacles in this
transformation. One obstacle is determining how to avoid the undesired
deprotonation reaction, which gives the alkenylation product (path b).8d
Another noticeable side reaction is the well-documented atom transfer radical
addition (ATRA) of α-bromocarboxylates to styrenes (path c).8b, 8c
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Scheme 2. Our strategy for the synthesis of γ-ketoesters
Br
OEt
OEt
OEt
Ph
Ph
Br
O
O
O
hv
path b
path c
Kornblum
oxidation
Ph
O
OEt
-e
Ph
OEt
OEt
OEt
Ph
Ph
path a
O
O
O
O
With these considerations in mind, we commenced our investigation with the
optimization of the reaction conditions by irradiating a degassed DMSO
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solution of 4-tertbutylstyrene (1a) and ethyl 2-bromopropanoate (2a) in the
presence of 1 mol% fac-Ir(ppy)3 and 2 equiv. of Na2CO3 under a 24 W
household fluorescent lamp. To our delight, the desired γ-ketoester 3a was
obtained in 83% isolated yield after 20 h of irradiation (entry 1). Based on this
encouraging preliminary result, the reaction parameters such as the
photocatalyst or base used were examined to obtain the optimal reaction
conditions, and the results are summarized in Table 1. As shown in Table 1,
[Ir(ppy)2(dtbbpy)](PF6) was also able to promote the reaction but to a lesser
extent than fac-Ir(ppy)3 (entry 2). Other common photocatalysts such as
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.
Ru(bpy)3Cl2 6H2O and the organic photocatalyst Rose Bengal, showed
comparatively less catalytic activity since these photocatalysts provided trace
amounts of 3a (entries 3 to 4). The base could influence the reaction efficiency
as it could potentially neutralize the byproduct HBr (entries 5 to 10). Replacing
Na2CO3 with other inorganic bases such as K2CO3, K3PO4 or NaHCO3 led to a
drop in isolated yield (entries 5 to 7). No improvement of the yield was
observed when organic bases were employed (entries 8 to 10). The effect of
bases on reaction outcomes was further confirmed by the observation of a
significant drop of yield when reaction was performed in the absence of base
(entry 11 vs entry 1). Control experiments showed that light and photoredox
catalysts were essential for the successful transformation because the reactions
did not proceed in the absence of light irradiation or a photocatalyst (entries 12
and 13).
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Table 1 Optimization of the reaction conditions a
8
standard conditions
9
O
1 mol% fac-Ir(ppy)3
OEt
OEt
+
Br
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2 equiv. Na2CO3
tBu
O
DMSO, N2, r.t, CFL
O
tBu
1a
2a
3a
entry
1
2
3
4
5
6
7
8
change from the “standard conditions”
standard conditions
yield (%)b
83
71
<2
<2
70
49
53
40
51
33
37
NRc
NRc
[Ir(ppy)2(dtbbpy)](PF6) instead of fac-Ir(ppy)3
Ru(bpy)3Cl2·6H2O instead of fac-Ir(ppy)3
Rose Bengal instead of fac-Ir(ppy)3
K2CO3 instead of Na2CO3
K3PO4 instead of Na2CO3
NaHCO3 instead of Na2CO3
Et3N instead of Na2CO3
DBU instead of Na2CO3
Pyridine instead of Na2CO3
No base
9
10
11
12
13
No photocatalyst
No light
a Reaction conditions: 1a (0.50 mmol, 1.00 equiv.), 2a (1.00 mmol, 2.00 equiv.), photocatalyst (5 μmol,
0.010 equiv.), base (1.00 mmol, 2.00 equiv.), DMSO (2 mL), 24 W CFL, N2, r.t., 20 h. b isolated yield,
C NR = No reaction.
With the optimized reaction conditions established, we then examined the
substrate scope of this transformation with an array of styrenes using ethyl
2-bromopropanoate 2a as the alkyl radical source. As shown in Scheme 3, a
variety of substituted vinylarenes was compatible with the optimal conditions
and afforded the corresponding γ-ketoesters in moderate to good yields. The
electronic effect of the arenes had little impact on the course of the reaction,
and terminal vinylarenes bearing electron-donating substituents such as methyl
(3c) and acetoxy (3d) groups and electron-withdrawing substituents such as
phenyl (3e) and halogen (3f-3i) groups at the para-position all delivered the
corresponding products in good yields. Additionally, 3-substituted styrene (1i)
and naphthalene-derived substrate 1j worked well in this reaction, and the
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corresponding ketoesters was obtained in acceptable yields. Furthermore, the
internal alkene 1k can react smoothly to give the desired product 3k in 69%
yield. Unfortunately, aliphatic alkenes failed to give desired products in this
transformation.
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Scheme 3. Scope of styrenes a
O
R'
1 mol% fac-Ir(ppy)3
2 equiv. Na2CO3
DMSO, N2, r.t, CFL
OEt
OEt
Br
+
R
R
O
O
1b 1k
-
2a
3b 3k
-
3c
R = Me (
R = OAc (
R = Ph (
R = F (
R = Cl (
R = Br (
)
70%
O
O
3d 68%
)
OEt
OEt
3e
)
62%
81%
85%
77%
3f
)
O
70%
O
3g
)
R
3c
3b
70%
3h
)
O
O
O
OEt
Br
OEt
OEt
Ph
O
O
O
3j
3k
69% (dr= 1:1)
52%
3i
73%
a
Reaction conditions: 1 (0.50 mmol, 1.00 equiv.), 2a (1.00 mmol, 2.00 equiv.), fac-Ir(ppy)3 (5 μmol,
0.010 equiv.), Na2CO3 (1.00 mmol, 2.00 equiv.), DMSO (2 mL), 24 W CFL, N2, r.t., 20 h.
Next, we examined the generality of this transformation with respect to different
α-bromoesters, and the results are summarized in Scheme 4. As depicted in Scheme 4,
this photoinduced oxidative coupling is effective for a variety of α-brominated
carboxylates. For example, methyl and tert-butyl 2-bromopropanoate as well as
isopropyl and n-butyl ethyl bromoacetate engage in the coupling in good yield
(4a-4d). In addition, tertiary α-carbonyl alkyl bromides worked well in the current
reaction system, and the corresponding γ-ketoesters were obtained in good yield (4e
and 4f). It is known that primary α-carbonyl alkyl bromides are less likely to
undergo single-electron reduction of C-Br bonds than are their secondary and tertiary
counterparts due to the relatively instability of the primary alkyl radicals generated.11
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To our delight, primary alkyl bromides 2g and 2h proved to be a compatible reaction
partner in the current transformation and afforded the desired products 4g and 4h,
respectively, in moderate isolated yield. Furthermore, γ-butyrolactone also exhibited
robust reactivity in the reaction, with the desired product obtained in good yield (4j).
Notably, this methodology can also be applied to more complex α-bromoesters
derived from geraniol and L-menthol, giving the desired product in good yields (4k
and 4l).
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Scheme 4. Scope of α-bromoesters a
O
R'
R'
1 mol% fac-Ir(ppy)3
OR
OR
+
2 equiv. Na2CO3
Br
O
DMSO, N2, r.t, CFL
tBu
1a
O
tBu
2
4
O
O
O
R'
OR
OR
OEt
O
O
4e
O
4c
4d
tBu
tBu
tBu
R = iPr
90%
69%
77%
4a
4b
70%
63%
R' = iPr
R' = nBu
R = Me
R = tBu
R = Me 4f 87%
O
O
Br
O
O
O
OR
O
O
tBu
tBu
O
4g
4h
55%
62%
R = Et
R = Bn
tBu
tBu
Me
4j
73%
tBu
4i
80%
O
O
O
O
O
O
4k
67%
4l
63% (dr = 1:1)
a
Reaction conditions: 1a (0.50 mmol, 1.00 equiv.), 2 (1.00 mmol, 2.00 equiv.), fac-Ir(ppy)3 (5 μmol,
0.010 equiv.), Na2CO3 (1.00 mmol, 2.00 equiv.), DMSO (2 mL), 24 W CFL, N2, r.t., 20 h.
To further evaluate the synthetic utility and generality of the current reaction,
we extend the application scope of this procedure to the preparation of other
functionalized ketones. As depicted in Scheme 5, γ‑ketonitrile (5a),12 β-CF3
ketone (5b)13 and β-nitro ketone (5c)14 could be readily synthesized from the
corresponding alkyl bromides through the oxidative alkylation of styrenes
under light-mediated conditions.15
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Scheme 5. Scope of alkyl bromides 2 a
8
9
O
O
1 mol% fac-Ir(ppy)3
+
Br
FG
FG
2 equiv. Na2CO3
DMSO, N2, r.t, CFL
tBu
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12
13
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1a
2
5
tBu
tBu
O
O
NO2
CN
CF3
5a
53%
5c 72%
5b
74%
tBu
tBu
a
Reaction conditions: 1a (0.50 mmol, 1.00 equiv.), 2 (1.00 mmol, 2.00 equiv.), fac-Ir(ppy)3 (5 μmol,
0.010 equiv.), Na2CO3 (1.00 mmol, 2.00 equiv.), DMSO (2 mL), 24 W CFL, N2, r.t., 20 h.
Scheme 6. Gram-scale reaction
standard
conditions
O
OEt
+
OEt
Br
tBu
O
O
tBu
1a
2a
5 mmol,
10 mmol,
1.81 g, 2 equiv.
3a
0.98 g 71%
0.80 g, 1 equiv.
To evaluate the scalability of the current protocol, a 5 mmol scale for the
synthesis of 3a was carried out (Scheme 6). The reaction of 5 mmol 1a with 10
mmol 2a could proceed smoothly under standard conditions and afforded the
γ-ketoester 3a in 71% isolated yield.
To gain further insight into the reaction mechanism, several control
experiments were carried out. First, no desired γ-ketoester 3b could be detected
when using acetophenone as the substrate instead of styrene, suggesting a
late-stage oxidation of the alkene double bond in this transformation (Scheme 7,
eq. 1). Second, the reaction was totally shut down in the presence of the radical
scavenger 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) (Scheme 7, eq. 2).
Additionally, alkyl radical A (Scheme 8) could be trapped with
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1,1-diphenylethylene to give the product 6 in 43% yield (Scheme 7, eq. 3).
These results, along with the control experiments shown in Table 1, suggested
both the visible-light- driven nature and the intermediacy of an alkyl radical in
the reaction. Third, trace amounts of 3a was detected when the reaction was
carried out in DMF, CH3CN or MeOH under otherwise identical conditions
(Scheme 7, eq. 4). It is possible that the residual O2 in the N2 gas reacted with
radical intermediate B (Scheme 8) to form compound 3a.16 Furthermore,
product 3a was obtained in 30% yield when reaction was performed under an
atmosphere of oxygen (Scheme 7, eq. 5). These results reveal that O2 was also
able to promote the reaction but not a major pathway. Finally, to classify the
oxidation of DMSO, the use of tetramethylene sulfoxide in place of DMSO also
led to 3a in moderate yield (Scheme 7, eq. 6). This result indicates that DMSO
plays a key role in this photoinduced oxidative coupling.
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Scheme 7. Mechanistic studies
O
O
standard
OEt
conditions
OEt
OEt
Br
+
eq. 1
O
O
O
3b
0%
standard
conditions
O
OEt
eq. 2
+
Br
3 equiv. TEMPO
tBu
O
tBu
2a
1a
3a
0%
Ph
standard conditions
3a
trace
1a
2a
+
+
OEt
eq. 3
2 equiv. 1,1-diphenylethylene
Ph
6
43%
O
1 mol% fac-Ir(ppy)3
3a
1a
+
2a
DMF or CH3CN 4%
MeOH 7%
eq. 4
eq. 5
2 equiv. Na2CO3, N2, r.t, CFL
1 mol% fac-Ir(ppy)3
3a
30%
1a
2a
+
2 equiv. Na2CO3, O2, r.t, CFL
DMF or CH3CN
1 mol% fac-Ir(ppy)3
1a
2a
3a
56%
eq. 6
+
2 equiv. Na2CO3, N2, r.t, CFL
tetramethylene sulfoxide (2 mL)
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According to the aforementioned information and previous reports,8d, 17
a
6
7
possible reaction pathway for this transformation is outlined in Scheme 8. First,
8
9
photocatalyst fac-IrIII(ppy)3 is irradiated with visible light to provide a
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IV/*III
photoexcited state, *fac-IrIII(ppy)3 (E1/2
= −1.73 V vs SCE in MeCN),18
which readily reduces α-bromoester 2a (Ered = −0.8 V vs SCE in MeCN)19 via
single electron transfer to generate the reactive alkyl radical A, along with the
oxidized photocatalyst fac-IrIV(ppy)3. Radical A then undergoes the rapid
addition reaction with styrene 1 to afford the new radical B. Subsequently,
intermediate B20 is oxidized by fac-IrIV(ppy)3 (E1/2
= +0.77 V vs SCE in
IV/III
MeCN)18 to produce carbocation C and close the photoredox catalytic cycle.
Finally, the Kornblum-type oxidation of intermediate C with DMSO affords the
corresponding γ-ketoesters.
Scheme 8. Tentative reaction pathway
OEt
OEt
SET
Br
A
O
O
2a
Ar
1
IrIII(ppy)3
IrIV(ppy)3
oxidative
quenching
*
OEt
Ar
T
E
O
S
hv
IrIII(ppy)3
B
Kornblum
oxidation
O
OEt
OEt
Ar
Ar
C
O
O
Me2S Me2SO
In summary, we have successfully developed a visible-light-induced reaction of
a wide variety of α-brominated carboxylates with styrenes to prepare various
synthetically important γ-ketoesters. A distinct advantage of this protocol over
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all previous methods is the use of inexpensive and readily available substrates
as well as the use of DMSO as both the solvent and the terminal oxidant. We
envisage that these features render the present protocol to be attractive in the
syntheses of an array of medicinally and agrochemically relevant carbonyl
compounds.
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Experimental Section
General experimental information: Reagents were used as received without
further purification unless otherwise indicated. Solvents were dried and
distilled prior to use. Reactions were monitored with thin layer chromatography
using silica gel GF254 plates. Organic solutions were concentrated in vacuo with
a rotavapor. Flash column chromatography was performed using silica gel
(200−300 meshes). Petroleum ether used had a boiling point range of 60−90°C.
Melting points were measured on a digital melting point apparatus without
correction of the thermometer. Nuclear magnetic resonance spectra were
recorded at ambient temperature (unless otherwise stated) at 400 MHz (100
13
MHz for C) in CDCl3. Chemical shifts were reported in ppm (δ) using TMS
as internal standard, and spin−spin coupling constants (J) were given in Hz.
High resolution mass spectrometry (HRMS) analyses were carried out on an
FTICR HR-ESI-MS.
General procedure for the synthesis of γ-ketoesters: fac-Ir(ppy)3 (5.00 μmol, 0.010
equiv.) and Na2CO3 (1.00 mmol, 2.00 equiv.) were added to a flame-dried Schlenk
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flask containing a stirring bar and purged by evacuating the flask and backfilling with
argon three times. Then anhydrous DMSO (2 mL), vinylarene (0.50 mmol, 1.00
equiv.) and bromocarboxylate (1.00 mmol, 2.00 equiv.) were added. The reaction
mixture was degassed by the freeze-pumpthaw method and then irradiated with a
24W household fluorescent lamp from a distance of 2 cm for 20 h. After completion
of the reaction, the mixture was added with 10 mL of H2O and extracted with ethyl
acetate (10 mL) for three times. The combined organic layer was dried (Na2SO4) and
concentrated to give crude residue which was purified by flash column
chromatography to give the corresponding product.
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Ethyl 4-(4-(tert-butyl)phenyl)-2-methyl-4-oxobutanoate (3a, known compound,
cas: 1522361-86-9). Compound 3a was obtained as an oil in 83% yield (115 mg) after
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flash chromatography (Silica gel, petroleum ether: ethyl acetate = 50:1). H NMR
(400 MHz, CDCl3) δ/ppm= 7.84 (d, J = 8.5 Hz, 2H), 7.40 (d, J = 8.5 Hz, 2H), 4.08 (q,
J = 7.1 Hz, 2H), 3.38 (dd, J = 17.4, 7.7 Hz, 1H), 3.11 – 2.98 (m, 1H), 2.93 (dd, J =
13
17.4, 5.7 Hz, 1H), 1.27 (s, 9H), 1.22 – 1.15 (m, 6H). C NMR (100 MHz, CDCl3)
δ/ppm= 197.8, 176.0, 156.9, 134.2, 128.0, 125.5, 60.6, 41.8, 35.1, 35.1, 31.1, 17.3,
14.2. Spectral data are in good agreement with literature values.7
Ethyl 2-methyl-4-oxo-4-phenylbutanoate (3b, known compound, cas: 6938-44-9).
Compound 3b was obtained as an oil in 70% yield (77 mg) after flash
1
chromatography (Silica gel, petroleum ether: ethyl acetate = 50:1). H NMR (400
MHz, CDCl3) δ/ppm= 7.94 – 7.81 (m, 2H), 7.56 – 7.44 (m, 1H), 7.43 – 7.32 (m, 2H),
4.08 (q, J = 7.1 Hz, 2H), 3.41 (dd, J = 17.5, 7.8 Hz, 1H), 3.21 – 2.99 (m, 1H), 2.94
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(dd, J = 17.5, 5.5 Hz, 1H), 1.28 – 1.15 (m, 6H). 13C NMR (100 MHz, CDCl3) δ/ppm=
198.1, 176.0, 136.7, 133.2, 128.6, 128.0, 60.6, 41.9, 35.1, 17.3, 14.2. Spectral data are
in good agreement with literature values.7
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Ethyl 2-methyl-4-oxo-4-phenylbutanoate (3c, known compound, cas:
1522361-90-5). Compound 3c was obtained as an oil in 70% yield (82 mg) after flash
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chromatography (Silica gel, petroleum ether: ethyl acetate = 60:1). H NMR (400
MHz, CDCl3) δ/ppm= 7.80 (d, J = 8.2 Hz, 2H), 7.18 (d, J = 8.2 Hz, 2H), 4.08 (q, J =
7.1 Hz, 2H), 3.38 (dd, J = 17.4, 7.8 Hz, 1H), 3.08 – 3.01 (m, 1H), 2.92 (dd, J = 17.5,
5.6 Hz, 1H), 2.34 (s, 3H), 1.23 – 1.14 (m, 6H). 13C NMR (100 MHz, CDCl3) δ/ppm=
197.8, 176.1, 144.0, 134.3, 129.3, 128.2, 60.6, 41.8, 35.1, 21.7, 17.5, 14.2. Spectral
data are in good agreement with literature values.7
Ethyl 4-(4-acetoxyphenyl)-2-methyl-4-oxobutanoate (3d, new compound).
Compound 3d was obtained as an oil in 68% yield (95 mg) after flash
1
chromatography (Silica gel, petroleum ether: ethyl acetate = 30:1). H NMR (400
MHz, CDCl3) δ/ppm=7.94 (d, J = 8.7 Hz, 2H), 7.12 (d, J = 8.7 Hz, 2H), 4.08 (q, J =
7.1 Hz, 2H), 3.39 (dd, J = 17.6, 8.0 Hz, 1H), 3.10 – 2.97 (m, 1H), 2.91 (dd, J = 17.6,
5.5 Hz, 1H), 2.25 (s, 3H), 1.23 – 1.15 (m, 6H). 13C NMR (100 MHz, CDCl3)
δ/ppm=195.9, 174.9, 167.9, 153.3, 133.3, 128.6, 120.8, 59.6, 40.9, 34.0, 20.1, 16.3,
13.1. HRMS (ESI/Q-TOF) m/z: [M+H]+ Calcd for C15H19O5 279.1232; Found
279.1228.
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Ethyl 4-([1,1'-biphenyl]-4-yl)-2-methyl-4-oxobutanoate (3e, new compound).
Compound 3e was obtained as white solid in 62% yield (92 mg) after flash
chromatography (Silica gel, petroleum ether: ethyl acetate = 60:1). mp= 80-82 ºC. 1H
NMR (400 MHz, CDCl3) δ/ppm=8.05 (d, J = 8.5 Hz, 2H), 7.69 (d, J = 8.4 Hz, 2H),
7.65 – 7.57 (m, 2H), 7.54 – 7.45 (m, 2H), 7.44 – 7.38 (m, 1H), 4.17 (q, J = 7.1 Hz,
2H), 3.52 (dd, J = 17.5, 7.8 Hz, 1H), 3.21 – 3.09 (m, 1H), 3.04 (dd, J = 17.4, 5.5 Hz,
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1H), 1.33 – 1.23 (m, 6H). C NMR (100 MHz, CDCl3) δ/ppm=196.7, 175.0, 144.8,
138.8, 134.4, 127.9, 127.6, 127.2, 126.2, 126.2, 59.6, 40.9, 34.1, 16.3, 13.2. HRMS
(ESI/Q-TOF) m/z: [M+H]+ Calcd for C19H21O3 297.1491; Found 297.1487
Ethyl 4-(4-fluorophenyl)-2-methyl-4-oxobutanoate (3f, known compound, cas:
1522361-88-1). Compound 3f was obtained as an oil in 81% yield (96 mg) after flash
1
chromatography (Silica gel, petroleum ether: ethyl acetate = 60:1). H NMR (400
MHz, CDCl3) δ/ppm= 8.04 – 7.84 (m, 2H), 7.13 – 6.99 (m, 2H), 4.08 (q, J = 7.1 Hz,
2H), 3.39 (dd, J = 17.6, 8.1 Hz, 1H), 3.12 – 2.96 (m, 1H), 2.90 (dd, J = 17.6, 5.4 Hz,
19
13
1H), 1.24 – 1.14 (m, 6H). F NMR (376 MHz, CDCl3) δ= -105.1. C NMR (100
MHz, CDCl3) δ/ppm=195.5, 174.9, 164.7 (d, J = 254.7 Hz), 132.1 (d, J = 3.0 Hz),
129.6 (d, J = 9.4 Hz), 114.7 (d, J = 21.8 Hz), 59.6, 40.8, 34.0, 16.3, 13.1. Spectral
data are in good agreement with literature values.7
Ethyl 4-(4-chlorophenyl)-2-methyl-4-oxobutanoate (3g, known compound, cas:
54029-07-1). Compound 3g was obtained as an oil in 85% yield (108 mg) after flash
1
chromatography (Silica gel, petroleum ether: ethyl acetate = 60:1). H NMR (400
MHz, CDCl3) δ/ppm= 7.83 (d, J = 8.6 Hz, 2H), 7.36 (d, J = 8.6 Hz, 2H), 4.07 (q, J =
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7.1 Hz, 2H), 3.38 (dd, J = 17.6, 8.1 Hz, 1H), 3.13 – 2.97 (m, 1H), 2.89 (dd, J = 17.6,
5.4 Hz, 1H), 1.25 – 1.14 (m, 6H). 13C NMR (100 MHz, CDCl3) δ/ppm= 196.9, 175.8,
139.6, 135.0, 129.5, 128.9, 60.7, 41.9, 35.0, 17.3, 14.2. Spectral data are in good
agreement with literature values.7
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Ethyl 4-(4-bromophenyl)-2-methyl-4-oxobutanoate (3h, known compound, cas:
1522361-87-0). Compound 3h was obtained as an oil in 77% yield (115 mg) after
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flash chromatography (Silica gel, petroleum ether: ethyl acetate = 60:1). H NMR
(400 MHz, CDCl3) δ/ppm= 7.76 (d, J = 8.6 Hz, 2H), 7.53 (d, J = 8.6 Hz, 2H), 4.08 (q,
J = 7.1 Hz, 2H), 3.38 (dd, J = 17.6, 8.1 Hz,1H), 3.18 – 2.96 (m, 1H), 2.88 (dd, J =
13
17.6, 5.3 Hz, 1H), 1.25 – 1.13 (m, 6H). C NMR (100 MHz, CDCl3) δ/ppm=196.1,
174.8, 134.4, 130.9, 128.5, 127.3, 59.7, 40.8, 34.0, 16.3, 13.1. Spectral data are in
good agreement with literature values.7
Ethyl 4-(3-bromophenyl)-2-methyl-4-oxobutanoate (3i, known compound, cas:
1522361-89-2). Compound 3i was obtained as an oil in 73% yield (109 mg) after
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flash chromatography (Silica gel, petroleum ether: ethyl acetate = 40:1). H NMR
(400 MHz, CDCl3) δ/ppm= 8.03 (t, J = 1.8 Hz, 1H), 7.82 (dt, J = 7.9, 1.3 Hz, 1H),
7.62 (ddd, J = 8.0, 2.0, 1.0 Hz, 1H), 7.28 (t, J = 7.9 Hz, 1H), 4.08 (q, J = 7.1 Hz, 2H),
3.39 (dd, J = 17.7, 8.2 Hz, 1H), 3.13 – 2.97 (m, 1H), 2.89 (dd, J = 17.7, 5.3 Hz, 1H),
1.25 – 1.16 (m, 6H). 13C NMR (100 MHz, CDCl3) δ/ppm=195.8, 174.7, 137.4, 135.0,
130.1, 129.2, 125.5, 121.9, 59.7, 40.9, 34.0, 16.3, 13.1. Spectral data are in good
agreement with literature values.7
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Ethyl 2-methyl-4-(naphthalen-2-yl)-4-oxobutanoate (3j, known compound, cas:
856810-67-8). Compound 3j was obtained as a white solid in 52% yield (70 mg) after
flash chromatography (Silica gel, petroleum ether: ethyl acetate = 40:1). mp= 56-58
ºC. 1H NMR (400 MHz, CDCl3) δ/ppm= 8.50 (d, J = 1.7 Hz, 1H), 8.03 (dd, J = 8.6,
1.8 Hz, 1H), 7.97 (dd, J = 8.0, 1.4 Hz, 1H), 7.94 – 7.82 (m, 2H), 7.63 – 7.54 (m, 2H),
4.17 (q, J = 7.1 Hz, 2H), 3.85 – 3.50 (m, 1H), 3.33 – 2.99 (m, 2H), 1.37 – 1.24 (m,
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6H). C NMR (100 MHz, CDCl3) δ/ppm=197.0, 175.0, 134.6, 133.0, 131.4, 128.7,
128.5, 127.5, 127.4, 126.7, 125.8, 122.7, 59.6, 41.0, 34.1, 16.4, 13.2. Spectral data are
in good agreement with literature values.21
Ethyl 2,3-dimethyl-4-oxo-4-phenylbutanoate (3k, known compound). Compound
3k was obtained as an oil in 69% yield (81 mg) after flash chromatography (Silica gel,
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petroleum ether: ethyl acetate = 20:1). H NMR (400 MHz, CDCl3) δ/ppm=7.95 –
7.89 (m, 2H), 7.59 – 7.45 (m, 1H), 7.46 – 7.39 (m, 2H), 4.12 – 4.05 (m, 1H), 4.03 –
3.97 (m, 1H), 3.75 – 3.64 (m, 1H), 3.03 – 2.78 (m, 1H), 1.25 – 1.14 (m, 4H), 1.14 –
1.05 (m, 5H). 13C NMR (100 MHz, CDCl3) δ/ppm=202.5, 201.6, 174.8, 174.6, 135.6,
135.0, 132.2, 131.9, 127.7, 127.6, 127.34, 127.30, 59.6, 59.5, 42.5, 42.0, 41.73, 40.7,
15.5, 15.2, 13.5, 13.2, 13.1, 13.0. Spectral data are in good agreement with literature
values.5c
Methyl 4-(4-(tert-butyl)phenyl)-2-methyl-4-oxobutanoate (4a, new compound).
Compound 4a was obtained as an oil in 70% yield (92 mg) after flash
1
chromatography (Silica gel, petroleum ether: ethyl acetate = 50:1). H NMR (400
MHz, CDCl3) δ/ppm=7.84 (d, J = 8.5 Hz, 2H), 7.40 (d, J = 8.5 Hz, 2H), 3.63 (s, 3H),
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3.39 (dd, J = 17.5, 7.8 Hz, 1H), 3.13 – 3.01 (m, 1H), 2.94 (dd, J = 17.5, 5.6 Hz, 1H),
1.27 (s, 9H), 1.20 (d, J = 7.2 Hz, 3H).13C NMR (100 MHz, CDCl3) δ/ppm=196.6,
175.5, 155.9, 133.0, 127.0, 124.5, 50.9, 40.8, 34.1, 33.9, 30.0, 16.3. HRMS
(ESI/Q-TOF) m/z: [M+H]+ Calcd for C16H23O3 263.1647; Found 263.1643.
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tert-Butyl 4-(4-(tert-butyl)phenyl)-2-methyl-4-oxobutanoate (4b, new compound).
Compound 4b was obtained as an oil in 63% yield (96 mg) after flash
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chromatography (Silica gel, petroleum ether: ethyl acetate = 40:1). H NMR (400
MHz, CDCl3) δ/ppm= 7.84 (d, J = 8.5 Hz, 2H), 7.40 (d, J = 8.5 Hz, 2H), 3.33 (dd, J =
17.1, 7.5 Hz, 1H), 3.01 – 2.89 (m, 1H), 2.86 (dd, J = 17.1, 5.8 Hz, 1H), 1.36 (s, 9H),
1.27 (s, 9H), 1.16 (d, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ/ppm=196.9,
174.3, 155.7, 133.3, 127.0, 124.5, 79.2, 40.8, 35.0, 34.1, 30.1, 27.0, 16.4. HRMS
(ESI/Q-TOF) m/z: [M+Na]+ Calcd for C19H28O3Na 327.1936; Found 327.1934.
Ethyl 4-(4-(tert-butyl)phenyl)-2-isopropyl-4-oxobutanoate
(4c, known
compound, cas:1522362-04-4). Compound 4c was obtained as an oil in 69% yield
(105 mg) after flash chromatography (Silica gel, petroleum ether: ethyl acetate =
1
40:1). H NMR (400 MHz, CDCl3) δ/ppm=7.85 (d, J = 8.6 Hz, 2H), 7.40 (d, J = 8.6
Hz, 2H), 4.15 – 4.00 (m, 2H), 3.47 – 3.37 (m, 1H), 3.00 – 2.78 (m, 2H), 2.17 – 1.91
13
(m, 1H), 1.26 (s, 9H), 1.18 (t, J = 7.1 Hz, 3H), 0.92 (dd, J = 6.9, 1.5 Hz, 6H). C
NMR (100 MHz, CDCl3) δ/ppm=197.4, 173.8, 155.7, 133.2, 127.0, 124.4, 59.3, 45.5,
36.3, 34.06, 30.1, 29.2, 19.3, 18.9, 13.2. Spectral data are in good agreement with
literature values.7
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Ethyl 2-(2-(4-(tert-butyl)phenyl)-2-oxoethyl)hexanoate (4d, new compound).
Compound 4d was obtained as an oil in 77% yield (123 mg) after flash
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chromatography (Silica gel, petroleum ether: ethyl acetate = 70:1). H NMR (400
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MHz, CDCl3) δ/ppm=7.84 (d, J = 8.5 Hz, 2H), 7.40 (d, J = 8.5 Hz, 2H), 4.08 (qd, J =
7.1, 2.4 Hz, 2H), 3.36 (dd, J = 18.6, 10.0 Hz, 1H), 3.06 – 2.86 (m, 2H), 1.69 – 1.51
(m, 2H), 1.30 – 1.21 (m, 13H), 1.18 (t, J = 7.1 Hz, 3H), 0.83 (t, J = 12.3 Hz, 3H). 13C
NMR (100 MHz, CDCl3) δ/ppm=197.0, 174.7, 155.8, 133.1, 127.0, 124.5, 59.4, 39.4,
39.3, 34.1, 30.9, 30.1, 28.3, 21.5, 13.2, 12.9. HRMS (ESI/Q-TOF) m/z: [M+H]+ Calcd
for C20H31O3 319.2273; Found 319.2269.
Isopropyl
4-(4-(tert-butyl)phenyl)-2,2-dimethyl-4-oxobutanoate
(4e,
new
compound). Compound 4e was obtained as an oil in 90% yield (137 mg) after flash
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chromatography (Silica gel, petroleum ether: ethyl acetate = 60:1). H NMR (400
MHz, CDCl3) δ/ppm=7.81 (d, J = 8.5 Hz, 2H), 7.39 (d, J = 8.5 Hz, 2H), 4.94 (p, J =
13
6.2 Hz, 1H), 3.18 (s, 2H), 1.27 (s, 9H), 1.23 (s, 6H), 1.11 (d, J = 6.2 Hz, 6H). C
NMR (100 MHz, CDCl3) δ/ppm=196.2, 175.8, 155.6, 133.6, 126.8, 124.4, 66.4, 47.3,
39.0, 34.1, 30.1, 24.7, 20.6. HRMS (ESI/Q-TOF) m/z: [M+H]+ Calcd for C19H29O3
305.2117; Found 305.2113.
Methyl 4-(4-(tert-butyl)phenyl)-2,2-dimethyl-4-oxobutanoate (4f, new compound).
Compound 4f was obtained as an oil in 87% yield (120 mg) after flash
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chromatography (Silica gel, petroleum ether: ethyl acetate = 60:1). H NMR (400
MHz, CDCl3) δ/ppm=7.81 (d, J = 8.6 Hz, 2H), 7.39 (d, J = 8.6 Hz, 2H), 3.59 (s, 3H),
13
3.21 (s, 2H), 1.26 (s, 9H), 1.24 (s, 6H). C NMR (100 MHz, CDCl3) δ/ppm=196.2,
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176.9, 155.8, 133.4, 126.9, 124.5, 50.9, 47.5, 39.0, 34.1, 30.0, 24.7. HRMS
(ESI/Q-TOF) m/z: [M+H]+ Calcd for C17H25O3 277.1804; Found 277.1802.
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Ethyl 4-(4-(tert-butyl)phenyl)-4-oxobutanoate (4g, known compound, cas:
75237-09-1). Compound 4g was obtained as an oil in 55% yield (72 mg) after flash
1
chromatography (Silica gel, petroleum ether: ethyl acetate = 70:1). H NMR (400
MHz, CDCl3) δ/ppm= 7.93 (d, J = 8.5 Hz, 2H), 7.48 (d, J = 8.5 Hz, 2H), 4.16 (q, J =
7.2 Hz, 2H), 3.30 (t, J = 6.7 Hz, 2H), 2.75 (t, J = 6.7 Hz, 2H), 1.39 – 1.26 (m, 12H).
13C NMR (100 MHz, CDCl3) δ/ppm= 196.8, 172.0, 155.9, 133.0, 127.0, 124.5, 59.6,
34.1, 32.3, 30.1, 27.3, 13.2. Spectral data are in good agreement with literature
values.22
Benzyl 4-(4-(tert-butyl)phenyl)-4-oxobutanoate (4h, new compound). Compound
4h was obtained as an oil in 61% yield (101 mg) after flash chromatography (Silica
gel, petroleum ether: ethyl acetate = 40:1). 1H NMR (400 MHz, CDCl3) δ/ppm= 7.85
(d, J = 8.6 Hz, 2H), 7.41 (d, J = 8.6 Hz, 2H), 7.35 – 7.22 (m, 5H), 5.08 (s, 2H), 3.25
(t, J = 6.7 Hz, 2H), 2.75 (t, J = 6.7 Hz, 2H), 1.27 (s, 9H). 13C NMR (100 MHz,
CDCl3) δ/ppm=196.7, 171.8, 155.9, 134.9, 132.9, 127.5, 127.2, 127.0, 124.5, 65.5,
34.1, 32.2, 30.1, 27.3. HRMS (ESI/Q-TOF) m/z: [M+H]+ Calcd for C21H25O3
325.1804; Found 325.1796.
4-Bromobenzyl 4-(4-(tert-butyl)phenyl)-2-methyl-4-oxobutanoate (4i, new
compound). Compound 4i was obtained as an oil in 80% yield (167 mg) after flash
1
chromatography (Silica gel, petroleum ether: ethyl acetate = 40:1). H NMR (400
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MHz, CDCl3) δ/ppm=7.82 (d, J = 8.6 Hz, 2H), 7.40 (d, J = 6.0 Hz, 2H), 7.38 (d, J =
6.0 Hz, 2H), 7.13 (d, J = 8.4 Hz, 2H), 5.05 – 4.96 (m, 2H), 3.39 (dd, J = 17.6, 8.0 Hz,
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1H), 3.17 – 3.04 (m, 1H), 2.95 (dd, J = 17.6, 5.4 Hz, 1H), 1.30 – 1.17 (m, 12H). C
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NMR (100 MHz, CDCl3) δ/ppm=196.5, 174.7, 156.0, 134.1, 133.0, 130.6, 128.7,
127.0, 124.5, 121.0, 64.5, 40.7, 34.1, 34.0, 30.1, 16.2. HRMS (ESI/Q-TOF) m/z:
[M+Na]+ Calcd for C22H25BrO3Na 439.0885; Found 439.0877.
3-(2-(4-(tert-Butyl)phenyl)-2-oxoethyl)dihydrofuran-2(3H)-one
(4j,
known
compound, cas: 1522362-11-3). Compound 4j was obtained as a white solid in 73%
yield (95 mg) after flash chromatography (Silica gel, petroleum ether: ethyl acetate =
30:1). mp= 112-114 ºC. 1H NMR (400 MHz, CDCl3) δ/ppm=7.85 (d, J = 8.5 Hz, 2H),
7.43 (d, J = 8.5 Hz, 2H), 4.38 (td, J = 8.9, 2.0 Hz, 1H), 4.22 (ddd, J = 10.4, 9.1, 6.6
Hz, 1H), 3.66 – 3.52 (m, 1H), 3.20 – 3.03 (m, 2H), 2.63 – 2.55 (m, 1H), 1.89 (dtd, J =
12.8, 10.4, 8.7 Hz, 1H), 1.28 (s, 9H). 13C NMR (100 MHz, CDCl3) δ/ppm=195.6,
178.3, 156.4, 132.5, 127.0, 124.7, 65.9, 38.3, 34.3, 34.2, 30.0, 28.2. Spectral data are
in good agreement with literature values.7
(E)-3,7-Dimethylocta-2,6-dien-1-yl
4-(4-(tert-butyl)phenyl)-2-methyl-4-oxobutanoate (4k, new compound). Compound
4k was obtained as an oil in 67% yield (129 mg) after flash chromatography (Silica
gel, petroleum ether: ethyl acetate = 30:1). 1H NMR (400 MHz, CDCl3) δ/ppm= 7.84
(d, J = 8.5 Hz, 2H), 7.40 (d, J = 8.6 Hz, 2H), 5.25 (tt, J = 5.7, 1.3 Hz, 1H), 5.00 (ddt, J
= 6.9, 5.4, 1.7 Hz, 1H), 4.68 – 4.43 (m, 2H), 3.38 (dd, J = 17.4, 7.6 Hz, 1H), 3.13 –
2.98 (m, 1H), 2.92 (dd, J = 17.4, 5.9 Hz, 1H), 2.06 – 1.92 (m, 4H), 1.63 – 1.59 (m,
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6H), 1.52 (s, 3H), 1.26 (s, 9H), 1.19 (d, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3)
δ/ppm=196.7, 175.0, 155.8, 141.0, 133.2, 130.7, 127.0, 124.5, 122.8, 117.3, 60.5,
40.8, 38.5, 34.1, 30.0, 25.3, 24.7, 16.7, 16.3, 15.4. HRMS (ESI/Q-TOF) m/z:
[M+Na]+ Calcd for C25H36O3Na 407.2562; Found 407.2554.
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(2S,5R)-2-Isopropyl-5-methylcyclohexyl
4-(4-(tert-butyl)phenyl)-2-methyl-4-oxobutanoate (4l, new compound). Compound
4l was obtained as an oil in 63% yield (122 mg) after flash chromatography (Silica
gel, petroleum ether: ethyl acetate = 50:1).1H NMR (400 MHz, CDCl3) δ/ppm= 7.84
(dd, J = 8.5, 1.8 Hz, 2H), 7.40 (d, J = 8.4 Hz, 2H), 4.59 (tt, J = 10.9, 4.4 Hz, 1H), 3.38
(ddd, J = 17.4, 9.7, 7.8 Hz, 1H), 3.16 – 2.97 (m, 1H), 2.96 – 2.75 (m, 1H), 2.00 – 1.84
(m, 1H), 1.80– 1.74 (m, 1H), 1.61 – 1.55 (m, 2H), 1.45 – 1.34 (m, 1H), 1.26 (s, 9H),
1.19 (dd, J = 7.1, 3.9 Hz, 4H), 1.03 – 0.88 (m, 2H), 0.86 – 0.79 (m, 6H), 0.77 (d, J =
7.1 Hz, 2H), 0.67 (dd, J = 9.9, 7.1 Hz, 6H). 13C NMR (100 MHz, CDCl3)
δ/ppm=196.7, 196.6, 174.5, 174.5, 155.6, 155.7, 133.3, 133.2, 127.0, 126.9, 124.4,
73.2, 73.2, 45.94, 40.8, 40.6, 39.7, 39.6, 34.4, 34.3, 34.1, 33.3, 30.4, 30.3, 30.1, 25.1,
25.0, 22.3, 22.2, 21.0, 21.0, 19.8, 19.7, 16.74, 15.2, 15.0. HRMS (ESI/Q-TOF) m/z:
[M+H]+ Calcd for C25H39O3 387.2899; Found 387.2889.
4-(4-(tert-Butyl)phenyl)-4-oxobutanenitrile
(5a,
known
compound,
cas:1154885-60-5). Compound 5a was obtained as a white solid in 53% yield (57 mg)
after flash chromatography (Silica gel, petroleum ether: ethyl acetate = 30:1). mp=
1
66-68 ºC. H NMR (400 MHz, CDCl3) δ/ppm=7.83 (d, J = 8.6 Hz, 2H), 7.44 (d, J =
8.6 Hz, 2H), 3.30 (t, J = 14.6 Hz, 2H), 2.71 (t, J = 14.6 Hz, 2H), 1.28 (s, 9H). 13C
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NMR (100 MHz, CDCl3) δ/ppm=193.9, 156.78, 132.0, 127.0, 124.8, 118.3, 34.2,
6
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33.1, 30.0, 10.8. Spectral data are in good agreement with literature values.12a
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1-(4-(tert-Butyl)phenyl)-4,4,4-trifluorobutan-1-one (5b, known compound, cas:
1468771-50-7). Compound 5b was obtained as a white solid in 74% yield (96 mg)
after flash chromatography (Silica gel, petroleum ether: ethyl acetate = 40:1). mp=
1
53-55 ºC. H NMR (400 MHz, CDCl3) δ/ppm=7.84 (d, J = 8.6 Hz, 2H), 7.42 (d, J =
19
8.6 Hz, 2H), 3.16 (t, J = 7.8 Hz, 2 H), 2.60 – 2.42 (m, 2H), 1.28 (s, 9H). F NMR
13
(376 MHz, CDCl3) δ/ppm=-66.4. C NMR (100 MHz, CDCl3) δ/ppm=195.0, 156.4,
132.5, 127.0, 124.7, 34.1, 30.0, 27.3 (q, J = 29.7 Hz). Spectral data are in good
agreement with literature values.13d
1-(4-(tert-Butyl)phenyl)-3-methyl-3-nitrobutan-1-one (5c, new compound).
Compound 5c was obtained as a white solid in 72% yield (95 mg) after flash
chromatography (Silica gel, petroleum ether: ethyl acetate = 30:1). mp= 113-135 ºC.
1H NMR (400 MHz, CDCl3) δ/ppm= 7.80 (d, J = 8.6 Hz, 2H), 7.41 (d, J = 8.6 Hz,
2H), 3.59 (s, 2H), 1.68 (s, 6H), 1.26 (s, 9H). 13C NMR (100 MHz, CDCl3)
δ/ppm=194.7, 157.5, 133.8, 128.0, 125.7, 84.9, 47.0, 35.2, 31.1, 26.7. HRMS
(ESI/Q-TOF) m/z: [M+H]+ Calcd for C15H22NO3 264.1600; Found 264.1596.
Gram-scale reaction for the synthesis of γ-ketoester 3a: fac-Ir(ppy)3 (32.75 mg,
0.050 mmol, 0.010 equiv.) and Na2CO3 (1.01g, 10.00 mmol, 2.00 equiv.) were added
to a flame-dried Schlenk flask containing a stirring bar and purged by evacuating the
flask and backfilling with argon three times. Then anhydrous DMSO (25 mL),
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4-tert-butylstyrene 1a (0.80 g, 5.00 mmol, 1.00 equiv.) and ethyl 2-bromopropanoate
2a (1.81 g, 10.00 mmol, 2.00 equiv.) were added. The reaction mixture was degassed
by the freeze-pumpthaw method and then irradiated with a 24W household
fluorescent lamp from a distance of 2 cm for 20 h. After completion of the reaction,
the mixture was added with 20 mL of H2O and extracted with ethyl acetate (30 mL)
for three times. The combined organic layer was dried (Na2SO4) and concentrated to
give crude residue which was purified by flash column chromatography (Silica gel,
petroleum ether: ethyl acetate = 50:1) to give 3a in 71% yield (0.98 g).
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Control experiments (Scheme 7. eq. 3). fac-Ir(ppy)3 (3 mg, 5.00 μmol, 0.010 equiv.)
and Na2CO3 (106 mg, 1.00 mmol, 2.00 equiv.) were added to a flame-dried Schlenk
flask containing a stirring bar and purged by evacuating the flask and backfilling with
argon three times. Then anhydrous DMSO (2 mL), 4-tert-butylstyrene 1a (80 mg,
0.50 mmol, 1.00 equiv.), ethyl 2-bromopropanoate 2a (181 mg, 1.00 mmol, 2.00
equiv.) and 1,1-diphenylethylene (180 mg, 1.00 mmol, 2.00 equiv.) were added. The
reaction mixture was degassed by the freeze-pumpthaw method and then irradiated
with a 24W household fluorescent lamp from a distance of 2 cm for 20 h. After
completion of the reaction, the mixture was added with 10 mL of H2O and extracted
with ethyl acetate (10 mL) for three times. The combined organic layer was dried
(Na2SO4) and concentrated to give crude residue which was purified by flash column
chromatography (Silica gel, petroleum ether: dichloromethane = 4:1) to give 6 as an
oil in 83% yield (60 mg).1H NMR (400 MHz, CDCl3) δ/ppm= 7.39 – 7.24 (m, 3H),
7.24 – 7.10 (m, 7H), 6.05 (d, J = 10.3 Hz, 1H), 4.06 (q, J = 7.1 Hz, 2H), 3.19 (dq, J =
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10.3, 7.0 Hz, 1H), 1.24 – 1.14 (m, 6H). C NMR (100 MHz, CDCl3) δ/ppm=173.9,
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141.9, 140.8, 138.3, 128.7, 127.3, 127.1, 126.8, 126.3, 126.2, 59.6, 39.4, 17.5, 13.2.
Spectral data are in good agreement with literature values.8d
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Associated content
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website.
Copies of NMR spectra for the obtained compounds (PDF).
Author Information
Corresponding Author
*E-mail: gqliu@ntu.edu.cn
Notes
The authors declare no competing financial interest.
Acknowledgements
This study was supported by the Natural Science Foundation of Jiangsu Province in
China (BK20170439), and Large Instruments Open Foundation of Nantong
University (KBJN1952). We thank Prof. Yanan Zhang (Nantong) for his support of
chemical reagents. We also thank Prof. Till Opatz (University of Mainz) for helpful
discussions.
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