Mn-Enabled Radical-Based Alkyl-Alkyl Cross-Coupling Reaction from 4-Alkyl-1,4-dihydropyridines

Article abstract of DOI:10.1021/acs.joc.9b02323

Highly efficient alkylation of β-chloro ketones and their derivatives was achieved by means of domino dehydrochlorination/Mn-enabled radical-based alkyl-alkyl cross-coupling reaction. In situ-generated α,β-unsaturated ketones and their analogues were identified as the reaction intermediates. Known bioactive compounds, such as melperone and azaperone, could be easily prepared from β-chloropropiophenone in two steps.

Full text of DOI:10.1021/acs.joc.9b02323

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Article
Mn-Enabled Radical-Based alkyl–alkyl Cross-
Coupling Reaction from 4-Alkyl-1,4-dihydropyridines
Jie Wang, Yu-Bo Pang, Na Tao, Runsheng Zeng, and Yingsheng Zhao
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02323 • Publication Date (Web): 01 Nov 2019
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Mn-Enabled Radical-Based alkyl–alkyl Cross-Coupling Reaction
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from 4-Alkyl-1,4-dihydropyridines
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Jie Wang,† Yu-Bo Pang, † Na Tao,† Run-Sheng Zeng*,† and Yingsheng Zhao*,†
† Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical
Engineering and Materials Science, Soochow University, Suzhou 215123, China
Email: yszhao@suda.edu.cn, zengrunsheng@suda.edu.cn
O
R2
O
R2
R1
R3
R1
Cl
Mn
R3 DHP
Domino reactions
Csp3-Csp3 cross-coupling
R3
sp3
sp3
sp3
X
ABSTRACT: Highly efficient alkylation of β-chloro ketones and their derivatives
were achieved by means of domino dehydrochlorination/Mn-Enabled radical-based
alkyl-alkyl cross-coupling reaction. In situ generated a,β-unsaturated ketone and their
analogues were identified as the reaction intermediates. Known bioactive compounds,
such as Meperone and Azaperone, could be easily prepared from
β-chloropropiophenone in two steps.
INTRODUCTION
Transition metal-catalyzed cross-coupling reactions with alkyl halides as electrophiles
and organometallics as nucleophiles have been extensively explored in the formation
of C(sp3)–C(sp3) bonds.1 A wide variety of primary alkyl halides/metals can be used
as effective substrates in cross-coupling,2 but the secondary alkyl halides/metals
usually remain as challenging substrates due to the side reaction of β-hydride
elimination and other undesired reactions.3 Due to the significance of alkyl-alkyl
cross-coupling reactions in constructing key intermediates for medical chemistry
and natural product synthesis, the development of novel routes to realize the
alkyl-alkyl cross-coupling reaction is highly attractive. Herein, a Mn-induced
cross-coupling of β-chloropropiophenone with alkyl radical derived from
4-alkyl-1,4-dihydropyridines was reported (Scheme 1).
A
variety of
β-chloropropiophenones were well tolerated, leading to the corresponding products in
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moderate to good yields. The bioactive compounds Meperone and Azaperone could
be easily synthesized from β-chloropropiophenone in two steps. The preliminary
mechanistic study revealed that a domino reaction sequence was involved in this
transformation.
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Scheme 1. Novel approach to construct C(sp3)-C(sp3) bonds.
a, Classical C(sp3)-C(sp3) cross-coupling reaction
[M]
R
R1
R1
M
R
X
+
M = Mg, Zn, B, Cu, etc
b, C(sp3)-C(sp3) cross-coupling reactio of substituted Hantzsch Ester
H
N
DTBP
R1 DHP
EtOOC
COOEt
+ R
X
R
R1
R1
Mn
DHP
Alkylphenones are a class of significant compounds, some of which are well-known
bioactive compounds, such as Melperone4, Azaperone5, Ebastine6, and Pipamperone
(Figure 1). However, to the best of our knowledge, the approach to directly realize
cross-coupling of β-chloropropiophenone with another secondary alkyl functional
group remains relatively unexplored. The major challenge for this alkyl-alkyl
cross-coupling reaction is that both coupling partners suffer from side reactions of
β-hydride elimination7. In 2012, the Yu group reported the efficient
rhodium(I)-catalyzed
arylation
of
β-chloroketones
via
the
domino
dehydrochlorination process8. 4-Alkyl-1,4-dihydropyridines(Alkyl-DHP)9, which can
be easily prepared from aldehyde in one step, are an important class of free radical
precursors. It has been demonstrated that free radicals can be generated via C–C bond
cleavage at the 4-position of the dihydro-pyridine ring under thermal or photoredox
conditions10, 29. Recently, it has been well apply to construct the C(sp3)–C(sp3) bonds
formation reactions. For example, the direct alkylation of unsaturated olefins11,
heterocycles12 and imines13 via the free radical pathway with the
4-Alkyl-1,4-dihydropyridines (Alkyl-DHP) have been well extensively reported.
Figure 1. Relevant bioactive alkylphenone compounds.
Me
N
O
N
O
N
N
F
Melperone
O
Azaperone
O
N
F
NH2
O
N
N
O
Pipamoperone
Ebastine
F
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Thus, the alkyl-alkyl cross-coupling of β-chloroketones with an alkyl radical might be
5
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achievable via the domino dehydrochlorination process.
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RESULTS AND DISCUSSION
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Table 1. Optimization of the Mn-induced alkylation of 1a with 2a.a
O
O
O
Base, Oxidant
Additive
DHP
Cl
+
+
PhCF3, Ar, 100 °C
1a
2a
3a
5
Yield
Entry
Base
Additive Oxidant
3a
5
1
2
K3PO4
-
-
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
BPO
10%
20%
28%
20%
25%
trace
15%
16%
23%
trace
trace
trace
trace
trace
trace
10%
trace
trace
trace
trace
K2CO3
3
KHCO3
-
4
KOAc
-
5
-
-
-
-
-
-
-
-
-
-
-
6
-
7
-
t-BuOOH trace
8
-
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
32%
35%
45%
37%
56%
65%
82%
9
Zn
Cu
In
Mn
Mn
Mn
10
11
12
13b
14b,c
aReaction conditions: 1a (0.1 mmol, 1.0 equiv), 2a (0.15 mmol, 1.5 equiv), Base (2 equiv),
b
c
Oxidant (2 equiv), Additive (2 equiv), 12 h. 0.5 equiv DTBP. Reaction time, 48 h. DTBP =
2-(tert-butylperoxy)-2-methylpropane), BPO = Benzoic peroxyanhydride).
With these conditions in mind, we first treated β-chloropropiophenone (1a) with
4-isopropyl-1,4-dihydropyridine (2a) in the presence of K2S2O8 and K3PO4, in
o
trifluoromethyl benzene at 100 C for 12 h to investigate whether the alkyl-alkyl
cross-coupling could be achieved. The cross-coupling product 3a was indeed obtained
at 10% yield, along with phenylvinylketone (5) in 15% yield (Table 1, entry 1).
Encouraged by this result, we next screened various bases, such as K2CO3, KHCO3,
and KOAc, to improve the selectivity of 3a and 5 (Table 1, entries 2-4). When KOAc
was used, a slightly improved yield of 3a was achieved, along with the side product 5
(entry 4). Interestingly, a better yield of 3a could be achieved when the reaction was
performed without a base (entry 5). A variety of oxidants including DTBP, BPO, and
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t-BuOOH, were next investigated to improve the yield of 3a (entries 6-8). The oxidant
DTBP was able to generate the product 3a in 32% yield, along with recovery of
starting material 1a. To further improve the efficiency of the alky-alkyl
cross-coupling reaction, a variety of additives were further explored. The results
showed that reducing metals, such as Zn, Cu, In, and Mn, modified the yield and
selectivity for this transformation (entries 9-12). When two equivalents of Mn were
used, the desired product 3a was obtained in 56% yield, along with trace amounts of 5.
Additionally, reducing the amount of DTBP to 0.5 equivalents gave an improved
yield of 3a at 65% yield. The yield of 3a can be improved to 82% when the reaction
duration was extended to 48 h(see ESI†).
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Scheme 2. Substrate scope of β-chloropropiophenone.a
R2
Mn (2 equiv)
DTBP (0.5 equiv)
O
R2
O
+
R3 DHP
R1
R3
R1
Cl
PhCF3, Ar, 100 °C, 48 h
1
2
3
O
O
O
Cy
Me
3b
3e
3d
, 80%
O
, 79%
O
3c,
61%
O
MeO
Ph
F
Br
3g
, 87%
O
, 72%
O
3f
, 72%
O
O
O
3j
, 62%
3h,
3i
, 68%
68%
O
O
O
N
O
3l
, 52%
3k
, 48%
3m
, 56%
aReaction conditions: 1 (0.1 mmol, 1.0 equiv), 2a (0.15 mmol, 1.5 equiv), DTBP (0.5 equiv), Mn
(2 equiv), PhCF3 (0.25 mL), 100 oC, 48 h, Ar.
With the optimized reaction conditions in hand, we firstly examined the substrate
scope of β-chloropropiophenone derivatives under standard reaction condition
(Scheme 2). Various functional groups, such as Me, t-Bu, Cy, MeO, F, and Br,
substituted on the phenyl ring were all compatible, leading to the corresponding
products (3b-h) in 60-90% yields. The disubstituted substrates all performed well,
yielding the corresponding products (3i and 3j) in good yields. The secondary
β-chlorodihydrochalcone was also well tolerated, generating the β-isopropylated
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dihydrochalcone (3k) in moderate yields, along with 17% dehydrochlorided
byproducts. The secondary alkyl chloride 1l performed well, leading to the alkylated
product 3l in 52% yield, along with recovery of the starting material. The
N-heterocycle substrate 1m was an effective substrate, affording the alkylated product
3m in 56% yield, along with 21% of the dehydrochlorided byproduct.
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Scheme 3. Substrate scope of Hantzsch esters.a
Mn (2 equiv)
DTBP (0.5 equiv)
R2
O
R2
O
R3 DHP
+
R1
R3
R1
Cl
PhCF3, Ar, 100 °C, 48 h
4
2
1
O
O
O
4a
, 82%
4b
, 72%
4c
, 89%
O
O
O
Ph
4d
4e
4h
4f
, 75%
, 60%
O
, 68%
O
O
Ph
CF3
4g,
67%
, 58%
O
4i
, 40%
, 30%
, trace
O
O
Ph
10
4j
4k
, 78%
, 77%
4l
O
O
O
CF3
Cl
4o
4n
4m
, 47%
, 40%
aReaction conditions: 1a (0.1 mmol, 1.0 equiv), 2 (0.15 mmol, 1.5 equiv), DTBP (0.5 equiv),
Mn (2 equiv), PhCF3 (0.25 mL), 100 oC, 48 h, Ar.
Various 4-alkyl-1,4-dihydropyridines, which were further used as substrates to
couple with 1a under standard reaction conditions, were synthesized. The isobutyl
(4b),
3-pentyl
(4c),
cyclohexyl
(4d),
cyclopentyl
(4e),
and
1-phenylethyl-1,4-dihydropyridines (4f) all performed well, generating the alkylated
products in 60-90% yields (Scheme 3). Importantly, the primary radical could be well
coupled with 1a, leading to the alkyl-alkyl coupling products in moderate to good
yields (4g-4k). The long unbranched carbon chain was compatible in this
cross-coupling reaction, but only provided a low yield of the product 4l. It may be due
to the fact that the long carbon chain free alkyl radical is slightly less reactive,
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resulting in the byproduct 5 in 35% yield. It is worth noting that there were not any
isomerized products formed in these reactions. Particularly, the chloride functional
group was well tolerated, yielding the corresponding product 4m in 40% yield.
Trifluoromethyl is a highly important functional group that usually modifies the
biochemical activity of a compound. The trifluoropropyl radical can be engaged with
1a, providing the desired product 4n in 47% yield, highlighting the synthetic
importance of this method. Unfortunately, the phenyl radicals were not tolerated,
where only the side product 5 was obtained.
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To further demonstrate the synthetic utility of this Mn-enabled radical-based
alkyl-alkyl cross-coupling reaction, Gram-scale reactions were further carried out.
The scale up reaction proceeded well, leading to the corresponding product 3a in good
yield. Melperone is a well-known drug for the treatment of confusion, anxiety,
restlessness (particularly in the elderly)14 and schizophrenia. Azaperone15 is capable
of eliciting neuroleptic, sedative and antiemetic effects. The key precursor for these
two compounds 4p could be easily prepared in good yield through the cross-coupling
of 1f with 2p. When the key precursor 2p was directly treated with the secondary
amine, the bioactive compounds, Meperone and Azaperone, were obtained in
excellent yields (Scheme 4).16
Scheme 4. The Gram scale reaction and synthetic application.
a) Gram scale reaction
O
O
Mn (2 equiv)
DTBP (0.5 equiv)
DHP
Cl
+
Ar, reflux, PhCF3, 4 d
1a
, 10 mmol
3a
, 1.3 g, 75%
b) The synthetic application
O
O
Mn (2 equiv)
DTBP (0.5 equiv)
Cl
DHP
Cl
+
Ar, 100°C, PhCF3, 48 h
F
Cl
2p
F
4p
, 51% yield
N
1f
O
HN
Melperone,
F
KI (10 mol%)
7
, 86% yield
NaHCO3 (2 equiv)
N
toluene (0.5 M)
100 °C, 36 h
O
N
N
N
HN
N
Azaperone,
F
8
, 73% yield
Several parallel reactions were performed to give insight of this reaction pathway
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(Scheme 5). First, when the free radical inhibitor TEMPO was added to the reaction,
the reaction was completely shut down, along with the recovery of product 6 in 35%
yield. This result strongly suggested that the reaction must undergo a radical
pathway17. Second, deuterated 1a was prepared and further subjected to the standard
reaction conditions18. The proportion of deuteration in the alkylated product changed
from 48% to 29%, which may indicate that the reaction may have undergone a
domino dehydrochlorination process (see ESI†).
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Scheme 5. Control Experiments
a) Reaction in the presence of TEMPO
O
Cl
+
Mn (2 equiv)
DTBP (0.5 equiv)
N
DHP
O
+
4h
+
TEMPO
Ar, 100 °C, PhCF3
1a
2f
1.5 equiv
6
2.5 equiv
0%
35%
b) Deuteration reaction
O
O
H
H (100%)
standard condition
DHP
Cl
H(D)
+
(D)H
H(D)
(D)H
78%
3a
-d, H/D = 2.4
1a
-d, H/D = 1.1
5
c) The route to generate key intermediate
O
O
5
5
5
Without additive: , trace
Mn, Ar, 100 °C
With DTBP:
, 45%
Cl
12 h, PhCF3
With t-BuONa:
, 75%
1a
5
d) Control reactions
O
O
DHP
DTBP (0.5 equiv)
PhCF3, Ar, 100 °C, 48 h
1) None
+
3a
2a
5
trace
51%
2) With Mn (2 equiv)
To further support this experimental result, the substrate 1a was subjected to
standard reaction conditions without 2a, which provided the dehydrochlorided
product 5 in 45% yield. When the reaction was carried out without DTBP, only trace
amounts of 5 were obtained. It is proposed that the in situ-generated tert-butanol
anion was the key factor to provide intermediate 5. We subsequently treated 1a with
sodium tert-butoxide. As expected, the dehydrochlorided product 5 was observed in
75% yield. These results indicated that the tert-butanol anion can result in the key
intermediate 5 from 1a. Finally, when 5 was treated with isopropyl-DHP and DTBP,
only trace amounts of 3a were obtained. Interestingly, the cross-coupling product 3
was obtained in 51% yield when the reactions were carried out under standard
reaction conditions. These result may indicate that the in situ-generated Mn(I) would
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coordinate with the olefin to accelerate the radical addition reaction19.
5
6
7
8
Based on these experiment results and previous reports20, a plausible reaction
pathway was proposed in Scheme 6. First, the reaction undergoes a
dehydrochlorination process under assistance of DTBP. The Mn complex coordinates
with vinylphenylketone 5 to activate the olefin, which is then followed by radical
addition21 and protonation to release product.
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Scheme 6. Plausible Mechanism
Mn
O
DTBP
O
DHP
O
O
Cl
1a
5
O
Mn(I)
MnI
Mn(I)
O
OH
Mn
O
t-BuO
O
3a
In conclusion, we have developed a highly efficient approach to realize the
alkyl-alkyl cross-coupling reaction through the direct combination of
β-chloropropiophenone and 4-alkyl-1,4-dihydropyridines using DTBP as the oxidant
and manganese(0) as the effective additive. A variety of β-chloropropiophenones
were well-tolerated, affording the alkylated products in moderate to good yields. The
known bioactive compounds Meperone(7) and Azaperone (8) could be easily
prepared from β-chloropropiophenone in two steps. The preliminary mechanistic
study indicated that the reaction proceeded through a radical pathway, while the in
situ-generated Mn complex coordinated with the olefin to facilitate the radical
addition.
EXPERIMENTAL SECTION
General. Unless otherwise noted, all reagents were purchased from commercial
suppliers and used without further purification. Column chromatography purifications
were performed using 200–300 mesh silica gel. NMR spectra were recorded on
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Varian Inova–400 MHz, Inova–300 MHz, Bruker DRX–400 or Bruker DRX–500
instruments and calibrated using residual solvent peaks as internal reference.
Multiplicities are recorded as: s = singlet, d = doublet, t = triplet, q = quartet, dd =
doublet of doublets, m = multiplet. HRMS analysis were carried out using a Bruker
micrOTOF–Q instrument or a TOF–MS instrument.
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General procedure for the β-chloropropiophenone derivatives: 22
General procedure A: To a solution of aluminium chloride (6.0 mmol, 1.2 equiv) in
dry CH2Cl2 (5 mL, 1.2 M), 3-chloropropionyl chloride (5.5 mmol, 1.1 equiv) was
o
added dropwise at 0 C, and followed by the addition of substituted benzene(5.0
mmol, 1 equiv) with stirring. The reaction mixture was allowed to warm up to room
temperature and stirred overnight. The reaction was quenched by slowly adding
o
crushed ice pieces at 0 C. The organic layer was separated and the aqueous phase
was extracted with CH2Cl2 (3×5 mL). The combined organic layer was washed with
brine (2×5 mL), dried over anhydrous Na2SO4 , and evaporated all the volatiles under
reduced pressure. The resulting residue was purified by column chromatography
(PE/EA = 10/1) on silica gel to give the product. 1b,23 1c,24 1e,25 1i26 and 1m8 are
known compounds.
o
3-chloro-1-(4-cyclohexylphenyl)propan-1-one (1d). White solid, 80%, mp: 46-50 C;
1H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.2 Hz, 2H), 3.92
(t, J = 6.9 Hz, 2H), 3.43 (t, J = 6.9 Hz, 2H), 2.57 (t, J = 11.3 Hz, 1H), 1.91 – 1.82 (m,
4H), 1.78 – 1.75 (m, 1H), 1.45 – 1.38 (m, 4H), 1.31 – 1.25 (m, 1H); 13C {1H} NMR
(100 MHz, CDCl3) δ 196.4, 154.3, 134.3, 128.3, 127.2, 44.7, 41.2, 38.9, 34.1, 26.7,
26.0. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C15H19ClONa 273.1022; found
273.1021.
1-([1,1'-biphenyl]-4-yl)-3-chloropropan-1-one (1h). White solid, 77%, mp: 105-110
oC; 1H NMR (400 MHz, CDCl3) δ 8.04 (d, J = 8.6 Hz, 2H), 7.71 (d, J = 8.6 Hz, 2H),
7.64 – 7.62 (m, 2H), 7.50 – 7.46 (m, 1H), 7.43 – 7.40 (m, 2H), 3.96 (t, J = 6.8 Hz, 2H),
3.50 (t, J = 6.8 Hz, 2H). 13C {1H} NMR (100 MHz, CDCl3) δ 196.5, 146.4, 139.8,
135.2, 129.1, 128.8, 128.6, 127.5, 127.4, 41.5, 38.9. HRMS (ESI-TOF) m/z: [M +
Na]+ Calcd for C15H13ClONa 267.0553; found 267.0555.
General procedure B: To a mixture of a, β-unsaturated ketone (5 mmol, 1 equiv) in
CH2Cl2 (20 mL, 0.4 M), t-BuOCl (5 mmol, 1 equiv) was added and the reaction
mixture was stirred at room temperature. On completion (the reaction was monitored
by TLC), the mixture was quenched with cold water, extracted with CHCl3, dried over
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anhydrous Na2SO4, and evaporated all the volatiles under reduced pressure. The
resulting residue was purified by column chromatography (PE/EA = 10/1) on silica
gel to give the product.
General procedure C:27 To a mixture of 1-phenylprop-2-en-1-one (264.1 mg, 2 mmol)
and DCl (74.0 mg, 2 mmol) in Et2O (10 mL, 0.2 M) and the reaction mixture was
stirred at room temperature. On completion (the reaction was monitored by TLC), the
mixture was quenched with cold water, extracted with EA, dried over anhydrous
Na2SO4, and evaporated all the volatiles under reduced pressure. The resulting residue
was purified by column chromatography (PE/EA = 10/1) on silica gel to give the
product.
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General Procedure for the substituted Hantzsch Ester28
General procedure D: Over a solution of ethyl ethyl acetoacetate (20 mmol, 2.0
equiv), ammonium acetate (20 mmol, 2.0 equiv) and the corresponding aldehyde (10
mmol, 1.0 equiv), VB1 (0.3 mmol, 3 mol %) was added in one portion. The vial was
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sealed and heated at 80 C oil bath for 0.5-2 h. After complete consumption of the
aldehyde, the reaction was cooled to rt and diluted with EtOAc. The solution was
poured into a separatory funnel containing brine and extracted three times with EtOAc.
After drying (Na2SO4), it was filtered and taken to dryness. The residue was purified
by chromatography on silica gel. The resulting residue was purified by column
chromatography (PE/EA = 20/1 – 8/1) on silica gel to give the product. 2a29, 2b, 2c,
2j30, 2d, 2e, 2f31, 2g, 2h, 2k and 2o28 are known compounds.
Diethyl
2,6-dimethyl-4-(4-(trifluoromethyl)phenethyl)-1,4-dihydropyridine-3,5-dicarboxylate
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(2i), Claybank solid, 65%, mp: 116-120 C; H NMR (400 MHz, CDCl3) δ 7.39 –
7.38 (m, 2H), 7.35 – 7.31 (m, 2H), 5.60 (br, 1H), 4.24 – 4.10 (m, 4H), 4.07 (t, J = 5.8
Hz, 1H), 2.63 – 2.57 (m, 2H), 2.29 (s, 6H), 1.71 – 1.64 (m, 2H), 1.28 (t, J = 7.1 Hz,
19
13
6H). F NMR (376 MHz, CDCl3) δ -62.49. C {1H} NMR (100 MHz, CDCl3) δ
168.0, 145.2, 144.2, 131.8, 130.5(q, JC-F = 31.7 Hz), 128.6, 125.0(q, JC-F = 3.8 Hz),
122.4(q, JC-F = 3.8 Hz), 124.5 (q, JC-F = 272.4 Hz), 103.0, 59.9, 38.0, 33.3, 31.4, 19.6,
+
14.5. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C22H26F3NO4 426.1892; found
426.1890.
Diethyl 4-(4-chlorobutyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (2m).
Yellow solid, 45%, mp: 62-65 oC; 1H NMR (400 MHz, CDCl3) δ 5.63 (br, 1H), 4.23 –
4.13 (m, 4H), 3.94 – 3.93 (m, 1H), 3.48 (t, J = 6.8 Hz, 2H), 2.28 (s, 6H), 1.76 – 1.68
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(m, 2H), 1.33 (dd, J = 6.3, 3.6 Hz, 4H), 1.29 (t, J = 7.1 Hz, 6H); 13C {1H} NMR (100
MHz, CDCl3) δ 168.0, 144.9, 103.0, 59.7, 45.2, 35.9, 32.8, 32.6, 22.3, 19.5, 14.4.
+
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C17H26ClNO4 344.1629; found
344.1627.
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Diethyl 4-undecyl-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (2l). Yellow
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viscous liquid, 36 %; H NMR (400 MHz, CDCl3) δ 5.69 (br, 1H), 4.25 – 4.09 (m,
4H), 3.90 (t, J = 5.8 Hz, 1H), 2.26 (s, 6H), 1.30 – 1.18 (m, 26 H), 0.86 (t, J = 6.9 Hz,
3H); 13C {1H} NMR (100 MHz, CDCl3) δ 168.2, 144.7, 103.3, 59.6, 36.9, 32.9, 31.9,
30.0, 29.8, 29.7, 29.7, 29.6, 29.3, 24.9, 22.7, 19.4, 14.4, 14.1. HRMS (ESI-TOF) m/z:
+
[M + H]+ Calcd for C24H41NO4 408.3114; found 408.3112.
General Procedure E: To a flask charged with ethyl acetoacetate (2.60 g, 20 mmol) ,
the aldehyde (10 mmol) and ethanol (20 mL) was added ammonia aqueous solution
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(4.0 mL, 28%, 60 mmol). The mixture was heated at 70 C oil bath for 8 hours. The
reaction was allowed to cool to room temperature. The solution was concentrated
under reduced pressure. A mixture of water and CH2Cl2 were added to the
concentrated residue and the layers were separated. The aqueous layer was extracted
with CH2Cl2 for 3 times. The combined organic layers were washed with brine, dried
(MgSO4), and filtered. The filtrate was concentrated under reduced pressure. The
residue was purified by chromatography on silica gel. The resulting residue was
purified by column chromatography (PE/EA = 20/1 – 8/1) on silica gel to give the
product.
Diethyl 4-chloromethyl-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (2p).
Yellow viscous liquid, 28 %; 1H NMR (400 MHz, CDCl3) δ 5.65 (br, 1H), 4.27 – 4.15
(m, 4H), 4.01 (t, J = 5.4 Hz, 1H), 3.46 (d, J = 5.1 Hz, 2H), 2.29 (s, 6H), 1.30 (t, J =
7.1 Hz, 6H); 13C {1H} NMR (100 MHz, CDCl3) δ 168.1, 146.0, 100.3, 67.0, 60.1,
+
36.7, 19.7, 14.4. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C14H20ClNO4 302.1159;
found 302.1161.
Diethyl
4-((3,3,3-trifluoropropyl))-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (2n).
Yellow viscous liquid, 50%; 1H NMR (400 MHz, CDCl3) δ 5.60 (br, 1H), 4.24 – 4.13
(m, 4H), 4.00 (t, J = 5.6 Hz, 1H), 2.31 (s, 6H), 2.03 – 1.96 (m, 2H), 1.61 – 1.54 (m,
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2H), 1.30 (t, J = 4.5 Hz, 6H); F NMR (376 MHz, CDCl3) δ -66.12; 13C {1H} NMR
(100 MHz, CDCl3) δ 167.7, 145.9, 127.8(q, JC-F = 276.0 Hz) 102.0, 60.0, 32.3, 30.0(q,
JC-F = 28.3 Hz)., 28.6(d, JC-F = 1.5 Hz), 19.6, 14.5. HRMS (ESI-TOF) m/z: [M + H]+
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+
Calcd for C16H22F3NO4 350.1579; found 350.1580.
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Experimental Procedure for the Alkyl–Alkyl Cross-Coupling Reaction: A mixture of 1
( 0.1 mmol,1 equiv), 2 (0.15 mmol, 1.5 equiv), Mn (10 mg, 0.4 mmol, 2 equiv),
DTBP (10 μL, 0.05 mmol, 0.5 equiv) and PhCF3 (0.25 mL, 0.8 M) in a 15 mL glass
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vial sealed under argon atmosphere was heated at 100 C oil bath for 48 hours, The
reaction mixture cooled to room temperature and concentrated in vacuo. The resulting
residue was purified by column chromatography (PE/EA = 200/1 - 20/1) on silica gel
to give the product 3 or 4.
Phenylprop-2-en-1-one (5). Yellow oil, 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 7.1
Hz, 2H), 7.60 – 7.58 (m, 1H), 7.51 – 7.47 (m, 2H), 7.16 (dd, J = 17.1, 10.6 Hz, 1H),
6.44 (dd, J = 17.1, 1.7 Hz, 1H), 5.94 (dd, J = 10.6, 1.7 Hz, 1H); 13C {1H} NMR (100
MHz, CDCl3) δ 191.0, 137.3, 133.0, 132.4, 130.1, 128.7, 128.6.
4-methyl-1-(p-tolyl)pentan-1-one32 (3b). Yellow oil, 15.1mg, 79%; H NMR (400
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MHz, CDCl3) δ 7.86 (d, J = 8.1 Hz, 2H), 7.25 (d, J = 6.7 Hz, 2H), 2.96 – 2.90 (m, 2H),
2.41 (s, 3H), 1.64 – 1.61 (m, 3H), 0.94 (d, J = 6.1 Hz, 6H);13C {1H} NMR (100 MHz,
CDCl3) δ 200.5, 143.8, 135.0, 129.2, 128.2, 36.6, 33.4, 27.9, 22.5, 21.6.
1-(4-(tert-butyl)phenyl)-4-methylpentan-1-one33 (3c). Yellow oil, 14.1mg, 61%; H
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NMR (400 MHz, CDCl3) δ 7.90 (d, J = 8.5 Hz, 2H), 7.47 (d, J = 8.5 Hz, 2H), 2.98 –
2.91 (m, 2H), 1.67 – 1.59 (m, 3H), 1.34 (s, 9H), 0.94 (d, J = 6.2 Hz, 6H); 13C {1H}
NMR (100 MHz, CDCl3) δ 200.5, 156.5, 134.5, 128.0, 125.5, 36.6, 35.1, 33.4, 31.1,
27.9, 22.5.
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1-(4-cyclohexylphenyl)-4-methylpentan-1-one (3d). Yellow oil, 20.6mg, 80%; H
NMR (400 MHz, CDCl3) (δ, ppm) δ 7.89 (d, J = 8.4 Hz, 2H), 7.28 (d, J = 8.2 Hz, 2H),
2.97 – 2.89 (m, 2H), 2.56 (t, J = 11.4 Hz, 1H), 1.86 (t, J = 6.1 Hz, 4H), 1.76 – 1.75 (m,
1H), 1.66 – 1.61 (m, 3H), 1.45 – 1.38 (m, 4H), 1.31 – 1.22 (m, 1H), 0.94 (d, J = 6.3
Hz, 6H); 13C {1H} NMR (100 MHz, CDCl3) δ 200.5, 153.5, 135.0, 128.3, 127.0, 44.7,
36.5, 34.1, 33.4, 27.9, 26.8, 26.1, 22.5. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C18H26O+ 259.2062; found 259.2059.
1
1-(4-methoxyphenyl)-4-methylpentan-1-one (3e). Yellow oil, 14.8mg, 72%; H NMR
(400 MHz, CDCl3) (δ, ppm) δ 7.94 (d, J = 8.9 Hz, 2H), 6.93 (d, J = 8.9 Hz, 2H), 3.86
(s, 3H), 2.94 – 2.88 (m, 2H), 1.64 – 1.60 (m, 3H), 0.94 (d, J = 6.3 Hz, 6H); 13C {1H}
NMR (100 MHz, CDCl3) (δ, ppm) δ 199.4, 163.3, 130.3, 130.2, 113.7, 55.5, 36.3,
33.5, 27.9, 22.5. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C13H18O2Na 229.1199;
found 229.1183.
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1-(4-fluorophenyl)-4-methylpentan-1-one (3f). Yellow oil, 18.4 mg, 72%; H NMR
(400 MHz, CDCl3) (δ, ppm) δ 7.98 (dd, J = 8.1, 5.8 Hz, 2H), 7.12 (t, J = 8.5 Hz, 2H),
2.97 – 2.90 (m, 2H), 1.66 – 1.59 (m, 3H), 0.94 (d, J = 5.7 Hz, 6H); 13C {1H} NMR
(100 MHz, CDCl3) (δ, ppm) δ 198.1, 164.6 (d, J = 254.3 Hz), 132.5 (d, J = 3.0 Hz),
129.6 (d, J = 9.3 Hz), 114.6 (d, J = 21.8 Hz), 35.5, 32.1, 26.8, 21.4. HRMS (ESI-TOF)
m/z: [M + Na]+ Calcd for C12H15FONa 217.1005; found 217.1005.
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1-(4-bromophenyl)-4-methylpentan-1-one (3g). Yellow oil, 23.4 mg, 87%; H NMR
(400 MHz, CDCl3) (δ, ppm) δ 7.84 (d, J = 8.6 Hz, 2H), 7.62 (d, J = 8.7 Hz, 2H), 2.99
– 2.86 (m, 2H), 1.79 – 1.68 (m, 2H), 1.61 – 1.57 (m, 1H), 1.40 – 1.21 (m, 4H), 0.92 (d,
J = 6.6 Hz, 6H); 13C {1H} NMR (100 MHz, CDCl3) (δ, ppm) δ 199.5, 135.8, 131.9,
129.6, 128.0, 38.8, 38.6, 27.9, 22.5, 22.1. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd
for C13H17BrONa 292.1718; found 292.1716.
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1-([1,1'-biphenyl]-4-yl)-4-methylpentan-1-one (3h). Yellow oil, 17.1mg, 68%; H
NMR (400 MHz, CDCl3) (δ, ppm) δ 8.04 (d, J = 8.5 Hz, 2H), 7.69 (d, J = 8.5 Hz, 2H),
7.63 (d, J = 7.1 Hz, 2H), 7.47 (d, J = 7.7 Hz, 2H), 7.42 – 7.38 (m, 1H), 3.03 – 2.96 (m,
2H), 1.70 – 1.64 (m, 3H), 0.97 (d, J = 6.3 Hz, 6H);13C {1H} NMR (100 MHz, CDCl3)
(δ, ppm) δ 200.5, 145.7, 140.1, 135.9, 129.1, 128.8, 128.3, 127.4, 127.3, 36.8, 33.5,
28.0, 22.6; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C18H20ONa 275.1412; found
275.1404.
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1-(2,4-dimethylphenyl)-4-methylpentan-1-one (3i). Yellow oil, 13.9 mg, 68%; H
NMR (400 MHz, CDCl3) (δ, ppm) δ 7.57 (d, J = 8.3 Hz, 1H), 7.05 (m, 2H), 2.91 –
2.83 (m, 2H), 2.47 (s, 3H), 2.35 (s, 3H), 1.63 – 1.55 (m, 3H), 0.93 (d, J = 6.0 Hz, 6H);
13C {1H} NMR (100 MHz, CDCl3) (δ, ppm) δ 204.4, 141.6, 138.4, 135.3, 132.8,
128.8, 126.2, 39.4, 33.5, 27.9, 22.5, 21.4, 21.3. HRMS (ESI-TOF) m/z: [M + Na]+
Calcd for C14H20ONa 227.1412; found 227.1414.
1-(benzo[d][1,3]dioxol-5-yl)-4-methylpentan-1-one (3j). Yellow oil, 13.6 mg, 62%;
1H NMR (400 MHz, CDCl3) (δ, ppm) δ 7.56 (dd, J = 8.2, 1.7 Hz, 1H), 7.44 (d, J = 1.6
Hz, 1H), 6.85 (d, J = 8.2 Hz, 1H), 6.04 (s, 2H), 2.92 – 2.82 (m, 2H), 1.63 – 1.59 (m,
3H), 0.94 (d, J = 6.2 Hz, 6H); 13C {1H} NMR (100 MHz, CDCl3) (δ, ppm) δ 197.9,
150.5, 147.1, 131.0, 123.2, 106.9, 106.8, 100.8, 35.4, 32.5, 26.9, 21.4; HRMS
(ESI-TOF) m/z: [M + Na]+ Calcd for C13H16O3Na 243.0997; found 243.0998.
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2-isopropylchroman-4-one (3k). Yellow oil, 9.1 mg, 48%; H NMR (400 MHz,
CDCl3) (δ, ppm) δ 7.87 (dd, J = 8.0, 1.4 Hz, 1H), 7.50 – 7.44 (m, 1H), 7.01 – 6.97 (m,
2H), 4.22 – 4.16 (m, 1H), 2.75 – 2.62 (m, 2H), 2.08 – 2.03 (m, 1H), 1.08 (d, J = 6.8
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Hz, 3H), 1.05 (d, J = 6.8 Hz, 3H);13C {1H} NMR (100 MHz, CDCl3) (δ, ppm) δ 193.1,
161.9, 135.9, 126.9, 121.1, 117.9, 82.5, 40.1, 32.2, 17.8. HRMS (ESI-TOF) m/z: [M +
Na]+ Calcd for C12H14O2Na 213.0891; found 213.0887.
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4-methyl-1,3-diphenylpentan-1-one (3l). Yellow oil, 13.1 mg, 52%; H NMR (400
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MHz, CDCl3) (δ, ppm) δ 7.90 – 7.85 (m, 2H), 7.54 – 7.50 (m, 1H), 7.44 – 7.40 (m,
2H), 7.26 – 7.23 (m, 3H), 7.21 – 7.13 (m, 2H), 3.36 (d, J = 6.7 Hz, 2H), 3.17 (q, J =
7.1 Hz, 1H), 1.97 – 1.92 (m, 1H), 0.99 (d, J = 6.7 Hz, 3H), 0.80 (d, J = 6.7 Hz, 3H);
13C {1H} NMR (100 MHz, CDCl3) (δ, ppm) δ 199.6, 143.8, 137.5, 132.9, 128.6,
128.5, 128.2, 128.1, 126.3, 48.0, 42.7, 33.4, 21.1, 20.5. HRMS (ESI-TOF) m/z: [M +
Na]+ Calcd for C18H20ONa 275.1412; found 275.1400.
4-methyl-1-(1-methyl-1H-pyrrol-2-yl)pentan-1-one (3m). Yellow oil, 10.0 mg, 56%;
1H NMR (400 MHz, CDCl3) (δ, ppm) δ 6.95 (dd, J = 4.1, 1.6 Hz, 1H), 6.79 – 6.78 (m,
1H), 6.11 (dd, J = 4.0, 2.5 Hz, 1H), 3.93 (s, 3H), 2.79 – 2.73 (m, 2H), 1.63 – 1.59 (m,
3H), 0.93 (d, J = 6.2 Hz, 6H); 13C {1H} NMR (100 MHz, CDCl3) (δ, ppm) δ 192.1,
130.9, 119.0, 107.9, 37.8, 37.3, 34.4, 28.1, 22.6; HRMS (ESI-TOF) m/z: [M + H]+
Calcd for C10H16NO 166.1232; found 166.1234.
4-methyl-1-phenylpentan-1-one (4a). Yellow oil, 14.2 mg, 82%; 1H NMR (400 MHz,
CDCl3) (δ, ppm) δ 7.9 (d, J = 7.2 Hz, 2H), 7.56 – 7.53 (m, 1H), 7.47 – 7.43 (m, 2H),
3.01 – 2.93 (m, 2H), 1.65 – 1.62 (m, 3H), 0.95 (d, J = 6.3 Hz, 6H); 13C {1H} NMR
(100 MHz, CDCl3) (δ, ppm) δ 200.8, 137.1, 132.9, 128.6, 128.1, 36.6, 33.3, 27.9, 22.5;
HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C12H16ONa 199.1099; found 199.1093.
4-methyl-1-phenylhexan-1-one34 (4b). Yellow oil, 13.6 mg, 72%; 1H NMR (400 MHz,
CDCl3) (δ, ppm) δ 7.96 (d, J = 7.1 Hz, 2H), 7.57 – 7.53 (m, 1H), 7.48 – 7.44 (m, 2H),
2.99 – 2.94 (m, 2H), 1.83 – 1.72 (m, 1H), 1.58 – 1.50 (m, 1H), 1.48 – 1.33 (m, 2H),
1.23 – 1.16 (m, 1H), 0.93 (d, J = 6.5 Hz, 3H), 0.89 (t, J = 7.2 Hz, 3H);13C {1H} NMR
(100 MHz, CDCl3) (δ, ppm) δ 201.1, 137.2, 133.0, 128.7, 128.2, 36.5, 34.4, 31.1, 29.5,
19.2, 11.5; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C13H18ONa 190.1358; found
190.1355.
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4-ethyl-1-phenylhexan-1-one (4c). Yellow oil, 18.2 mg, 89%; H NMR (400 MHz,
CDCl3) (δ, ppm) δ 7.96 (m, 2H), 7.57 – 7.53 (m, 1H), 7.48 – 7.44 (m, 2H), 2.97 –
2.91 (m, 2H), 1.72 – 1.67 (m, 2H), 1.37 – 1.32 (m, 5H), 0.88 (t, J = 7.3 Hz, 6H); 13C
{1H} NMR (100 MHz, CDCl3) (δ, ppm) δ 201.0, 137.1, 132.9, 128.6, 128.1, 40.2,
36.1, 27.3, 25.3, 10.9; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C14H20ONa
227.1412; found 227.1414.
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3-cyclohexyl-1-phenylpropan-1-one (4d). Yellow oil, 16.1 mg, 75%; H NMR (400
MHz, CDCl3) (δ, ppm) δ 7.96 (d, J = 7.1 Hz, 2H), 7.57 – 7.53 (m, 1H), 7.47 – 7.44 (m,
2H), 3.01 – 2.93 (m, 2H), 1.80 – 1.68 (m, 4H), 1.66 – 1.60 (m, 4H), 1.34 – 1.30 (m,
1H), 1.23 – 1.15 (m, 2H), 1.01 – 0.91 (m, 2H); 13C {1H} NMR (100 MHz, CDCl3) (δ,
ppm) δ 201.1, 137.2, 133.0, 128.7, 128.2, 37.6, 36.3, 33.4, 31.9, 26.7, 26.4; HRMS
(ESI-TOF) m/z: [M + Na]+ Calcd for C15H20ONa 239.1412; found 239.1404.
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3-cyclopentyl-1-phenylpropan-1-one (4e). Yellow oil, 12.0 mg, 60%; H NMR (400
MHz, CDCl3) (δ, ppm) δ 7.96 (d, J = 8.4, 1.3 Hz, 2H), 7.57 – 7.53 (m, 1H), 7.48 –
7.44 (m, 2H), 3.02 – 2.95 (m, 2H), 1.88 – 1.68 (m, 4H), 1.66 – 1.58 (m, 4H), 1.56 –
1.51 (m, 1H), 1.18 – 1.11 (m, 2H); 13C {1H} NMR (100 MHz, CDCl3) (δ, ppm) δ
200.9, 137.2, 133.0, 128.7, 128.2, 40.0, 38.1, 32.7, 30.8, 25.3; HRMS (ESI-TOF) m/z:
[M + Na]+ Calcd for C14H18ONa 225.1255; found 225.1242.
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1,4-diphenylpentan-1-one (4f). Yellow oil, 16.2 mg, 68%; H NMR (400 MHz,
CDCl3) (δ, ppm) δ 7.85 (d, J = 7.1 Hz, 2H), 7.54 – 7.51 (m, 1H), 7.43 – 7.39 (m, 2H),
7.33 – 7.29 (m, 2H), 7.22 – 7.20 (m, 3H), 2.88 – 2.80 (m, 3H), 2.14 – 1.94 (m, 2H),
1.32 (d, J = 6.9 Hz, 3H); 13C {1H} NMR (100 MHz, CDCl3) (δ, ppm) δ 200.4, 146.6,
137.0, 132.9, 128.5, 128.0, 127.1, 126.2, 39.5, 36.7, 32.5, 22.6; HRMS (ESI-TOF)
m/z: [M + Na]+ Calcd for C17H18ONa 261.1255; found 261.1252.
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5-methyl-1-phenylhexan-1-one (4g). Yellow oil, 14.8 mg, 67%; H NMR (400 MHz,
CDCl3) (δ, ppm) δ 7.96 (d, J = 7.7 Hz, 2H), 7.55 (m, 1H), 7.46 (m, 2H), 2.95 (t, J =
7.4 Hz, 2H), 1.74 (m, 2H), 1.27 (m, 3H), 0.90 (d, J = 6.6 Hz, 6H); 13C {1H} NMR
(100 MHz, CDCl3) (δ, ppm) δ 200.6, 137.1, 132.9, 128.6, 128.1, 38.9, 38.6, 27.9, 22.5,
22.3; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C13H18ONa 213.1255; found
213.1253.
1-phenylhexan-1-one (4h). Yellow oil, 10.2 mg, 58%; 1H NMR (400 MHz, CDCl3) (δ,
ppm) δ 7.96 (d, J = 7.7 Hz, 2H), 7.57 – 7.53 (m, 1H), 7.48 – 7.44 (m, 2H), 2.96 (t, J =
7.4 Hz, 2H), 1.76 – 1.71 (m, 2H), 1.38 – 1.35 (m, 4H), 0.91 (d, J = 7.0 Hz, 3H); 13C
{1H} NMR (100 MHz, CDCl3) (δ, ppm) δ 200.8, 137.3, 133.0, 128.7, 128.2, 38.8,
31.7, 24.2, 22.7, 14.1; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C12H16ONa
199.1099; found 199.1093.
1-phenyl-5-(4-(trifluoromethyl)phenyl)pentan-1-one (4i). Claybank oil, 12.2 mg, 40%;
1H NMR (400 MHz, CDCl3) (δ, ppm) δ 7.96 – 7.94 (m, 2H), 7.58 – 7.54 (m, 1H),
7.49 – 7.42 (m, 4H), 7.40 – 7.36 (m, 2H), 3.01 (t, J = 7.0 Hz, 2H), 2.77 – 2.68 (m, 2H),
1.86 – 1.68 (m, 4H); 19F NMR (377 MHz, CDCl3) δ -62.54; 13C {1H} NMR (100 MHz,
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CDCl3) (δ, ppm) δ 200.2, 143.2, 137.1, 133.2, 132.0, δ 130.8 (d, JC-F = 31.9 Hz),
128.9, 128.7, δ 128.5 (d, JC-F = 58.8 Hz), δ 124.4 (q, JC-F = 272.0 Hz), δ 124.0 (d, JC-F
= 11.4, 3.6 Hz). 38.4, 35.8, 31.0, 24.0; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
C18H17F3ONa 329.1129; found 329.1125.
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1-phenylpentan-1-one (4j). Yellow oil, 12.6 mg, 78%; 1H NMR (400 MHz, CDCl3) (δ,
ppm) δ 7.96 (d, J = 7.6 Hz, 2H), 7.57 – 7.53 (m, 1H), 7.48 – 7.44 (m, 2H), 2.97 (t, J =
7.4 Hz, 2H), 1.78 – 1.66 (m, 2H), 1.47 – 1.36 (m, 2H), 0.96 (t, J = 7.3 Hz, 3H); 13C
{1H} NMR (100 MHz, CDCl3) (δ, ppm) δ 200.5, 137.0, 132.7, 128.4, 127.9, 38.2,
26.3, 22.3, 13.8; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C11H14ONa 185.0942;
found 185.0940.
1,4-diphenylbutan-1-one (4k). Yellow oil, 17.2 mg, 77%; 1H NMR (400 MHz, CDCl3)
(δ, ppm) δ 7.98 (d, J = 7.1 Hz, 2H), 7.62 – 7.58 (m, 1H), 7.52 – 7.48 (m, 2H), 7.38 –
7.32 (m, 2H), 7.26 (d, J = 7.2 Hz, 3H), 3.04 (t, J = 7.3 Hz, 2H), 2.78 (t, J = 7.6 Hz,
2H), 2.21 – 2.04 (m, 2H); 13C {1H} NMR (100 MHz, CDCl3) (δ, ppm) δ 200.3, 141.8,
137.1, 133.1, 128.7, 128.7, 128.5, 128.2, 126.1, 37.8, 35.3, 25.9; HRMS (ESI-TOF)
m/z: [M + Na]+ Calcd for C16H16ONa 247.1099; found 247.1085.
1-phenyltetradecan-1-one (4l). Yellow oil, 7.2 mg, 30%; 1H NMR (400 MHz, CDCl3)
(δ, ppm) δ 7.97 – 7.95 (m, 2H), 7.57 – 7.53 (m, 1H), 7.48 – 7.43 (m, 2H), 2.99 – 2.93
(m, 2H), 1.78 – 1.69 (m, 2H), 1.26 (s, 20H), 0.88 (t, J = 6.8 Hz, 3H); 13C {1H} NMR
(100 MHz, CDCl3) (δ, ppm) δ 200.8, 137.2, 133.0, 128.7, 128.2, 38.8, 32.1, 29.8, 29.8,
29.8, 29.8, 29.7, 29.6, 29.5, 29.5, 24.6, 22.8, 14.3; HRMS (ESI-TOF) m/z: [M + Na]+
Calcd for C20H32ONa 311.2351; found 311.2348.
7-chloro-1-phenylheptan-1-one (4m)35. Yellow oil, 9.0 mg, 40%; 1H NMR (400 MHz,
CDCl3) (δ, ppm) δ 7.98 (d, J = 7.1 Hz, 2H), 7.60 – 7.56 (m, 1H), 7.50 – 7.47 (m, 2H),
3.56 (t, J = 6.7 Hz, 2H), 3.00 (t, J = 7.3 Hz, 2H), 1.84 – 1.75 (m, 4H), 1.54 – 1.42 (m,
4H); 13C {1H} NMR (100 MHz, CDCl3) (δ, ppm) δ 200.3, 137.0, 133.0, 128.6, 128.0,
45.1, 38.4, 32.4, 28.6, 26.7, 24.1; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
C13H17ClONa 224.0968; found 224.0970.
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6,6,6-trifluoro-1-phenylhexan-1-one (4n). Yellow oil, 10.7 mg, 47%; H NMR (400
MHz, CDCl3) (δ, ppm) δ 7.96 (d, J = 7.4 Hz, 2H), 7.59 – 7.55 (m, 1H), 7.49 – 7.45 (m,
2H), 3.02 (t, J = 7.1 Hz, 2H), 2.18 – 2.11 (m, 2H), 1.89 – 1.78 (m, 2H), 1.71 – 1.61 (m,
2H); 19F NMR (377 MHz, CDCl3) δ -66.33, -66.35, -66.38;13C {1H} NMR (100 MHz,
CDCl3) (δ, ppm) δ 198.4, 135.8, 132.1, 127.6, 127.0, 126.1 (q, JC-F=275), 36.9, 32.7
(q, JC-F = 28.5 Hz), 22.1, 20.7 (q, JC-F = 3.0 Hz); HRMS (ESI-TOF) m/z: [M + Na]+
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Calcd for C12H13F3ONa 253.0816; found 253.0816.
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4-chloro-1-(4-fluorophenyl)butan-1-one (4p)36. Yellow oil, 51%; H NMR (400
MHz, CDCl3) (δ, ppm) δ 8.02 – 7.96 (m, 2H), 7.15 – 7.09 (m, 2H), 3.68 – 3.65 (m,
2H), 3.14 (t, J = 7.0 Hz, 2H), 2.25 – 2.17 (m, 2H); 19F NMR (377 MHz, CDCl3) δ
-105.06; 13C {1H} NMR (100 MHz, CDCl3) (δ, ppm) δ 197.3, δ 165.8 (d, JC-F = 254.7
Hz)., δ 133.2 (d, JC-F = 3.0 Hz), 130.7 (d, JC-F = 9.4 Hz), 115.7 (d, JC-F = 22.0 Hz),
44.6, 35.2, 26.7.
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General Procedure for the synthetic application4: The ketone (0.5 mmol) was placed
in a vial equipped with a magnetic bar and potassium iodide (10 mol %), sodium
bicarbonate (2 equiv), anhydrous toluene (0.5 M), and the corresponding amine (1−2
equiv). The vial was closed and heated in a preheated oil bath at 100 oC for 36 h under
magnetic stirring. The resulting mixture was purified by column chromatography or
preparative TLC on silica to obtain the final aminobutyrophenones.
Melperone14 (7). Claybank solid, 86%, mp: 78-82 oC; 1H NMR (400 MHz, CDCl3) (δ,
ppm) δ 7.97 (dd, J = 8.5, 5.6 Hz, 2H), 7.11 – 7.07 (m, 2H), 2.95 – 2.92 (m, 2H), 2.83
(d, J = 11.5 Hz, 2H), 2.35 (t, J = 7.3 Hz, 2H), 1.95 – 1.84 (m, 4H), 1.56 (d, J = 13.1
Hz, 2H), 1.36 – 1.25 (m, 1H), 1.19 – 1.09 (m, 2H), 0.87 (d, J = 6.5 Hz, 3H);19F NMR
(377 MHz, CDCl3) δ -105.86; 13C {1H} NMR (100 MHz, CDCl3) (δ, ppm) δ 198.5, δ
165.6 (d, J = 254.1 Hz), δ 133.6 (d, JC-F = 3.0 Hz), 130.7 (d, JC-F = 9.3 Hz) , 115.51 (d,
JC-F = 21.8 Hz), 58.1, 53.9, 36.4, 34.22, 30.8, 21.9.
Azaperone36 (8). Claybank solid, 73%, mp: 87-89 oC; 1H NMR (400 MHz, CDCl3) (δ,
ppm) δ 8.13 (dd, J = 4.9, 1.2 Hz, 1H), 7.98 – 7.94 (m, 2H), 7.43 – 7.39 (m, 1H), 7.09
– 7.05 (m, 2H), 6.61 – 6.53 (m, 2H), 3.48 – 3.39 (m, 4H), 2.96 (t, J = 7.1 Hz, 2H),
2.55 – 2.46 (m, 4H), 2.41 (t, J = 7.1 Hz, 2H), 1.98 – 1.89 (m, 2H); 19F NMR (377
MHz, CDCl3) δ -105.61; 13C {1H} NMR (100 MHz, CDCl3) (δ, ppm) δ 198.4, δ 165.6
(d, JC-F = 254.3 Hz)., 159.5, 147.9, 137.4, δ 133.6 (d, JC-F = 2.9 Hz), 130.7 (d, JC-F
9.1 Hz), 115.58 (d, JC-F = 21.8 Hz), 113.2, 107.0, 57.7, 52., 45.1, 36.1, 21.5.
=
2,2,6,6-tetramethyl-1-(1-phenylethoxy)piperidine (6). 1H NMR (400 MHz, CDCl3) (δ,
ppm) δ 7.32 – 7.19 (m, 5H), 4.78 (q, J = 6.7 Hz, 1H), 1.48 (d, J = 6.7 Hz, 6H), 1.37 –
1.29 (m, 6H), 1.17 (s, 3H), 1.03 (s, 3H), 0.66 (s, 3H); 13C {1H} NMR (100 MHz,
CDCl3) (δ, ppm) δ 145.9, 128.1, 126.9, 126.7, 83.2, 59.8, 40.5, 34.6, 34.2, 23.7, 20.5,
17.3.
ASSOCIATED CONTENT
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Supporting Information
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The Supporting Information is available free of charge on the ACS Publications
website at http://pubs.acs.org.
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1H, and 13C NMR spectra for all products (PDF)
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AUTHOR INFORMATION
Corresponding Authors
Email: yszhao@suda.edu.cn (Y. Z.).
Email: zengrunsheng@suda.edu.cn (R.Z.).
Notes
There are no conflicts of interest
ACKNOWLEDGMENTS
We are grateful for the financial support from Natural Science Foundation of China
(Nos. 21772139, 21572149), Jiangsu Province Natural Science Fund for
Distinguished Young Scholars (BK20180041), Prospective Study Program of Jiangsu
(BY2015039-08), Project of Scientific and Technologic Infrastructure of Suzhou
(SZS201708), Prospective Study Program of Jiangsu (BY2015039-08) and the PAPD
Project are also gratefully acknowledged.
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