Pd(II)-Catalyzed Chemoselective Acetoxylation of C(sp2)-H and C(sp3)-H Bonds in Tertiary Amides

Article abstract of DOI:10.1021/acs.joc.1c00629

Palladium-catalyzed chemoselective C(sp2)-H and C(sp3)-H acetoxylation of synthetically useful tertiary amides is reported under relatively mild reaction conditions. This protocol proceeds through the assistance of a weakly coordinated directing group (Ca? O) and requires low catalyst (1.0 mol %) loading. Diverse functionalities, such as C(sp2)-Cl, C(sp3)-Cl,-CF3,-COOEt, and-NO2 groups, including morpholinyl, piperazinyl, and pyrrolidinyl heterocycles, are compatible under the reaction conditions. Further functionalization of this protocol is demonstrated by hydrolysis to alcohols, alcohol-acids, as well as reduction to tertiary amines. A preliminary kinetic isotope effect study supported the rate-limiting C-H bond activation process.

Full text of DOI:10.1021/acs.joc.1c00629

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Article
Pd(II)-Catalyzed Chemoselective Acetoxylation of C(sp2)−H and
C(sp3)−H Bonds in Tertiary Amides
Muniyappa Vijaykumar and Benudhar Punji*
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ABSTRACT: Palladium-catalyzed chemoselective C(sp2)−H and
C(sp3)−H acetoxylation of synthetically useful tertiary amides is
reported under relatively mild reaction conditions. This protocol
proceeds through the assistance of a weakly coordinated directing
group (CO) and requires low catalyst (1.0 mol %) loading. Diverse
functionalities, such as C(sp2)−Cl, C(sp3)−Cl, −CF3, −COOEt, and
−NO2 groups, including morpholinyl, piperazinyl, and pyrrolidinyl
heterocycles, are compatible under the reaction conditions. Further
functionalization of this protocol is demonstrated by hydrolysis to
alcohols, alcohol−acids, as well as reduction to tertiary amines. A preliminary kinetic isotope effect study supported the rate-limiting
C−H bond activation process.
known, the oxygenation of unactivated β C(sp3)−H bond on
INTRODUCTION
Transition-metal-catalyzed C−H bond functionalization has
■
privileged and multifunctional tertiary amides with a weakly
coordinating group (CO) is less explored.13 The primary
emerged as an elegant and effective tool for molecular sciences,
difficulty associated with the weaker coordinating directing
empowering application toward pharmaceuticals and func-
tional materials. In this context, directing-group-assisted C−H
groups is the hardship in generating the less favored
cyclometalated intermediate.14 Nevertheless, the groups of
oxygenation has been recognized as a robust technique for
Ackermann,15 Jeganmohan,16 and Yu17 have independently
constructing chemo- and regioselective C−O bonds.1 Since
amide is a versatile functional group with easy transformative
tendencies into useful functionalities like carboxylic acid and
aldehyde, the selective C−H oxygenation of amide-containing
substrates becomes imperative. In that direction, with the
established the C(sp2)−H oxygenation of tertiary benzamides
(Scheme 1c). In contrast, thus far, the unactivated C(sp3)−H
oxygenation of native tertiary amides by weak coordination
assistance is unprecedented, and attempts were unsuccessful.
As a part of our research interest in sustainable C−H
support of monodentate or bidentate auxiliaries, diverse C−O
functionalization,18 herein we report the palladium-catalyzed
selective C(sp3)−H acetoxylation of tertiary amides under
relatively mild conditions that proceeds via a weakly
coordinated O-chelation (Scheme 1d). Notable features of
this protocol are (i) C(sp3)−H and C(sp2)−H acetoxylation of
tertiary amides, (ii) low catalyst loading and mild conditions,
(iii) excellent regio- and chemoselectivity, and (iv) a
preliminary reaction mechanism.
bond formations such as alkoxylation,2 acetoxylation,3
acyloxylation,4 and hydroxylation5 of C(sp2)−H bond on
aromatic amides have been extensively studied. In particular,
most of these oxygenations are demonstrated for the primary
and secondary amides, wherein the strong coordination of N-
amidate efficiently facilitates the C−H activation by instigating
thermodynamically stable metallacycle. Several research groups
have independently demonstrated the β-C(sp3)−H acylox-
ylation/alkoxylation with the help of strong N-coordination by
introducing bidentate directed 8-aminoquinolinyl,6 2-(pyri-
dine-2-yl)isopropyl (PIP),2a picolinamide,7 sulfoximine,8 and
sulfinyl aniline9 directing groups (Scheme 1a).10 In a
significant contribution, Lu has demonstrated the C(sp3)−H
acyloxylation of secondary amides via monodentate −CONHR
coordination (Scheme 1b).11 Unfortunately, this protocol
failed to give acyloxylation of tertiary amides. Recently, Yu
disclosed a palladium-catalyzed β-C(sp3)−H acyloxylation of
free carboxylic acids, wherein a well-designed mono-N-
protected β-amino acid ligand is essential.12
RESULTS AND DISCUSSION
■
Optimization of Reaction Parameters. The screening of
reaction parameters for the acetoxylation of C(sp3)−H bond in
tertiary amide, 2,2-dimethyl-1-(pyrrolidin-1-yl)propan-1-one
Received: March 17, 2021
Published: May 26, 2021
Though the C(sp2)−H and C(sp3)−H oxygenations for
strongly coordinating secondary amide (−CONHR) are well-
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Scheme 1. C(sp2)−H and C(sp3)−H Bond Oxygenation on
(pyrrolidin-1-yl)propyl acetate (3aa) and diacetoxylated
product 3aa’ in 44% and 12% yields, respectively, when the
reaction was performed in the acetic acid solvent at 120 °C
(Table 1, entry 1). Notably, the reaction in the mixture of
AcOH and Ac2O (9:1) led to the improvement in yield and
selectivity of monoacetoxylation to 68% (entry 2). Relatively
mild inorganic oxidants, such as Na2S2O8, K2S2O8, and AgOAc,
were less effective and provided a moderate yield (35−56%) of
3aa (entries 3−5). The use of other Pd(II) or Pd(0)
precursors, such as PdCl2, Pd(cod)Cl2, Pd2(dba)3, and
Pd(PPh3)4 as catalysts, afforded a low to moderate yield.
The acetoxylation reaction in toluene or methanol solvents was
inefficient, whereas reaction in TFA/TFAA led to the
decomposition of 1a (entry 6). Notably, the acetoxylation in
the solvent HFIP/Ac2O resulted in quantitative conversion,
and 3aa was isolated in 69% yield (entry 7). Surprisingly, upon
lowering the reaction temperature to 80 °C in HFIP/Ac2O
solvent system, the reaction provided 94% of 3aa with high
selectivity for monoacetoxylation (entry 8). The acetoxylation
progressed effortlessly even with 1.0 mol % loading of
Pd(OAc)2 (entry 9); however, further lowering of catalyst
loading to 0.5 mol % led to low conversion. The employment
of low catalyst loading significant and could be beneficial for
large-scale synthesis. The use of 2.0 equiv of PhI(OAc)2 in
place of 3.0 equiv resulted in incomplete conversion. Notably,
the reaction proceeded smoothly even with 0.7 mL of solvent
and 20 h of reaction time (entry 10). The acetoxylation was
failed in the absence of an external oxidant or Pd catalyst
(entries 11, 12), indicating the essential role of these
components. Thus, the optimal reaction conditions were
found to be as follows: 1a (0.3 mmol), 2a (0.9 mmol),
Pd(OAc)2 (1 mol %) in HFIP/Ac2O (0.7 mL) at 80 °C for 20
h.
Amides
(1a), with diacetoxyiodobenzene (2a) was initiated employing
Pd(OAc)2 as a catalyst (Table 1, see Table S1 in the
Supporting Information for details). The reaction could afford
both the mono acetoxylated product 2,2-dimethyl-3-oxo-3-
Substrate Scope of Acetoxylation. After successfully
optimizing the reaction parameters for the Pd-catalyzed
C(sp3)−H acetoxylation of the tertiary amide with PhI(OAc)2,
we have investigated the scope and limitations of acetoxylation
of diverse aliphatic as well as aromatic amides. First, various
N,N-disubstituted pivalamides were tested for the acetoxyla-
tion with PhI(OAc)2 (Scheme 2). Amides with cyclic
substituents, such as pyrrolidinyl and piperidinyl pivalamides,
gave excellent yields of desired acetoxylated products (3aa,
3ba). The pivalamides containing morpholinyl and ester
groups were tolerated under the reaction conditions and
provided 49% and 59% yields (3ca, 3da), respectively. Simple
dialkyl amides with varying steric properties smoothly
underwent the acetoxylation to generate the β-acetoxy amides,
3ea−3ia, in good to excellent yields. Notably, the N,N-
diisopropylpivalamide (1g) afforded a significant amount of
diacetoxylated compound 3ga′ (25%) in addition to the
monoacetoxylated 3ga. The steric feature of isopropyl on
amide might help bring a second methyl group of the
monoacetoxylated product (3ga) close to the palladium center
for further functionalization. It should be noted that the
acetoxylation of N,N-dialkyl-substituted tertiary amides using
Pd was previously unsuccessful.11 The Weinreb amide 1j
provided acetoxylated product 3ja in 44% yield at 120 °C. The
aryl-substituted pivalamides also reacted smoothly, affording
the desired acetoxylated compounds in good yields (3ka−
3na). Synthetically essential functionalities, such as −Cl, −CF3,
and −NO2 groups, were well tolerated under the reaction
conditions. Interestingly, except for 1g, the diacetoxylation was
not detected or observed only in a negligible amount in most
a
Table 1. Optimization of Reaction Parameters
b
yield (%)
entry
oxidant
T (°C)
solvent
AcOH
3aa
3aa′
1
2
3
4
5
6
7
8
PhI(OAc)2
PhI(OAc)2
K2S2O8
Na2S2O8
AgOAc
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
−
120
120
120
120
120
120
120
80
80
80
80
80
47 (44)
70 (68)
42
56
35
12
8
AcOH/Ac2O
AcOH/Ac2O
AcOH/Ac2O
AcOH/Ac2O
TFA/TFAA
HFIP/Ac2O
HFIP/Ac2O
HFIP/Ac2O
HFIP/Ac2O
HFIP/Ac2O
HFIP/Ac2O
−
−
−
−
8
−
−
−
−
−
−
72 (69)
98 (94)
97 (93)
96 (93)
−
c
9
cd
,
10
11
12
e
PhI(OAc)2
−
a
Reaction conditions: 1a (0.047 g, 0.30 mmol), oxidant (0.90 mmol),
[Pd] (0.015 mmol, 5.0 mol %), solvent (1 mL; HFIP/Ac2O = 9:1).
GC yield using n-dodecane as internal standard, isolated yield is in
parentheses. 1.0 mol % of Pd(OAc)2 used. 0.7 mL of solvent
(HFIP:Ac2O = 9:1) used and reaction was performed for 20 h.
b
c
d
e
Without Pd(OAc)2 catalyst. HFIP = hexafluoro-2-propanol.
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a
Scheme 2. β-C(sp3)−H Acetoxylation of Tertiary Amides
Scheme 3. Scope for C(sp3)−H and C(sp2)−H
a
Acyloxylation of Tertiary Amides
a
a
Conditions: substrate 1 (0.30 mmol), 2a (0.29 g, 0.9 mmol), HFIP/
Conditions: substrate 1 (0.30 mmol), 2a (0.29 g, 0.9 mmol), HFIP/
b
c
b
c
Ac2O (9:1, 0.7 mL). Reaction performed at 120 °C. NMR yield.
Ac2O (9:1, 0.7 mL). NMR yield. Diacetoxylated compound was
obtained in 25% yield. Reaction was performed at 120 °C.
d
3ya). The distal C−H bond acetoxylation, 3ya, is notable
under the present reaction protocol.
of the pivalamides. Moreover, acetoxylation of the C(sp3)−H
bonds on N-alkyl substituents of amide was not observed, even
though a five-membered palladacycle involving this carbon
center is feasible. Particularly, the acetoxylation of methylene
C(sp3)−H bond on tertiary amides and cyclic amides was
unsuccessful (Scheme 2). Similarly, simple carboxylic acid and
esters were failed to undergo acetoxylation under the present
conditions.
The acetoxylation protocol was applied to the tertiary
amides bearing a methyl group and two different alkyl
substituents (Scheme 3). Notably, the present protocol was
selective for the acetoxylation of primary β-C(sp3)−H bond
over the γ- or δ-C(sp3)−H bonds or the secondary β-C(sp3)−
H (methylene) bond of amides (3oa−3ra). The long alkyl
chain and aliphatic halide substituents like chloride were
tolerated and provided an excellent yield of products, 3qa and
3ra. The isobutyramide-containing piperidinyl and diisobutyl
substituents afforded 3sa and 3ta in 53% and 67% yields,
respectively, albeit at an elevated temperature 120 °C. When
both the β-C(sp3)−H and γ-C(sp2)−H bonds were present on
amides (1u, 1v), the γ-C(sp2)−H bonds selectively acetoxy-
lated over the β-C(sp3)−H bond (3ua, 3va). We have
extended this protocol to the C(sp2)−H acetoxylation of
phenyl acetyl amide and pyrolidinehydrocinnamic amide to
achieve an excellent yield of mono- or diacetoxylation (3wa−
The current methodology was further extended to the
acyloxylation using diversely substituted iodonium oxidants,
PhI(OCOR)2 (Scheme 3). Thus, the acyloxylated compounds,
2,2-dimethyl-3-oxo-3-(pyrrolidin-1-yl)propyl propionate (3ab)
and 2,2-dimethyl-3-oxo-3-(pyrrolidin-1-yl)propyl 3-(2-
methoxyphenyl)propanoate (3ac), were synthesized in good
yields using the desired iodonium salts under the optimized
conditions. Notably, we did not observe acetoxylated (−OAc)
products in these reactions although Ac2O was used in the
reaction.
The substrate scope could be expanded to the acetoxylation
of β-C(sp3)−H bonds on secondary amides (Scheme 4). Thus,
the secondary pivalamides with N-alkyl, methoxyalkyl, and
alkyl ester substituents underwent acetoxylation at 120 °C to
produce the desired products in moderate to good yields.
Remarkably, tertiary amide reactivity is superior to the
secondary pivalamides that can be seen from the product
yields and employed reaction conditions.
A gram-scale acetoxylation reaction was performed to
demonstrate the practical utility of this Pd-catalyzed method.
Thus, the treatment of 1.2 g of substrate 1a with PhI(OAc)2
(7.46 g) under the standard reaction conditions using 1.0 mol
% of Pd(OAc)2 and HFIP/Ac2O [9:1] (25.0 mL) afforded
1.41 g (86%) of 3aa.
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Scheme 4. Scope for β-C(sp3)−H Acetoxylation of
Secondary Amides
through carbonyl oxygen followed by the C−H cleavage
leading to an alkyl-Pd(II) intermediate A (Figure 1). Next, the
Synthetic Utility and Mechanistic Perspective. We
have demonstrated the synthetic utility of acetoxylated tertiary
amides by converting them to various useful compounds. The
acetyl group of 3aa and 3ba was smoothly removed by treating
with K2CO3 in methanol to achieve β-hydroxy amides 6aa and
6ba in 86% and 85% yields, respectively (Scheme 5a). The
Figure 1. Plausible reaction mechanism.
oxidation of Pd(II) to Pd(IV) by PhI(OAc)2 would result in
the formation of intermediate B.21 Subsequent reductive
elimination of 3 will lead to the regeneration of Pd(II) for
further catalysis.
Scheme 5. Functionalization of Acetoxylated Amides
CONCLUSION
■
In summary, we have developed a Pd(II)-catalyzed protocol
for the chemoselective C(sp2)−H and C(sp3)−H acetoxylation
of diverse tertiary amides through the weak coordination of the
CO group. Notably, the reaction uses a low loading of
palladium unlike the precedented strong N-chelating acetox-
ylation that employs a substantial loading of Pd (>5 mol %).
The reaction demonstrated the tolerability of synthetically
important functionalities, like chloro, fluoroalkyl, fluoroarene,
ester, and nitro groups, in addition to the heterocycles. The
synthetic utility is demonstrated by a gram-scale reaction and
further functionalization into alcohols, tertiary amines, and
alcohol acids. A preliminary KIE study indicated that the C−H
activation step is rate-limiting.
EXPERIMENTAL SECTION
■
General Information. All manipulations were conducted under
an argon atmosphere either in a glovebox or using standard Schlenk
techniques in predried glasswares. The catalytic reactions were
performed in flame-dried reaction vessels with Teflon screw cap.
Solvents were dried over Na/benzophenone or CaH2 and distilled
prior to use. Liquid reagents were flushed with argon prior to use. The
secondary and tertiary amides10c and iodonium salts14i were
synthesized according to the previously described procedures. High-
resolution mass spectrometry (HRMS) mass spectra were recorded
on a Thermo Scientific Q-Exactive, Accela 1250 pump. NMR: (1H
and 13C) spectra were recorded at 400 or 500 MHz (1H), 100 or 125
MHz {13C, DEPT (distortionless enhancement by polarization
transfer)}, 377 MHz (19F), respectively in CDCl3 solutions, if not
otherwise specified; chemical shifts (δ) are given in ppm. The 1H and
13C NMR spectra are referenced to residual solvent signals (CDCl3: δ
H = 7.26 ppm, δ C = 77.2 ppm).
acetoxylated amide 3ua can be reduced to 7ua in 79% by
LiAlH4 in diethyl ether (Scheme 5b). Pleasingly, the
acetoxylated amide 3aa was hydrolyzed with HCl (3 N) at
100 °C to afford 3-hydroxy-2,2-dimethylpropanoic acid (8aa)
in 56% yield (Scheme 5c).8 These transformations highlight
the importance of acetoxylated tertiary amides in generating
privileged functionalities.
The mechanism of the Pd-catalyzed acetoxylation reaction
using PhI(OAc)2 is well precedented.19 Controlled studies
suggested that the Pd(II) is a more effective catalyst than the
Pd(0), tentatively highlighting the direct participation of a
Pd(II) species. Independent reaction rate determination using
amide 1p and [D]-1p provided a significant kinetic isotopic
effect (KIE; kH/kD = 5.6) (Figure S1), which supports the
probable involvement of C−H bond activation in the rate-
limiting step.20 Based on our preliminary study, and with the
support of literature precedents,19 we assume that the reaction
begins with tertiary amide coordination to Pd(II) species
Procedure for Kinetic Isotope Effect (KIE) Study. To a flame-
dried screw-cap tube equipped with a magnetic stir bar were
introduced Pd(OAc)2 (0.00047 g, 0.002 mmol, 1.0 mol %, 100 μL
from stock solution), 2-ethyl-2-methyl-1-(pyrrolidin-1-yl)butan-1-one
(1p; 0.037 g, 0.20 mmol), {or [D]-1p (0.038 g, 0.20 mmol)},
PhI(OAc)2 (2a; 0.193 g, 0.60 mmol), and n-dodecane (0.020 mL,
0.088 mmol, 0.088 M, internal standard), and HFIP/Ac2O (9:1)
(0.88 mL) was added to make the total volume to 1.0 mL. The
reaction mixture was then stirred at 120 °C in a preheated oil bath. At
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regular intervals (5, 10, 20, 30, 45, 60 min), the reaction vessel was
cooled to ambient temperature and an aliquot of sample was
withdrawn to the GC vial. The sample was diluted with EtOAc and
subjected to GC analysis. The concentration of product 3pa (or D-
3pa) obtained in each sample was determined with respect to the
internal standard n-dodecane. The data of the concentration of the
product vs time (min) plot was drawn (Figure 1) with Origin Pro 8,
and the rate was determined by initial rate method (up to 60 min).
The data were taken from the average of two independent
experiments.
Procedure A. Synthesis of N-(4-Chlorophenyl)-N-methylpivala-
mide (1l). In an oven-dried Schlenk flask, a solution of N-(4-
chlorophenyl)pivalamide (1.0 g, 4.72 mmol) in DMF (10 mL) was
slowly added to NaH (60% dispersion in mineral oil, 0.283 g, 7.10
mmol) in DMF (5.0 mL) at 0 °C, and the reaction mixture was stirred
for 30 min at room temperature. The reaction mixture was further
cooled to 0 °C, and iodomethane (1.01 g, 7.11 mmol) was added
dropwise. The resultant reaction mixture was warmed to room
temperature and stirred overnight. The reaction was quenched with
addition of NH4Cl (aq), diluted with EtOAc, and washed with water
and brine. The combined organic layers were dried over anhydrous
Na2SO4 and concentrated in vacuo. The crude residue was purified by
column chromatography on neutral alumina (petroleum ether/
EtOAc: 10/1) yielded 1l (0.81 g, 76%) as a white solid. Mp = 83−
85 °C. 1H NMR (400 MHz, CDCl3): δ = 7.37−7.34 (m, 2H), 7.17−
7.14 (m, 2H), 3.18 (s, 3H), 1.04 (s, 9H). 13C{1H}-NMR (100 MHz,
CDCl3): δ = 178.2, 144.0, 133.7, 130.3, 129.7, 41.5, 41.0, 29.6. HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C12H16NOCl + H+ 226.0993;
Found 226.0994.
2-Ethyl-2-methyl-1-(pyrrolidin-1-yl)butan-1-one (1p). The repre-
sentative procedure B was followed using 2-ethyl-2-methylbutanoic
acid (0.50 g, 3.84 mmol), N-(3-(dimethylamino)propyl)-N′-ethyl-
carbodiimidehydrochloride (0.81 g, 4.22 mmol), and pyrrolidine
(0.35 mL, 4.22 mmol), 4-(dimethylamino)pyridine (0.023 g, 0.19
mmol, 5 mol %). Purification by column chromatography on neutral
alumina (petroleum ether/EtOAc: 10/1) yielded 1p (0.61 g, 87%) as
1
a light-yellow liquid. H NMR (400 MHz, CDCl3): δ = 3.50 (vt, J =
6.9 Hz, 4H), 1.80−1.71 (m, 6H), 1.44−1.35 (m, 2H), 1.14 (s, 3H),
0.81 (t, J = 7.6 Hz, 6H). 13C{1H}-NMR (100 MHz, CDCl3): δ =
175.0, 48.1, 47.5, 31.1, 27.6, 23.2, 22.5, 9.2. HRMS (ESI-TOF) m/z:
[M + H]+ Calcd for C11H21NO + H+ 184.1701; Found 184.1698.
2-Ethyl-2-(methyl-d3)-1-(pyrrolidin-1-yl)butan-1-one ([D]-1p).
The representative procedure B was followed, using 2-ethyl-2-
deuterated methylbutanoic acid (0.50 g, 3.75 mmol), N-(3-
(dimethylamino)propyl)-N′-ethylcarbodiimide hydrochloride (0.79
g, 4.13 mmol), pyrrolidine (0.34 mL, 4.13 mmol), and 4-
(dimethylamino)pyridine (0.023 g, 0.188 mmol, 5 mol %).
Purification by column chromatography on neutral alumina
(petroleum ether/EtOAc: 10/1) yielded [D]-1p (0.57 g, 82%) as a
light-yellow liquid. 1H NMR (400 MHz, CDCl3): δ = 3.51 (vt, J = 6.7
Hz, 4H), 1.80−1.71 (m, 6H), 1.44−1.35 (m, 2H), 0.82 (t, J = 7.5 Hz,
6H). 13C{1H}-NMR (100 MHz, CDCl3): δ = 175.1, 48.0, 47.3, 31.1,
27.4, 23.1, 21.6, 9.2. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C11H18D3NO + H+ 187.1813; Found 187.1808.
2,2-Dimethyl-1-(pyrrolidin-1-yl)octadecan-1-one (1q). The rep-
resentative procedure B was followed, using 2,2-dimethyloctadecanoic
acid (0.50 g, 1.60 mmol), N-(3-(dimethylamino)propyl)-N′-ethyl-
carbodiimide hydrochloride (0.34 g, 1.76 mmol), 4-(dimethylamino)-
pyridine (0.0098 g, 0.08 mmol, 5 mol %), and pyrrolidine (0.145 mL,
1.76 mmol). Purification by column chromatography on neutral
alumina (petroleum ether/EtOAc: 10/1) yielded 1q (0.42 g, 72%) as
N-Methyl-N-(4-(trifluoromethyl)phenyl)pivalamide (1m). The
representative procedure
A was followed using N-(4-
(trifluoromethyl)phenyl)pivalamide (1.0 g, 4.10 mmol), NaH (60%;
0.245 g, 6.12 mmol), and iodomethane (0.87 g, 6.12 mmol).
Purification by column chromatography on neutral alumina
(petroleum ether/EtOAc: 10/1) yielded 1m (0.72 g, 68%) as a
white solid. Mp = 83−85 °C. 1H NMR (500 MHz, CDCl3): δ = 7.66
(d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.4 Hz, 2H), 3.23 (s, 3H), 1.06 (s,
9H). 13C{1H}-NMR (125 MHz, CDCl3): δ = 178.2, 148.8, 130.0,
129.3, 126.6, 123.9, 41.4, 41.1, 29.6. 19F-NMR (377 MHz, CDCl3): δ
= −62.5 (s). HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C13H16NOF3 + H+ 260.1257; Found 260.1254.
1
a light-yellow liquid. H NMR (500 MHz, CDCl3): δ = 3.52 (br s,
4H), 1.86−1.81 (m, 4H), 1.56−1.53 (m, 2H), 1.30−1.24 (m, 28H),
1.22 (s, 6H), 0.87 (t, J = 6.9 Hz, 3H). 13C{1H}-NMR (125 MHz,
CDCl3): δ = 176.0, 47.6, 42.9, 40.2, 32.1, 30.5, 29.9, 29.7, 29.6, 26.4,
25.1, 22.9, 14.3. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C24H47NO + H+ 366.3730; Found 366.3739.
6-Chloro-2,2-dimethyl-1-(pyrrolidin-1-yl)hexan-1-one (1r). The
representative procedure B was followed, using 6-chloro-2,2-
dimethylhexanoic acid (0.50 g, 2.80 mmol) and N-(3-
(dimethylamino)propyl)-N′-ethylcarbodiimide hydrochloride (0.60
g, 3.08 mmol), 4-(dimethylamino)pyridine (0.019 g, 0.154 mmol, 5
mol %), and pyrrolidine (0.25 mL, 3.08 mmol). Purification by
column chromatography on neutral alumina (petroleum ether/
N-Methyl-N-(4-nitrophenyl)pivalamides (1n). The representative
procedure A was followed, using N-(4-nitrophenyl)pivalamide (1.0 g,
4.50 mmol), NaH (60%; 0.270 g, 6.75 mmol), and iodomethane
(0.96 g, 6.75 mmol). Purification by column chromatography on
neutral alumina (petroleum ether/EtOAc: 10/1) yielded 1n (0.80 g,
75%) as yellow solid. Mp = 101−103 °C. 1H NMR (500 MHz,
CDCl3): δ = 8.25 (d, J = 9.2 Hz, 2H), 7.38 (d, J = 9.2 Hz, 2H), 3.26
(s, 3H), 1.10 (s, 9H). 13C{1H}-NMR (125 MHz, CDCl3): δ = 178.2,
151.5, 146.6, 129.3, 124.9, 41.1, 41.0, 29.4. HRMS (ESI-TOF) m/z:
[M + H]+ Calcd for C12H16N2O3 + H+ 237.1234; Found 237.1232.
Procedure B. Synthesis of 2,2-Diphenyl-1-(pyrrolidin-1-yl)-
propan-1-one (1u). To a stirring solution of 2,2-diphenylpropanoic
acid (1.0 g, 4.42 mmol) and N-(3-(dimethylamino)propyl)-N′-
ethylcarbodiimide hydrochloride (0.93 g, 4.86 mmol) in CH2Cl2
(20 mL) were added pyrrolidine (0.40 mL, 4.86 mmol) and 4-
(dimethylamino)pyridine (0.027 g, 0.22 mmol, 5 mol %). The
reaction was allowed to stir at room temperature for 24 h. The
reaction was quenched with water (15 mL) and extracted with ethyl
acetate (20 mL × 3). The combined organic layer was dried over
anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude
residue was purified by column chromatography on neutral alumina
(petroleum ether/EtOAc: 10/1) yielded 1u (0.88 g, 71%) as a white
1
EtOAc: 10/1) yielded 1r (0.55 g, 85%) as a light-yellow liquid. H
NMR (400 MHz, CDCl3): δ = 3.52−3.49 (m, 6H), 1.94−1.80 (m,
4H), 1.77−1.70 (m, 2H), 1.59−1.54 (m, 2H), 1.42−1.35 (m, 2H),
1.22 (s, 6H). 13C{1H}-NMR (100 MHz, CDCl3): δ = 175.5, 48.0,
44.9, 42.7, 39.7, 33.2, 26.1, 22.4. HRMS (ESI-TOF) m/z: [M + H]+
Calcd for C12H22NOCl + H+ 232.1463; Found 232.1469.
Synthesis of N-n-Dodecylpivalamide (4a). In an oven-dried
Schlenk flask, pivaloyl chloride (0.80 mL, 6.50 mmol) was dissolved
in DCM (20 mL), and n-dodecylamine (1.0 g, 5.40 mmol) and
triethylamine (1.5 mL, 10.80 mmol) in DCM (10 mL) were added
dropwise at 0 °C. The reaction mixture was warmed to room
temperature and stirred for 8 h. Upon completion of the reaction, the
organic layer was washed with 0.1 M HCl (aq) and NaHCO3 (aq).
The combined organic layers were dried over anhydrous Na2SO4,
filtered, and concentrated in vacuo. The crude residue was purified by
column chromatography on neutral alumina (petroleum ether/
EtOAc: 10/1) yielded 4a (1.30 g, 89%) as a white solid. Mp =
1
38−40 °C. H NMR (500 MHz, CDCl3): δ = 5.61 (br s, 1H), 3.22
(q, J = 6.6, 2H), 1.50−1.46 (m, 2H), 1.29−1.23 (m, 18H), 1.18 (s,
9H), 0.87 (t, J = 6.8 Hz, 3H). 13C{1H}-NMR (125 MHz, CDCl3): δ =
178.5, 39.8, 38.8, 32.1, 29.8, 29.8, 29.7, 29.5, 27.8, 27.1, 22.9, 14.3.
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C17H35NO + H+
270.2791; Found 270.2790.
1
solid. Mp = 115−117 °C. H NMR (500 MHz, CDCl3): δ = 7.36−
7.23 (m, 10H), 3.62 (vt, J = 7.3 Hz, 2H), 2.53 (t, J = 6.5 Hz, 2H),
1.92 (s, 3H), 1.74−1.67 (m, 2H), 1.60−1.54 (m, 2H). 13C{1H}-NMR
(125 MHz, CDCl3): δ = 173.4, 143.4, 128.5, 128.2, 126.7, 57.6, 48.0,
47.8, 31.8, 26.7, 23.5. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C19H21NO + H+ 280.1696; Found 280.1695.
Synthesis of Phenyl-Iodanediyl Bis(3-(2-methoxyphenyl)-
propanoate) (2c). In a round-bottom flask, PhI(OAc)2 (3.23 g,
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10.03 mmol) and (2-methoxyphenyl)propanoic acid (3.61 g, 20.06
mmol) were dissolved in CHCl3 (20 mL) and heated at 50 °C for 3 h.
At ambient temperature, the volatiles were evaporated under reduced
pressure, and the resulted solid was washed with cold solvent mixture
(pentane/CH2Cl2: 10/1). The colorless solid was dried under high
vacuum to yield 2c, which was used without further purification.
Hz, 6H). 13C{1H}-NMR (100 MHz, CDCl3): δ = 173.8, 171.2, 71.4,
42.7, 41.7, 23.3, 21.1, 13.5. HRMS (ESI-TOF) m/z: [M + H]+ Calcd
for C11H21NO3 + H+ 216.1594; Found 216.1594.
3-(Diisopropylamino)-2,2-dimethyl-3-oxopropyl Acetate (3ga).
Compound 3ga was isolated as a light-yellow solid (0.035 g, 48%) by
a column chromatography on neutral alumina (petroleum ether/
1
1
Yield: 3.56 g (63%). H NMR (500 MHz, CDCl3): δ = 7.98−7.95
EtOAc: 10/1). H NMR (400 MHz, CDCl3): δ = 4.24 (br s, 1H),
(m, 2H), 7.56 (tt, J = 7.5, 1.5 Hz, 1H), 7.45 (vt, J = 7.7 Hz, 2H), 7.18
(td, J = 7.8, 1.6 Hz, 2H), 7.08 (dd, J = 7.5, 1.7 Hz, 2H), 6.86−6.80
(m, 4H), 3.78 (s, 6H), 2.87 (vt, J = 7.7 Hz, 4H), 2.57 (vt, J = 7.7 Hz,
4H). 13C{1H}-NMR (125 MHz, CDCl3): δ = 178.6, 157.6, 137.7,
135.0, 131.7, 131.0, 130.1, 129.3, 127.6, 120.5, 110.3, 55.3, 34.1, 27.0.
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C26H27O6I + H+
563.0925; Found 563.0871.
4.15 (s, 2H), 3.28 (br s, 1H), 2.05 (s, 3H), 1.38 (d, J = 5.3 Hz, 6H),
1.27 (s, 6H), 1.19 (d, J = 6.2 Hz, 6H). 13C{1H}-NMR (100 MHz,
CDCl3): δ = 173.4, 171.3, 71.4, 48.2, 47.0, 43.1, 23.3, 21.1, 20.8.
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C13H25NO3 + H+
244.1907; Found 244.1909.
2-(Diisopropylcarbamoyl)-2-methylpropane-1,3-diyl Diacetate
(3ga′). Compound 3ga′ was isolated as a yellow solid (0.023 g,
25%) by column chromatography on neutral alumina (petroleum
ether/EtOAc: 10/1). Mp = 66−68 °C. 1H NMR (500 MHz, CDCl3):
δ = 4.31−4.14 (m, 5H), 3.31 (br s, 1H), 2.04 (s, 6H), 1.36 (br s, 6H),
1.27 (s, 3H), 1.19 (br s, 6H). 13C{1H}-NMR (125 MHz, CDCl3): δ =
170.9, 170.3, 66.3, 47.9, 47.2, 46.6, 21.0, 20.7, 17.9. HRMS (ESI-
TOF) m/z: [M + H]+ Calcd for C15H27NO5 + H+ 302.1962; Found
302.1963.
Representative Procedure for Acetoxylation. Synthesis of
2,2-Dimethyl-3-oxo-3-(pyrrolidin-1-yl)propyl Acetate (3aa). To an
oven-dried screw-cap tube equipped with magnetic stir bar were
introduced 2,2-dimethyl-1-(pyrrolidin-1-yl)propan-1-one (1a; 0.047
g, 0.302 mmol), PhI(OAc)2 (0.292 g, 0.908 mmol), Pd(OAc)2
(0.00068 g, 0.00302 mmol, 1.0 mol %; from a stock solution in
HFIP), and HFIP/Ac2O (9:1; 0.7 mL). The resultant reaction
mixture was immersed in a preheated oil bath at 80 °C and stirred for
20 h. The reaction mixture was allowed to cool to room temperature,
and all the volatiles were removed under reduced pressure. The
remaining residue was purified by column chromatography on neutral
alumina (petroleum ether/EtOAc: 5/1) yielding 3aa (0.060 g, 93%)
3-(Dibutylamino)-2,2-dimethyl-3-oxopropyl Acetate (3ha).
Compound 3ha was isolated as a light-yellow liquid (0.058 g, 71%)
by a column chromatography on neutral alumina (petroleum ether/
1
EtOAc: 10/1). H NMR (400 MHz, CDCl3): δ = 4.16 (s, 2H), 3.28
(t, J = 8.0 Hz, 4H), 2.04 (s, 3H), 1.55−1.47 (m, 4H), 1.34−124 (m,
4H), 1.27 (s, 6H), 0.92 (t, J = 7.3 Hz, 6H). 13C{1H}-NMR (100
MHz, CDCl3): δ = 174.0, 171.3, 71.5, 47.6, 42.8, 30.4, 23.4, 21.1,
20.4, 14.1. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C15H29NO3
+ H+ 272.2220; Found 272.2223.
1
as a yellow liquid. H NMR (500 MHz, CDCl3): δ = 4.17 (s, 2H),
3.52 (br s, 4H), 2.03 (s, 3H), 1.84 (br s, 4H), 1.25 (s, 6H). 13C{1H}-
NMR (125 MHz, CDCl3): δ = 173.5, 171.2, 70.9, 48.1, 42.8, 27.3,
23.2, 22.5, 21.1. HRMS (ESI-TOF): m/z Calcd for C11H19NO3 + H+
[M + H]+ 214.1438; Found 214.1439.
3-(Diisobutylamino)-2,2-dimethyl-3-oxopropyl Acetate (3ia).
Compound 3ia was isolated as a light-yellow liquid (0.068 g, 84%)
by a column chromatography on neutral alumina (petroleum ether/
2,2-Dimethyl-3-oxo-3-(piperidin-1-yl)propyl Acetate (3ba). Com-
pound 3ba was isolated as a light-yellow liquid (0.062 g, 91%) by a
column chromatography on neutral alumina (petroleum ether/
EtOAc: 5/1). 1H NMR (400 MHz, CDCl3): δ = 4.15 (s, 2H,
CH2), 3.52 (vt, J = 5.3 Hz, 4H), 2.03 (s, 3H), 1.64−1.59 (m, 2H),
1.55−1.49 (m, 4H), 1.27 (s, 6H). 13C{1H}-NMR (100 MHz,
CDCl3): δ = 173.3, 171.3, 71.2, 46.2, 42.4, 26.2, 24.7, 23.1, 21.1.
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C12H21NO3 + H+
228.1594; Found 228.1595.
2,2-Dimethyl-3-morpholino-3-oxopropyl acetate (3ca). Com-
pound 3ca was isolated as a light-yellow liquid (0.034 g, 49%) by a
column chromatography on neutral alumina (petroleum ether/
EtOAc: 5/1). 1H NMR (400 MHz, CDCl3): δ = 4.16 (s, 2H),
3.68−3.63 (m, 8H), 2.06 (s, 3H), 1.29 (s, 6H). 13C{1H}-NMR (100
MHz, CDCl3): δ = 173.8, 171.2, 70.9, 67.0, 45.8, 42.4, 23.2, 21.1.
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C11H19NO4 + H+
230.1387; Found 230.1386.
1
EtOAc: 10/1). H NMR (500 MHz, CDCl3): δ = 4.15 (s, 2H), 3.20
(d, J = 7.6 Hz, 4H), 2.01 (s, 3H), 1.98−1.91 (m, 2H), 1.28 (s, 6H),
0.85 (d, J = 6.9 Hz, 12H). 13C{1H}-NMR (125 MHz, CDCl3): δ =
175.3, 171.2, 71.8, 53.1, 43.2, 26.3, 24.0, 21.1, 20.1. HRMS (ESI-
TOF) m/z: [M + H]+ Calcd for C15H29NO3 + H+ 272.2220; Found
272.2223.
3-(Methoxy(methyl)amino)-2,2-dimethyl-3-oxopropyl Acetate
(3ja). Compound 3ja was isolated as a light-yellow liquid (0.027 g,
44%) by a column chromatography on neutral alumina (petroleum
1
ether/EtOAc: 5/1). H NMR (500 MHz, CDCl3): δ = 4.20 (s, 2H),
3.68 (s, 3H), 3.19 (s, 3H), 2.05 (s, 3H), 1.27 (s, 6H). 13C{1H}-NMR
(125 MHz, CDCl3): δ = 176.1, 171.3, 70.5, 60.9, 43.4, 33.9, 22.5,
21.1. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C9H17NO4 + H+
204.1230; Found 204.1230.
3-(Ethyl(phenyl)amino)-2,2-dimethyl-3-oxopropyl Acetate (3ka).
Compound 3ka was isolated as a light-yellow liquid (0.062 g, 78%) by
a column chromatography on neutral alumina (petroleum ether/
EtOAc: 5/1). 1H NMR (500 MHz, CDCl3): δ = 7.41−7.33 (m, 3H),
7.20−7.18 (m, 2H), 3.86 (s, 2H), 3.66 (q, J = 6.9 Hz, 2H), 2.06 (s,
3H), 1.11 (t, J = 6.9 Hz, 3H), 0.98 (s, 6H). 13C{1H}-NMR (125
MHz, CDCl3): δ = 174.1, 171.0, 142.9, 129.7, 129.3, 128.4, 72.0, 48.1,
44.6, 24.7, 21.1, 12.8. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C15H21NO3 + H+ 264.1594; Found 264.1589.
Ethyl-1-(3-Acetoxy-2,2-dimethylpropanoyl)piperidine-4-carbox-
ylate (3da). Compound 3da was isolated as a light-yellow liquid
(0.053 g, 59%) by a column chromatography on neutral alumina
1
(petroleum ether/EtOAc: 5/1). H NMR (400 MHz, CDCl3): δ =
4.22 (d, J = 13.5 Hz, 2H), 4.14 (s, 2H), 4.12−4.09 (m, 2H), 2.96 (t, J
= 12.2 Hz, 2H), 2.54−2.49 (m, 1H), 2.03 (s, 3H), 1.90 (d, J = 12.5
Hz, 2H), 1.63 (q, J = 10.9 Hz, 2H), 1.27 (s, 6H), 1.22 (t, J = 7.1 Hz,
3H). 13C{1H}-NMR (100 MHz, CDCl3): δ = 174.3, 173.5, 171.2,
71.1, 60.7, 44.5, 42.4, 41.2, 28.4, 23.1, 21.1, 14.3. HRMS (ESI-TOF)
m/z: [M + H]+ Calcd for C15H25NO5 + H+ 300.1805; Found
300.1807.
3-(4-Chlorophenyl)(methyl)amino)-2,2-dimethyl-3-oxopropyl
Acetate (3la). Compound 3la was isolated as a light-yellow solid
(0.048 g, 56%) by a column chromatography on neutral alumina
1
3-(Dimethylamino)-2,2-dimethyl-3-oxopropyl Acetate (3ea).
(petroleum ether/EtOAc: 5/1). Mp = 39−41 °C. H NMR (500
1
Product 3ea was obtained as a volatile compound (70%, H NMR
MHz, CDCl3): δ = 7.36 (d, J = 8.4 Hz, 2H), 7.17 (d, J = 8.4 Hz, 2H),
3.93 (s, 2H), 3.19 (s, 3H), 2.06 (s, 3H), 1.00 (s, 6H). 13C{1H}-NMR
(125 MHz, CDCl3): δ = 175.0, 171.0, 143.2, 134.2, 130.0, 129.8, 71.9,
44.5, 41.6, 24.6, 21.1. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C14H18NClO3 + H+ 284.1048; Found 284.1045.
yield). 1H NMR (400 MHz, CDCl3): δ = 4.19 (s, 2H), 3.04 (s, 6H),
2.06 (s, 3H), 1.30 (s, 6H). 13C{1H}-NMR (100 MHz, CDCl3): δ =
174.8, 171.3, 71.2, 42.5, 38.4, 23.1, 21.2. HRMS (ESI-TOF) m/z: [M
+ H]+ Calcd for C9H17NO3 + H+ 188.1281; Found 188.1282.
3-(Diethylamino)-2,2-dimethyl-3-oxopropyl Acetate (3fa). Com-
pound 3fa was isolated as a light-yellow liquid (0.061 g, 94%) by a
column chromatography on neutral alumina (petroleum ether/
EtOAc: 10/1). 1H NMR (400 MHz, CDCl3): δ = 4.16 (s, 2H),
3.37 (q, J = 6.8 Hz, 4H), 2.04 (s, 3H), 1.27 (s, 6H), 1.12 (t, J = 7.0
2,2-Dimethyl-3-(methyl(4-(trifluoromethyl)phenyl)amino)-3-ox-
opropyl Acetate (3ma). Compound 3ma was isolated as a light-
yellow liquid (0.071 g, 75%) by a column chromatography on neutral
alumina (petroleum ether/EtOAc: 10/1). 1H NMR (400 MHz,
CDCl3): δ = 7.67 (d, J = 8.1 Hz, 2H), 7.38 (d, J = 8.1 Hz, 2H), 3.97
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(s, 2H), 3.24 (s, 3H), 2.07 (s, 3H), 1.01 (s, 6H). 13C{1H}-NMR (100
MHz, CDCl3): δ = 175.0, 170.9, 148, 130.5, 129 1, 126.8, 123.8, 71.9,
44.6, 41.5, 24.6, 21.1. 19F-NMR (377 MHz, CDCl3): δ = −62.5 (s).
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C15H18NF3O3 + H+
318.1312; Found 318.1307.
Hz, 3H). 0.89 (dd, J = 6.9, 1.5 Hz, 6H), 0.84 (dd, J = 6.9, 3.1 Hz,
6H). 13C{1H}-NMR (100 MHz, CDCl3): δ = 174.4, 170.9, 67.0, 55.5,
53.8, 35.3, 28.4, 26.7, 20.9, 20.2, 20.2, 19.9, 14.7. HRMS (ESI-TOF)
m/z: [M + H]+ Calcd for C14H27NO3 + H+ 258.2064; Found
258.2065.
2,2-Dimethyl-3-(methyl(4-nitrophenyl)amino)-3-oxopropyl Ace-
tate (3na). Compound 3na was isolated as a light-yellow solid (0.056
g, 63%) by a column chromatography on neutral alumina (petroleum
ether/EtOAc: 5/1). Mp = 78−80 °C. H NMR (500 MHz, CDCl3):
(1-Oxo-1-(pyrrolidin-1-yl)propane-2,2-diyl)bis(2,1 phenylene) Di-
acetate (3ua). Compound 3ua was isolated as a light-yellow liquid
(0.085 g, 72%) by column chromatography on neutral alumina
1
1
(petroleum ether/EtOAc: 5/1). H NMR (400 MHz, CDCl3): δ =
δ = 8.28 (d, J = 9.2 Hz, 2H), 7.43 (d, J = 9.2 Hz, 2H), 4.01 (s, 2H),
3.28 (s, 3H), 2.08 (s, 3H), 1.06 (s, 6H). 13C{1H}-NMR (125 MHz,
CDCl3): δ = 175.1, 170.9, 150.8, 147.0, 129.3, 125.1, 71.8, 44.8, 41.3,
24.6, 21.1. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C14H18N2O5
+ H+ 295.1288; Found 295.1283.
7.34−7.29 (m, 2H), 7.19 (d, J = 7.6 Hz, 2H), 7.14−7.10 (m, 2H),
7.04−7.02 (m, 2H), 3.50 (t, J = 6.9 Hz, 2H), 2.42 (br s, 2H), 2.11 (s,
6H), 2.07 (s, 3H), 1.68−1.64 (m, 2H), 1.57−1.53 (m, 2H). 13C{1H}-
NMR (100 MHz, CDCl3): δ = 171.3, 169.1, 149.0, 133.7, 129.6,
128.1, 125.6, 124.7, 55.6, 48.2, 26.9, 25.9, 23.3, 21.6. HRMS (ESI-
TOF) m/z: [M + H]+ Calcd for C23H25NO5 + H+ 396.1805; Found
396.1810.
2-(1-Oxo-1-(piperidin-1-yl)propan-2-yl)-1,3-phenylene Diacetate
(3va). Compound 3va was isolated as a light-yellow liquid (0.069 g,
69%) by a column chromatography on neutral alumina (petroleum
ether/EtOAc: 5/1). 1H NMR (500 MHz, CDCl3): δ = 7.23 (t, J = 8.4
Hz, 1H), 6.92 (d, J = 8.4 Hz, 2H), 3.76 (q, J = 7.1 Hz, 1H), 3.55−
3.52 (m, 1H), 3.40−3.37 (m, 1H), 3.06−2.96 (m, 2H), 2.26 (s, 6H),
1.43 (br s, 4H), 1.29 (d, J = 7.6 Hz, 3H), 1.21−1.17 (m, 1H), 1.0−
0.97 (m, 1H). 13C{1H}-NMR (125 MHz, CDCl3): δ = 170.5, 169.3,
148.9, 127.7, 127.5, 121.1, 46.2, 43.3, 35.3, 25.5, 25.3, 24.5, 20.8, 17.1.
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C18H23NO5 + H+
334.1649; Found 334.1643.
2-(2-Oxo-2-(pyrrolidin-1-yl)ethyl)-1,3-phenylene Diacetate
(3wa). Compound 3wa was isolated as a light-yellow liquid (0.078
g, 85%) by a column chromatography on neutral alumina (petroleum
ether/EtOAc: 5/1). 1H NMR (500 MHz, CDCl3): δ = 7.29 (t, J = 8.2
Hz, 1H), 7.01 (d, J = 8.1 Hz, 2H), 3.53 (s, 2H), 3.42 (t, J = 6.9 Hz,
2H), 3.20 (t, J = 6.9 Hz, 2H), 2.30 (s, 6H), 1.89−1.85 (m, 2H),
1.82−1.78 (m, 2H). 13C{1H}-NMR (125 MHz, CDCl3): δ = 169.0,
168.0, 150.0, 128.0, 121.1, 120.4, 46.8, 46.4, 32.4, 26.4, 24.3, 21.1.
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C16H19NO5 + H+
306.1336; Found 306.1332.
2-Methyl-2-(pyrrolidine-1-carbonyl)butyl Acetate (3oa). Com-
pound 3oa was isolated as a light-yellow liquid (0.053 g, 78%) by a
column chromatography on neutral alumina (petroleum ether/
1
EtOAc: 5/1). H NMR (500 MHz, CDCl3): δ = 4.28 (d, J = 11.1
Hz, 1H), 4.12 (d, J = 11.1 Hz, 1H), 3.51 (vt, J = 6.2 Hz, 4H), 2.02 (s,
3H), 1.86−1.83 (m, 4H), 1.75−1.66 (m, 1H), 1.58−1.49 (m, 1H),
1.24 (s, 3H), 0.83 (t, J = 7.5 Hz, 3H). 13C{1H}-NMR (125 MHz,
CDCl3): δ = 172.7, 171.2, 68.9, 47.1, 46.9, 27.6, 21.1, 20.8, 8.9.
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C12H21NO3 + H+
228.1594; Found 228.1595.
2-Ethyl-2-(pyrrolidine-1-carbonyl)butyl Acetate (3pa). Com-
pound 3pa was isolated as a light-yellow liquid (0.057 g, 79%) by a
column chromatography on neutral alumina (petroleum ether/
1
EtOAc: 5/1). H NMR (500 MHz, CDCl3): δ = 4.32 (s, 2H), 3.53
(t, J = 6.8 Hz, 4H), 2.04 (s, 3H), 1.85 (br s, 4H), 1.68−1.61 (m, 4H),
0.83 (t, J = 7.5 Hz, 6H). 13C{1H}-NMR (125 MHz, CDCl3): δ =
172.3, 171.1, 63.6, 50.8, 47.7, 27.5, 25.5, 23.1, 21.2, 8.9. HRMS (ESI-
TOF) m/z: [M + H]+ Calcd for C13H23NO3 + H+ 242.1756; Found
242.1747.
2-Methyl-2-(pyrrolidine-1-carbonyl)octadecyl Acetate (3qa).
Compound 3qa was isolated as a white solid (0.109 g, 86%) by a
column chromatography on neutral alumina (petroleum ether/
1
EtOAc: 5/1). Mp = 43−45 °C. H NMR (500 MHz, CDCl3): δ =
3-Methoxy-2-(2-oxo-2-(pyrrolidin-1-yl)ethyl)phenyl Acetate
(3xa). Compound 3xa was isolated as a light-yellow liquid (0.067 g,
81%) by a column chromatography on neutral alumina (petroleum
ether/EtOAc: 5/1). 1H NMR (400 MHz, CDCl3): δ = 7.03 (t, J = 8.3
Hz, 1H), 6.53 (d, J = 8.4 Hz, 1H), 6.49−6.47 (m, 1H), 3.59 (s, 3H),
3.35 (s, 2H), 3.21 (vt, J = 6.9 Hz, 2H), 3.13 (vt, J = 6.7 Hz, 2H), 2.05
(s, 3H), 1.69−1.66 (m, 2H), 1.61−1.57 (m, 2H). 13C{1H}-NMR
(100 MHz, CDCl3): δ = 169.6, 169.2, 158.3, 150.4, 128.0, 117.1,
115.1, 108.2, 56.1, 46.7, 46.2, 31.0, 26.4, 24.5, 21.1. HRMS (ESI-
TOF) m/z: [M + H]+ Calcd for C15H19NO4 + H+ 278.1387; Found
278.1384.
4.32 (d, J = 11.1 Hz, 1H, CH2), 4.11 (d, J = 11.1 Hz, 1H), 3.53 (br s,
4H), 2.04 (s, 3H), 1.86 (br s, 4H), 1.69−1.62 (m, 1H), 1.52−1.45
(m, 1H), 1.28−1.23 (m, 31H), 0.87 (t, J = 6.8 Hz, 3H). 13C{1H}-
NMR (125 MHz, CDCl3): δ = 173.1, 171.3, 69.3, 47.9, 46.7, 35.1,
32.09, 30.3, 29.9, 29.8, 29.8, 29.7, 29.6, 29.5, 24.4, 22.9, 21.4, 21.2,
14.3. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C26H49NO3 + H+
424.3785; Found 424.3793.
6-Chloro-2-methyl-2-(pyrrolidine-1-carbonyl)hexyl Acetate
(3ra). Compound 3ra was isolated as a light-yellow liquid (0.071 g,
82%) by a column chromatography on neutral alumina (petroleum
1
ether/EtOAc: 5/1). H NMR (500 MHz, CDCl3): δ = 4.28 (d, J =
2-(3-Oxo-3-(pyrrolidin-1-yl)propyl)phenyl Acetate (3ya). Com-
pound 3ya was isolated as a light-yellow liquid (61%, 1H NMR yield).
1H NMR (400 MHz, CDCl3): δ = 7.30−7.28 (m, 1H), 7.25−7.21 (m,
11.1 Hz, 1H), 4.15 (d, J = 11.1 Hz, 1H), 3.53−3.49 (m, 6H), 2.04 (s,
3H), 1.88 (br s, 4H), 1.78−1.48 (m, 4H), 1.43−1.37 (m, 2H), 1.29
(s, 3H). 13C{1H}-NMR (125 MHz, CDCl3): δ = 172.7, 171.2, 69.0,
47.8, 46.5, 44.7, 34.4, 32.9, 27.3, 23.3, 21.8, 21.1. HRMS (ESI-TOF)
m/z: [M + H]+ Calcd for C14H24NClO3 + H+ 290.1517; Found
290.1522.
2-Methyl-3-oxo-3-(piperidin-1-yl)propyl Acetate (3sa). Com-
pound 3sa was isolated as a light-yellow liquid (0.034 g, 53%) by a
column chromatography on neutral alumina (petroleum ether/
EtOAc: 5/1). 1H NMR (500 MHz, CDCl3): δ = 4.28−4.23 (m,
1H), 4.07−4.03 (m, 1H), 3.56−3.52 (m, 2H), 3.46−3.43 (m, 2H),
3.11−3.03 (m, 1H), 2.01 (s, 3H), 1.64−1.61 (m, 2H), 1.59−1.51 (m,
4H), 1.11 (d, J = 6.9 Hz, 3H). 13C{1H}-NMR (125 MHz, CDCl3): δ
= 172.3, 171.2, 66.7, 46.9, 43.3, 35.0, 26.9, 25.8, 24.7. 21.1, 14.6.
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C11H19NO3 + H+
214.1438; Found 214.1438.
1H), 7.19−7.15 (m, 1H), 7.03−6.99 (m, 1H), 3.46 (t, J = 6.6 Hz,
2H), 3.27 (t, J = 6.5 Hz, 2H), 2.91 (t, J = 7.8 Hz, 2H), 2.51 (t, J = 7.8
Hz, 2H), 2.33 (s, 3H), 1.90−1.80 (m, 4H, CH2). 13C{1H}-NMR (100
MHz, CDCl3): δ = 170.7, 169.8, 149.0, 133.4, 130.5, 127.5, 126.3,
122.5, 46.7, 45.8, 35.2, 26.1, 25.6, 24.5, 21.1. HRMS (ESI-TOF) m/z:
[M + H]+ Calcd for C15H19NO3 + H+ 262.1438; Found 262.1435.
2,2-Dimethyl-3-oxo-3-(pyrrolidin-1-yl)propyl Propionate (3ab).
Compound 3ab was isolated as a light-yellow liquid (0.047 g, 69%) by
a column chromatography on neutral alumina (petroleum ether/
1
EtOAc: 5/1). H NMR (400 MHz, CDCl3): δ = 4.17 (s, 2H), 3.51
(br s, 4H), 2.30 (q, J = 7.6 Hz, 2H), 1.83 (br s, 4H), 1.25 (s, 6H),
1.09 (t, J = 7.6 Hz, 3H). 13C{1H}-NMR (100 MHz, CDCl3): δ =
174.5, 173.4, 70.5, 48.0, 42.9, 27.7, 27.3, 23.1, 22.6, 9.3. HRMS (ESI-
TOF) m/z: [M + H]+ Calcd for C12H21NO3 + H+ 228.1594; Found
228.1590.
2,2-Dimethyl-3-oxo-3-(pyrrolidin-1-yl)propyl 3-(2-
methoxyphenyl)propanoate (3ac). Compound 3ac was isolated as
a light-yellow liquid (0.057 g, 57%) by a column chromatography on
neutral alumina (petroleum ether/EtOAc: 5/1). 1H NMR (400 MHz,
3-(Diisobutylamino)-2-methyl-3-oxopropyl Acetate (3ta). Com-
pound 3ta was isolated as a light-yellow liquid (0.052 g, 67%) by a
column chromatography on neutral alumina (petroleum ether/
EtOAc: 5/1). 1H NMR (400 MHz, CDCl3): δ = 4.24−4.19 (m,
1H), 4.09−4.05 (m, 1H), 3.26−3.20 (m, 1H), 3.13−3.02 (m, 4H),
1.99−1.95 (m, 1H), 1.97 (s, 3H), 1.90−1.85 (m, 1H), 1.08 (d, J = 6.9
8178
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Article
CDCl3): δ = 7.19−7.11 (m, 2H), 6.85−6.81 (m, 2H), 4.19 (s, 2H),
3.80 (s, 3H), 3.51 (t, J = 6.1 Hz, 4H), 2.92 (t, J = 8.0 Hz, 2H), 2.61 (t,
J = 8.0 Hz, 2H), 1.83 (br s, 4H), 1.24 (s, 6H). 13C{1H}-NMR (100
MHz, CDCl3): δ = 173.5, 173.5, 157.6, 130.0, 128.9, 127.7, 120.5,
110.3, 70.7, 55.3, 47.9, 42.9, 34.3, 27.4, 26.2, 23.4, 22.7. HRMS (ESI-
TOF) m/z: [M + H]+ Calcd for C19H27NO4 + H+ 334.2013; Found
334.2014.
ene) diacetate (3ua; 0.10 g, 0.252 mmol) in Et2O (10 mL) was
added to LiAlH4 (0.096 g, 2.52 mmol) at 0 °C, and the reaction
mixture was stirred for 12 h at room temperature. The reaction was
slowly quenched with cold water (15 mL) at 0 °C, and the product
was extracted with diethyl ether (20 mL × 3). The combined organic
layer was dried over anhydrous Na2SO4, filtered, and concentrated in
vacuo. The crude residue was purified by column chromatography on
silica gel (petroleum ether/EtOAc: 3/1) yielded 7ua (0.059 g, 79%)
3-(Dodecylamino)-2,2-dimethyl-3-oxopropyl Acetate (5aa).
Compound 5aa was isolated as a yellow liquid (0.032 g, 33%) by a
column chromatography on neutral alumina (petroleum ether/
1
as a white solid. H NMR (400 MHz, CDCl3): δ = 7.20−7.11 (m,
4H), 6.88−6.81 (m, 4H), 3.26 (s, 2H), 3.77 (br s, 4H), 1.85−1.82
(m, 4H), 1.77 (s, 3H). 13C{1H}-NMR (100 MHz, CDCl3): δ = 156.1,
131.4, 129.1, 127.9, 120.3, 119.2, 65.0, 56.0, 49.2, 27.0, 23.9. HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C19H23NO2 + H+ 298.1807;
Found 298.1788.
1
EtOAc: 5/1). H NMR (500 MHz, CDCl3): δ = 5.77 (br s, 1H),
4.08 (s, 2H), 3.24 (q, J = 5.9 Hz, 2H), 2.05 (s, 3H), 1.50−1.46 (m,
2H), 1.30−1.24 (m, 18H) 1.19 (s, 6H), 0.86 (t, J = 6.9 Hz, 3H).
13C{1H}-NMR (125 MHz, CDCl3): δ = 175.3, 170.9, 70.7, 42.4, 39.8,
32.0, 29.8, 29.7, 29.5, 29.5, 27.0, 22.8, 21.0, 14.3. HRMS (ESI-TOF)
m/z: [M + H]+ Calcd for C19H37NO3 + H+ 328.2846; Found
328.2849.
Procedure for Hydrolysis of β-Acetoxylated Compound. Syn-
thesis of 3-Hydroxy-2,2-dimethylpropanoic Acid (8aa).8 In a
Schlenk flask the mixture of 2-methyl-3-(pyrrolidin-1-yl)but-3-en-2-
yl acetate (0.10 g, 0.47 mmol) and 3 N HCl (aq, 3 mL) was refluxed
for 12 h. The reaction mixture was neutralized and extracted with
ethyl acetate (20 mL x 3). The combined organic layer was dried over
anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude
residue was purified by column chromatography on silica gel
(petroleum ether/EtOAc: 3/1) yielded 8aa (0.031 g, 56%) as a
3-(Methoxyamino)-2,2-dimethyl-3-oxopropyl Acetate (5ba).
Compound 5ba was isolated as a light-yellow liquid (0.036 g, 55%)
by a column chromatography on neutral alumina (petroleum ether/
EtOAc: 5/1). 1H NMR (500 MHz, CDCl3): δ = 6.22 (br s, 1H), 4.08
(s, 2H), 3.46−3.42 (m, 4H), 3.35 (s, 3H), 2.05 (s, 3H), 1.20 (s, 6H).
13C{1H}-NMR (125 MHz, CDCl3): δ = 175.6, 170.8, 71.3, 70.6, 59.0,
1
white solid. H NMR (500 MHz, CDCl3): δ = 3.60 (s, 2H), 1.24 (s,
42.4, 39.5, 22.8, 21.0. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
6H). 13C{1H}-NMR (125 MHz, CDCl3): δ = 183.4, 69.5, 44.2, 22.1.
TOF MS ES+ m/z: [M]+ Calcd for C5H10O3 118.0630; Found
118.0859.
C10H19NO4 + H+ 218.1387; Found 218.1387.
3-(Methoxycarbonyl)amino)-2,2-dimethyl-3-oxopropyl Acetate
(5ca). Compound 5ca was isolated as a light-yellow liquid (0.044 g,
60%) by a column chromatography on neutral alumina (petroleum
1
ASSOCIATED CONTENT
ether/EtOAc: 5/1). H NMR (500 MHz, CDCl3): δ = 6.54 (br s,
■
1H), 4.05 (s, 2H), 3.68 (s, 3H), 3.51 (q, J = 5.9 Hz, 2H), 2.52 (t, J =
5.9 Hz, 2H), 2.04 (s, 3H), 1.17 (s, 6H). 13C{1H}-NMR (125 MHz,
CDCl3): δ = 175.5, 173.4, 170.8, 70.5, 51.9, 42.3, 35.1, 33.7, 22.7,
20.9. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C11H19NO5 + H+
246.1336; Found 246.1336.
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00629.
1H and 13C NMR spectra of all compounds (PDF)
2-Methyl-2-(pyrrolidine-1-carbonyl)propane-1,3-diyl Diacetate
1
FAIR data, including the primary NMR FID files, for
compounds 1l−1n, 1p−1r, 1u, [D]−1p, 2c, 4a, 3aa−
3ya, 3ab, 3ac, 3aa′, 5aa−5ca, 6aa, 6ba, 7ua, and 8aa
(ZIP)
(3aa′). Compound 3aa′ obtained as a light-yellow liquid. H NMR
(400 MHz, CDCl3): δ = 4.38−4.18 (m, 4H), 3.54 (br s, 4H), 2.04 (s,
6H), 1.88 (br s, 4H), 1.28 (s, 3H). 13C{1H}-NMR (100 MHz,
CDCl3): δ = 171.0, 170.6, 65.8, 47.9, 46.6, 27.2, 23.3, 21.0, 17.3.
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C13H21NO5 + H+
272.1492; Found 272.1489.
Alcoholysis of β-Acetoxylated Compounds. Representative
Procedure: Synthesis of 3-Hydroxy-2,2-dimethyl-1-(pyrrolidin-1-
yl)propan-1-one (6aa).22 In an oven-dried Schlenk flask, a mixture
of 2-methyl-3-(pyrrolidin-1-yl)but-3-en-2-yl acetate (3aa; 0.10 g,
0.469 mmol) and K2CO3 (0.065 g, 0.47 mmol) in MeOH (3 mL) was
refluxed for 12 h. At ambient temperature, the solvent was evaporated
under reduced pressure, quenched with H2O (15 mL), and extracted
with EtOAc (20 mL x 3). The combined organic layer was dried over
anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude
residue was purified by column chromatography on silica gel
(petroleum ether/EtOAc: 3/1) yielded 6aa (0.069 g, 86%) as a
AUTHOR INFORMATION
■
Corresponding Author
Benudhar Punji − Organometallic Synthesis and Catalysis
Lab, Chemical Engineering Division, CSIR−National
Chemical Laboratory (CSIR−NCL), Pune 411 008, India;
Academy of Scientific and Innovative Research (AcSIR),
Ghaziabad 201002, India; orcid.org/0000-0002-9257-
5236; Email: b.punji@ncl.res.in
Author
1
white solid. H NMR (500 MHz, CDCl3): δ = 3.96 (s, 1H), 3.60−
Muniyappa Vijaykumar − Organometallic Synthesis and
Catalysis Lab, Chemical Engineering Division,
CSIR−National Chemical Laboratory (CSIR−NCL), Pune
411 008, India; Academy of Scientific and Innovative
Research (AcSIR), Ghaziabad 201002, India
3.48 (m, 6H), 1.85 (br s, 4H), 1.24 (s, 6H). 13C{1H}-NMR (125
MHz, CDCl3): δ = 176.9, 72.7, 47.9, 43.4, 27.1, 23.2, 21.2. HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C9H17NO2 + H+ 172.1332;
Found 172.1331.
Synthesis of 3-Hydroxy-2,2-dimethyl-1-(piperidin-1-yl)propan-1-
one) (6ba). The representative was followed, using 2,2-dimethyl-3-
oxo-3-(piperidin-1-yl)propyl acetate (3ba; 0.10 g, 0.44 mmol) and
K2CO3 (0.061 g, 0.44 mmol). Purification by column chromatography
on silica gel (petroleum ether/EtOAc: 3/1) yielded 6ba (0.069 g,
85%) as a white solid. 1H NMR (500 MHz, CDCl3): δ = 3.55 (t, J =
5.7 Hz, 4H), 3.48 (s, 2H), 1.68−1.64 (m, 2H), 1.59−1.54 (m, 4H),
1.27 (s, 6H). 13C{1H}-NMR (125 MHz, CDCl3): δ = 176.4, 73.2,
46.0, 43.2, 26.2, 24.7, 22.1. HRMS (ESI-TOF) m/z: [M + H]+ Calcd
for C10H19NO2 + H+ 186.1489; Found 186.1484.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00629
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by SERB, New Delhi,
India (EMR/2016/000989). V.K.M. thanks CSIR-New Delhi
for a research fellowship.
Procedure for Reduction of Acetoxylated Compound. Synthesis
of 2,2′-(1-(Pyrrolidin-1yl)propane-2,2-diyl)diphenol) (7ua). A sol-
ution of (1-oxo-1-(pyrrolidin-1-yl)propane-2,2-diyl)bis(2,1-phenyl-
8179
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J. Org. Chem. 2021, 86, 8172−8181

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
Catalyzed Chemo- and Regioselective β-C(sp3)−H Acyloxylation of
Aliphatic Amides. ACS Omega 2019, 4, 331−343.
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