A chemoselective Reformatsky-Negishi approach to α-haloaryl esters

Article abstract of DOI:10.1016/j.tet.2013.12.053

A practical synthesis of α-haloaryl esters has been achieved via a chemoselective Negishi coupling of poly-halogenated aromatics and Reformatsky reagents in the presence of catalytic Pd(dba)₂ and Xantphos. This chemistry tolerates a variety of aryl halides and was successfully applied to the synthesis of Ibuprofen. The α-haloaryl ester products, exemplified by ethyl 2-(4-bromo-2-chlorophenyl)acetate (3a), can be further functionalized via palladium or copper catalysis to afford an array of α-aryl esters.

Full text of DOI:10.1016/j.tet.2013.12.053

Tetrahedron 70 (2014) 1508e1515
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A chemoselective ReformatskyeNegishi approach to a-haloaryl
esters
Brian Wong a, Xin Linghu a, James J. Crawford b, Joy Drobnick b, Wendy Lee b,
,
Haiming Zhang a
*
a Small Molecule Process Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States
b Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A practical synthesis of a-haloaryl esters has been achieved via a chemoselective Negishi coupling of
Received 6 November 2013
Received in revised form 18 December 2013
Accepted 19 December 2013
Available online 31 December 2013
poly-halogenated aromatics and Reformatsky reagents in the presence of catalytic Pd(dba)2 and Xant-
phos. This chemistry tolerates a variety of aryl halides and was successfully applied to the synthesis of
Ibuprofen. The
a-haloaryl ester products, exemplified by ethyl 2-(4-bromo-2-chlorophenyl)acetate (3a),
can be further functionalized via palladium or copper catalysis to afford an array of
a
-aryl esters.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Palladium
Catalysis
Chemoselective
Reformatsky reagent
Negishi coupling
1. Introduction
namely, (1) BuchwaldeHartwig arylation of ester enolates (Scheme
1A);3 (2) cross-coupling of Reformatsky reagents with aryl halides
a-Aryl esters and their carboxylic acid derivatives are the core
(Scheme 1B);4 (3) coupling of
a-haloesters with arylmetallic species,
structure for numerous biologically active compounds, such as Nap-
roxen, Ibuprofen, Flurbiprofen, and Tolmetin, which are widely used
to treat inflammatory diseases and to relieve pain (Fig. 1).1 In the past
decade, various transition metal-catalyzed methods have been de-
veloped for the synthesis of
are four major catalytic strategies for the synthesis of
such as silanes,5 Grignard reagents,6 or boron compounds7 catalyzed
by nickel, iron or palladium (Scheme 1C); and (4) nickel-catalyzed
coupling of aryl halides and a
-haloesters (Scheme 1D).8 Although
each strategy has its own limitations, the combination of these four
methods provides a powerful tool to effectively assemble a variety of
highly functionalized a-aryl esters and their derivatives.
a
-aryl esters and their derivatives.2 There
-aryl esters,
a
Scheme 1. Catalytic strategies to a-aryl esters.
To support an internal drug research program, we were faced with
the need to develop a divergent synthesis of a wide spectrum of
functionalized
studies. Our decision was to focus on a chemoselective Reformat-
skyeNegishi reaction9 of poly-halogenated aromatics to generate
a-aryl esters for structureeactivity relationship (SAR)
Fig. 1. Biologically active a-aryl carboxylic acids.
a-
haloaryl esters, which can potentially be further functionalized via
palladium or copper catalysis (Scheme 2). Herein, we report a facile
* Corresponding author. Tel.: þ1 650 467 8758; fax: þ1 650 225 6238; e-mail
address: zhang.haiming@gene.com (H. Zhang).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.12.053

B. Wong et al. / Tetrahedron 70 (2014) 1508e1515
1509
Table 1
chemoselective synthesis of
catalyzed Negishi coupling of multi-halogen substituted aromatics
with Reformatsky reagents and preliminary results of further func-
a-haloaryl esters by a palladium-
Optimization of ReformatskyeNegishi couplinga
tionalization of a representative a-haloaryl ester product (Scheme 2).
b
Entry
L, mol %
2a (equiv)
Temp (ꢁC),
time (h)
3a:3a0
Conv’n (%)b
1
2
3
4
5
6
7
8
Qphos, 1
SPhos, 5
RuPhos, 5
JohnPhos, 5
DavePhos, 5
DPPF, 5
DPPM, 5
BINAP, 5
Xantphos, 5
Xantphos, 2.5
Xantphos, 2.5
Xantphos, 1
Xantphos, 2.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.2
1.2
1.2
23, 16
65, 16
65, 16
65, 16
65, 16
65, 16
65, 16
65, 16
65, 1.5
65, 1.5
65, 4
71:29
d
67
8
11
51
58
4
18
10
d
29:71
30:70
d
Scheme 2. Chemoselective ReformatskyeNegishi reaction.
d
d
2. Results and discussion
9
93:7
91:9
93:7
91:9
97:3
99(80)c
99(78)c
99(80)c
77
10
11
12
13
Hartwig reported that aryl bromides4a,c and chlorides4b un-
derwent cross-coupling with Reformatsky reagents in the presence
of Pd(dba)2 and Qphos,10 or {[P(tBu)3]PdBr}2,11 affording good to
65, 16
40, 16
53
excellent yields of the desired
a-aryl esters. However, only two
Bold emphasizes the optimized conditions.
a
dihalides, namely 1-bromo-4-chlorobenzene and 1-bromo-2-
fluorobenzene, among nearly 30 halogenated aromatics were ex-
amined. In addition, more than half of the reactions employed the
tert-butyl Reformatsky reagent. Other zinc reagents from non-tert-
butyl esters typically required low temperature (ꢀ78 to ꢀ20 ꢁC)
and glove box technique to generate, thus making the reaction less
practical, especially on scale. Our initial goal was to explore a cat-
alytic system that may promote chemoselective Negishi coupling of
multi-halogenated aromatics with the ethyl Reformatsky reagent.12
Reaction conditions: 1a (0.63 g, 2.0 mmol), 2a (0.40 M in THF, 1.2 or 1.5 equiv),
Pd(dba)2 (1e5 mol %), ligand (1e5 mol %), THF (6.0 mL).
b
Determined by HPLC analysis at 220 nm.
The numbers in parentheses are isolated yields of 3a.
c
Phosphine ligands
The resulting products,
a-haloaryl ethyl esters, could be further
functionalized on the aromatic ring.
Our investigation commenced with the Negishi coupling of 4-
bromo-2-chloro-1-iodobenzene (1a) with Reformatsky reagent
ethyl 2-bromozincacetate (2a) to form ethyl 2-(4-bromo-2-
chlorophenyl)acetate (3a). The coupling reaction of halide 1a
with 1.5 equiv of Reformatsky reagent 2a under Hartwig’s optimal
conditions,4a,c which employed 1 mol % Pd(dba)2 and 1 mol %
Qphos in THF at 23 ꢁC, was first examined (Table 1, entry 1). Un-
fortunately, the reaction was stalled at 67% conversion after 16 h
and generated a 71:29 ratio of the desired ester 3a and a major
diester by-product 3a0 arising from Negishi reactions at both the
iodo- and bromo- positions of halide 1a. The relatively low con-
version and formation of multiple impurities rendered the re-
action impractical. Realizing that the combination of Pd(dba)2 and
Qphos was too active to distinguish CeI and CeBr bonds, we
proceeded to screen various phosphine ligands in order to tune
the reactivity and selectivity with higher initial catalyst/ligand
loading (5 mol %) at an elevated temperature (65 ꢁC). A screen of
a subset of Buchwald ligands,13 i.e., SPhos, RuPhos, JohnPhos and
DavePhos, resulted in lower conversions (Table 1, entries 2e5), so
did that of bidentate ligands DPPF, DPPM and BINAP (Table 1,
entries 6e8). To our delight, when Xantphos14,15 was employed,
the reaction readily reached completion in 1.5 h with a 93:7 ratio
of 3a to 3a0 based on HPLC analysis, presumably because the
unique combination of steric and electronic effects of Xantphos
ligand facilitates both the oxidative addition and the trans-
metallation processes. The desired product 3a was subsequently
isolated in 80% yield (Table 1, entry 9). Further optimization in-
cluding catalyst loading and stoichiometry of the Reformatsky
reagent 2a (Table 1, entries 10e12), reaction temperature (Table 1,
entry 13) and solvent16 led to the optimized conditions employing
2.5 mol % Pd(dba)2, 2.5 mol % Xantphos, 1.2 equiv of 2a in THF at
65 ꢁC. Under this set of conditions, the reaction reached comple-
tion in 4 h with a 93:7 ratio of 3a to 3a0 and ethyl ester 3a was
isolated in 80% yield (Table 1, entry 11).
With optimal conditions available, we then set out to investigate
the scope and limitations of this chemoselective Reformat-
skyeNegishi coupling reaction (Table 2). A scaled-up reaction using
10.0 g of halide 1a (31.5 mmol) and reagent 2a produced the same
isolated yield of 80% as the smaller scale (2.0 mmol of 1a), which
attests the scalability of this chemistry (Table 2, entry 1). Moving to
other halide substrates, a para-dihalide 1-bromo-4-iodobenzene
(1b) readily afforded the desired ethyl ester in 81% in 1.5 h (Table
2, entry 2). When a substrate bearing an ortho-substituent to the
iodide, namely 4-bromo-1-iodo-2-methylbenzene (1c) was
employed, the coupling reaction not only required 1.5 equiv Refor-
matskyreagent2a toreach highconversion,but alsoproduced lower
isolated yield of 58%, presumably due to a steric effect caused by the
ortho-methyl group (Table 2, entry 3). Substituents at meta-position
to the iodide, whether electron donating (MeO) or electron with-
drawing (CF3, F, CO2Et), all readily generated good yields of the de-
sired ester products 3deg (Table 2, entries 4e7). Dihalides 1h and 1i
with a meta bromoeiodo substitution pattern proceeded smoothly,
affording 80% and 71% yields of ethyl esters 3h and 3i, respectively
(Table 2, entries 8e9). Finally, simple ortho-dihalide 1-bromo-2-
iodobenzene (1j) and heterocyclic dihalide 5-bromo-2-chloro-4-
methylpyridine (1k) also gave good yields of the desired products
3j and 3k in 61% and 71%, albeit requiring 1.5 equiv of the Refor-
matsky reagent 2a to reach high conversion (Table 2, entries 10e11).
Surprisingly, when
a-methyl substituted Reformatsky reagent2b
was subjected to the Negishi coupling reaction with halide 1a, low

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B. Wong et al. / Tetrahedron 70 (2014) 1508e1515
conversion and multiple by-products wereobserved (Scheme 3). We
reasoned that the increased steric hindrance brought by the
Table 2
a
-
Chemoselective ReformatskyeNegishi coupling of halides 1 with 2aa
methyl group in 2b and the 2-chloro group in halide 1a might
hamper the transmetallation process, thus resulting in an inferior
reaction. To confirm our hypothesis, halides 1l and 1b with smaller
substituents, such as fluorine and hydrogen atom at the 2-position
were reacted with 2b under our standard conditions. To our satis-
faction, both reactions afforded excellent yields of the desired esters
3m and 3n in 87% and 89%, respectively (Scheme 3). These results
clearly indicate that steric effect plays an influential role in this
coupling reaction.
Entry
1
Halide
Product
Time (h)
4
Yield (%)b
80(80)c
3a
1a
2
3
4
1.5
4
81
1b
1c
3b
3c
58d
68
Scheme 3. Negishi coupling using Reformatsky reagent 2b.
Ester 3n could be readily converted to Ibuprofen without puri-
fying any intermediate. In fact, ester 3n was subjected to a Negishi
coupling reaction with iBuZnBr in the presence of 2 mol % of
Pd(dba)2 and 2 mol % of Qphos, followed by TFA deprotection of t-
Bu group to afford Ibuprofen in 88% isolated yield (Scheme 4).
Overall, Ibuprofen was readily synthesized in three transformations
featuring two Negishi couplings in 78% yield from 1-bromo-4-
iodobenzene (1b).
5
3d
3e
3f
1d
1e
1f
5
0.5
72
57
77
80
71
6
4
Scheme 4. Synthesis of Ibuprofen from ester 3n.
7
3
Next, we focused on using 1-bromo-4-iodobenzene (1b) to ex-
amine the scope of the Reformatsky reagents. The tert-butyl
Reformatsky reagent 2c generated the desired ester 3o un-
eventfully in 73% yield in 1 h (Table 3, entry 1). However, when
3g
3h
1g
1h
8
1.5
Table 3
Negishi coupling of halide 1b with zinc reagents
9
4
1i
1j
3i
3j
Entry
1
Zinc reagent
Product
Time (h)
1
Yield (%)a
73b
10
5
3
61d
2c
3o
11
71d
2
3
3
4
<10b,c
1k
3k
2d
2e
3p
3q
a
Reaction conditions: 1a (2.0 mmol), Pd(dba)2 (2.5 mol %), Xantphos (2.5 mol %),
2a (0.40 M in THF, 6.0 mL, 1.2 equiv), THF (6.0 mL), 65 ꢁC.
b
Isolated yield.
<10b,d
c
Yield in parentheses is for reaction employing 10.0 g (31.5 mmol) of 1a.
1.5 equiv of 2a was employed.
d

B. Wong et al. / Tetrahedron 70 (2014) 1508e1515
1511
Table 3 (continued )
of the corresponding products (Scheme 5C and D); Buch-
waldeHartwigamination13,21 of 3awithmorpholine alsosuccessfully
afforded good yield (67%) of ethyl 2-(2-chloro-4-morpholinophenyl)
acetate while copper catalyzed sulfonylation22 of 3a with sodium
benzenesulfinate gave the desired sulfone compound in 51% yield
(Scheme 5E and F).
Entry
Zinc reagent
Product
Time (h)
16
Yield (%)a
71e
4
2f
3r
3. Conclusion
5
5
74e
In summary, we have developed an efficient protocol for the
2g
3s
synthesis of
a-haloaryl esters via a palladium-catalyzed chemo-
a
Isolated yield.
selective ReformatskyeNegishi coupling reaction. This coupling
chemistry is scalable as demonstrated at 10-gram scale and toler-
ates a variety of aryl halides, but is sensitive to steric hindrance
b
Reaction conditions: 1b (2.0 mmol), Pd(dba)2 (2.5 mol %), Xantphos (2.5 mol %),
2 (1.2 equiv), THF (12 mL), 65 ꢁC.
c
Stalled at 65% conversion in 3 h with multiple products observed.
Stalled at 25% conversion in 4 h with multiple products observed.
Reaction conditions: 1b (2.0 mmol), Pd(dba)2 (2.5 mol %), Xantphos (2.5 mol %),
d
introduced by both the ortho-position of the halides and the
position of the Reformatsky reagents. The reaction can also be ex-
tended to the synthesis of -haloaryl amides using zinc reagents
a-
e
amide precursor (1.2 equiv), NaHMDS (1.3 equiv), ZnCl2 (2.6 equiv), THF (16 mL),
PhMe (8 mL), 65 ꢁC.
a
generated from the corresponding acetamides. The synthetic utility
of this chemistry was demonstrated by a three-step synthesis of
Ibuprofen from readily available starting materials. The product a-
extra steric hindrance at the
a-position was introduced to the
haloaryl esters can be further functionalized at the remaining ha-
lide position as exemplified by a diverse set of metal-catalyzed
transformations using ethyl 2-(4-bromo-2-chlorophenyl)acetate
(3a).
Reformatsky reagent, for example, zinc reagent 2d with a 2,2-
dimethyl substituent, lower conversion and multiple products
were observed (Table 3, entry 2). To our disappointment, the cou-
pling reaction employing an electron-deficient Reformatsky re-
agent 2e did not afford significant amount of product 3q,
presumably because the lessened nucleophilicity of the zinc re-
agent prevents an efficient transmetallation process (Table 3, entry
3). Therefore, we summarized that this chemistry is sensitive to the
steric and electronic properties of the individual Reformatsky re-
agent under our conditions. Gratifyingly, although we were unable
to prepare the Reformatsky reagents of amides by direct zinc in-
4. Experimental section
4.1. General
Unless stated otherwise, reactions were performed under an
ambient atmosphere of nitrogen in 20 mL vials sealed by Teflon-
lined caps. All solvents and commercially obtained reagents were
used as received, unless specified otherwise. Zinc powder (median
6e9 micron, Alfa Aesar) was used for the preparation of Refor-
matsky reagents. Reformatsky reagent ethyl 2-bromozincacetate
(2a) was prepared according to previously reported procedure
and titrated to be 0.40 M.12a Pd(dba)2 and Xantphos were pur-
chased from Johnson Matthey and used directly. Microwave re-
actions were performed on a CEM Discover Explorer 48 reactor.
Thin-layer chromatography (TLC) was conducted with EMD silica
gel 60 F254 pre-coated plates and visualized using UV light
(254 nm). Flash column chromatography was performed with pre-
packed RediSep silica gel columns on a CombiFlash ISCO system
using gradient EtOAc in hexanes (or heptane) as eluent and
detected with both 220 and 254 nm wavelengths. Analytical HPLC
analyses were performed with an Agilent 1290 Infinity Series HPLC
instrument. 1H NMR spectra were recorded on a Bruker 300 (at
300 MHz) or a Bruker 400 (at 400 MHz) and are reported relative to
sertion, zinc reagents 2f and 2g obtained by treating the corre-
4a,c
sponding amides with NaHMDS and ZnCl2
selective Negishi coupling, producing the desired
underwent the
-haloaryl amides
a
3r and 3s in 71% and 74% yield, respectively (Table 3, entries 4e5).
To demonstrate the synthetic utility of this chemoselective
ReformatskyeNegishi coupling chemistry, we converted compound
3a to various functionalized
a-aryl esters. For example, Suzu-
kieMiyaura17 coupling of 3a with 3-trifluoromethylphenylboronic
acid or potassium cyclopropyltrifluoroborate18 generated good
yields of the coupling products in 68% and 86%, respectively (Scheme
5A and B); MizorokieHeck19 and Sonogashira20 coupling of 3a with
tert-butyl acrylate and phenylacetylene produced 92% and 68% yields
the residual solvent peak (d C
7.26 for CDCl3, 2.50 for DMSO-d6). 13
NMR spectra were recorded on a Bruker 300 (at 75 MHz) or
a Bruker 400 (at 101 MHz), and are reported relative to the residual
solvent peak (
d
77.0 for CDCl3, 39.5 for DMSO-d6). Melting points
€
are uncorrected and were recorded on a Buchi Melting Point B-540
apparatus. IR spectra were recorded on a Bruker Alpha Platinum-
ATR spectrometer and are reported in frequency of absorption
(cmꢀ1). HRMS data were obtained on an LTQ Orbitrap Discovery
(Thermo Fisher Scientific) at Genentech, Inc.
4.2. General procedure for the formation of Reformatsky
reagents
Scheme 5. Reagents and conditions: (A) 3a, 3-CF3C6H4B(OH)2 (1.2 equiv), Pd(PPh3)2Cl2
(12 mol %), Na2CO3 (3.0 equiv), MeCN/H2O,
m
w, 110 ꢁC, 0.5 h. (B) 3a, c-PrBF3K
(1.2 equiv), Pd(OAc)2 (10 mol %), nBuAd2P (15 mol %), Cs2CO3 (3.0 equiv), PhMe/H2O,
80 ꢁC, 16 h. (C) 3a, CH2]CHCO2 tBu (1.4 equiv), Pd(dtbpf)Cl2 (2 mol %), TBAC (10 mol %),
Cy2NMe (1.5 equiv), DMA, 80 ꢁC, 20 h. (D) 3a, PhC^CH (3.0 equiv), Pd(PPh3)4 (5 mol %),
CuBr$Me2S (10 mol %), Et3N, DMF, 90 ꢁC, 16 h. (E) 3a, morpholine (1.2 equiv), Pd(OAc)2
(10 mol %), Xantphos (10 mol %), Cs2CO3 (2.0 equiv), 1,4-dioxane, 110 ꢁC, 20 h. (F) 3a,
To a 125 mL 3-neck round-bottom flask equipped with a con-
denser, a 60 mL addition funnel and a needle thermocouple under
nitrogen was added zinc powder (2.45 g, 1.50 equiv), THF (15 mL)
and the mixture was vacuumed and backfilled with nitrogen (3ꢂ).
TMSCl (5 mol %, 0.16 mL) was added and the mixture was stirred for
PhSO2Na (2.0 equiv), Cu(OTf)2 (20 mol %), MeNHCH2CH2NHMe (50 mol %), DMSO,
mw,
130 ꢁC, 2 h.

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B. Wong et al. / Tetrahedron 70 (2014) 1508e1515
15 min. A slight exotherm (ca. 2e3 ꢁC) was observed. To the addi-
tion funnel was syringed in THF (35 mL) and 2-bromoester
(25.0 mmol) and the well-mixed solution was added to the
round-bottom flask in 1e2 min. Significant exotherm was usually
observed after the addition. The mixture was then slowly cooled to
room temperature and stirring was discontinued. A portion of the
mixture was transferred into a 10 mL syringe through a TargetÒ
film, cmꢀ1) 2979, 1734, 1473, 1159; 1H NMR (300 MHz, DMSO-d6)
d
7.72 (d, J¼1.8 Hz, 1H), 7.54 (dd, J¼8.2, 2.0 Hz, 1H), 7.38 (d, J¼8.2 Hz,
1H), 4.10 (q, J¼7.1 Hz, 2H), 3.80 (s, 2H), 1.18 (t, J¼7.1 Hz, 3H); 13C
NMR (75 MHz, DMSO-d6)
d 169.6, 134.9, 133.7, 132.3, 131.2, 130.2,
120.7, 60.5, 37.9, 14.0; HRMS (ESIþ) calcd for
C10H11BrClO2
([MþH]þ), 276.9625; found, 276.9615.
Nylon 0.45
mm filter (1.25-inch OD) and titrated using a solution of
4.3.2. Ethyl
2-(4-bromophenyl)acetate
(3b). 1-Bromo-4-
iodine (254 mg, 1.00 mmol) in 0.5 M THF solution of LiCl (3.0 mL) to
determine the concentration.23 The reagent was used right after the
titration.24
iodobenzene (1b, 566 mg, 2.00 mmol) was employed. Compound
3b was purified using EtOAc in hexanes (0e10%) and obtained as
a pale yellow oil (392 mg, 81%). FTIR (thin film, cmꢀ1) 2981, 1730,
1488, 1153; 1H NMR (300 MHz, DMSO-d6)
d
7.61e7.41 (m, 2H), 7.23
4.2.1. tert-Butyl 2-bromozincpropionate (2b). Zinc powder (2.45 g,
1.5 equiv) and tert-butyl 2-bromopropionate (25.0 mmol, 5.23 g,
4.15 mL) were employed. Exotherm was observed right after the
addition and the internal temperature rose to Tmax at 57 ꢁC without
external cooling. The concentration was determined to be 0.23 M.
(d, J¼8.4 Hz, 2H), 4.08 (q, J¼7.1 Hz, 2H), 3.66 (s, 2H), 1.18 (t, J¼7.1 Hz,
3H); 13C NMR (75 MHz, DMSO-d6)
d 170.7, 133.9, 131.6, 131.1, 120.0,
60.3, 14.0; HRMS (ESIþ) calcd for C10H12BrO2 ([MþH]þ), 243.0015;
found, 243.0009.
4.3.3. Ethyl 2-(4-bromo-2-methylphenyl)acetate (3c). 4-Bromo-1-
iodo-2-methylbenzene (1c, 594 mg, 2.00 mmol) and ethyl 2-
bromozincacetate (2a) in THF (0.40 M, 7.5 mL, 1.5 equiv) were
employed. Compound 3c was purified using EtOAc in hexanes
(0e10%) and obtained as a colorless oil (299 mg, 58%). FTIR (thin
film, cmꢀ1) 2980, 1730, 1484, 1152; 1H NMR (300 MHz, DMSO-d6)
4.2.2. tert-Butyl 2-bromozincacetate (2c). Zinc powder (2.45 g,
1.5 equiv) and tert-butyl 2-bromoacetate (25.0 mmol, 4.88 g,
3.69 mL) were employed. Exotherm was not observed after the
addition. The mixture was warmed up with a warm water bath (ca.
45 ꢁC). When the internal temperature reached ca. 35 ꢁC, the re-
action was initiated and significant exotherm was observed with
Tmax reaching refluxing 65 ꢁC without external cooling. The con-
centration was determined to be 0.22 M.
d
7.41 (d, J¼1.8 Hz, 1H), 7.33 (dd, J¼8.1, 2.0 Hz, 1H), 7.14 (d, J¼8.1 Hz,
1H), 4.08 (q, J¼7.1 Hz, 2H), 3.66 (s, 2H), 2.21 (s, 3H), 1.17 (t, J¼7.1 Hz,
3H); 13C NMR (75 MHz, DMSO-d6)
170.5, 139.6, 132.8, 132.30,
d
132.25, 128.6, 119.9, 60.3, 37.8, 18.7, 14.0; HRMS (ESIþ) calcd for
4.2.3. Methyl 2-bromozinc-2-methylpropionate (2d). Zinc powder
(2.45 g, 1.5 equiv) and methyl 2-bromo-2-methylpropionate
(25.0 mmol, 4.53 g, 3.24 mL) were employed. Exotherm was ob-
served after the addition with Tmax reaching 57 ꢁC without external
cooling. The concentration was determined to be 0.16 M.
C
11H14BrO2 ([MþH]þ), 257.0172; found, 257.0163.
4.3.4. Ethyl 2-(4-bromo-3-methoxyphenyl)acetate (3d). 4-Bromo-3-
methoxy-1-iodobenzene (1d, 616 mg, 2.00 mmol) was employed.
Compound 3d was purified using EtOAc in hexanes (0e10%) and
obtained as a yellow oil (370 mg, 68%). FTIR (thin film, cmꢀ1) 2980,
4.2.4. Ethyl 2-bromozinc-2,2-difluoroacetate (2e). Zinc powder
(2.45 g, 1.5 equiv) and ethyl 2-bromo-2,2-difluoroacetate
(25.0 mmol, 5.07 g) were employed. Exotherm was observed after
the addition with Tmax reaching refluxing 65 ꢁC without external
cooling. The concentration was determined to be 0.16 M.25
1730, 1486, 1154; 1H NMR (300 MHz, DMSO-d6)
d
7.49 (d, J¼8.0 Hz,
1H), 7.03 (d, J¼1.7 Hz, 1H), 6.79 (dd, J¼8.1, 1.8 Hz, 1H), 4.08 (q,
J¼7.1 Hz, 2H), 3.83 (s, 3H), 3.66 (s, 2H), 1.19 (t, J¼7.1 Hz, 3H); 13C
NMR (75 MHz, DMSO-d6)
d 170.7, 155.1, 135.6, 132.5, 122.9, 113.9,
108.9, 60.3, 56.1, 39.9, 14.0; HRMS (ESIþ) calcd for C11H14BrO3
([MþH]þ), 273.0121; found, 273.0111.
4.3. General procedure for the ReformatskyeNegishi coupling
employing ethyl 2-bromozincacetate (2a)
4.3.5. Ethyl 2-(4-bromo-3-trifluoromethylphenyl)acetate (3e). 4-
Bromo-3-trifluoromethyl-1-iodobenzene (1e, 702 mg, 2.00 mmol)
was employed. Compound 3e was purified using EtOAc in hexanes
(0e10%) and obtained as a yellow oil (450 mg, 72%). FTIR (thin film,
To a 20 mL vial with a stir bar was added aryl halide 1
(2.00 mmol), Pd(dba)2 (28.8 mg, 2.5 mol %), Xantphos (28.9 mg,
2.5 mol %). The vial was sealed with a Teflon-lined cap and THF
(6.0 mL) was added. The mixture was vacuumed and backfilled
with nitrogen (3ꢂ). A solution of ethyl 2-bromozincacetate (2a) in
THF (0.40 M, 6.0 mL, 1.2 equiv) filtered through a TargetÒ Nylon
cmꢀ1) 2985, 1732, 1317, 1126; 1H NMR (300 MHz, DMSO-d6)
d 7.84
(d, J¼8.2 Hz, 1H), 7.78 (d, J¼1.9 Hz, 1H), 7.50 (dd, J¼8.2, 1.8 Hz, 1H),
4.09 (q, J¼7.1 Hz, 2H), 3.81 (s, 2H), 1.19 (t, J¼7.1 Hz, 3H); 13C NMR
(75 MHz, DMSO-d6)
d
170.4, 135.4, 135.1, 134.8, 129.1 (q, J¼5.3 Hz),
0.45
m
m filter (1.25-inch OD) was syringed in and the reaction
128.1 (q, J¼30.8 Hz), 122.9 (q, J¼271.5 Hz), 117.2 (q, J¼2.3 Hz), 67.0,
60.5, 38.9, 25.1, 14.0; HRMS (ESIþ) calcd for C11H9BrF3O2 ([MꢀH]ꢀ),
308.9744; found, 308.9745.
mixture was then heated to 65 ꢁC and monitored by HPLC. Upon
reaction completion based on HPLC analysis (ꢃ95% conversion
unless the reaction was stalled), the mixture was cooled to room
temperature and quenched with 1 M aq HCl (5.0 mL), followed by
addition of brine (5.0 mL). The organic layer was separated and
concentrated in vacuum. The residue was purified by silica gel
column chromatography using gradient EtOAc in hexanes.
4.3.6. Ethyl 2-(4-bromo-3-fluorophenyl)acetate (3f). 4-Bromo-3-
fluoro-1-iodobenzene (1f, 602 mg, 2.00 mmol) was employed.
Compound 3f was purified using EtOAc in hexanes (0e10%) and
obtained as a pale yellow oil (298 mg, 57%). FTIR (thin film, cmꢀ1
)
2983, 1731, 1486, 1150; 1H NMR (300 MHz, DMSO-d6)
d 7.65 (t,
4.3.1. Ethyl 2-(4-bromo-2-chlorophenyl)acetate (3a). 4-Bromo-2-
chloro-1-iodobenzene (1a, 635 mg, 2.00 mmol) was employed.
Compound 3a was purified using EtOAc in hexanes (0e5%) and
obtained as a pale yellow oil (444 mg, 80%). The 10-gram scale-up
reaction was performed in a 250 mL 3-neck round-bottom flask
using 4-bromo-2-chloro-1-iodobenzene (1a, 10.0 g, 31.5 mmol),
Pd(dba)2 (0.453 g, 2.5 mol %), Xantphos (0.456 g, 2.5 mol %) and
ethyl 2-bromozincacetate (2a) in THF (0.40 M, 96 mL, 1.2 equiv).
Compound 3a was isolated as a yellow oil (7.03 g, 80%). FTIR (thin
J¼7.9 Hz, 1H), 7.32 (dd, J¼10.0, 1.8 Hz, 1H), 7.09 (dd, J¼8.2, 1.8 Hz,
1H), 4.09 (q, J¼7.1 Hz, 2H), 3.72 (s, 2H), 1.19 (t, J¼7.1 Hz, 3H); 13C
NMR (75 MHz, DMSO-d6)
d
170.4, 157.9 (d, J¼243 Hz), 136.8 (d,
J¼7.4 Hz), 133.1, 127.3 (d, J¼3.3 Hz), 117.8 (d, J¼22.5 Hz), 106.2 (d,
J¼20.3 Hz), 60.4, 39.2 (d, J¼1.5 Hz), 14.0; HRMS (ESIþ) calcd for
C
10H11BrFO2 ([MþH]þ), 260.9921; found, 260.9912.
4.3.7. Ethyl 2-bromo-5-(2-ethoxy-2-oxoethyl)benzoate (3g). Ethyl
2-bromo-5-iodobenzoate (1g, 710 mg, 2.00 mmol) was employed.

B. Wong et al. / Tetrahedron 70 (2014) 1508e1515
1513
Compound 3g was purified using EtOAc in hexanes (0e10%) and
obtained as a yellow oil (485 mg, 77%). FTIR (thin film, cmꢀ1) 2982,
160.2 (d, J¼249 Hz), 129.7 (d, J¼5.3 Hz), 127.7 (d, J¼7.5 Hz), 127.4 (d,
J¼3.8 Hz), 120.6 (d, J¼9.8 Hz), 119.0 (d, J¼25.5 Hz), 81.0, 39.1, 28.0,
17.3; HRMS (ESIþ) calcd for C13H15BrFO2 ([MꢀH]ꢀ), 301.0245;
found, 301.0246.
1726,1250,1027; 1H NMR (300 MHz, DMSO-d6)
d 7.74e7.62 (m, 2H),
7.38 (dd, J¼8.2, 2.3 Hz, 1H), 4.33 (q, J¼7.1 Hz, 2H), 4.09 (q, J¼7.1 Hz,
2H), 3.75 (s, 2H),1.32 (t, J¼7.1 Hz, 3H),1.19 (t, J¼7.1 Hz, 3H); 13C NMR
(75 MHz, DMSO-d6)
d
170.5, 165.6, 134.5, 134.0, 133.7, 132.5, 131.6,
4.3.13. tert-Butyl 2-(4-bromophenyl)propionate (3n). 4-Bromo-1-
iodobenzene (1b, 566 mg, 2.00 mmol), THF (1.5 mL) and tert-bu-
tyl 2-bromozincpropionate (2b) in THF (0.23 M, 10.5 mL, 1.2 equiv)
were employed. Compound 3n was purified using EtOAc in hexanes
(0e8%) and obtained as a pale yellow oil (505 mg, 89%). FTIR (thin
118.3, 61.4, 60.4, 39.0, 13.99, 13.96; HRMS (ESIþ) calcd for
C
13H16BrO4 ([MþH]þ), 315.0226; found, 315.0222.
4.3.8. Ethyl 2-(3-bromo-4-methylphenyl)acetate (3h). 2-Bromo-4-
iodotoluene (1h, 594 mg, 2.00 mmol) was employed. Compound
3h was purified using EtOAc in hexanes (0e10%) and obtained as
a pale yellow oil (409 mg, 80%). FTIR (thin film, cmꢀ1) 2981, 1731,
film, cmꢀ1) 2977, 1725, 1367, 1144; 1H NMR (300 MHz, CDCl3)
d 7.44
(d, J¼9.0 Hz, 2H), 7.17 (d, J¼9.0 Hz, 2H), 3.57 (q, J¼6.0 Hz, 1H), 1.43
(d, J¼6.0 Hz, 3H), 1.39 (s, 9H); 13C NMR (75 MHz, CDCl3)
d 173.3,
1149, 1030; 1H NMR (300 MHz, DMSO-d6)
d
7.53e7.45 (m, 1H), 7.29
140.1,131.5,129.2,120.7, 80.8, 46.0, 27.9,18.4; HRMS (ESIþ) calcd for
(d, J¼7.8 Hz, 1H), 7.17 (dd, J¼7.8, 1.4 Hz, 1H), 4.08 (q, J¼7.1 Hz, 2H),
C
13H16BrO2 ([MꢀH]ꢀ), 283.0339; found, 283.0341.
3.65 (s, 2H), 2.32 (s, 3H), 1.18 (t, J¼7.1 Hz, 3H); 13C NMR (75 MHz,
DMSO-d6)
d
170.8, 135.6, 134.2, 132.8, 130.8, 128.7, 123.8, 60.3, 39.1,
4.3.14. tert-Butyl
2-(4-bromophenyl)acetate
(3o). 4-Bromo-1-
21.9, 14.0; HRMS (ESIþ) calcd for C11H14BrO2 ([MþH]þ), 257.0172;
iodobenzene (1b, 566 mg, 2.00 mmol), THF (1.1 mL) and tert-bu-
tyl 2-bromozincacetate (2c) in THF (0.22 M,10.9 mL,1.2 equiv) were
employed. Compound 3o was purified using EtOAc in hexanes
(0e8%) and obtained as a yellow oil (393 mg, 73%). FTIR (thin film,
found, 257.0172.
4.3.9. Ethyl 2-(3-bromo-4-fluorophenyl)acetate (3i). 2-Bromo-1-
fluoro-4-iodobenzene (1i, 602 mg, 2.00 mmol) was employed.
Compound 3i was purified using EtOAc in hexanes (0e10%) and
cmꢀ1) 2978, 1729, 1488, 1136; 1H NMR (300 MHz, CDCl3)
d 7.44 (d,
J¼9.0 Hz, 2H), 7.15 (d, J¼9.0 Hz, 2H), 3.47 (s, 2H), 1.43 (s, 9H); 13C
obtained as a pale yellow oil (370 mg, 71%). FTIR (thin film, cmꢀ1
)
NMR (75 MHz, CDCl3) d 170.3, 133.7, 131.5, 130.9, 120.9, 81.1, 42.0,
2983, 1730, 1494, 1244; 1H NMR (300 MHz, DMSO-d6)
d
7.64 (d,
28.0; HRMS (ESIþ) calcd for C12H14BrO2 ([MꢀH]ꢀ), 269.0183;
J¼7.0 Hz, 1H), 7.36e7.29 (m, 2H), 4.10 (q, J¼7.1 Hz, 2H), 3.71 (s, 2H),
found, 269.0185.
1.19 (t, J¼7.1 Hz, 3H); 13C NMR (75 MHz, DMSO-d6)
d 170.7 (d,
J¼1.2 Hz), 158.7 (d, J¼17.3 Hz), 134.2, 132.6 (d, J¼3.7 Hz), 130.8 (d,
J¼7.4 Hz), 116.4 (d, J¼21.8 Hz), 107.5 (d, J¼21.0 Hz), 60.4, 38.6, 14.0;
HRMS (ESIþ) calcd for C10H11BrFO2 ([MþH]þ), 260.9921; found,
260.9922.
4.3.15. 2-(4-Bromophenyl)-N,N-dimethylacetamide (3r). In a glove
box, to a 50 mL round bottom flask with a stir bar was added NaHMDS
(487 mg, 2.60 mmol), and toluene (8.0 mL). To a 20 mL vial with a stir
bar was added anhydrous ZnCl2 (709 mg, 2.6 equiv), THF (6.0 mL) and
themixturewasagitated untilZnCl2 dissolved. The flask and vial were
sealed and removed from the glove box. The mixture in round bottom
flask was cooled in an ice-water bath to 0e5 ꢁC. Dimethylacetamide
(209 mg, 2.40 mmol) was added. The mixture was stirred for 30 min,
followed by the addition of ZnCl2 in THF solution. The mixture was
cooled to 0e5 ꢁC and stirred for 30 min. To a 20 mL vial with a stir bar
was added 1-bromo-4-iodo-benzene (1b, 556 mg, 2.00 mmol),
Pd(dba)2 (28.5 mg, 2.5 mol %), Xantphos (28.9 mg, 2.5 mol %), and
toluene (10.0 mL). The mixture was agitated until all solids dissolved,
vacuumed and backfilled with nitrogen (3ꢂ), and added to the 50 mL
round bottom flask via syringe. The reaction mixture was then heated
to 65 ꢁC and monitored by HPLC. Upon reaction completion based on
HPLC analysis, the mixture was cooled to room temperature and
neutralized with 1 M aq HCl (2.5 mL) and brine (5.0 mL). The organic
layer was separated and concentrated in vacuum. The residue was
purified by silica gel column chromatography using EtOAc in hexanes
(0e95%) to afford compound 3r as a yellow amorphous solid (345 mg,
71%). FTIR (thin film, cmꢀ1) 2927, 1637, 1487, 1403; 1H NMR (300 MHz,
4.3.10. Ethyl
2-(2-bromophenyl)acetate
(3j). 2-Bromo-1-
iodobenzene (1j, 566 mg, 2.00 mmol) and ethyl 2-
bromozincacetate (2a) in THF (0.40 M, 7.5 mL, 1.5 equiv) were
employed. Compound 3j was purified using EtOAc in hexanes
(0e10%) and obtained as a pale yellow oil (295 mg, 61%). FTIR (thin
film, cmꢀ1) 2981, 1731, 1156, 1025; 1H NMR (300 MHz, DMSO-d6)
d
7.61 (dd, J¼7.9, 1.1 Hz, 1H), 7.45e7.30 (m, 2H), 7.23 (dt, J¼1.9,
7.6 Hz, 1H), 4.10 (q, J¼7.1 Hz, 2H), 3.81 (s, 2H), 1.19 (t, J¼7.1 Hz, 3H);
13C NMR (75 MHz, DMSO-d6)
d 169.9,134.5,132.3,132.2,129.1,127.7,
124.5, 60.4, 40.9, 14.0; HRMS (ESIþ) calcd for C10H12BrO2 ([MþH]þ),
243.0015; found, 243.0012.
4.3.11. Ethyl
2-(6-chloro-4-methylpyridin-3-yl)acetate
(3k). 5-
Bromo-2-chloro-4-methylpyridine (1k, 413 mg, 2.00 mmol) and
ethyl 2-bromozincacetate (2a) in THF (0.40 M, 7.5 mL, 1.5 equiv)
were employed. The reaction mixture was quenched with 1 M
K2HPO4/KH2PO4 aq buffer solution (pH¼7, 3.0 mL) and filtered. The
mixture was added brine (5.0 mL) and the organic layer was sep-
arated and concentrated. Compound 3k was purified using EtOAc in
hexanes (0e25%) and obtained as a yellow oil (305 mg, 71%). FTIR
(thin film, cmꢀ1) 2982, 1729, 1589, 1158; 1H NMR (300 MHz, CDCl3)
DMSO-d6)
d
7.48 (d, J¼8.3 Hz, 2H), 7.17 (d, J¼8.3 Hz, 2H), 3.67 (s, 2H),
3.00 (s, 3H), 2.82 (s, 3H); 13C NMR (75 MHz, DMSO-d6)
d
169.7, 135.5,
131.5,130.9,119.4, 38.8, 37.0, 35.0; HRMS (ESIþ) calcd for C10H13BrNO
([MþH]þ), 242.0175; found, 242.0172.
d
8.16 (s, 1H), 7.17 (s, 1H), 4.16 (q, J¼9.0 Hz, 2H), 3.61 (s, 2H), 2.31 (s,
3H), 1.25 (t, J¼9.0 Hz, 3H); 13C NMR (75 MHz, CDCl3)
d
170.1, 150.5,
4.3.16. 2-(4-Bromophenyl)-1-(pyrrolidin-1-yl)ethanone
(3s).
150.3,149.6,128.2,125.3, 61.3, 35.8,19.1,14.1; HRMS (ESIþ) calcd for
Compound 3s was prepared in a same fashion as 3r but using 1-
acetylpyrrolidine (272 mg, 2.40 mmol) as a yellow solid (396 mg,
74%). Mp 114.8e116.7 ꢁC; FTIR (thin film, cmꢀ1) 2969, 2877, 1630,
C
10H13ClNO2 ([MþH]þ), 214.0629; found, 214.0625.
4.3.12. tert-Butyl 2-(4-bromo-2-fluorophenyl)propionate (3m). 4-
Bromo-2-fluoro-1-iodobenzene (1l, 602 mg, 2.00 mmol), THF
(1.5 mL) and tert-butyl 2-bromozincpropionate (2b) in THF (0.23 M,
10.5 mL, 1.2 equiv) were employed. Compound 3m was purified
using EtOAc in hexanes (0e8%) and obtained as a pale yellow oil
(527 mg, 87%). FTIR (thin film, cmꢀ1) 2979, 1727, 1486, 1147; 1H
1586; 1H NMR (300 MHz, DMSO-d6)
d
7.48 (d, J¼8.3 Hz, 2H), 7.19 (d,
J¼8.3 Hz, 2H), 3.60 (s, 2H), 3.45 (t, J¼6.7 Hz, 2H), 3.28 (t, J¼6.8 Hz,
2H), 1.86 (d, J¼6.4 Hz, 2H), 1.81e1.70 (m, 2H); 13C NMR (75 MHz,
DMSO-d6)
d 168.0, 135.3, 131.6, 130.9, 119.4, 46.2, 45.5, 40.1, 25.6,
23.9; HRMS (ESIþ) calcd for C12H15BrNO ([MþH]þ), 268.0332;
found, 268.0326.
NMR (300 MHz, CDCl3)
d
7.27e7.14 (m, 3H), 3.86 (q, J¼9.0 Hz, 1H),
Ibuprofen. To
a 5 mL vial was charged tert-butyl 2-(4-
1.43 (d, J¼9.0 Hz, 3H), 1.40 (s, 9H); 13C NMR (75 MHz, CDCl3)
d 172.6,
bromophenyl)propionate (3n, 180 mg, 0.631 mmol), Pd(dba)2

1514
B. Wong et al. / Tetrahedron 70 (2014) 1508e1515
(7.4 mg, 2 mol %) and Qphos (10.4 mg, 2 mol %) followed by iBuZnBr
in THF (0.50 M, 2.0 mL, 1.4 equiv). The mixture was vacuumed and
backfilled with nitrogen (3ꢂ) and then heated to 55 ꢁC for 30 min.
HPLC analysis showed >98% conversion. The mixture was cooled,
diluted with EtOAc and quenched with 10 wt % aq NaH2PO4 with
stirring. The mixture was filtered to remove solids and phases were
separated. The organic layer was washed with water and brine,
dried over Na2SO4 and filtered. The solution was concentrated and
re-dissolved in DCM (2.0 mL). The mixture was charged TFA
(0.14 mL, 3.0 equiv) and stirred at room temperature for 40 h. HPLC
analysis showed ca. 85% conversion. The mixture was charged with
TFA (0.10 mL, 2.0 equiv) and stirred at room temperature for 5 h.
HPLC analysis showed 100% conversion. The reaction was cooled to
134.4, 131.4, 131.1, 129.3, 126.7, 124.4, 60.9, 38.8, 14.9, 14.2, 9.3;
HRMS (ESIþ) calcd for C13H16ClO2 ([MþH]þ), 239.0839; found,
239.0827.
4.3.19. (E)-tert-Butyl
3-(3-chloro-4-(2-ethoxy-2-oxoethyl)phenyl)
acrylate (4c). To a 5 mL vial was added ethyl 2-(4-bromo-2-
chlorophenyl)acetate (3a, 110 mg, 0.396 mmol), TBAC (11.0 mg,
10 mol %), 1,10-bis(di-tert-butylphosphino)ferrocene palladium
dichloride (5.2 mg, 2 mol %), DMA (1.5 mL), Cy2NMe (0.127 mL,
1.5 equiv) and tert-butyl acrylate (71.1 mg, 0.082 mL, 1.4 equiv) and
the mixture was degassed with nitrogen for 5 min. The reaction
was then heated to 80 ꢁC for 19 h. The cooled reaction mixture
was filtered through Celite and the cake was washed with EtOAc
(40 mL). The mixture was washed with water and brine, dried over
Na2SO4, filtered, and concentrated. The crude material was puri-
fied by chromatography on silica eluted with 0e50% EtOAc in
heptane. Compound 4c was obtained as a colorless oil (119 mg,
92%). FTIR (thin film, cmꢀ1) 2979, 1735, 1704, 1638, 1144; 1H NMR
0
ꢁC and quenched with 1 M aq NaOH and diluted with DCM
(5.0 mL). Phases were separated and the aqueous layer was washed
with EtOAc (5.0 mL). The aqueous layer was then adjusted its pH
with concd HCl to pH 1e2 and extracted with EtOAc (5.0 mL, 2ꢂ).
The combined organic layers were washed with water and con-
centrated under vacuum to give Ibuprofen as a thick yellow oil
(115 mg, 88%). FTIR (thin film, cmꢀ1) 2954, 2925, 1702, 1229; 1H
(400 MHz, CDCl3)
d
7.53 (d, J¼1.8 Hz, 1H), 7.49 (d, J¼16.0 Hz, 1H),
7.36 (dd, J¼8.0, 1.8 Hz, 1H), 7.29 (d, J¼8.0 Hz, 1H), 6.35 (d,
NMR (300 MHz, CDCl3)
d
10.80 (br s, 1H), 7.27 (d, J¼8.1 Hz, 2H), 7.15
J¼16.0 Hz, 1H), 4.18 (q, J¼7.1 Hz, 2H), 3.77 (s, 2H), 1.53 (s, 9H), 1.26
(d, J¼8.1 Hz, 2H), 3.75 (q, J¼7.2 Hz, 1H), 2.49 (d, J¼7.2 Hz, 2H), 1.88
(t, J¼7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3)
d 170.2, 165.8, 141.5,
(m, 1H), 1.54 (d, J¼3.6 Hz, 3H), 0.94 (d, J¼7.2 Hz, 6H); 13C NMR
135.5, 135.1, 134.1, 131.8, 128.6, 126.3, 121.6, 80.8, 61.1, 39.1, 28.2,
14.1; HRMS (ESIþ) calcd for C17H21O4ClNa ([MþNa]þ), 347.1026;
found, 347.1021.
(75 MHz, CDCl3)
d 181.2, 140.9, 137.0, 129.4, 127.3, 45.1, 45.0, 30.2,
22.4, 18.1; HRMS (ESIþ) calcd for C13H17O2 ([MꢀH]ꢀ), 205.1234;
found, 205.1235. Data were in accordance with those previously
reported in the literature.26
4.3.20. Ethyl 2-(2-chloro-4-(phenylethynyl)phenyl)acetate (4d). To
a 5 mL vial was added ethyl 2-(4-bromo-2-chlorophenyl)acetate (3a,
122 mg, 0.440 mmol), Pd(PPh3)4 (25.4 mg, 5 mol %), CuBr$Me2S
(9.04 mg, 10 mol %), Et3N (1.0 mL), and DMF (2.2 mL). The reaction
mixture was degassed with nitrogen for 20 min, and phenylacetylene
(0.14 mL, 1.30 mmol, 3.0 equiv) was added. The reaction mixture was
stirred at 90 ꢁC for 16 h and quenched with 5% aq ammonia in satd
NH4Cl solution, and then diluted with EtOAc (10 mL). The organic
layer was washed with water and brine, dried over Na2SO4, filtered,
and concentrated. The residue was purified by flash column chro-
matography eluted with EtOAc/heptane to afford compound 4dꢀa1s
4.3.17. Ethyl
2-(3-chloro-30-(trifluoromethyl)-[1,10-biphenyl]-4-yl)
acetate (4a). In a 5 mL microwave vial was added ethyl 2-(4-
bromo-2-chlorophenyl)acetate (3a, 100 mg, 0.36 mmol), 3-(tri-
fluoromethyl)phenylboronic acid (84 mg, 1.2 equiv), PdCl2(PPh3)2
(30 mg, 12 mol %), MeCN (1.1 mL) and 1 M aq Na2CO3 solution
(1.1 mL). The reaction mixture was microwaved at 110 ꢁC for
30 min. The mixture was cooled and layers were separated. The aq
layer was extracted with DCM (2ꢂ). The combined organic layers
were dried over Na2SO4, filtered, and concentrated. The residue
was purified by flash column chromatography eluted with EtOAc
in heptane to afford compound 4a as a yellow oil (84 mg, 68%).
FTIR (thin film, cmꢀ1) 2984, 1735, 1332, 1120; 1H NMR (400 MHz,
a yellow solid (89.8 mg, 68%). Mp 57.2e59.0 ꢁC; FTIR (thin film, cm
)
3063, 2988,1736,1330; 1H NMR (400 MHz, CDCl3)
d
7.57 (d, J¼1.7 Hz,
1H), 7.52 (ddt, J¼6.0, 5.2, 3.2 Hz, 2H), 7.41e7.33 (m, 4H), 7.27 (d,
J¼7.5 Hz,1H), 4.19 (q, J¼7.2 Hz, 2H), 3.77 (s, 2H),1.27 (t, J¼7.1 Hz, 3H);
CDCl3)
d 7.80e7.76 (m, 1H), 7.73e7.68 (m, 1H), 7.64e7.59 (m, 2H),
7.57e7.50 (m, 1H), 7.44 (dd, J¼7.9, 1.9 Hz, 1H), 7.38 (d, J¼8.1 Hz,
13C NMR (101 MHz, CDCl3)
d 170.3, 134.5, 132.7, 132.2, 131.7, 131.3,
1H), 4.20 (q, J¼7.1 Hz, 2H), 3.81 (s, 2H), 1.30e1.25 (t, J¼7.1 Hz, 3H);
130.0, 128.6, 128.4, 123.9, 122.7, 90.6, 87.7, 61.2, 39.2, 14.2; HRMS
13C NMR (101 MHz, CDCl3)
d
170.4, 140.4, 140.2, 135.2, 132.3, 132.0,
(ESIþ) calcd for C18H16O2Cl ([MþH]þ), 299.0839; found, 299.0818.
131.3 (q, J¼32 Hz), 130.3, 129.4, 128.1, 125.6, 124.5 (q, J¼3.8 Hz),
124.1 (q, J¼272 Hz), 123.8 (q, J¼3.8 Hz), 61.1, 38.9, 14.2; HRMS
4.3.21. Ethyl
2-(2-chloro-4-morpholinophenyl)acetate
(4e). To
(ESIþ) calcd for
C
17H15ClF3O2 ([MþH]þ), 343.0713; found,
a 5 mL vial was added ethyl 2-(4-bromo-2-chlorophenyl)acetate (3a,
112 mg, 0.404 mmol), morpholine (42.2 mg, 0.042 mL, 1.2 equiv),
Pd(OAc)2 (9.1 mg, 10 mol %), Xantphos (23.4 mg, 10 mol %), Cs2CO3
(263 mg, 2.0 equiv) and 1,4-dioxane (2.0 mL). The mixture was
degassed with nitrogen for 5 min and heated at 110 ꢁC for 19 h. The
cooled reaction mixture was filtered through Celite and the cake was
washed with EtOAc (40 mL). The mixture was washed with satd aq
NH4Cl and brine, dried over Na2SO4, filtered, and concentrated. The
crude material was purified by chromatography on silica eluted with
0e100% EtOAc in heptane. Compound 4e was obtained as a yellow
solid (77 mg, 67%). Mp 61.8e63.1 ꢁC; FTIR (thin film, cmꢀ1) 2971,
343.0699.
4.3.18. Ethyl
2-(2-chloro-4-cyclopropylphenyl)acetate
(4b). To
a 5 mL vial was added ethyl 2-(4-bromo-2-chlorophenyl)acetate
(3a, 100 mg, 0.36 mmol), potassium cyclopropyltrifluoroborate
(66 mg, 1.2 equiv), Pd(OAc)2 (8.1 mg, 10 mol %), butyl di-1-
adamantylphosphine (20 mg, 15 mol %), Cs2CO3 (352 mg,
3.0 equiv), water (0.24 mL) and toluene (2.2 mL). The mixture was
purged with nitrogen for 1 min and heated at 80 ꢁC for 19 h. The
reaction mixture was cooled, diluted with water and DCM and the
layers were separated. The aqueous layer was extracted with DCM
(2ꢂ). The combined organic layers were dried over Na2SO4, fil-
tered, and concentrated. The residue was purified by flash column
chromatography to afford compound 4b as a yellow oil (73 mg,
86%). FTIR (thin film, cmꢀ1) 3083, 2982, 1734, 1158; 1H NMR
2841, 1723, 1505, 1172; 1H NMR (400 MHz, CDCl3)
d
7.16 (d, J¼8.5 Hz,
1H), 6.90 (d, J¼2.6 Hz, 1H), 6.76 (dd, J¼8.5, 2.6 Hz, 1H), 4.17 (q,
J¼7.1 Hz, 2H), 3.89e3.78 (m, 4H), 3.67 (s, 2H), 3.17e3.09 (m, 4H),1.25
(t, J¼7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3)
d 171.1,151.4,135.2,131.7,
123.3, 116.1, 114.1, 66.7, 60.9, 48.9, 38.3, 14.2; HRMS (ESIþ) calcd for
(400 MHz, CDCl3)
d
7.14 (d, J¼7.9 Hz, 1H), 7.07 (d, J¼1.9 Hz, 1H),
C
14H19ClNO3 ([MþH]þ), 284.1053; found, 284.1049.
6.92 (dd, J¼7.9, 1.9 Hz, 1H), 4.16 (q, J¼7.1 Hz, 2H), 3.70 (s, 2H), 1.84
(dt, J¼8.4, 5.1 Hz, 1H), 1.29e1.21 (t, J¼7.1 Hz, 3H), 1.00e0.91 (m,
4.3.22. Ethyl 2-(2-chloro-4-(phenylsulfonyl)phenyl)acetate (4f). To
a 5 mL microwave vial was added ethyl 2-(4-bromo-2-
2H), 0.72e0.63 (m, 2H); 13C NMR (101 MHz, CDCl3)
d
170.8, 145.1,

B. Wong et al. / Tetrahedron 70 (2014) 1508e1515
1515
Hama, T.; Ge, S.; Hartwig, J. F. J. Org. Chem. 2013, 78, 8250e8266; (d) Duez, S.;
Bernhardt, S.; Heppekausen, J.; Fleming, F. F.; Knochel, P. Org. Lett. 2011, 13,
1690e1693; (e) Hlavinka, M. L.; Hagadorn, J. R. Organometallics 2007, 26,
4105e4108; (f) Orsini, F.; Pelizzoni, F.; Vallarino, L. M. J. Organomet. Chem. 1989,
367, 375e382.
chlorophenyl)acetate (3a, 100 mg, 0.36 mmol), sodium benzene-
sulfinate (121.3 mg, 2.0 equiv), N,N0-dimethylethylenediamine
(16 mg, 50 mol %), Cu(OTf)2 (26.2 mg, 20 mol %) and degassed
DMSO (3.6 mL). The reaction mixture was irradiated in the micro-
wave at 130 ꢁC for 2 h, diluted with EtOAc and filtered through
a pad of Celite. The organic layer was washed with water and brine,
dried over Na2SO4, filtered, and concentrated. The residue was
purified by flash column chromatography eluted with EtOAc/hep-
tane to afford compound 4f as a yellow solid (62.3 mg, 51%).
Mp 71.0e73.0 ꢁC; FTIR (thin film, cmꢀ1) 2981, 1736, 1317, 1155; 1H
5. Dai, X.; Strotman, N. A.; Fu, G. C. J. Am. Chem. Soc. 2008, 130, 3302e3303.
6. Nakamura, M.; Jin, M. Chem. Lett. 2011, 40, 1012e1014.
7. Molander, G. A.; Traister, K. M.; Barcellos, T. J. Org. Chem. 2013, 78,
4123e4131.
ꢀ
8. Durandetti, M.; Gosmini, C.; Perichon, J. Tetrahedron 2007, 63, 1146e1153.
9. For reviews on Negishi coupling, see: (a) Negishi, E.-i.; Zeng, X.; Tan, Z.;
Qian, M.; Hu, Q.; Huang, Z. In Metal-catalyzed Cross-coupling Reactions, 2nd
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2004; pp 815e889; (b) Negishi, E.-i. Angew. Chem., Int. Ed. 2011, 50,
6738e6764.
NMR (400 MHz, CDCl3)
d
7.97e7.94 (m, 2H), 7.93 (t, J¼1.8 Hz, 1H),
7.81e7.77 (m, 1H), 7.62e7.56 (m, 1H), 7.56e7.49 (m, 2H), 7.44 (d,
J¼8.1 Hz, 1H), 4.17 (q, J¼7.1 Hz, 2H), 3.79 (s, 2H), 1.25 (t, J¼7.1 Hz,
10. (a) Shelby, Q.; Kataoka, N.; Mann, G.; Hartwig, J. J. Am. Chem. Soc. 2000, 122,
10718e10719; (b) Kataoka, N.; Shelby, Q.; Stambuli, J. P.; Hartwig, J. F. J. Org.
Chem. 2002, 67, 5553e5566.
3H); 13C NMR (101 MHz, CDCl3)
d 169.5, 142.1, 140.8, 138.1, 135.8,
ꢁ
ꢁ
11. Dura-Vila, V.; Mingos, D. M. P.; Vilar, R.; White, A. J. P.; Williams, D. J. J. Orga-
nomet. Chem. 2000, 600, 198e205.
133.6, 132.4, 129.5, 128.6, 127.8, 126.0, 61.5, 39.1, 14.1; HRMS (ESIþ)
calcd for C16H16O4ClS ([MþH]þ), 339.0458; found, 339.0428.
12. (a) Miki, S.; Nakamoto, K.; Kawakami, J.-i.; Handa, S.; Nuwa, S. Synthesis
2008, 40, 409e412; (b) Lombardo, M.; Trombini, C. In The Chemistry of
Organozinc Reagents; Marek, I., Rappoport, Z., Eds.; John Wiley
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& Sons:
Acknowledgements
13. Surry, D. S.; Buchwald, S. L. Chem. Sci. 2011, 2, 27e50.
14. Kranenburg, M.; van der Burgt, Y. E. M.; Kamer, P. C. J.; van Leeuwen, P. W. N. M.;
Goubitz, K.; Fraanje, J. Organometallics 1995, 14, 3081e3089.
15. Xantphos is a relatively inexpensive ligand. Strem price at largest package for
Xantphos is $770/25 g ($18/mmol), for Qphos is $2135/10 g ($153/mmol), and
for {[P(tBu)3]PdBr}2 is $578/2 g ($222/mmol).
16. Reactions performed in PhMe (6.0 mL) and NMP (6.0 mL) under otherwise
identical conditions were stalled in 2 h at 80% and 58% conversion with 94:6
and 91:9 ratio of 3a/3a0, respectively.
We thank Drs. Chong Han, Sushant Malhotra, Francis Gosselin,
Greg Sowell, Chudi Ndubaku and Joachim Rudolph for helpful
discussion, and Dr. Chunang Gu and Mr. Deven Wang for collecting
HRMS data.
Supplementary data
17. For reviews on SuzukieMiyaura coupling, see: (a) Miyaura, N.; Suzuki, A. Chem.
Rev. 1995, 95, 2457e2483; (b) Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz, E.;
Lemaire, M. Chem. Rev. 2002, 102, 1359e1470.
Supplementary data associated with this article including copies
of 1H and 13C NMR spectra for compounds 3aek, 3meo, 3res,
Ibuprofen, and 4aef. Supplementary data associated with this ar-
ticle can be found, in the online version, at http://dx.doi.org/
10.1016/j.tet.2013.12.053.
18. For a recent review on cross-coupling reactions of organotrifluoroborate salts,
see: Molander, G. A.; Jean-Gerald, L. Org. React. 2013, 79, 1e316.
19. For a recent review on Mizoroki-Heck reactions, see: The Mizoroki-Heck Re-
action; Oestreich, M., Ed.; Wiley: Chichester, UK, 2009.
ꢀ
20. For a recent review on Sonogashira coupling, see: Chinchilla, R.; Najera, C.
Chem. Rev. 2007, 107, 874e922.
21. Hartwig, J. F. Angew. Chem., Int. Ed. 1998, 37, 2046e2067.
22. (a) Baskin, J. M.; Wang, Z. Org. Lett. 2002, 4, 4423e4425; (b) Suzuki, H.; Abe, H.
Tetrahedron Lett. 1995, 36, 6239e6242.
23. Krasovskiy, A.; Knochel, P. Synthesis 2006, 38, 890e891.
24. All Reformatsky reagents should be used right after preparation and titration as
they tend to decompose upon storage.
25. The quenching of this zinc reagent by iodine is slow due to its diminished
nucleophilicity. The iodine solution was added 0.5 mL zinc solution and stirred
for 3 min before addition of the next portion of 0.5 mL zinc solution. This
process was repeated until a visible discoloration of the iodine solution was
observed.
References and notes
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a-arylation of carbonyl
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