Minimizing the amount of nitromethane in palladium-catalyzed cross-coupling with aryl halides

Article abstract of DOI:10.1021/jo401249y

A method for the formation of arylnitromethanes is described that employs readily available aryl halides or triflates and small amounts of nitromethane in a dioxane solvent, thereby reducing the hazards associated with this reagent. Specifically, 2-10 equiv (1-5% v/v) of nitromethane can be employed in comparison to prior work that used nitromethane as solvent (185 equiv). The present transformation provides high yields at relatively low temperatures and tolerates an array of functionality, including heterocycles and substantial steric encumbrance.

Full text of DOI:10.1021/jo401249y

Note
pubs.acs.org/joc
Minimizing the Amount of Nitromethane in Palladium-Catalyzed
Cross-Coupling with Aryl Halides
Ryan R. Walvoord and Marisa C. Kozlowski*
Penn Merck High Throughput Experimentation Laboratory, Department of Chemistry, University of Pennsylvania, Philadelphia,
Pennsylvania 19104-6323, United States
S
* Supporting Information
ABSTRACT: A method for the formation of arylnitromethanes is
described that employs readily available aryl halides or triflates and
small amounts of nitromethane in a dioxane solvent, thereby
reducing the hazards associated with this reagent. Specifically, 2−
10 equiv (1−5% v/v) of nitromethane can be employed in
comparison to prior work that used nitromethane as solvent (185 equiv). The present transformation provides high yields at
relatively low temperatures and tolerates an array of functionality, including heterocycles and substantial steric encumbrance.
itroalkanes comprise a synthetically important class of
Scheme 2. Nitromethylation of Aryl Halides
N
compounds,1,2 capable of efficient, stereoselective C−C
bond-forming reactions3−5 and subsequent transformation into
numerous other functional groups (Scheme 1).6,7 Higher order
Scheme 1. Utility of Nitroalkane Intermediates
temperature and pressure. However, under certain conditions,
particularly high pressure and temperature, nitromethane can be
explosive.21,22 Caution must also be exercised under basic
conditions to avoid formation and isolation of several hazardous
species.23,24 Nitronate salts, for example, explode with heat or
shock, particularly when dry. Methazonic acid (nitroacetalde-
hyde oxime) and/or fulminate salts may also be generated, which
are highly sensitive compounds and readily detonate with
friction, heat, or shock. Despite the routine use of nitromethane
as a polar organic solvent, the aforementioned concerns provided
ample impetus to reinvestigate the title transformation with the
goal of reducing the amount of nitromethane.25 Herein, we
report an improved method for the nitromethylation of aryl
halides and triflates using 2−10 equiv of the nitromethane
coupling partner (Scheme 2).
With the goal of finding suitable conditions engendering
adequate reactivity while minimizing the amount of nitro-
methane, a focused parallel microscale experimentation (96
reactions on the 20 μmol halide/100 μL reaction volume scale)26
study was designed building on data from prior examination of
the coupling reaction.20 Specifically, the coupling of 4-
bromoanisole (1a) with nitromethane (2 equiv) was examined
while varying the ligand, base, and solvent.27 Sufficient reactivity
was observed at 70 °C, and several trends emerged. Bases with
conjugate acid pKa values close to that of nitromethane (pKa
nitroalkanes have been used to good effect as key intermediates
in total synthesis, as demonstrated in recent syntheses of
manzamine A8 and (−)-nutlin-3.9 Despite their utility, synthetic
access to this class of compounds remains challenging. The
generation of arylnitromethanes is particularly challenging.9,10
The inherent limitation in the classical Meyer reaction of metal
nitrites11 on benzyl halides arises from the ambident nature of the
nitrite nucleophile, resulting in significant quantities of nitrite
ester and other byproducts.12 Additionally, even slight steric
hindrance on the benzyl halide electrophile (e.g., any ortho-
substitution) inhibits the attack of the weak nitrite nucleophile.13
Encouraged by the success of weak carbon nucleophiles,
including higher nitroalkyl congeners,14−18 as partners in cross-
coupling reactions,19 we recently developed a palladium-
catalyzed coupling of nitromethane and aryl/heteroaryl halides
to afford arylnitromethanes in high yield under mild conditions
(Scheme 2).20 Because of its weakly nucleophilic nature,
nitromethane was employed as a solvent (0.1 M, 185 equiv) to
optimize the yield. Nitromethane is often used as a polar organic
solvent in small-scale processes and is stable at ambient
Received: June 10, 2013
© XXXX American Chemical Society
A
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The Journal of Organic Chemistry
Note
Table 1. Bench-Scale (0.5 mmol) Results from Selected HTE Leads
a
b
entry
ligand
solvent
THF
equiv MeNO2
L:Pd
P:SM at 5 h
yield (%)
c
1
2
3
4
5
6
7
cataCXium POMetB
cataCXium POMetB
XPhos
2
2
2:1
2:1
93:7
66
c
1,4-dioxane
THF
89:11
67:33
59:41
90:10
90:10
62:38
67
2
2:1
42
81
85
92
79
XPhos
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
2
2:1
XPhos
5
2:1
XPhos
10
2
2:1
XPhos
1.2:1
a
b
c
Determined by GC. Yield after column chromatography. 9 h reaction time.
∼10) performed best. Carbonate (pKa ∼10) and phosphate (pKa
∼13) appeared optimal, while bicarbonate (pKa ∼6) yielded only
small amounts of product, and tert-butoxide (pKa ∼19) led to
significant product decomposition. Mild sodium bases (Na2CO3
and NaHCO3) displayed minimal reactivity, likely due to limited
solubility. Both THF and 1,4-dioxane provided improved
reactivity relative to CPME. The XPhos, BrettPhos, and
CataCXium POMetB ligands all showed comparable reactivity,
though examination of the HPLC chromatograms revealed that
XPhos possessed the cleanest reaction profile. Verification of the
high throughput experimentation (HTE) results (0.020 mmol)
and final optimization were performed on bench-scale (0.5
mmol) reactions (Table 1).
Under several conditions, increased starting material con-
sumption was independent from yield due to competing
decomposition pathways. Specifically, THF and CataCXium
POMetB displayed superior rates in comparison to 1,4-dioxane
and XPhos, respectively, yet provided poor yield (entries 1−4).28
The product arylnitromethane 2a was afforded in high yield
(81%) with just 2 equiv of nitromethane using XPhos, dioxane,
and K3PO4 (entry 4). As anticipated, increasing the amount of
nitromethane to 5 or 10 equiv increased rates and yields (entries
5 and 6). The ligand to palladium ratio could be decreased to
1.2:1 with minimal affect on reaction efficiency (entry 7).
With optimized conditions (Table 2, enties 6 and 7) secured
for the desired transformation, the scope was explored (Table 2).
Using 10 equiv of nitromethane, the coupling proceeds smoothly
with electron-rich (entries 1 and 6) and electron-deficient aryl
bromides (entries 2−5). Various functional groups, including
carbonyls (entries 2−4) and nitro (entry 5), are well tolerated. It
is especially noteworthy that acidic ketone 1d did not compete
even though coupling of ketones, via the enols, has been reported
in other systems15,29,30 at the higher temperature used here
compared to the initial report with nitromethane as solvent.20
Bromoindole 1g also provided the nitromethylated heteroarene
in high yield (entry 7). Notably, ortho-substitution does not
inhibit the reactivity or yield, as determined with a variety of
sterically hindered substrates (entries 5, 6, 12, and 13) including
the very hindered 2-bromomesitylene 1f. Aryl chlorides proved
capable coupling partners (entries 8−10), although more forcing
conditions were required and more complex reaction profiles
were observed. Sufficient disparity in the reactivity is observed
between aryl bromides and chlorides such that chlorides can be
carried through to the product (entry 11), providing the
opportunity for an additional orthogonal coupling. Biphenyl
triflate 1k smoothly afforded the corresponding nitroalkyl
product (entry 12), demonstrating the utility of nitromethane
in homologating phenolic precursors. In contrast, aryl iodides
performed poorly in the transformation, reacting very slowly
(entry 13).31 This method is not restricted to nitromethane,
being effective with nitroethane14 (Scheme 3), the product of
which decomposes far less readily, which accounts for the very
high yield (98%).
Select examples were exposed to the optimized conditions
with just 2 equiv of nitromethane and afforded the products in
moderate to good yields, albeit requiring longer reaction times
(Table 3). Under these coupling conditions, incomplete
conversion was observed for several substrates, and increasing
the reaction time further resulted in more decomposition of the
products.
In conclusion, an improved method for the formation of
arylnitromethanes has been discovered that employs readily
available aryl halides or triflates and a small excess of
nitromethane. The present transformation provides good
reactivity at relatively low temperatures and tolerates an array
of functionality, including considerable steric encumbrance.
Significantly, the amount of nitromethane has been reduced from
solvent (100% v/v, 185 equiv) to 5% (10 equiv) or 1% (2 equiv)
of the volume utilized in the original protocol, providing a more
attractive method for large scale processes. The product
arylnitromethanes are produced in high yields and may be
readily transformed into the corresponding aldehydes, oximes,
and other functionalities.
EXPERIMENTAL SECTION
■
Nitromethylation of 4-Bromoanisole; Optimization (Table 1).
In a glovebox, an oven-dried microwave vial was charged with Pd2dba3
(11.4 mg, 0.0125 mmol), ligand, and K3PO4 (127 mg, 0.60 mmol). The
solvent was added (2.5 mL), followed by nitromethane (2, 5, or 10
equiv) and 4-bromoanisole (62.6 μL, 0.50 mmol). The vial was sealed
with a Teflon cap, briefly stirred, removed from the glovebox, and heated
to 70 °C with vigorous stirring for the indicated time. After cooling to rt,
the mixture was diluted with CH2Cl2 (20 mL) and washed with 1 M aq
HCl, which was then extracted with CH2Cl2 (2 × 20 mL). The
combined organics were dried over Na2SO4, filtered, and concentrated.
Purification by chromatography (5% EtOAc/Hex) afforded pure 1-
methoxy-4-(nitromethyl)benzene as a yellow oil.
B
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The Journal of Organic Chemistry
Note
Table 2. Scope of the Coupling of Aryl Halides and Triflates with 10 equiv of Nitromethane
a
b
Yield after column chromatography. 5 mol % Pd2dba3, 12 mol % XPhos, 80 °C.
Scheme 3. Example of Nitroethane Coupling
General Method for the Nitromethylation of Aryl Halides. In a
glovebox, an oven-dried vial was charged with Pd2dba3 (11.4 mg, 0.0125
mmol), XPhos (14.3 mg, 0.030 mmol), K3PO4 (127 mg, 0.60 mmol),
and substrate (0.50 mmol). The vial was sealed with a Teflon cap and
removed from the glovebox, and 1,4-dioxane (2.5 mL) was added,
followed by nitromethane (270 μL, 5.0 mmol = General Method A, or
54 μL, 1.0 mmol = General Method B). The mixture was heated to 70
°C with vigorous stirring for the indicated time, then cooled to rt, diluted
with CH2Cl2 (15 mL), and washed with 1 M aq HCl (15 mL), which was
then extracted with CH2Cl2 (3 × 15 mL). The combined organics were
dried over Na2SO4, filtered, and concentrated in vacuo. Purification by
chromatography afforded the desired product. All spectral data for
known compounds were in good agreement with literature values.20
C
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The Journal of Organic Chemistry
Note
Table 3. Coupling of Aryl Bromides with 2 equiv of Nitromethane
a
Yield after column chromatography.
1-Methoxy-4-(nitromethyl)benzene (2a). (Table 2, entry 1)
General Method A was carried out on 4-bromoanisole with a reaction
time of 7 h. Purification by chromatography (5% EtOAc/Hex) afforded
the title compound as a pale yellow oil (78.4 mg, 94%): 1H NMR (500
MHz, CDCl3) δ 7.39 (d, J = 8.6 Hz, 2H), 6.95 (d, J = 8.7 Hz, 2H), 5.38
(s, 2H), 3.83 (s, 3H).
(Table 3, entry 1) General Method B was carried out on 4-
bromoanisole with a reaction time of 18 h and afforded the title
compound after purification as a yellow oil (66.1 mg, 79%).
Ethyl 4-(Nitromethyl)benzoate (2b). (Table 2, entry 2) General
Method A was carried out on ethyl 4-bromobenzoate with a reaction
time of 18 h. Purification by chromatography (20% EtOAc/Hex)
afforded the title compound as a colorless solid (80.7 mg, 77%): mp 71−
72 °C (lit.20 70−71 °C); 1H NMR (500 MHz, CDCl3) δ 8.12 (d, J = 8.5
Hz, 2H), 7.54 (d, J = 8.2 Hz, 2H), 5.51 (s, 2H), 4.41 (q, J = 7.1 Hz, 2H),
1.41 (t, J = 7.1 Hz, 3H).
(74.5 mg, 82%): mp 60−63 °C (lit.20 62−64 °C); 1H NMR (500 MHz,
CDCl3) δ 8.28 (dd, J = 8.1, 1.3 Hz, 1H), 7.77 (td, J = 7.6, 1.3 Hz, 1H),
7.71 (td, J = 8.0, 1.5 Hz, 1H), 7.52 (dd, J = 7.5, 1.3 Hz, 1H), 5.85 (s, 2H).
(Table 3, entry 3) General Method B was carried out on 1-bromo-2-
nitrobenzene with a reaction time of 24 h and afforded the title
compound after purification as a tan solid (50.1 mg, 55%): mp 60−62
°C.
1,3,5-Trimethyl-2-(nitromethyl)benzene (2f). (Table 2, entry 6)
General Method A was carried out on 2-bromomesitylene with a
reaction time of 8 h. Purification by chromatography (3% EtOAc/Hex)
afforded the title compound as pale needles after trituration with
hexanes (80.7 mg, 90%): mp 71−72 °C (lit.32 70−71 °C); H NMR
1
(500 MHz, CDCl3) δ 6.96 (s, 2H), 5.58 (s, 2H), 2.39 (s, 6H), 2.32 (s,
3H).
(Table 3, entry 4) General Method B was carried out on 2-
bromomesitylene with a reaction time of 24 h and afforded the title
compound after purification as a colorless solid (51.3 mg, 55%): mp 71−
73 °C.
5-(Nitromethyl)-1H-indole (2g). (Table 2, entry 7) General
Method A was carried out on 5-bromoindole with a reaction time of 7
h. Purification by chromatography (15% EtOAc/Hex) afforded the title
compound as a tan solid (70.9 mg, 80%): mp 96−97 °C (lit.20 92−94
°C); 1H NMR (500 MHz, CDCl3) δ 8.35 (bs, 1H), 7.75 (s, 1H), 7.40 (d,
J = 8.3 Hz, 1H), 7.25−7.29 (m, 2H), 6.59−6.61 (m, 1H), 5.55 (s, 2H).
(Table 3, entry 5) General Method B was carried out on 5-
bromoindole with a reaction time of 21 h and afforded the title
compound after purification as a tan solid (57.3 mg, 65%): mp 93−95
°C.
(4-(Nitromethyl)phenyl)(phenyl)methanone (2c). (Table 2,
entry 3) General Method A was carried out on 4-bromobenzophenone
with a reaction time of 18 h. Purification by chromatography (10% to
20% EtOAc/Hex) afforded the title compound as a colorless solid (99.4
mg, 82%): mp 86−88 °C (lit.20 88−90 °C); H NMR (500 MHz,
1
CDCl3) δ 7.87 (d, J = 8.0 Hz, 2H), 7.80−7.83 (m, 2H), 7.62 (tt, J = 7.4,
1.4 Hz, 1H), 7.60 (d, J = 8.1 Hz, 2H), 7.51 (t, J = 7.7 Hz, 2H), 5.55 (s,
2H).
(Table 2, entry 8) General Method A was carried out on 4-
chlorobenzophenone with a reaction time of 18 h and afforded the title
compound after purification as a light tan solid (93.6 mg, 77%): mp 85−
87 °C.
(Table 3, entry 2) General Method B was carried out on 4-
bromobenzophenone with a reaction time of 30 h and afforded the title
compound after purification as a tan solid (67.5 mg, 56%): mp 79−84
°C.
1-Nitro-4-(nitromethyl)benzene (2h). (Table 2, entry 9) General
Method A was carried out on 1-chloro-4-nitrobenzene using 5 mol %
Pd2dba3 and 12 mol % XPhos at 80 °C with a reaction time of 5 h.
Purification by chromatography (12% EtOAc/Hex) afforded the title
compound as a yellow solid (45.6 mg, 50%): mp 82−86 °C (lit.33 84−86
°C); 1H NMR (300 MHz, CDCl3) δ 8.32 (d, J = 8.7 Hz, 2H), 7.68 (d, J =
8.6 Hz, 2H), 5.57 (s, 2H).
1,3-Dimethoxy-5-(nitromethyl)benzene (2i). (Table 2, entry
10) General Method A was carried out on 1-chloro-3,5-dimethox-
ybenzene using 5 mol % Pd2dba3 and 12 mol % XPhos at 80 °C with a
reaction time of 5.5 h. Purification by chromatography (15% EtOAc/
Hex) afforded the title compound as a tan solid (75.6 mg, 77%): mp 56−
58 °C (lit.34 88 °C); 1H NMR (500 MHz, CDCl3) δ 6.58 (d, J = 2.3 Hz,
2H), 6.52 (t, J = 2.2 Hz, 1H), 5.36 (s, 2H), 3.80 (s, 6H); 13C NMR (125
MHz, CDCl3) δ 161.3, 131.6, 108.0, 101.9, 80.2, 55.6; IR (film) 2916,
1-(2-(Nitromethyl)phenyl)ethan-1-one (2d). (Table 2, entry 4)
General Method A was carried out on 2′-bromoacetophenone with a
reaction time of 18 h. Purification by chromatography (20% EtOAc/
Hex) afforded the title compound as a tan solid after trituration with
hexanes (62.8 mg, 70%): mp 76−77 °C (lit.20 87−89 °C); H NMR
1
(500 MHz, CDCl3) δ 7.94−7.98 (m, 1H), 7.59−7.62 (m, 2H), 7.38−
7.42 (m, 1H), 5.79 (s, 2H), 2.66 (s, 3H).
1-Nitro-2-(nitromethyl)benzene (2e). (Table 2, entry 5) General
Method A was carried out on 1-bromo-2-nitrobenzene with a reaction
time of 18 h. Purification by chromatography (20% EtOAc/Hex)
afforded the title compound as a tan solid after trituration with hexanes
D
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The Journal of Organic Chemistry
Note
2848, 1597, 1551, 1456, 1430, 1372, 1206, 1153, 1066 cm−1; HRMS
(CI) calcd for C9H11O2 [M − NO2]+ m/z = 151.0759, found 151.0758.
1-Chloro-4-(nitromethyl)benzene (2j). (Table 2, entry 11)
General Method A was carried out on 1-bromo-4-chlorobenzene with
a reaction time of 8 h. Purification by chromatography (5% EtOAc/
Hex) afforded the title compound as a waxy material that partially
melted when handling at room temperature (73.5 mg, 86%): 1H NMR
(500 MHz, CDCl3) δ 7.39−7.46 (m, 4H), 5.42 (s, 2H).
(RO1GM087605) for financial support. We thank Accelrys
and Virscidian for providing software for the high throughput
screening and analysis. Partial instrumentation support was
provided by the NIH for MS (1S10RR023444) and NMR
(1S10RR022442). We thank Dr. Simon Berritt (Penn Merck
HTE Laboratory) and Dr. Spencer Dreher (Merck Research
Laboratories) for helpful discussions.
(Table 3, entry 6) General Method B was carried out on 1-bromo-4-
chlorobenzene with a reaction time of 30 h and afforded the title
compound after purification as a waxy material that partially melted
when handling at room temperature (39.4 mg, 46%).
2-(Nitromethyl)-1,1′-biphenyl (2k). (Table 2, entry 12) General
Method A was carried out on 1,1′-biphenyl-2-trifluoromethanesulfo-
nate35 with a reaction time of 18 h. Purification by chromatography (3%
EtOAc/Hex) afforded the title compound as a colorless oil (92.1 mg,
86%): 1H NMR (300 MHz, CDCl3) δ 7.36−7.56 (m, 7H), 7.28−7.34
(m, 2H), 5.42 (s, 2H); 13C NMR (75 MHz, CDCl3) δ 143.9, 139.8,
131.3, 130.8, 130.1, 129.2, 128.8, 128.3, 128.1, 127.5, 77.5. IR (film)
2920, 2852, 1551, 1481, 1372; HRMS (ESI) calcd for C13H11 [M −
NO2]+ m/z = 167.0861, found 167.0858.
Methyl 2-(Nitromethyl)benzoate (2l). (Table 2, entry 13)
General Method A was carried out on methyl-2-iodobenzoate with a
reaction time of 18 h. Purification by chromatography (8% EtOAc/Hex)
afforded the title compound after trituration with hexanes as a colorless
solid (23.6 mg, 24%): mp 66−67 °C (lit.36 64−65 °C); 1H NMR (500
MHz, CDCl3) δ 8.15 (dd, J = 7.7, 1.4 Hz, 1H), 7.62 (td, J = 7.5, 1.4 Hz,
1H), 7.56 (td, J = 7.6, 1.3 Hz, 1H), 7.4 (dd, J = 7.6, 1.0 Hz, 1H), 5.86 (s,
2H), 3.91 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 166.8, 133.3, 133.2,
131.8, 130.8, 130.4, 130.2, 77.7, 52.6; IR (film) 3024, 2960, 1714, 1569,
1429, 1377, 1285, 1086 cm−1; HRMS (CI) calcd for C9H9O2 [M −
NO2]+ m/z = 149.0602, found 149.0597.
REFERENCES
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(4-(1-Nitroethyl)phenyl)(phenyl)methanone (3). In a glovebox,
an oven-dried vial was charged with Pd2dba3 (11.4 mg, 0.0125 mmol),
XPhos (14.3 mg, 0.030 mmol), K3PO4 (127 mg, 0.60 mmol), and 4-
bromobenzophenone (130.6 mg, 0.50 mmol). The vial was sealed with a
Teflon cap and removed from the glovebox, and 1,4-dioxane (2.5 mL)
was added, followed by nitroethane (360 μL, 5.0 mmol). The mixture
was heated to 70 °C with vigorous stirring for 4 h, then cooled to rt,
diluted with CH2Cl2 (15 mL), and washed with 1 M aq HCl (15 mL),
which was then extracted with CH2Cl2 (3 × 15 mL). The combined
organics were dried over Na2SO4, filtered, and concentrated in vacuo.
Purification by chromatography (10% EtOAc/Hex) afforded the title
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compound as a yellow oil (125.2 mg, 98%): H NMR (500 MHz,
CDCl3) δ 7.84 (d, J = 8.3 Hz, 2H), 7.80 (m, 2H), 7.62 (t, J = 7.6 Hz, 1H),
7.59 (d, J = 8.4 Hz, 2H), 7.50 (t, J = 7.7 Hz, 2H), 5.71 (q, J = 7.0 Hz, 1H),
1.95 (d, J = 6.9 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 196.0, 139.5,
139.1, 137.3, 133.0, 130.8, 130.2, 128.6, 127.6, 85.9, 19.7; IR (film) 3058,
2927, 1654, 1546, 1446, 1276, 924 cm−1; HRMS (ESI) calcd for
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ASSOCIATED CONTENT
■
S
* Supporting Information
(23) Markofsky, S. B. Nitro Compounds, Aliphatic. In Ullmann’s
Encyclopedia of Industrial Chemistry, Electronic Release; Wiley-VCH:
Weinheim, October 2011.
General methods, parallel microscale experimentation procedure
1
and data, H NMR spectroscopic data for all compounds, and
13C NMR for all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
(24) Bretherick, L. Bretherick’s Handbook of Reactive Chemical Hazards,
4th ed.; Butterworths: Boston, 1990.
(25) We have not experienced any adverse events in handling the
substrates, reaction mixtures, or products via our prior protocol or via
the protocol reported herein.
AUTHOR INFORMATION
Corresponding Author
*E-mail: marisa@sas.upenn.edu.
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(26) Dreher, S. D.; Dormer, P. G.; Sandrock, D. L.; Molander, G. A. J.
Am. Chem. Soc. 2008, 130, 9257−9259.
(27) See Supporting Information for complete HTE data.
(28) Similarly poor yields were obtained upon halting these reactions
earlier.
Notes
The authors declare no competing financial interest.
(29) Biscoe, M. R.; Buchwald, S. L. Org. Lett. 2009, 11, 1773−1775.
(30) Culkin, D. A.; Hartwig, J. F. Acc. Chem. Res. 2003, 36, 234−245.
(31) Per ref 20, aryl iodides couple successfully when using
nitromethane as the solvent. The results here are consistent with prior
ACKNOWLEDGMENTS
We are grateful to the NSF for funding of the High Throughput
Laboratory (GOALI CHE-0848460) and NIH
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