Palladium-catalyzed α-arylation of 2-chloroacetates and 2-chloroacetamides

Article abstract of DOI:10.1021/jo400488q

A method has been developed for the Pd-catalyzed synthesis of α-(hetero)aryl esters and amides through a Suzuki-Miyaura cross-coupling reaction. This method avoids the use of strong base, does not necessitate inert or low temperature formation of reagents, and does not require the use of a large excess of organometallic reagent. Utilization of organotrifluoroborate salts as nucleophilic partners allows a variety of functional groups and heterocyclic compounds to be tolerated.

Full text of DOI:10.1021/jo400488q

Article
pubs.acs.org/joc
Palladium-Catalyzed α‑Arylation of 2‑Chloroacetates and
2‑Chloroacetamides
Gary A. Molander,* Kaitlin M. Traister, and Thiago Barcellos
Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia,
Pennsylvania, 19104-6323, United States
S
* Supporting Information
ABSTRACT: A method has been developed for the Pd-catalyzed
synthesis of α-(hetero)aryl esters and amides through a Suzuki−
Miyaura cross-coupling reaction. This method avoids the use of
strong base, does not necessitate inert or low temperature
formation of reagents, and does not require the use of a large
excess of organometallic reagent. Utilization of organotrifluor-
oborate salts as nucleophilic partners allows a variety of functional groups and heterocyclic compounds to be tolerated.
Mixtures of mono- and diarylated products are frequently
obtained.1b,3 In a similar manner, Hartwig has employed a
Reformatsky reagent generated from an α-bromoester or amide
in cross-coupling with a variety of aryl bromides.4 Although
functional group tolerance is improved by this method, the
preformation of the metal enolate under low-temperature, inert
conditions is required, and all coupling reactions were carried
out in a glovebox or in Schlenkware.
A complementary strategy that alleviates a number of these
problems reverses the polarity of the reaction, employing an α-
halo ester or amide as an electrophile, which is then coupled
with an arylmetallic species (Scheme 1, route b). One example
of this polarity reversal employs aryl Grignard reagents in an
iron-catalyzed reaction with α-bromo esters.5 This method still
requires inert, in situ formation of the organometallic reagent
and has low functional group tolerance.
INTRODUCTION
■
The synthesis of α-aryl esters and amides through metal-
catalyzed C−C bond-forming reactions has been extensively
investigated over the past decade.1 The α-aryl ester and amide
moieties, as well as their carboxylic acid derivatives, are of
biological importance and can be readily observed in the cores
of numerous nonsteroidal anti-inflammatory drugs (NSAIDs)
and analgesics (Figure 1).2 Although several methods have
been developed for the construction of these biologically
important structures, none solve all of the challenges associated
with their synthesis.
Although in principle Suzuki−Miyaura cross-coupling
reactions can provide some improvements in these trans-
formations in terms of functional group compatibility,6 in fact
the use of aryl 9-BBN compounds for this modified reaction
suffers from many of the same limitations as methods described
above.7 Arylboronic acids, on the other hand, are advantageous
in that they avoid the use of a strong base and the necessity for
preformation of air- and temperature-sensitive reagents.
Methods using these reagents face a different set of challenges,
however, because many arylboronic acids are prone to
protodeboronation,8 and homocoupling9 under Pd-catalyzed
conditions is often inherently more prevalent in arylboronic
acid cross-coupling than in organotrifluoroborates, for exam-
ple.10 To account for the instability of the boronic acids under
employed conditions, either a large excess (20−50 mol %) of
the arylboronic acid is required,11 or a more stable arylboron
species, such as a boronate ester, is necessary.12 Addition of a
phase transfer catalyst is required to aid quick transmetalation
Figure 1. Examples of NSAIDS that contain the α-aryl- or
heteroarylacetic acid motif.
There are two common strategies for the synthesis of α-aryl
esters and amides (Scheme 1). The first involves enolate
formation of an ester or amide, which is reacted with an aryl or
heteroaryl halide under Pd-catalyzed conditions (Scheme 1,
route a).1a,b In his seminal study, Buchwald illustrates this
method using a strong base (LiHMDS or NaHMDS) to
deprotonate a variety of esters, amides, and ketones, which are
subsequently reacted with an aryl halide.3 This method presents
several limitations: (1) The use of strong base prevents the
presence of many important functional groups within the aryl
electrophile, including ketone, nitro, and carboxylic acid
moieties.1a (2) Competition with a Claisen side reaction
(between two molecules of the enolate) necessitates either the
use of a large excess of ester or a sterically encumbered group
on the ester to prevent formation of acetoacetates.1a,b,3 (3)
Received: March 7, 2013
© XXXX American Chemical Society
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Scheme 1. Approaches to the Synthesis of α-(Hetero)aryl Esters and Amides
of the boronic acid if a large excess of the organoboron species
is not employed.13
catalyst capable of rapid reductive elimination to a reactive,
monoligated Pd(0) species, emerged as an ideal catalyst for the
reaction of benzyl chloroacetate with aryl trifluoroborates. This
species, which contains a bulky monodentate biaryl ligand, has
been shown to be a model catalyst for Suzuki−Miyaura cross-
coupling reactions of sensitive aryl and heteroarylboronic acids
under mild conditions.17 Recently, XPhos was found to be the
ligand of choice for the enolate arylation of aryl benzylsulfo-
nates.18
Initial reactions were performed with this catalyst in a 4:1
THF/H2O solvent system, and several bases were tested at two
different temperatures. The results of the base screening
showed that increased temperature aided the reaction and that
K3PO4, Cs2CO3, and KF were all viable options for promoting
the reaction (Figure 3).
The method described herein follows the latter approach
(Scheme 1, route b), but employs potassium aryl and
heteroaryltrifluoroborate salts to overcome the drawbacks of
previously reported approaches. Organotrifluoroborate salts,
which are air and moisture stable, crystalline solids or free-
flowing powders at room temperature, are less prone to
protodeboronation,14 and the presence of water in the reaction
system allows the slow release of a hydrated species capable of
transmetalation.10,15 Because of their enhanced stability,16
a
large excess of the organoboron species is not required, and
furthermore the materials are all bench-stable and able to be
weighed in air without special considerations. Using this
protocol, the substrate scope has been expanded from previous
methods to include heteroaryl substrates, and the current
method boasts acceptance of several functional groups that are
not tolerated by other methods. It is demonstrated that a wide
range of esters and amides can be employed in this reaction.
RESULTS AND DISCUSSION
■
Initial conditions for the general reaction of potassium
aryltrifluoroborate salts with benzyl bromoacetate were
developed through a limited screening process in which several
Pd sources were evaluated. Using a system of [Pd(allyl)Cl]2,
good conversions to cross-coupled products were observed by
GC−MS (eq 1).
Figure 3. Screening results from the reaction of methyl chloroacetate
with potassium phenyltrifluoroborate (1 mol % XPhos-Pd-G2, 0.25 M
in 4:1 THF/H2O, 18 h) in the presence of 3 equiv of each base at the
shown temperature.
Because of the significantly increased commercial availability
of α-chloro esters and amides compared to the corresponding
bromides, we sought to optimize the reaction for C−C bond
formation between chlorinated electrophiles and (hetero)aryl
trifluoroborates. Although product formation was observed
from benzyl chloroacetate under the above conditions,
significant amounts of undesired homocoupled biaryl product
and protodeboronated starting material were prevalent. After
further optimization, XPhos-Pd-G2 (Figure 2), a preformed Pd
The four bases were tested on a 0.5 mmol scale in the
reaction of benzyl chloroacetate with potassium 2-methox-
yphenyltrifluoroborate at 80 °C, and the conversions were
followed by GC−MS (Table 1), which pointed to the increased
Table 1. GC−MS Conversions for the Reaction of Benzyl
Chloroacetate with Potassium 2-
Methoxyphenyltrifluoroborate in the Presence of Four
a
Bases
base
KF
% conversion
42
81
92
77
K3PO4
Cs2CO3
K2CO3
a
3 equiv of each base shown; 1 mol % XPhos-Pd-G2, 0.25 M in 4:1
THF/H2O, 18 h, 80 °C.
Figure 2. Structure of XPhos-Pd-G2 precatalyst.
B
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Figure 4. Screening results for the reaction of benzyl chloroacetate with potassium 3-pyridyltrifluoroborate (1 mol % XPhos-Pd-G2, 3 equiv base,
0.25 M, 80 °C, 18 h).
activity of Cs2CO3 in this reaction system. Although the
conversion with K3PO4 was good, this base promoted a
significant amount of homocoupled biaryl product from the
trifluoroborate; therefore, Cs2CO3 and K2CO3 appeared to
serve as the two best bases for the reaction if it was run to
completion.
Table 2. Cross-Coupling of Benzyl Chloroacetate with Aryl
and Heteroaryl Trifluoroborates
a
Using Cs2CO3 and K2CO3 for further optimization, several
solvent systems were screened for activity in the presence of
XPhos and SPhos on a more challenging system of benzyl
chloroacetate with potassium 3-pyridyltrifluoroborate. It was
quickly evident that Cs2CO3 was superior to K2CO3, and
XPhos showed increased activity over SPhos regardless of the
solvent system (Figure 4). Although within the context of
screening on a small scale (25 μmol), THF, CPME, and 2-
MeTHF in a 4:1 ratio with H2O were successful, upon scaling
the reactions to a 0.5 mmol scale, it was determined that a 4:1
THF/H2O combination was superior.
On the basis of these results, benzyl chloroacetate was
successfully cross-coupled with a wide range of aryl
trifluoroborate salts in good yields (Table 2). Although
hydrolysis of the benzyl ester was observed in the presence
of most nitrogen-containing heterocyclic substrates, 6-quinoli-
nyltrifluoroborate was successfully cross-coupled in good yield
(entry 4). The conditions allowed successful cross-coupling of
electron-rich (entry 6) and ortho-substituted trifluoroborates
(entries 2 and 3). Electron-deficient, fluorinated substrates
(entry 7) could be isolated in moderate yield. In the cross-
coupling of benzyl esters, both K2CO3 and Cs2CO3 allow the
reaction to go to completion, and both provide good yields for
nonsterically hindered substrates (entries 8 and 9). Under the
optimized conditions, formation of the desired cross-coupled
product was not observed when α-chloro ketones or secondary
α-haloesters were employed, and protodehalogenated products
were observed in these reactions.
a
General conditions: Benzyl ester (0.50 mmol), trifluoroborate (0.525
mmol), XPhos-Pd-G2 (0.005 mmol), Cs2CO3 (1.50 mmol) in THF
(1.6 mL)/H2O (0.40 mL) at 100 °C for 18 h. K2CO3 used as base.
Although cross-couplings with benzyl chloroacetate were
accompanied by a noticeable amount of hydrolyzed ester, alkyl
esters did not suffer from this fate and could be employed as
b
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more effective substrates. Thus, under the same conditions, tert-
butyl chloroacetate and methyl chloroacetate were successfully
cross-coupled with a variety of aryl (Table 3) and heteroaryl
Table 4. Cross-Coupling of Alkyl Chloroacetates with
Heteroaryltrifluoroborates
a
Table 3. Cross-Coupling of Alkyl Chloroacetates with
a
Aryltrifluoroborates
a
General conditions: Ester (0.50 mmol), trifluoroborate (0.525
mmol), XPhos-Pd-G2 (0.005 mmol), Cs2CO3 (1.50 mmol) in THF
b
(1.6 mL)/H2O (0.40 mL) at 100 °C for 18 h. Isolated on 5.0 mmol
scale using 0.5 mol % XPhos-Pd-G2.
(Table 4) partners. It was illustrated that ester (Table 3, entry
4), ketone (Table 3, entry 5 and Table 4, entry 8), and terminal
alkenyl (Table 3, entry 2) functional groups remain intact
under the employed conditions. Electron-deficient groups
(Table 3, entries 3−6) were tolerated, although in some
cases the desired products were isolated in lower yields. For
challenging substrates, an increase to 2 mol % Pd was
attempted, but yields did not dramatically increase (Table 4,
entry 3). However, we were able to demonstrate that increasing
the scale 10-fold to 5.0 mmol led to comparable yields, even
with the catalyst loading cut in half (from 1 to 0.5 mol %, Table
3, entry 1).
The scope of the reaction was next broadened to include α-
chloro amides as electrophilic coupling partners (Table 5). A
variety of α-chloro tertiary amides were successfully cross-
coupled under the same conditions, and both aryl and
heteroaryl nucleophilic partners were employed. Both furyl
(entries 6 and 7) and benzothienyltrifluoroborates (entry 9)
were successful coupling partners, as was an indolinyltrifluor-
oborate (entry 8). Neither unprotected indoles nor those with
base-labile protecting groups (Boc) were successful under these
conditions. Somewhat surprisingly, this method allowed the
cross coupling of a furyltrifluoroborate bearing a free carboxylic
acid (entry 7). Electron-poor functional groups (entries 4 and
5) were cross-coupled in moderate yields.
a
General conditions: Ester (0.50 mmol), trifluoroborate (0.525
mmol), XPhos-Pd-G2 (0.005 mmol), Cs2CO3 (1.50 mmol) in THF
(1.6 mL)/H2O (0.40 mL) at 100 °C for 18 h. 2 mol % XPhos-Pd-G2
(0.010 mmol).
b
A challenge was observed in coupling of secondary α-chloro
amides, which under the developed conditions showed very low
conversions. Attempts were made to increase catalyst loading,
but this only led to the production of homocoupled
trifluoroborate (biaryl product). On the basis of successful
results of Deng and Duan, who successfully cross-coupled
arylboronic acids with α-bromo amides using catalytic Pd in the
presence of Cu2O,6a it was hypothesized that the addition of a
catalytic source of Cu(I) could aid in the cross-coupling of
secondary amides. After conducting a small screen to examine
the addition of several Cu(I) salts to the reaction conditions,
Cu2O was determined to be superior to CuCl and CuI, and
XPhos worked better in the reaction than other structurally
similar ligands (e.g., SPhos and RuPhos, Figure 5). Increasing
the amount of base did not aid the reaction. The addition of 5
mol % of Cu2O to the originally developed conditions allowed
these reactions to proceed in moderate to good yields with aryl
or heteroaryl coupling partners (Table 6). Aryl (entries 2 and
3) as well as quinolinyl (entry 1), isoquinolinyl (entry 6), and
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Table 5. Cross-Coupling of Tertiary Amides with Aryl and
a
Heteroaryltrifluoroborates
Figure 5. Screen results of the addition of Cu(I) sources to the
reaction of N-benzyl chloroacetamide with potassium 4-methylphenyl-
trifluoroborate (1 mol % XPhos-Pd-G2, 3 equiv of Cs2CO3, 0.25 M
4:1 THF/H2O, 100 °C, 18 h).
Table 6. Cross-Coupling of Secondary Amides with Aryl and
a
Heteroaryltrifluoroborates
a
General conditions: Amide (0.50 mmol), trifluoroborate (0.525
a
General conditions: Amide (0.50 mmol), trifluoroborate (0.525
mmol), XPhos-Pd-G2 (0.005 mmol), Cu2O (0.025 mmol), Cs2CO3
mmol), XPhos-Pd-G2 (0.005 mmol), Cs2CO3 (1.50 mmol) in THF
(1.6 mL)/H2O (0.40 mL) at 100 °C for 18 h.
(1.50 mmol) in THF (1.6 mL)/H2O (0.40 mL) at 100 °C for 18 h.
b
Isolated on 5.0 mmol scale using 0.5 mol % XPhos-Pd-G2.
furyl (entry 4) trifluoroborate salts were successfully cross-
coupled using these modified conditions. The addition of Cu2O
to a sampling of reactions performed with esters and tertiary
amides did not increase the yields of those reactions. Finally,
because the reactions were optimized on a 0.5 mmol scale, we
showed that increasing the scale 10-fold to 5.0 mmol led to
comparable yields, with the catalyst loading cut in half (from 1
to 0.5 mol %, entry 2).
In conclusion, we have developed a versatile, scalable
reaction system in which potassium aryl and heteroaryltri-
fluoroborate salts can be cross-coupled with α-chloroesters and
amides. Although limited in some respects by the availability
and structure of the α-halo carbonyl substrates, this method
nevertheless avoids many of the limitations of current methods
for the synthesis of α-aryl esters and amides through the use of
air-stable reagents and reaction conditions that tolerate
common functional groups as well as heteroaryl substrates.
EXPERIMENTAL SECTION
General Considerations. Both THF and deionized H2O were
thoroughly degassed with Ar prior to use. All solids were weighed out
in the air, and the reactions were conducted under an Ar atmosphere.
■
All 2-chloroacetates and 2-chloroacetamides were purchased from
1
commercial sources and used without further purification. H and 13
C
NMR spectra were obtained at 500 and 125.8 MHz, respectively.
HRMS data was obtained by ESI using a TOF mass spectrometer.
E
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General Procedure A for Cross-Coupling of (Hetero)-
aryltrifluoroborates with 2-Chloroacetates and Tertiary 2-
Chloroacetamides. An oven-dried Biotage 10 mL microwave vial
equipped with a magnetic stirbar was charged with the (hetero)aryl
trifluoroborate (0.525 mmol, 1.05 equiv), Cs2CO3 (1.5 mmol, 3
equiv), and XPhos-Pd-G2 (3.93 mg, 5.0 μmol, 1 mol %). A disposable
Teflon septum cap was used to seal the vial, which was evacuated and
purged with Ar three times. THF (1.6 mL), H2O (0.4 mL), and the
electrophile (0.5 mmol, 1 equiv) were added via syringe with stirring
under Ar. In cases where the electrophile was a solid, it was added
along with the solid materials before sealing the vial. The solution was
heated at 100 °C overnight. After cooling to rt, the mixture was
extracted with EtOAc (3 × 3 mL), and the combined organic layers
were dried (Na2SO4). The crude products were purified by flash
column chromatography, eluting with a gradient of EtOAc in hexanes.
Benzyl 2-(3-Methoxyphenyl)acetate (2a). General procedure A
was employed. Column chromatography (hexanes/EtOAc = 9:1 to
1:3) provided the title compound as a yellow oil in 80% yield (102
1455, 1146 cm−1; HRMS (ESI) m/z calcd. For C21H27O2 (M + H)+
311.2011, found 311.2011.
Benzyl 2-(2,4-Difluorophenyl)acetate (2g). General procedure
A was employed. Column chromatography (hexanes/EtOAc = 9:1 to
1:3) provided the title compound as a white solid in 58% yield (76
1
mg): mp 33−34 °C; H NMR (500 MHz, CDCl3) δ 7.36−7.31 (m,
5H), 7.21 (dd, J = 8.2, 6.6 Hz, 1H), 6.84−6.79 (m, 2H), 5.14 (s, 2H),
3.67 (s, 2H); 13C NMR (125.8 MHz, CDCl3) δ 170.5, 162.7 (dd, J =
158.5, 12.0 Hz), 160.7 (dd, J = 159.0, 11.9 Hz), 135.8, 132.1 (dd J =
9.9, 5.5 Hz), 128.7, 128.5, 128.3, 117.3 (dd, J = 16.3, 3.7 Hz), 111.3
(dd, J = 21.2, 3.6 Hz), 103.9 (t, J = 25.7 Hz), 67.0, 33.9 (d, J = 2.5 Hz);
IR (neat) 2920, 1739, 1507, 1137, 970 cm−1; HRMS (ESI) m/z calcd.
For C15H12F2O2Na (M + Na)+ 285.0703, found 285.0702.
Benzyl 2-(Furan-3-yl)acetate (2h). General procedure A was
employed. Column chromatography (hexanes/EtOAc = 9:1 to 1:3)
provided the title compound as an orange oil in 84% yield (91 mg):
1H NMR (500 MHz, CDCl3) δ 7.38 (s, 2H), 7.35−7.33 (m, 5H), 6.29
(s, 1H), 5.15 (s, 2H), 3.52 (s, 2H); 13C NMR (125.8 MHz, CDCl3) δ
171.3, 143.2, 140.6, 135.9, 128.8, 128.5, 128.4, 117.3, 111.5, 66.9, 31.0;
IR (neat) 3034, 1736, 1455, 1163 cm−1; HRMS (ESI) m/z calcd. For
C13H12O3Na (M + Na)+ 239.0684, found 239.0685.
1
mg): H NMR (500 MHz, CDCl3) δ 7.33−7.30 (m, 5H), 7.24−7.22
(m, 1H), 6.92 (d, J =7.5 Hz, 1H), 6.87−6.85 (m, 2H), 5.12 (s, 2H),
3.76 (s, 3H), 3.63 (s, 2H); 13C NMR (125.8 MHz, CDCl3) δ 171.4,
159.9, 136.0, 135.4, 129.7, 128.7, 128.3, 128.3, 121.8, 115.0, 113.0,
66.8, 55.3, 41.5; IR (neat) 2919, 1736, 1490, 1261, 1147 cm−1; HRMS
(ESI) m/z calcd. For C16H17O3 (M + H)+, 257.1178, found 257.1171.
Benzyl 2-(2-Methoxyphenyl)acetate (2b). General procedure A
was employed. Column chromatography (hexanes/EtOAc = 9:1 to
1:3) provided the title compound as a yellow oil in 66% yield (84 mg):
1H NMR (500 MHz, CDCl3) δ 7.38−7.34 (m, 5H), 7.29−7.26 (m,
1H), 7.22−7.20 (m, 1H), 6.95−6.93 (m, 1H), 6.87−6.86 (m, 1H),
5.16 (s, 2H), 3.75 (s, 3H), 3.68 (s, 2H); 13C NMR (125.8 MHz,
CDCl3) δ 171.9, 157.7, 136.4, 131.1, 128.8, 128.7, 128.6, 128.2, 128.2,
123.1, 120.6, 110.5, 66.4, 55.5, 36.2; IR (neat) 2924, 1737, 1495, 1247,
1148 cm−1; HRMS (ESI) m/z calcd. For C16H16O3Na (M + Na)+
279.0997, found 279.0997.
Benzyl 2-(4-Chlorophenyl)acetate (2i).20 General procedure A
was employed, with the only modification being the use of K2CO3 (3
equiv, 1.5 mmol) rather than Cs2CO3. Column chromatography
(hexanes/EtOAc = 9:1 to 1:3) provided the title compound as a white,
opaque oil in 84% yield (110 mg). Spectral data were in accordance
1
with those published: H NMR (500 MHz, CDCl3) δ 7.35−7.29 (m,
7H), 7.23 (d, J = 8.4 Hz, 2H), 5.14 (s, 2H), 3.64 (s, 2H); 13C NMR
(125.8 MHz, CDCl3) δ 171.1, 135.9, 133.3, 132.5, 130.9, 128.9, 128.8,
128.5, 128.4, 67.0, 40.8.
tert-Butyl 2-(p-Tolyl)acetate (3a).21 General procedure A was
employed. Column chromatography (hexanes/EtOAc = 9:1 to 3:1)
provided the title compound as a light brown oil in 95% yield (98 mg).
Spectral data were in accordance with those published: 1H NMR (500
MHz, CDCl3) δ 7.17−7.11 (m, 4H), 3.47 (s, 2H), 2.32 (s, 3H), 1.42
(s, 9H); 13C NMR (125.8 MHz, CDCl3) δ 171.1, 136.3, 131.6, 129.1,
129.0, 80.6, 42.1, 28.0, 21.0.
Benzyl 2-(o-Tolyl)acetate (2c). General procedure A was
employed. Column chromatography (hexanes/EtOAc = 9:1 to 1:3)
provided the title compound as a light yellow oil in 87% yield (104
1
mg): H NMR (500 MHz, CDCl3) δ 7.31−7.29 (m, 5H), 7.18−7.16
tert-Butyl 2-[2-{(Pent-4-en-1-yloxy)methyl}phenyl]acetate
(3b). General procedure A was employed. Column chromatography
(hexanes/EtOAc = 9:1 to 3:1) provided the title compound as a
(m, 4H), 5.12 (s, 2H), 3.67 (s, 2H), 2.28 (s, 3H); 13C NMR (125.8
MHz, CDCl3) δ 171.4, 137.0, 136.1, 132.8, 130.5, 130.3, 128.7, 128.3,
128.2, 127.6, 126.3, 66.7, 39.3, 19.7; IR (neat) 1734, 1498, 1455, 1257,
1146 cm−1; HRMS (ESI) m/z calcd. For C16H16O2Na (M + Na)+
263.1048, found 263.1048.
1
colorless oil in 63% yield (92 mg): H NMR (500 MHz, CDCl3) δ
7.38 (d, J = 7.1 Hz, 1H), 7.28−7.22 (m, 3H), 5.82−5.81 (m, 1H),
5.02−4.98 (m, 2H), 4.53 (s, 2H), 3.65 (s, 2H), 3.51 (q, J = 6.3 Hz,
2H), 2.17 (q, J = 7.3 Hz, 2H), 1.74−1.71 (m, 2H), 1.43 (s, 9H); 13C
NMR (125.8 MHz, CDCl3) δ 171.1, 138.4, 136.9, 133.8, 130.8, 129.3,
128.1, 127.2, 114.9, 80.9, 71.4, 70.0, 39.6, 30.5, 29.1, 28.2; IR (neat)
2979, 1731, 1641, 1150, 1093, 913 cm−1; HRMS (ESI) m/z calcd. For
C18H27O3 (M + H)+ 291.1960, found 291.1952.
Benzyl 2-(Quinolin-6-yl)acetate (2d). General procedure A was
employed. Column chromatography (hexanes/EtOAc = 9:1 to 1:3)
provided the title compound as a brown oil in 80% yield (111 mg): 1H
NMR (500 MHz, CDCl3) δ 8.91 (br s, 1H), 8.12−8.07 (m, 2H), 7.72
(s, 1H), 7.69−7.67 (m, 1H), 7.43−7.42 (m, 1H), 7.37−7.34 (m, 5H),
5.16 (s, 2H), 3.86 (s, 2H); 13C NMR (125.8 MHz, CDCl3) δ 171.2,
150.4, 147.6, 136.0, 135.8, 132.5, 131.3, 129.9, 128.7, 128.5, 128.4,
128.1, 121.5, 67.0, 41.3; IR (neat) 2980, 1732, 1500, 1152 cm−1;
HRMS (ESI) m/z calcd. For C18H16NO2 (M + H)+ 278.1181, found
278.1182.
tert-Butyl 2-(3-Nitrophenyl)acetate (3c).22 General procedure
A was employed. Column chromatography (hexanes/EtOAc = 9:1 to
3:1) provided the title compound as a yellow oil in 60% yield (71 mg).
Spectral data were in accordance with those published: 1H NMR (500
MHz, CDCl3) δ 8.18 (s, 1H), 8.15 (d, J = 8.2 Hz, 1H), 7.61 (d, J = 7.7
Hz, 1H), 7.54−7.51 (m, 1H), 3.64 (s, 2H), 1.45 (s, 9H); 13C NMR
(125.8 MHz, CDCl3) δ 161.5, 148.2, 136.5, 135.5, 129.2, 124.2, 122.0,
81.6, 41.9, 27.9.
Benzyl 2-(2,3-Dihydrobenzo[1,4]dioxin-6-yl)acetate (2e).19
General procedure A was employed. Column chromatography
(hexanes/EtOAc = 9:1 to 1:3) provided the title compound as a
yellow oil in 84% yield (119 mg). Spectral data were in accordance
Methyl 3-{2-(tert-Butoxy)-2-oxoethyl}benzoate (3d). General
procedure A was employed. Column chromatography (hexanes/
EtOAc = 9:1 to 3:1) provided the title compound as a colorless oil in
1
with those published: H NMR (500 MHz, CDCl3) δ 7.34−7.32 (m,
5H), 6.84 (t, J = 4.0 Hz, 2H), 6.78−6.76 (m, 1H), 5.13 (s, 2H), 4.24
(s, 4H), 3.55 (s, 2H); 13C NMR (125.8 MHz, CDCl3) δ 171.7, 143.6,
142.9, 136.0, 128.7, 128.4, 128.3, 127.1, 122.4, 118.3, 117.4, 66.7, 64.5,
40.7.
1
82% yield (103 mg): H NMR (500 MHz, CDCl3) δ 7.97−7.95 (m,
2H), 7.48 (d, J = 7.7 Hz, 1H), 7.43 (t, J = 7.6 Hz, 1H), 3.91 (s, 3H),
3.57 (s, 2H), 1.43 (s, 9H); 13C NMR (125.8 MHz, CDCl3) δ 170.2,
166.8, 135.0, 133.7, 130.3, 130.3, 128.4, 128.0, 81.0, 51.9, 42.2, 27.9; IR
(neat) 2977.68, 1723.06, 1284.86, 1144.00 cm−1; HRMS (ESI) m/z
calcd. For C14H18O4Na (M + Na)+ 273.1103, found 273.1098.
tert-Butyl 2-(3-Acetylphenyl)acetate (3e). General procedure A
was employed. Column chromatography (hexanes/EtOAc = 9:1 to
3:1) provided the title compound as a brown oil in 98% yield (115
mg): 1H NMR (500 MHz, CDCl3) δ 7.86−7.84 (m, 2H), 7.49 (t, J =
5.6 Hz, 1H), 7.44−7.41 (m, 1H), 3.59 (s, 2H), 2.61 (s, 3H), 1.44 (s,
Benzyl 2-(3,5-Diisopropylphenyl)acetate (2f). General proce-
dure A was employed. Column chromatography (hexanes/EtOAc =
9:1 to 1:3) provided the title compound as a yellow oil in 63% yield
1
(98 mg): H NMR (500 MHz, CDCl3) δ 7.40−7.39 (m, 1H), 7.36−
7.31 (m, 5H), 7.01−6.99 (m, 2H), 5.14 (s, 2H), 3.64 (s, 2H), 2.89−
2.85 (m, 2H), 1.24 (d, J = 6.9 Hz, 12 H); 13C NMR (125.8 MHz,
CDCl3) δ 171.8, 149.3, 136.1, 135.1, 133.8, 128.9, 128.7, 128.3, 128.2,
125.0, 123.7, 68.1, 66.6, 41.7, 34.3, 24.2; IR (neat) 2959, 1737, 1601,
F
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9H); 13C NMR (125.8 MHz, CDCl3) δ 198.0, 170.5, 137.4, 135.4,
134.1, 129.3, 128.8, 127.1, 81.2, 42.4, 28.1, 26.8; IR (neat) 2979.63,
1729.22, 1685.75, 1367.15, 1275.50, 1144.21 cm−1; HRMS (ESI) m/z
calcd. For C14H18O3Na (M + Na)+ 257.1154, found 257.1161.
Methyl 2-(4-Fluorophenyl)acetate (3f).23 General procedure A
was employed. Column chromatography (hexanes/EtOAc = 9:1 to
3:1) provided the title compound as a yellow oil in 67% yield (56 mg).
Spectral data were in accordance with those published: 1H NMR (500
MHz, CDCl3) δ 7.26−7.21 (m, 2H), 7.01−6.98 (m, 2H), 3.68 (s, 3H),
3.58 (s, 2H); 13C NMR (125.8 MHz, CDCl3) δ 172.0, 162.0 (d, J =
244.8 Hz), 130.9 (d, J = 8.2 Hz), 129.8, 115.5 (d, J = 21.5 Hz), 52.3,
40.4.
Spectral data were in accordance with those published: 1H NMR (500
MHz, CDCl3) δ 8.56−8.54 (m, 2H), 7.21−7.20 (m, 2H), 3.53 (s, 2H),
1.44 (s, 9H); 13C NMR (125.8 MHz, CDCl3) δ169.4, 150.0, 143.6,
124.6, 81.7, 42.1, 28.1.
tert-Butyl 2-(Furan-3-yl)acetate (4g). General procedure A was
employed. Column chromatography (hexanes/EtOAc = 9:1 to 3:1)
provided the title compound as a dark brown oil in 88% yield (80 mg):
1H NMR (500 MHz, CDCl3) δ 7.36 (dd, J = 6.1, 1.0 Hz, 2H), 6.36 (s,
1H), 3.32 (s, 2H), 1.44 (s, 9H); 13C NMR (125.8 MHz, CDCl3) δ
170.4, 142.7, 140.1, 117.8, 111.3, 80.8, 32.1, 27.9; IR (neat) 2977,
1729, 1149 cm−1; HRMS (CI) m/z calcd. For C10H14O3 (M)+,
182.0943 found 182.0945.
Methyl 2-(p-Tolyl)acetate (3g).24 General procedure A was
employed. Column chromatography (hexanes/EtOAc = 9:1 to 3:1)
provided the title compound as a yellow oil in 80% yield (66 mg).
Spectral data were in accordance with those published: 1H NMR (500
MHz, CDCl3) δ 7.14−7.12 (m, 4H), 3.66 (s, 3H), 3.57 (s, 2H), 2.31
(s, 2H); 13C NMR (125.8 MHz, CDCl3) δ 172.4, 136.9, 131.1, 129.5,
129.3, 52.2, 40.9, 21.2.
tert-Butyl 2-(2-Acetylthiophen-3-yl)acetate (4h). General
procedure A was employed. Column chromatography (hexanes/
EtOAc = 9:1 to 3:1) provided the title compound as a brown oil in
1
76% yield (91 mg): H NMR (500 MHz, CDCl3) δ 7.45−7.44 (m,
1H), 7.07−7.06 (m, 1H), 3.97 (s, 2 H), 2.53 (s, 3H), 1.45 (s, 9H); 13C
NMR (125.8 MHz, CDCl3) δ 191.0, 170.0, 141.1, 136.8, 132.3, 129.7,
81.1, 36.8, 29.6, 28.2; IR (neat) 2981, 1731, 1665, 1148 cm−1; HRMS
(ESI) m/z calcd. For C12H16O3SNa (M + Na)+, 263.0718, found
263.0715.
tert-Butyl 2-(Quinolin-6-yl)acetate (4a).20 General procedure A
was employed. Column chromatography (hexanes/EtOAc = 9:1 to
3:1) provided the title compound an orange-brown oil in 92% yield
tert-Butyl 2-(2-Acetylthiophen-3-yl)acetate (4i). General pro-
cedure A was employed. Column chromatography (hexanes/EtOAc =
9:1 to 3:1) provided the title compound as a yellow oil in 75% yield
1
(112 mg). Spectral data were in accordance with those published: H
NMR (500 MHz, CDCl3) δ 8.89−8.87 (m, 1H), 8.16 (dd, J = 8.1, 4.6
Hz, 1H), 8.10−8.08 (m, 1H), 7.69 (s, 1H), 7.68−7.66 (m, 1H), 7.42−
7.40 (m, 1H), 3.70 (s, 2H), 1.43 (s, 9H); 13C NMR (125.8 MHz,
CDCl3) δ 170.7, 150.3, 147.6, 135.9, 133.3, 131.3, 129.6, 128.3, 127.8,
121.4, 81.3, 42.7, 28.2.
1
(74 mg): H NMR (500 MHz, CDCl3) δ 7.19−7.17 (m, 1H), 6.94−
6.92 (m, 1H), 6.90−6.89 (m, 1H), 3.72 (s, 2 H), 1.44 (s, 9H); 13C
NMR (125.8 MHz, CDCl3) δ 169.8.0, 136.0, 126.8, 126.6, 125.0, 81.5,
37.0, 28.1.
Methyl 2-(Furan-3-yl)acetate (4j).27 General procedure A was
employed. Column chromatography (hexanes/EtOAc = 9:1 to 3:1)
provided the title compound as a yellow oil in 79% yield (55 mg).
Spectral data were in accordance with those published: 1H NMR (500
MHz, CDCl3) δ 7.37 (s, 2H), 6.34 (s, 1H), 3.70 (s, 3H), 3.45 (s, 2H);
13C NMR (125.8 MHz, CDCl3) δ 171.8, 143.2, 140.5, 117.4, 111.5,
tert-Butyl 2-(Isoquinolin-5-yl)acetate (4b). General procedure
A was employed. Column chromatography (hexanes/EtOAc = 9:1 to
3:1) provided the title compound as an orange-brown oil in 94% yield
(114 mg): 1H NMR (500 MHz, CDCl3) δ 9.24 (s, 1H), 8.60 (t, J = 5.0
Hz, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.77−7.76 (m, 1H), 7.65 (d, J = 6.9
Hz, 1H), 7.58−7.56 (m, 1H), 3.94 (s, 2H), 1.39 (s, 9H); 13C NMR
(125.8 MHz, CDCl3) δ 170.4, 153.2, 143.3, 135.0, 132.1, 130.8, 129.1,
127.4, 127.1, 117.1, 81.6, 39.8, 28.1; IR (neat) 2977, 1728, 1367, 1253,
1145 cm−1; HRMS (ESI) m/z calcd. For C15H18NO2 (M + H)+
244.1338, found 244.1338.
52.2, 30.8.
1-Morpholino-2-(p-tolyl)ethan-1-one (5a).28 General proce-
dure A was employed. Column chromatography (hexanes/EtOAc =
9:1 to 1:3) provided the title compound as an orange solid in 81%
yield (89 mg). Spectral data were in accordance with those published:
mp 77−78 °C (lit. 80−81.5 °C) 1H NMR (500 MHz, CDCl3) δ 7.12−
7.11 (m, 4H), 3.69 (s, 2H), 3.64−3.63 (m, 4H), 3.50 (d, J = 5.1 Hz,
2H), 3.46 (d, J = 5.1 Hz, 2H), 2.32 (s, 3H); 13C NMR (125.8 MHz,
CDCl3) δ 170.0, 136.6, 131.8, 129.6, 128.5, 66.9, 66.6, 46.6, 42.5, 40.6,
21.2.
tert-Butyl 2-(Pyridin-3-yl)acetate (4c).25 General procedure A
was employed, with the only modification being that 2 mol % of
XPhos-Pd-G2 was used. Column chromatography (hexanes/EtOAc =
9:1 to 3:1) provided the title compound as a brown oil in 57% yield
1
(55 mg). Spectral data were in accordance with those published: H
NMR (500 MHz, CDCl3) δ 8.51−8.50 (m, 2H), 7.64−7.62 (m, 1H),
7.26−7.24 (m, 1H), 3.53 (s, 2H), 1.44 (s, 9H); 13C NMR (125.8
MHz, CDCl3) δ170.1, 150.5, 148.5, 136.9, 130.5, 123.5, 81.6, 39.9,
28.1.
1-Morpholino-2-(naphthalen-2-yl)ethan-1-one (5b). General
procedure A was employed. Column chromatography (hexanes/
EtOAc = 9:1 to 1:3) provided the title compound as a white solid in
88% yield (112 mg): mp 118−119 °C; 1H NMR (500 MHz, CDCl3) δ
7.85 (d, J = 8.0 Hz, 2H), 7.82 (d, J = 7.7 Hz, 1H), 7.71 (s, 1H), 7.50−
7.48 (m, 2H), 7.42 (d, J = 8.4 Hz, 1H), 3.88 (d, J = 1.4 Hz, 2H), 3.65−
3.64 (m, 4H), 3.45 (d, J = 2.2 Hz, 4H); 13C NMR (125.8 MHz,
CDCl3) δ 169.5, 133.5, 132.3, 132.2, 128.5, 127.6, 127.5, 127.0, 126.7,
126.2, 125.7, 66.7, 66.4, 46.5, 42.1, 41.0; IR (neat) 2860, 1643, 1428,
1115 cm−1; HRMS (ESI) m/z calcd. For C16H17NO2 (M + H)+
256.1338, found 256.1337.
tert-Butyl 2-(2,4-Dimethoxypyrimidin-5-yl)acetate (4d). Gen-
eral procedure A was employed. Column chromatography (hexanes/
EtOAc = 9:1 to 3:1) provided the title compound as a yellow solid in
1
93% yield (118 mg): mp 40−42 °C; H NMR (500 MHz, CDCl3) δ
8.02 (s, 1H), 3.96 (s, 6H), 3.36 (s, 2H), 1.41 (s, 9H); 13C NMR
(125.8 MHz, CDCl3) δ 169.9, 169.5, 164.8, 158.0, 109.3, 81.2, 54.8,
54.0, 33.5, 28.1; IR (neat) 2985, 1730, 1569, 1470, 1380, 1227, 1147
cm−1; HRMS (ESI) m/z calcd. For C12H19N2O4 (M + H)+ 255.1345,
found 255.1347.
2-(2,3-Dihydrobenzo[1,4]dioxin-6-yl)-1-morpholinoethan-1-
one (5c). General procedure A was employed. Column chromatog-
raphy (hexanes/EtOAc = 9:1 to 1:3) provided the title compound as
tert-Butyl 2-(Isoquinolin-4-yl)acetate (4e). General procedure
A was employed, with the only modification being that 2 mol % of
XPhos-Pd-G2 was used. Column chromatography (hexanes/EtOAc =
9:1 to 3:1) provided the title compound as an orange-brown oil in
1
an orange oil in 98% yield (129 mg): H NMR (500 MHz, CDCl3) δ
6.78 (d, J = 9.6 Hz, 1H), 6.71 (d, J = 1.8 Hz, 1H), 6.65 (dd, J = 8.2, 1.8
Hz, 1H), 4.21 (s, 4H), 3.63−3.61 (m, 6H), 3.48 (t, J = 4.7 Hz, 2H),
3.41 (t, J = 4.7 Hz, 2H); 13C NMR (125.8 MHz, CDCl3) δ 169.7,
143.5, 142.4, 127.8, 121.3, 117.4, 117.2, 66.7, 66.4, 64.2, 64.2, 46.4,
42.0, 40.0; IR (neat) 2979, 1639, 1507, 1285, 1067 cm−1; HRMS
(ESI) m/z calcd. For C14H18NO4 (M + H)+, 264.1236, found
264.1235.
1
80% yield (97 mg): H NMR (500 MHz, CDCl3) δ 9.19−9.18 (m,
1H), 8.43−8.42 (m, 1H), 8.00−7.97 (m, 2H), 7.75−7.72 (m, 1H),
7.62−7.61 (m, 1H), 3.93 (s, 2H), 1.40 (s, 9H); 13C NMR (125.8
MHz, CDCl3) δ 170.1, 151.9, 147.3, 135.8, 129.3, 129.3, 128.0, 127.7,
126.9, 81.6, 40.1, 28.1; IR (neat) 2977, 1728, 1367, 1141 cm−1; HRMS
(ESI) m/z calcd. For C15H18NO2 (M + H)+ 244.1338, found
244.1336.
2-(3-Acetylphenyl)-1-morpholinoethan-1-one (5d). General
procedure A was employed. Column chromatography (hexanes/
EtOAc = 9:1 to 1:3) provided the title compound as a yellow oil in
tert-Butyl 2-(Pyridin-4-yl)acetate (4f).26 General procedure A
was employed. Column chromatography (hexanes/EtOAc = 9:1 to
3:1) provided the title compound as a brown oil in 40% yield (39 mg).
1
70% yield (86 mg): H NMR (500 MHz, CDCl3) δ 7.84−7.83 (m,
G
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1H), 7.49−7.48 (m, 1H), 7.40−7.38 (m, 1H), 7.29−7.28 (m, 1H),
4.04 (s, 2H), 3.74−3.69 (m, 8H), 2.63 (s, 3H); 13C NMR (125.8
MHz, CDCl3) δ 201.7, 169.9, 137.1, 135.7, 132.5, 132.1, 130.1, 127.2,
66.7, 46.3, 42.4, 40.8, 38.8, 29.1; IR (neat) 2980, 1676, 1646, 1435,
1113 cm−1; HRMS (ESI) m/z calcd. For C14H18NO3 (M + H)+,
248.1287, found 248.1283.
2H), 3.41 (q, J = 6.8 Hz, 2H), 3.31 (q, J = 7.1 Hz, 2H), 2.34 (s, 3H),
1.12 (dt, J = 14.8, 7.3 Hz, 6H); 13C NMR (125.8 MHz, CDCl3) δ
170.4, 136.3, 132.5, 129.4, 128.6, 42.4, 40.6, 40.2, 21.2, 14.3, 13.1.
General Procedure B for Cross-Coupling of (Hetero)-
aryltrifluoroborates with Secondary 2-Chloroacetamides. An
oven-dried Biotage 10 mL microwave vial equipped with a magnetic
stirbar was charged with the (hetero)aryl trifluoroborate (0.525 mmol,
1.05 equiv), Cs2CO3 (1.5 mmol, 3 equiv), XPhos-Pd-G2 (3.93 mg, 5.0
μmol, 1 mol %), and Cu2O (3.6 mg, 25 μmol, 5 mol %). A disposable
Teflon septum cap was used to seal the vial, which was evacuated and
purged with Ar three times. THF (1.6 mL), H2O (0.4 mL), and the
electrophile (0.5 mmol, 1 equiv) were added via syringe with stirring
under Ar. In cases where the electrophile was a solid, it was added
along with the solid materials before sealing the vial. The solution was
heated at 100 °C overnight. After cooling to rt, the mixture was
extracted with EtOAc (3 × 3 mL), and the combined organic layers
were dried (Na2SO4). The crude products were purified by flash
column chromatography, eluting with a gradient of EtOAc in hexanes.
N-Benzyl-2-(quinolin-6-yl)acetamide (6a). General procedure B
was employed. Column chromatography (hexanes/EtOAc = 9:1 to
1:4) provided the title compound as a light orange solid in 55% yield
(76 mg): mp 135−137 °C; 1H NMR (500 MHz, CDCl3) δ 8.89−8.88
(m, 1H), 8.10−8.06 (m, 2H), 7.75 (s, 1H), 7.62 (d, J = 8.6 Hz, 1H),
7.41 (ddd, J = 8.2, 4.2, 1.0 Hz 1H), 7.29−7.26 (m, 3H), 7.22 (t, J = 5.7
Hz, 2H), 5.84 (br s, 1H), 4.43 (d, J = 5.8 Hz, 2H), 3.79 (s, 2H); 13C
NMR (125.8 MHz, CDCl3) δ 170.4, 150.6, 138.1, 136.5, 136.0, 133.4,
131.1, 130.3, 129.3, 128.8, 128.4, 128.2, 127.8, 127.7, 126.2, 121.7,
43.9, 43.8; IR (neat) 3229, 2361, 1628, 1554, 1328 cm−1; HRMS
(ESI) m/z calcd. For C18H17N2O (M + H)+ 277.1341, found
277.1339.
2-(4-Fluorophenyl)-1-morpholinoethan-1-one (5e).27 General
procedure A was employed. Column chromatography (hexanes/
EtOAc = 9:1 to 1:3) provided the title compound as a white solid in
68% yield (76 mg). Spectral data were in accordance with those
1
published: mp 79−81 °C; H NMR (500 MHz, CDCl3) δ 7.20−7.18
(m, 2H), 7.02 (t, J = 8.7 Hz, 2H), 3.67 (s, 2H), 3.63 (s, 4H), 3.51 (t, J
= 4.7 Hz, 2H), 3.42 (d, J = 4.9 Hz, 2H); 13C NMR (125.8 MHz,
CDCl3) δ 169.6, 161.9 (d, J =245.2 Hz), 130.4 (d, J =3.3 Hz), 130.3
(d, J =7.7 Hz), 115.7 (d, J =21.6), 66.9, 66.6, 46.6, 42.3, 39.0.
2-(Furan-3-yl)-1-morpholinoethan-1-one (5f). General proce-
dure A was employed. Column chromatography (hexanes/EtOAc =
9:1 to 1:3) provided the title compound as a light brown solid in 85%
yield (83 mg): mp 75−77 °C; 1H NMR (500 MHz, CDCl3) δ 7.39 (t,
J = 1.2 Hz, 1H), 7.34 (s, 1H), 6.35 (s, 1H), 3.65−3.63 (m, 4H), 3.59−
3.58 (m, 2H), 3.52 (d, J = 1.9 Hz, 2H), 3.47 (s, 2H); 13C NMR (125.8
MHz, CDCl3) δ 169.1, 143.2, 139.8, 118.1, 111.0, 66.7, 66.4, 46.4,
42.0, 30.3; IR (neat) 2855, 1645, 1634, 1439., 1229, 1112 cm−1;
HRMS (ESI) m/z calcd. For C10H14NO3 (M + H)+, 196.0974, found
196.0972.
2-(2-Morpholino-2-oxoethyl)furan-3-carboxylic acid (5g).
General procedure A was employed. Column chromatography
(hexanes/EtOAc = 9:1 to 1:3) provided the title compound as a
1
light orange solid in 71% yield (85 mg): mp 108−110 °C; H NMR
(500 MHz, CDCl3) δ 8.10 (s, 1H), 7.44 (t, J = 1.6 Hz, 1H), 6.78 (t, J =
0.9 Hz, 1H), 4.88 (s, 2H), 3.71 (d, J = 4.4 Hz, 4H), 3.64 (d, J = 3.9 Hz,
2H), 3.44 (d, J = 3.8 Hz, 2H); 13C NMR (125.8 MHz, CDCl3) δ
165.0, 162.4, 148.3, 143.8, 118.4, 109.8, 66.7, 66.3, 61.1, 45.0, 42.1; IR
(neat) 2961, 1733, 1667, 1469, 1311, 1144 cm−1; HRMS (ESI) m/z
calcd. For C11H14NO5 (M + H)+, 240.0872, found 240.0875.
N-Benzyl-2-(p-tolyl)acetamide (6b).31 General procedure B was
employed. Column chromatography (hexanes/EtOAc = 9:1 to 1:4)
provided the title compound as a white solid in 75% yield (90 mg).
Spectral data were in accordance with those published: mp 134−135
°C (lit. 136); 1H NMR (500 MHz, CDCl3) δ 7.33 (t, J = 7.2 Hz, 2H),
7.27−7.26 (m, 1H), 7.21 (d, J = 7.2 Hz, 2H), 7.18 (s, 4H), 5.67 (br s,
1H), 4.41 (d, J = 5.6 Hz, 2H), 3.60 (s, 2H), 2.33 (s, 3H); 13C NMR
(125.8 MHz, CDCl3) δ 171.3, 138.4, 137.2, 131.8, 129.9, 129.5, 128.8,
127.6, 127.5, 43.7, 43.6, 21.2.
N-Cyclopropyl-2-(p-tolyl)acetamide (6c). General procedure B
was employed. Column chromatography (hexanes/EtOAc = 9:1 to
1:4) provided the title compound as a white solid in 67% yield (63
mg): mp 117−118 °C; 1H NMR (500 MHz, CDCl3) δ 7.16−7.14 (m,
4H), 5.43 (br s, 1H), 3.50 (s, 2H), 2.67−2.63 (m, 1H), 2.34 (s, 3H),
0.71 (dd, J =7.0, 1.3 Hz, 2H), 0.39−0.38 (m, 2H); 13C NMR (125.8
MHz, CDCl3) δ 172.9, 137.0, 132.0, 129.7, 129.3, 43.3, 22.9, 21.2, 6.6;
IR (neat) 3280, 1644, 1545, 1266 cm−1; HRMS (ESI) m/z calcd. For
C12H16NO (M + H)+ 190.1232, found 190.1238.
1-Morpholino-2-{1-(phenylsulfonyl)-1H-indol-3-yl}ethan-1-
one (5h). General procedure A was employed. Column chromatog-
raphy (hexanes/EtOAc = 9:1 to 1:3) provided the title compound as
an orange oil in 85% yield (157 mg): 1H NMR (500 MHz, CDCl3) δ
8.02−8.00 (m, 1H), 7.88−7.87 (m, 2H), 7.55−7.53 (m, 2H), 7.45 (dt,
J=J = 12.5, 6.4 Hz, 3H), 7.35−7.34 (m, 1H), 7.27−7.26 (m, 1H), 3.74
(s, 2H), 3.65−3.64 (m, 4H), 3.43−3.40 (m, 4H); 13C NMR (125.8
MHz, CDCl3) δ 168.3, 138.0, 135.1, 133.8, 130.2, 129.2, 126.6, 125.1,
123.8, 123.4, 119.6, 116.2, 113.6, 66.7, 66.3, 46.4, 42.1, 30.7; IR (neat)
2979, 1643, 1446, 1365, 1174, 1115 cm−1; HRMS (ESI) m/z calcd.
For C20H21N2O4S (M + H)+, 385.1222, found 385.1215.
2-(Benzothiophen-2-yl)-1-morpholinoethan-1-one (5i). Gen-
eral procedure A was employed. Column chromatography (hexanes/
EtOAc = 9:1 to 1:3) provided the title compound as a light orange
N-Cyclopropyl-2-(furan-3-yl)acetamide (6d). General proce-
dure B was employed. Column chromatography (hexanes/EtOAc =
9:1 to 1:4) provided the title compound as a white solid in 70% yield
1
solid in 62% yield (81 mg): mp 118−120 °C; H NMR (500 MHz,
CDCl3) δ 7.79 (d, J = 7.8 Hz, 1H), 7.70 (d, J = 7.9 Hz, 1H), 7.33−7.29
(m, 3H), 3.98 (s, 2H), 3.68−3.67 (m, 4H), 3.59 (t, J = 4.3 Hz, 2H),
3.54−3.53 (m, 2H); 13C NMR (125.8 MHz, CDCl3) δ 167.9, 139.7,
139.6, 137.3, 124.3, 124.0, 123.1, 122.6, 122.1, 66.6, 66.4, 46.6, 42.2,
35.7; IR (neat) 2920, 1644, 1436, 1229, 1113 cm−1; HRMS (ESI) m/z
calcd. For C14H16NO2S (M + H)+, 262.0902, found 262.0898.
1-(Piperidin-1-yl)-2-(p-tolyl)ethan-1-one (5j).29 General proce-
dure A was employed. Column chromatography (hexanes/EtOAc =
9:1 to 1:3) provided the title compound as a white solid in 86% yield
(93 mg). Spectral data were in accordance with those published: mp
1
(58 mg): mp 60−62 °C; H NMR (500 MHz, CDCl3) δ 7.43 (d, J =
1.3 Hz, 1H), 7.37 (s, 1H), 6.33 (s, 1H), 5.77 (br s, 1H), 3.37 (s, 2H),
2.71−2.68 (m, 1H), 0.77 (q, J = 6.9 Hz, 2H), 0.45 (dd, J = 2.2, 1.1 Hz,
2H); 13C NMR (125.8 MHz, CDCl3) δ 172.1, 143.7, 140.8, 118.4,
111.3, 32.9, 22.8, 6.6; IR (neat) 3287, 1650, 1539, 1022 cm−1; HRMS
(ESI) m/z calcd. For C9H12NO2 (M + H)+ 166.0868, found 166.0870.
N-Cyclopropyl-2-(naphthalen-1-yl)acetamide (6e).32 General
procedure B was employed. Column chromatography (hexanes/
EtOAc = 9:1 to 1:4) provided the title compound as a white solid in
71% yield (80 mg). Spectral data were in accordance with those
published: mp 134−136 °C (lit. 140−141); 1H NMR (500 MHz,
CDCl3) δ 7.96 (t, J = 6.1 Hz, 1H), 7.91 (q, J = 6.7 Hz, 1H), 7.85 (d, J
= 8.2 Hz, 1H), 7.55−7.52 (m, 2H), 7.46−7.43 (m, 1H), 7.38−7.36 (m,
1H), 5.38 (br s, 1H), 3.99 (s, 2H), 2.60−2.57 (m, 1H), 0.65 (q, J = 6.3
Hz, 2H), 0.26−0.25 (m, 2H); 13C NMR (125.8 MHz, CDCl3) δ 172.2,
133.9, 131.9, 131.1, 128.7, 128.4, 128.1, 126.7, 126.1, 125.5, 123.7,
41.7, 22.6, 6.4.
1
59−60 °C; H NMR (500 MHz, CDCl3) δ 7.11−7.10 (m, 4H), 3.66
(s, 2H), 3.54 (t, J = 5.4 Hz, 2H), 3.33 (t, J = 5.5 Hz, 2H), 2.29 (s, 3H),
1.57−1.55 (m, 2H), 1.50−1.49 (m, 2H), 1.32 (qt, J = 5.2 Hz, 2H); 13C
NMR (125.8 MHz, CDCl3) δ 169.6, 136.3, 132.4, 129.5, 128.5, 47.4,
43.0, 41.0, 26.3, 25.6, 24.6, 21.2.
N,N-Diethyl-2-(p-tolyl)acetamide (5k).30 General procedure A
was employed. Column chromatography (hexanes/EtOAc = 9:1 to
1:3) provided the title compound as a white solid in 72% yield (74
mg). Spectral data were in accordance with those published: mp 103−
N-Cyclopropyl-2-(isoquinolin-5-yl)acetamide (6f). General
procedure B was employed. Column chromatography (hexanes/
1
105 °C; H NMR (500 MHz, CDCl3) δ 7.17−7.12 (m, 4H), 3.67 (s,
H
dx.doi.org/10.1021/jo400488q | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
EtOAc = 9:1 to 1:4) provided the title compound as a light orange
solid in 62% yield (70 mg): mp 145−147 °C; H NMR (500 MHz,
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1
CDCl3) δ 9.26 (s, 1H), 8.57−8.56 (m, 1H), 7.94−7.92 (m, 1H), 7.78
(t, J = 4.5 Hz, 1H), 7.58−7.57 (m, 2H), 5.49 (br s, 1H), 3.94 (s, 2H),
2.63−2.61 (m, 1H), 0.68 (dd, J = 7.0, 1.4 Hz, 2H), 0.31 (td, J = 2.5,
1.1 Hz, 2H); 13C NMR (125.8 MHz, CDCl3) δ 171.7, 153.2, 143.7,
135.0, 132.2, 130.9, 129.1, 127.8, 127.2, 117.0, 40.7, 23.0, 6.6; IR
(neat) 3281, 1648, 1544 cm−1; HRMS (ESI) m/z calcd. For
C14H15N2O (M + H)+ 227.1184, found 227.1190.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Figures of H and 13C NMR spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: gmolandr@sas.upenn.edu.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
NIGMS (R01 GM035249) and NSF (GOALI) are acknowl-
edged for funding of this research. Generous donations are
acknowledged from Frontier Scientific for organotrifluorobo-
rates and Johnson Matthey for palladium. The National
Council for Scientific and Technological Development
(CNPq − Brazil) is acknowledged for funding the postdoctoral
fellowship of Thiago Barcellos. Dr. Simon Berritt and Steven
Wisniewski (University of Pennsylvania) are acknowledged for
their assistance with high throughput experimentation. Dr.
Rakesh Kohli (University of Pennsylvania) is acknowledged for
acquisition of HRMS spectra.
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Date, S. K; Chavan, S. P.; Sonawane, H. R. J. J. Org. Chem. 2002, 67,
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