Synthesis of N -arylisatins by the reaction of arynes with methyl 2-Oxo-2-(arylamino)acetates

Article abstract of DOI:10.1021/jo200651b

N-Arylisatins are efficiently prepared by the reaction of 2-oxo-2-(arylamino)acetates and arynes under mild reaction conditions

Full text of DOI:10.1021/jo200651b

ARTICLE
pubs.acs.org/joc
Synthesis of N-Arylisatins by the Reaction of Arynes with Methyl
2-Oxo-2-(arylamino)acetates
Donald C. Rogness and Richard C. Larock*
Department of Chemistry, Iowa State University, Ames, Iowa 50011, United States
S Supporting Information
b
ABSTRACT: N-Arylisatins are efficiently prepared by the
reaction of 2-oxo-2-(arylamino)acetates and arynes under mild
reaction conditions
’ INTRODUCTION
benzoates afford medicinally relevant acridones, xanthones, and
thioxanthones (eq 3).16 Also, in 2009, it was shown that methyl-
2-indolecarboxylates react with arynes in a similar way to form
indoloindolones (eq 4).17 The success of the aforementioned
reactions led us to explore the possibility of reacting N-substi-
tuted methyl oxamates with arynes (eq 5).
Isatins are highly sought after compounds because of their
biological and medicinal activities.1 They exhibit a broad array of
biologically important properties, including antifungal,2 antiviral,3
anti-HIV,4 anti-AIDS,4 antiprotozoal,5 anticancer,1b antitumor,6
and antileukemia properties.7
N-Arylisatins remain underexplored, however, in part because
of their limited synthetic accessibility. There are only a few
methods currently available for synthesizing N-arylisatins, and
most suffer from poor yields and limited diversification. For
example, a newer method involves reacting NꢀH isatins with
aryl boronic acids and copper reagents.8 However, yields are low
and only para- or meta-substituted aryl boronic acids seem to
react well. A slightly older method utilizes N,N-diarylamines and
oxalyl chlorides.9 A disadvantage of this method is not only the
poor yields but also the fact that only symmetrical N,N-diaryla-
mines can be utilized, for the most part.10 Because isatins have
exhibited impressive biological properties and convenient meth-
ods for synthesizing N-arylisatins are lacking, our group decided
to examine an aryne-based method for producing them.
Aryne methodologies have recently proven valuable in the
synthesis of a large number of heteroatom-containing structures.11
Mechanistically, many of these methodologies are initiated by
nucleophilic attack of a heteroatom, usually oxygen or nitrogen,
onto the transient aryne intermediate. In fact, our group has shown
that a variety of heteroatoms can undergo this process, includ-
ing sulfonamides and anilines.12 Shortly thereafter, we published
the insertion reaction of arynes into the nitrogenꢀcarbon bond
of N-aryltrifuoroacetamides and N-arylsulfinamides.13 Later on,
Greaney et al. extended this methodology by demonstrating that
arynes can undergo the same insertion with simple carboxamides
(eq 1).14 These reactions presumably involve a charged four-
membered ring intermediate, which will be further highlighted
herein. A similar mechanism has been proposed for the reaction of
ureas and arynes (eq 2).15
’ RESULTS AND DISCUSSION
Initial experiments suggested that the reaction of this parent
system (R = Ph) worked; however, further optimization of the
reaction conditions was needed in order to improve the yield.
In recent years, our group has published related methodolo-
gies where nucleophilic heteroatoms attack benzyne. For exam-
ple, the reaction of arynes and ortho-heteroatom-substituted
Received: March 28, 2011
Published: May 12, 2011
r
2011 American Chemical Society
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Table 1. Reaction of Various Methyl 2-Oxo-2-(arylamino)acetates with 2-(Trimethylsilyl)phenyl Trifluoromethanesulfonatea
a Reaction conditions: 0.50 mmol of amide, 1.0 mmol of benzyne, 3.0 mmol of CsF, 1.0 mmol of NaHCO3, MeCN (5 mL) at rt for 1 d.
b Isolated Yield. c A complicated mixture was observed on TLC d 4.1 mmol scale reaction of amide. Only 1.5 equiv of the benzyne precursor were
employed.
HPLC yield analysis was employed in order to conveniently
observe the affects imparted by a variety of bases, solvents, times,
temperatures, and the stoichiometry of the process. A direct
relationship between the yield of N-phenylisatin and the amount
of the benzyne precursor used (1.5ꢀ3.0 equiv) was observed.
Out of cost concerns, 2.0 equiv of the benzyne precursor was
chosen as an upper limit. NaHCO3 was identified as the most
effective base in this reaction. Ambient temperatures were
optimal, as higher temperatures seemed to promote unwanted,
unidentified side reactions. Acetonitrile was the best solvent for
the ambient temperature employed, presumably due to its
favorable solubility of CsF relative to other typical solvents used
in benzyne chemistry, such as THF, DME, and toluene. For the
parent system, optimal conditions were obtained when 2 equiv of
the benzyne precursor, 2 equiv of NaHCO3, 6 equiv of CsF, and
MeCN (0.1 M) were employed under ambient temperatures for
24 h (Table 1, entry 1).
electronically diverse substituents was studied by substituting at
the para position of the methyl 2-oxo-2-(phenylamino)acetate,
thus avoiding steric effects (entries 1ꢀ11). Compared to the
parent substrate (1a), it was observed that electron-rich substit-
uents seem to promote this reaction to a small extent (entries 2
and 3), whereas electron-poor substituents seem to lower the
yield of this reaction (entries 8ꢀ11). Unfortunately, a compli-
cated mixure was observed for the reaction of a substrate
containing a nitro substituent (8a, entry 8). However, this came
as no surprise, since this problem has been observed previously.17
It is likely that the nitro moeity itself is reacting with benzyne.
On the other hand, we were pleased to see that this reaction is
little affected by ortho substitution (entries 13ꢀ18). For example,
good yields were obtained when even bulky substituents, such as
a tert-butyl group (entry 13) or an iodide (entry 18), were placed
ortho to the reacting nitrogen atom. Furthermore, a 67% yield
was obtained for substrate 16a, where both ortho positions were
substituted with methyl groups. Attempts were made to scale up
the preparation of product 18aa using only 1.5 equiv of the
With optimal conditions in hand, the scope and limitations of
this reaction were explored (Table 1). The effect imparted by
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benzyne precursor (as opposed to 2.0 equiv). However, as
expected, a lower yield of 58% was obtained.
was allowed to react with 2a, producing 21aa in an excellent
86% yield.
Our process was also carried out using a substrate bearing two
amide groups (Scheme 1). Using our optimized conditions with
twice the amount of benzyne precursor, a low yield of the desired
bis-isatin 22aa was isolated (33%). On the other hand, using
reaction conditions similar to those of Greeney (eq 1), an
increased yield of 40% was obtained.
The scope and limitations of this reaction were further explored
by examining other benzyne precursors (Figure 1). Unsymmetrical
benzyne precursors were tested in order to observe the regioselec-
tivity of the reaction. In fact, an excellent yield of a single regioisomer
(19aa) was isolated from the reaction of 2a with 2-methoxy-
6-(trimethylsilyl)phenyl trifluoromethanesulfonate. Likewise,
although in a lower yield, 20aa was isolated as a single regioi-
somer from the reaction of 2a with 2-(trimethylsilyl)naphthalen-
1-yl trifluoromethanesulfonate. In addition to the unsymmetrical
benzyne precursors, a symmetrical dimethoxybenzyne precursor
Other substrates have also been examined for compatibility in
this annulation reaction. In most cases, however, significant
limitations have been observed. For example, N-alkylamides do
not work. Significant amounts of starting material and minimal
amounts of the desired products were observed by GCꢀMS
analysis. Further attempts to optimize this reaction failed.
Another disappointing observation was that the correspond-
ing p-tolylsulfonamide (p-TolSO2NHCOCO2Me) did not
react favorably. Only the N-arylation product was isolated, as
noted previously by our group for other N-arylsulfonamides.18
Lastly, in an attempt to form a six-membered ring hetero
cycle using our methodology, methyl 2,2-dimethyl-3-oxo-
3-(phenylamino)propanoate was synthesized and subjected to
our reaction conditions. However, none of the desired product
was formed, even after screening a variety of reaction conditions.
Finally, it should be mentioned that various heteroaromatic
substrates, including substrates with a pyridine or an isoxazole
ring, proved to be problematic and complicated product mixtures
were observed upon TLC analysis.
Figure 1. Products using other benzyne precursors.
Scheme 1. Double Annulation
On the other hand, it was pleasing to see that a ketone, as
opposed to the methyl ester, underwent the annulation
reaction to afford a 3-hydroxyoxindole, an emerging new
scaffold for drug discovery, which possesses potential antic-
ancer properties, in addition to other favorable properties
(Scheme 2).19 Initial experiments with the ketone 2-oxo-N,2-
diphenylacetamide provided only poor yields using our ear-
lier optimized conditions. However, again using 2.3 equiv of
TBAT and toluene at 50 °C, the desired 3-hydroxyindole
(23aa, R = Ph) was obtained in a good yield when 1.75 equiv
of the benzyne precursor was used. However, when R = Me, a
complicated mixture was observed on TLC analysis and the
desired product was not isolated.
Scheme 2. Reaction of 2-Oxo-N,2-diphenylacetamide with
2-(Trimethylsilyl)phenyl Trifluoromethanesulfonate
Scheme 3. Possible Mechanisms
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It is believed that two mechanisms are possible for this process,
routes A and B in Scheme 3. Both suggested routes share a
common first step, nucleophilic attack by nitrogen on the
benzyne, resulting in an aryl carbanion. From there, at least
two possibilities exist with regard to how the desired isatin is
formed. Route A suggests that the aryl carbanion attacks the
distant ester carbonyl and displaces a methoxy group. This type
of mechanism has also been suggested in our earlier work (see
eqs 3 and 4). On the other hand, Greaney’s work (eq 1) suggests
another possibility, route B. This route involves attack of the aryl
carbanion onto the nearest carbonyl group, the amide carbonyl,
forming a strained four-membered ring intermediate, which then
fragments into a structure where the nitrogen can now attack the
ester carbonyl. Both routes eventually lead to the desired isatin.
However, the carbonyl groups end up in different places depend-
ing on the route. Further efforts are underway in order to shed
light on this process.
CDCl3) δ 161.7, 153.8, 136.4, 129.5, 125.8, 120.1, 54.3; HRMS (EI)
calcd for [M þ H]þ (M = C9H9NO3) 180.0689, found 180.0680.
Methyl 2-Oxo-2-(p-tolylamino)acetate (2a). The product was
1
isolated as a white solid: mp = 148ꢀ150 °C; H NMR (400 MHz,
CDCl3) δ 8.91 (s, 1 H), 7.52 (d, J = 8.3 Hz, 2 H), 7.14 (d, J = 8.2 Hz,
2 H), 3.92 (s, 3 H), 2.31 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 161.6,
153.6, 135.4, 133.8, 129.8, 119.9, 54.1, 21.1; HRMS (EI) calcd for [M þ
H]þ (M = C10H11NO3) 194.0812, found 194.0809.
Methyl 2-Oxo-2-[(4-phenoxyphenyl)amino]acetate (3a).
1
The product was isolated as a tan solid: mp =97ꢀ99 °C; H NMR
(400 MHz, CDCl3) δ 9.04 (s, 1 H), 7.63 (d, J = 8.9 Hz, 2 H), 7.73 (t, J =
7.9 Hz, 2 H), 7.10 (t, J = 7.4 Hz, 1 H), 7.10ꢀ6.99 (m, 4 H), 3.93 (s, 3 H);
13C NMR (100 MHz, CDCl3) δ 161.5, 157.1, 154.7, 153.7, 131.7, 129.9,
123.5, 121.7, 119.5, 118.9, 54.1; HRMS (EI) calcd for [M þ H]þ (M =
C15H13NO4) 272.0917, found 272.0916.
Methyl 2-[(4-Fluorophenyl)amino]-2-oxoacetate (4a). The
1
product was isolated as a white solid: mp = 154ꢀ156 °C; H NMR
(400 MHz, CDCl3) δ 8.90 (s, 1 H), 7.65ꢀ7.61 (m, 2 H), 7.07 (t, J = 8.6
Hz, 2 H), 3.97 (s, 3 H); 13C NMR (100 MHz, CDCl3, extra peaks due to
CꢀF coupling) δ 163.3, 161.5, 161.4, 158.9, 153.7, 132.48, 132.45,
121.84, 121.76, 117.6, 116.3, 116.1, 54.3; HRMS (EI) calcd for [M þ
H]þ (M = C9H8FNO3) 198.0561, found 198.0558.
’ CONCLUSION
In conclusion, N-arylisatins appear to possess a number of
highly desirable biological properties but have proven difficult
to access synthetically. Our group has developed a convenient and
efficient methodology for synthesizing a diverse array of func-
tionally substituted N-arylisatins under mild reaction conditions.
The necessary starting materials are easily prepared in high
yields by reacting anilines with methyl 2-chloro-2-oxoacetate.
The methodology proceeds efficiently under mild reaction
conditions and tolerates a broad range of functionally diverse
substituents, with respect to both electronic and steric effects. In
addition, a 3-hydroxyoxindole, another medicinally relevant scaf-
fold, has been synthesized using a slightly modified version of
Greaney’s amide insertion conditions and 2-oxo-N,2-diphenyla-
cetamide. Two mechanistic possibilities appear to exist for this
process, and further studies are underway to distinguish which is
more likely.
Methyl 2-[(4-Chlorophenyl)amino]-2-oxoacetate (5a). The
product was isolated as a white solid: mp = 166ꢀ168 °C; 1H NMR (400
MHz, CDCl3) δ 8.90 (s, 1 H), 7.61 (d, J = 8.8 Hz, 2 H), 7.34 (d, J = 8.7
Hz, 2 H), 3.97 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 161.4, 153.7,
134.9, 130.9, 129.5, 121.2, 54.4; HRMS (EI) calcd for [M þ H]þ (M =
C9H8ClNO3) 214.0265, found 214.0264.
Methyl 2-[(4-Bromophenyl)amino]-2-oxoacetate (6a). The
product was isolated as a white solid: mp = 170ꢀ172 °C; 1H NMR (400
MHz, CDCl3) δ 8.89 (s, 1 H), 7.56 (d, J = 8.9 Hz, 2 H), 7.49 (d, J = 8.8
Hz, 2 H), 3.97 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 161.4, 153.7,
135.4, 132.5, 121.5, 118.6, 54.4; HRMS (EI) calcd for [M þ H]þ (M =
C9H8BrNO3) 257.9760, found 257.9759.
Methyl 2-[(4-Iodophenyl)amino]-2-oxoacetate (7a). The
1
product was isolated as a tan solid: mp = 172ꢀ174 °C; H NMR
(400 MHz, CDCl3) δ 8.86 (s, 1 H), 7.69 (d, J = 8.8 Hz, 2 H), 7.43 (d, J =
8.8 Hz, 2 H), 3.98 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 161.4,
153.7, 138.4, 136.1, 121.8, 89.5, 54.4; HRMS (EI) calcd for [M þ H]þ
(M = C9H8INO3) 305.9622, found 305.9623.
’ EXPERIMENTAL SECTION
General. The 1H and 13C NMR spectra were recorded at 300 and
75.5 MHz or 400 and 100 MHz, respectively. Thin layer chromatogra-
phy was performed using commercially prepared 60-mesh silica gel
plates, and visualization was effected with short wavelength UV light
(254 nm). All melting points are uncorrected. All reagents were used
directly as obtained commercially.
Methyl 2-[(4-Nitrophenyl)amino]-2-oxoacetate (8a). The
product was isolated as a yellow solid: mp =230ꢀ233 °C; 1H NMR (400
MHz, CDCl3) δ 9.11 (s, 1 H), 8.29 (d, J = 9.0 Hz, 2 H), 7.84 (d, J = 9.2
Hz, 2 H), 4.01 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ 160.4, 155.8,
143.7, 143.3, 124.7, 120.4, 53.4; HRMS (EI) calcd for [M þ H]þ (M =
C9H8N2O5) 225.0506, found 225.0504.
Methyl 2-[(4-Cyanophenyl)amino]-2-oxoacetate (9a). The
product was isolated as a tan solid: mp =210ꢀ212 °C; 1H NMR (400
MHz, CDCl3) δ 9.03 (s, 1 H), 7.80 (d, J = 8.8 Hz, 2 H), 7.69 (d, J = 8.8
Hz, 2 H), 4.01 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 161.0, 154.0,
140.2, 133.7, 120.1, 118.6, 109.0, 54.6; HRMS (EI) calcd for [M þ H]þ
(M = C10H8N2O3) 205.0608, found 205.0607.
Ethyl 4-(2-Methoxy-2-oxoacetamido)benzoate (10a). The
product was isolated as a pale yellow solid: mp = 147ꢀ149 °C; 1H NMR
(400 MHz, CDCl3) δ 9.19 (s, 1 H), 8.01 (d, J = 8.7 Hz, 2 H), 7.73 (d, J =
8.7 Hz, 2 H), 4.33 (q, J = 7.1 Hz, 2 H), 3.91 (s, 3 H), 1.35 (t, J = 7.1 Hz,
3 H); 13C NMR (100 MHz, CDCl3) δ 165.9, 161.1, 154.0, 140.3, 130.9,
127.3, 119.4, 61.1, 54.2, 14.4; HRMS (EI) calcd for [M þ H]þ (M =
C12H13NO5) 252.0866, found 252.0868.
Methyl 2-Oxo-2-[(4-(trifluoromethyl)phenyl)amino]acetate
(11a). The product was isolated as a white solid: mp = 154ꢀ156 °C; 1H
NMR (400 MHz, CDCl3) δ 8.99 (s, 1 H), 7.87 (d, J = 8.0 Hz, 2 H), 7.66
(d, J = 7.8 Hz, 2 H), 4.01 (s, 3 H); 13C NMR (75 MHz, DMSO-d6, extra
peaks due to CꢀF coupling) δ 160.6, 155.6, 141.1, 126.1, 126.03, 125.98,
Typical Experimental Procedure for Starting Materials
1aꢀ18a and 22a. To a cold solution (0 °C) of the desired amine
(10.0 mmol) and triethylamine (1aꢀ18a: 12 mmol, 1.67 mL; 22a: 24.0
mmol, 3.35 mL) in anhydrous dichloromethane (50 mL) was added
methyl 2-chloro-2-oxoacetate (1aꢀ18a: 10.5 mmol, 0.967 mL; 22a:
21.0 mmol, 1.933 mL) dropwise. The ice bath was removed, and the
resulting mixture was allowed to stir overnight before it was quenched
with HCl (1 N) and extracted with ethyl acetate. The combined organic
layers were washed with saturated NaHCO3 and finally water before
being dried with anhydrous MgSO4 and concentrated in vacuo. The
crude product was purified by washing with Et2O/Hex (1:1), acetone, or
dichloromethane until most of the color disappeared. In some cases, the
solids were recrystallized from toluene. The solids obtained were finally
dried under vacuum.
Methyl 2-Oxo-2-(phenylamino)acetate (1a). The product
was isolated as a white solid: mp = 112ꢀ114 °C; 1H NMR (300
MHz, CDCl3) δ 8.83 (s, 1 H), 7.61 (d, J = 8.2 Hz, 2 H), 7.35 (t, J = 7.8
Hz, 2 H), 7.16 (t, J = 7.4 Hz, 1 H), 3.94 (s, 3 H); 13C NMR (75 MHz,
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125.93, 125.0, 124.6, 122.4, 120.5, 53.3; HRMS (EI) calcd for [M þ H]þ
(M = C10H8F3NO3) 248.0556, found 248.0527.
too quickly.) The mixture was allowed to stir in an ice bath until bubbling
ceased. At this point, the entire reaction mixture was slowly cannulated
over to a cold solution (0 °C) of aniline (10.0 mmol, 0.91 mL) and
triethylamine (15 mmol, 2.1 mL) in anhydrous dichloromethane
(25 mL). The ice bath was removed, and the resulting mixture was
allowed to stir overnight before it was quenched with HCl (1 N) and
extracted with ethyl acetate. The combined organic layers were washed
with saturated NaHCO3 and then water before being dried with
anhydrous MgSO4 and concentrated in vacuo. The crude product was
purified via flash chromatography using gradient solvent mixtures of
ethyl acetate/hexanes. Isolated was a yellow solid: mp = 64ꢀ66 °C; 1H
NMR (300 MHz, CDCl3) δ 9.00 (s, 1 H), 8.42 (d, J = 7.2 Hz, 2 H),
7.74ꢀ7.64 (m, 3 H), 7.52 (t, J = 7.6 Hz, 2 H), 7.41 (t, J = 7.9 Hz, 2 H),
7.21 (t, J = 7.4 Hz, 1 H); 13C NMR (75 MHz, CDCl3) δ 187.6, 159.1,
136.8, 134.8, 133.2, 131.6, 129.4, 128.7, 125.5, 120.1; HRMS (EI) calcd
for [M þ H]þ (M = C14H11NO2) 226.0863, found 226.0861.
Methyl 2-Oxo-2-[(3-(trifluoromethyl)phenyl)amino]acetate
(12a). The product was isolated as a white solid: mp = 112ꢀ115 °C; 1H
NMR(400 MHz, CDCl3) δ 9.19 (s, 1 H), 7.93ꢀ7.89 (m, 2 H), 7.48 (t, J =
7.9 Hz, 1 H), 7.42 (d, J = 7.7 Hz, 1 H), 3.94 (s, 3 H); 13C NMR (100 MHz,
CDCl3, extra peaks due to CꢀF coupling) δ 161.3, 154.1, 137.0, 131.8,
131.5, 130.0, 125.1, 123.2, 122.4, 122.3, 122.2, 116.95, 116.91, 116.87,
116.8, 54.4; HRMS (EI) calcd for [M þ H]þ (M = C10H8F3NO3)
248.0556, found 248.0530.
Methyl 2-[(2-(tert-Butyl)phenyl)amino]-2-oxoacetate (13a).
The product was isolated as a tan solid: mp = 57ꢀ61 °C; 1H NMR (400
MHz, CDCl3) δ 9.17 (s, 1 H), 7.89 (dd, J = 1.2, 8.0 Hz, 1 H), 7.35 (dd, J =
1.3, 7.9 Hz, 1 H), 7.19 (td, J = 1.3, 7.9 Hz, 1 H), 7.11 (td, J = 1.3, 7.8 Hz,
1 H), 3.89 (s, 3 H), 1.39 (s, 9 H); 13C NMR (100 MHz, CDCl3) δ 161.8,
153.3, 140.9, 133.8, 126.9, 126.5, 126.2, 124.5, 53.9, 34.2, 30.5; HRMS (EI)
calcd for [M þ H]þ (M = C13H17NO3) 236.1281, found 236.1288.
Methyl 2-[(1,10-Biphenyl)-2-ylamino]-2-oxoacetate (14a).
The product was isolated as a white solid: mp = 85ꢀ88 °C; 1H NMR
(400 MHz, CDCl3) δ 9.11 (s, 1 H), 8.44 (d, J = 8.15 Hz, 1 H), 7.46 (t, J =
7.3 Hz, 2 H), 7.41ꢀ7.32 (m, 4 H), 7.24 (d, J = 6.3 Hz, 1 H), 7.18 (t, J =
7.2 Hz, 1 H), 3.76 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 160.8,
153.0, 136.8, 133.0, 132.3, 129.9, 128.8, 128.7, 128.2, 127.9, 125.0, 120.2,
53.4; HRMS (EI) calcd for [M þ H]þ (M = C15H13NO3) 256.0968,
found 256.0972.
Methyl 2-[(2,5-Dimethoxyphenyl)amino]-2-oxoacetate (15a).
The product was isolated as a white solid: mp = 105ꢀ107 °C; 1H NMR (300
MHz, CDCl3) δ 9.36 (s, 1 H), 8.00 (d, J = 2.9 Hz, 1 H), 6.73 (d, J = 8.9 Hz,
1 H), 6.55(dd, J =2.9, 9.0 Hz, 1H), 3.88(s, 3 H), 3.78(s, 3H), 3.70 (s, 3 H);
13C NMR (100 MHz, CDCl3) δ 161.0, 153.5, 153.3, 142.6, 126.4, 110., 109.6,
106.2, 56.1, 55.6, 53.8; HRMS (EI) calcd for [M þ H]þ (M = C11H13NO5)
240.0866, found 240.0866.
Methyl 2-(Mesitylamino)-2-oxoacetate (16a). The product
was isolated as a white solid: mp = 99ꢀ101 °C; 1H NMR (400 MHz,
CDCl3) δ 8.44 (s, 1 H), 6.87 (s, 2 H), 3.90 (s, 3 H), 2.24 (s, 3 H) 2.15
(s, 6 H); 13C NMR (100 MHz, CDCl3) δ 161.2, 154.5, 137.5, 134.6,
129.4, 128.9, 53.6, 20.8, 18.2; HRMS (EI) calcd for [M þ H]þ (M =
C12H15NO3) 222.1125, found 222.1122.
Typical Procedure for Synthesis of the Isatin Derivatives
1aaꢀ21aa. To a dry 5 dram vial containing a solution of the amide
(0.5 mmol) and the aryne precursor (1.0 mmol) in MeCN (5 mL,
anhydrous) was added NaHCO3 (1.0 mmol) and CsF (3.0 mmol). The
vial was sealed and allowed to stir for 24 h at rt. The reaction mixture was
then filtered through a plug of silica gel using ethyl acetate, concentrated
in vacuo, and purified by flash chromatography using gradient solvent
combinations of ethyl acetate/hexanes or dichloromethane/hexanes.
1-Phenylindoline-2,3-dione (1aa). The product was isolated as
1
an orange solid (96.3 mg, 78%): mp = 136ꢀ139 °C; H NMR (300
MHz, CDCl3) δ 7.70 (ddd, J = 0.6, 1.3, 7.5 Hz, 1 H), 7.60ꢀ7.41 (m,
6 H), 7.18 (td, J = 0.8, 7.6 Hz, 1 H), 6.91 (d, J = 8.1 Hz, 1 H); 13C NMR
(75 MHz, CDCl3) δ 183.1, 157.5, 151.9, 138.5, 133.4, 130.2, 129.0,
126.2, 125.8, 124.5, 117.7, 111.5; HRMS (EI) calcd for [M þ H]þ (M =
C14H9NO2) 224.0706, found 224.0707.
1-p-Tolylindoline-2,3-dione (2aa). The product was isolated as
a red-orange solid (97.2 mg, 82%): mp = 137ꢀ139 °C; 1H NMR (400
MHz, CDCl3) δ 7.80 (d, J = 7.5 Hz, 1 H), 7.66 (t, J = 7.3 Hz, 1 H), 7.49
(d, J = 8.2 Hz, 2 H), 7.42 (d, J = 8.3 Hz, 2 H), 7.30 (d, J = 7.5 Hz, 1 H),
7.00 (d, J = 8.1 Hz, 1 H), 2.56 (s, 3 H); 13C NMR (100 MHz, CDCl3)
δ 183.2, 157.6, 152.0, 139.1, 138.5, 130.7, 130.3, 126.0, 125.6, 124.3,
117.6, 111.4, 21.4; HRMS (EI) calcd for C15H11NO2 237.0790, found
237.0791.
Methyl 2-(Naphthalen-1-ylamino)-2-oxoacetate (17a). The
product was isolated as a white solid: mp = 112ꢀ114 °C; 1H NMR (400
MHz, CDCl3) δ 9.41 (s, 1 H), 8.12 (d, J = 7.5 Hz, 1 H), 7.86ꢀ7.84 (m,
1-(4-Phenoxyphenyl)indoline-2,3-dione (3aa). The product
was isolated as a yellow-orange solid (129.2 mg, 82%): mp =
1
2 H), 7.72 (d, J = 8.2 Hz, 1 H), 7.56ꢀ7.46 (m, 3 H), 3.98 (s, 3 H); 13
C
145ꢀ148 °C; H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 7.4 Hz,
1 H), 7.54 (t, J = 7.8 Hz, 1 H), 7.40ꢀ7.34 (m, 4 H), 7.18ꢀ7.11 (m, 4 H),
7.07 (d, J = 8.2 Hz, 2 H), 6.88 (d, J = 7.97 Hz, 1 H); 13C NMR (100
MHz, CDCl3) δ 183.0, 157.9, 157.6, 156.2, 151.8, 138.5, 130.1, 127.7,
127.4, 125.6, 124.4, 124.3, 119.8, 119.5, 117.5, 111.3; HRMS (EI) calcd
for C20H13NO3 315.0895, found 315.0899.
NMR (100 MHz, CDCl3) δ 161.7, 154.2, 134.0, 130.7, 129.0, 126.8, 126.6,
126.4, 126.2, 125.8, 120.1, 119.7, 54.3; HRMS (EI) calcd for [M þ H]þ
(M = C13H11NO3) 230.0812, found 230.0810.
Methyl 2-[(2-Iodophenyl)amino]-2-oxoacetate (18a). The
product was isolated as a light brown solid: mp = 116ꢀ118 °C; 1H NMR
(400 MHz, CDCl3) δ 9.29 (s, 1 H), 8.28 (d, J = 8.0 Hz, 1 H), 7.78 (d, J =
7.6 Hz, 1 H), 7.35 (t, J = 7.4 Hz, 1 H), 6.88 (t, J = 7.1 Hz, 1 H), 3.96
(s, 3 H); 13C NMR (75 MHz, CDCl3) δ 161.1, 153.7, 139.2, 137.0,
129.5, 127.2, 121.5, 89.8, 54.3; HRMS (EI) calcd for [M þ H]þ (M =
C9H8INO3) 305.9622, found 305.9629.
1-(4-Fluorophenyl)indoline-2,3-dione (4aa). The product was
isolated as a bright orange solid (108.5 mg, 90%): mp = 235ꢀ237 °C; 1H
NMR (400 MHz, CDCl3) δ 7.72 (d, J = 7.5 Hz, 1 H), 7.57 (t, J = 7.8 Hz,
1 H), 7.44ꢀ7.40 (m, 2 H), 7.29ꢀ7.24 (m, 2 H), 7.20 (t, J = 7.6 Hz, 1 H),
6.86 (d, J = 8.0 Hz, 1 H); 13C NMR (100 MHz, CDCl3, extra peaks due to
CꢀF coupling) δ 182.8, 163.7, 161.2, 157.6, 151.7, 138.6, 129.0, 128.9,
128.3, 128.2, 125.9, 124.7, 117.7, 117.4, 117.2, 111.3; HRMS (EI) calcd for
C14H8FNO2 241.0539, found 241.0539.
1-(4-Chlorophenyl)indoline-2,3-dione (5aa). The product
was isolated as an orange solid (82.2 mg, 64%): mp = 194ꢀ197 °C;
1H NMR (400 MHz, CDCl3) δ 7.71 (d, J = 7.5 Hz, 1 H), 7.59ꢀ7.53
(m, 3 H), 7.39 (d, J = 8.6 Hz, 2 H), 7.20 (t, J = 7.6 Hz, 1 H), 6.90 (d, J =
6.9 Hz, 1 H); 13C NMR (100 MHz, CDCl3) δ 182.6, 157.4, 151.3, 138.6,
134.7, 131.5, 130.4, 127.5, 126.0, 124.7, 117.7, 111.3; HRMS (EI) calcd
for C14H8ClNO2 257.0244, found 257.0248.
Dimethyl 2,20-[1,3-Phenylenebis(azanediyl)]bis(2-oxoacetate)
(22a). The product was isolated as a white solid: mp = 186ꢀ191 °C; 1H
NMR (400 MHz, DMSO-d6) δ 10.85 (s, 2 H), 8.21 (s, 1 H), 7.47 (d, J = 7.2
Hz, 2 H), 7.31 (t, J = 7.8 Hz, 1 H), 3.83 (s, 6 H); 13C NMR (100 MHz,
DMSO-d6) δ161.7, 156.1, 138.4, 129.7, 117.8, 113.5, 53.83; HRMS (EI) calcd
for [M þ H]þ (M = C12H12N2O6) 281.0768, found 281.0771.
Experimental Procedure for 2-Oxo-N,2-diphenylaceta-
mide (23a). To a cold solution (0 °C) of 2-oxo-2-phenylacetic acid
(11 mmol, 1.65 g) in anhydrous dichloromethane (25 mL) was added
oxalyl chrolide (12 mmol, 1.03 mL) followed by anhydrous DMF
(1.3 mmol, 0.1 mL) via syringe in a dropwise fashion (Caution! The
addition of DMF can initiate an extremely rapid release of gas if added
1-(4-Bromophenyl)indoline-2,3-dione (6aa). The product was
1
isolated as a light orange solid (97.8 mg, 65%): mp = 178ꢀ180 °C; H
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NMR (400 MHz, CDCl3) δ 7.69ꢀ7.66 (m, 3 H), 7.56 (t, J = 7.8 hz, 1 H),
7.32 (d, J = 8.5 Hz, 2 H), 7.20 (t, J = 7.5 Hz, 1 H), 6.90 (d, J = 8.0 Hz, 1 H);
13C NMR (100 MHz, CDCl3) δ 182.5, 157.2, 151.1, 138.6, 133.3, 132.0,
127.7, 125.9, 124.7, 122.6, 117.6, 111.3; HRMS (EI) calcd for C14H8BrNO2
300.9738, found 300.9742.
7.02ꢀ6.96 (m, 2 H), 6.86 (d, J = 2.6 Hz, 1 H), 6.59 (d, J = 8.0 Hz, 1 H),
3.77 (s, 3 H), 3.73 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 183.1,
157.7, 154.0, 152.2, 149.3, 138.4, 125.3, 124.0, 121.6, 117.6, 116.0, 114.7,
113.7, 111.8, 56.4, 56.0; HRMS (EI) calcd for C16H13NO4 283.0845,
found 283.0839.
1-(4-Iodophenyl)indoline-2,3-dione (7aa). The product was
1-Mesitylindoline-2,3-dione (16aa). The product was isolated
as a yellow-orange solid (88.8 mg, 67%): mp = 164ꢀ168 °C; 1H NMR
(400 MHz, CDCl3) δ 7.70 (d, J = 7.2 Hz, 1 H), 7.51 (t, J = 7.7 Hz, 1 H),
7.16 (t, J = 7.5 Hz, 1 H), 7.03 (s, 2 H), 6.44 (d, J = 7.8 Hz, 1 H), 2.35 (s,
3 H), 2.14 (s, 6 H); 13C NMR (100 MHz, CDCl3) δ 183.2, 157.5, 151.7,
139.8, 138.8, 136.3, 129.9, 128.0, 125.8, 124.3, 117.7, 111.2, 21.3, 18.1;
HRMS (EI) calcd for C17H15NO2 265.1100, found 265.1103.
1-(Naphthalen-1-yl)indoline-2,3-dione (17aa). The product
was isolated as an orange solid (120.2 mg, 88%): mp = 130ꢀ133 °C; 1H
NMR (400 MHz, CDCl3) δ 8.02 (d, J = 8.2 Hz, 1 H), 7.98 (d, J = 8.2 Hz,
1 H), 7.75 (d, J = 7.3 Hz, 1 H), 7.70 (t, J = 8.4 Hz, 1 H), 7.64ꢀ7.49 (m,
4 H) 7.45 (td, J = 1.1, 7.9 Hz, 1 H), 7.17 (t, J = 7.5 Hz, 1 H), 6.44 (d, J =
8.0 Hz, 1 H); 13C NMR (100 MHz, CDCl3) δ 183.1, 158.2, 152.8, 138.8,
135.0, 130.4, 129.5, 129.0, 127.6, 127.1, 126.2, 126.0, 125.7, 124.4, 122.6,
117.6, 112.0; HRMS (EI) calcd for C18H11NO2 273.0790, found
273.0786.
1
isolated as an orange solid (125.6 mg, 72%): mp = 198ꢀ201 °C; H
NMR (400 MHz, CDCl3) δ 7.88 (d, J = 8.5 Hz, 2 H), 7.69 (d, J = 7.51
Hz, 1 H), 7.56 (t, J = 7.8 Hz, 1 H), 7.21ꢀ7.17 (m, 3 H), 6.90 (d, J = 8.0
Hz, 1 H); 13C NMR (100 MHz, CDCl3) δ 182.5, 157.2, 151.1, 139.3,
138.6, 132.7, 127.8, 126.0, 124.8, 117.6, 111.3, 94.1; HRMS (EI) calcd
for C14H8INO2 348.9600, found 348.9601.
4-(2,3-Dioxoindolin-1-yl)benzonitrile (9aa). The product was
isolated as a light orange solid (77.2 mg, 62%): mp = 282ꢀ284 °C; 1H
NMR (400 MHz, CDCl3) δ 8.08 (d, J = 8.3 Hz, 2 H), 7.714ꢀ7.705 (m,
3 H), 7.64 (t, J = 7.8 Hz, 1 H), 7.23 (t, J = 7.51 Hz, 1 H), 6.99 (d, J = 7.9
Hz, 1 H); 13C NMR (100 MHz, CDCl3) δ 181.9, 157.2, 150.0, 137.9,
137.6, 133.8, 127.0, 124.9, 124.1, 118.4, 117.9, 110.9, 110.5; HRMS (EI)
calcd for [M þ H]þ (M = C15H8N2O2) 249.0659, found 249.0656.
Ethyl 4-(2,3-Dioxoindolin-1-yl)benzoate (10aa). The pro-
duct was isolated as a light orange solid (100.3 mg, 68%): mp =
1
127ꢀ129 °C; H NMR (400 MHz, CDCl3) δ 8.21 (d, J = 8.6 Hz,
1-(2-Iodophenyl)indoline-2,3-dione (18aa). The product was
1
2 H), 7.70 (d, J = 7.5 Hz, 1 H), 7.59ꢀ7.52 (m, 3 H), 7.20 (t, J = 7.5 Hz,
1 H), 6.97 (d, J = 8.1 Hz, 1 H), 4.40 (q, J = 7.1 Hz, 2 H), 1.41 (t, J = 7.1
Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ 182.3, 165.6, 157.1, 150.9,
138.6, 136.9, 131.3, 130.6, 126.0, 125.5, 124.8, 117.7, 111.4, 61.5, 14.5;
HRMS (EI) calcd for C17H13NO4 295.0839, found 295.0845.
1-[4-(Trifluoromethyl)phenyl]indoline-2,3-dione (11aa).
The product was isolated as a bright orange solid (74.2 mg, 51%):
mp = 177ꢀ181 °C; 1H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 8.4 Hz,
2 H), 7.73 (d, J = 6.9 Hz, 1 H), 7.62ꢀ7.59 (m, 3 H), 7.23 (t, J = 7.5 Hz,
1 H), 6.98 (d, J = 8.1 Hz, 1 H); 13C NMR (100 MHz, CDCl3, extra peaks
due to CꢀF coupling) δ 182.2, 157.2, 150.8, 138.7, 136.2, 131.0, 130.6,
128.9, 127.33, 127.29, 127.26, 127.22, 126.3, 126.1, 125.1, 125.0, 122.4,
117.7, 111.3; HRMS (EI) calcd for C15H8F3NO2 291.0507, found
291.0509.
isolated as a ruby red solid (156.2 mg, 84%): mp = 173ꢀ176 °C; H
NMR (400 MHz, CDCl3) δ 8.01 (d, J = 7.9 Hz, 1 H), 7.70 (d, J = 7.4 Hz,
1 H), 7.53ꢀ7.51 (m, 2 H), 7.36 (d, J = 7.6 Hz, 1 H), 7.26ꢀ7.15 (m, 2 H),
6.49 (d, J = 8.0 Hz, 1 H); 13C NMR (100 MHz, CDCl3) δ 182.6, 157.0,
151.3, 140.8, 138.7, 136.2, 131.5, 130.2, 129.7, 125.8, 124.5, 117.4, 111.8,
98.1; HRMS (EI) calcd for [M þ Na]þ (M = C14H8INO2) 371.9492,
found 371.9497.
4-Methoxy-1-phenylindoline-2,3-dione (19aa). The pro-
duct was isolated as a dark orange solid (118.1 mg, 93%): mp =
1
198ꢀ202 °C; H NMR (400 MHz, CDCl3) δ 7.54 (t, J = 6.9 Hz,
2 H), 7.49ꢀ7.38 (m, 4 H), 6.66 (d, J = 8.6 Hz, 1 H), 6.42 (d, J = 7.9 Hz,
1 H), 4.00 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 179.5, 159.2, 157.9,
152.5, 140.4, 133.2, 130.0, 128.9, 126.5, 107.9, 106.1, 103.7, 56.6; HRMS
(EI) calcd for [M þ Na]þ (M = C15H11NO3) 254.0812, found
254.0812.
1-[3-(Trifluoromethyl)phenyl]indoline-2,3-dione (12aa).
The product was isolated as a yellow-orange solid (80.0 mg, 55%):
3-Phenyl-1H-benzo[e]indole-1,2(3H)-dione (20aa). The pro-
duct was isolated as a dark red solid (87.9 mg, 61%): mp = 221ꢀ224 °C;
1H NMR (400 MHz, CDCl3) δ 8.71 (d, J = 8.4 Hz, 1 H), 8.06 (d, J =
8.8 Hz, 1 H), 7.79 (d, J = 8.1 Hz, 1 H), 7.69 (t, J = 7.6 Hz, 1 H), 7.45 (d, J =
7.4 Hz, 1 H), 7.38 (d, J = 8.0 Hz, 2 H), 7.32 (d, J = 8.0 Hz, 2 H), 7.08 (d, J =
8.7 Hz, 1 H), 2.46 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 182.3, 158.4,
155.4, 140.7, 139.2, 131.7, 130.9, 130.6, 130.4, 129.5, 129.3, 126.4, 126.0,
123.8, 111.6, 109.4, 21.6; HRMS (EI) calcd for [M þ H]þ (M =
C19H13NO2) 288.1019, found 288.1012.
1
mp = 124ꢀ127 °C; H NMR (400 MHz, CDCl3) δ 7.74ꢀ7.65 (m,
5 H), 7.60 (td, J = 1.2, 8.0 Hz, 1 H), 7.23 (t, J = 7.6 Hz, 1 H), 6.92 (d, J =
8.1 Hz, 1 H); 13C NMR (100 MHz, CDCl3, extra peaks due to CꢀF
coupling) δ 182.3, 157.3, 150.9, 138.7, 133.7, 130.9, 129.6, 126.1,
125.74, 125.70, 125.0, 123.04, 123.00, 117.7, 111.2; HRMS (EI) calcd
for C15H8F3NO2 291.0507, found 291.0507.
1-(2-tert-Butylphenyl)indoline-2,3-dione (13aa). The product
was isolated as a light orange solid (114.4 mg, 82%): mp = 109ꢀ113 °C; 1H
NMR (400 MHz, CDCl3) δ 7.66 (t, J = 7.9 Hz, 2 H), 7.51 (td, J = 1.1,
7.8 Hz, 1 H), 7.44 (t, J = 7.7 Hz, 1 H), 7.34 (td, J = 1.3, 7.5 Hz, 1 H), 7.14
(t, J = 7.5 Hz, 1 H), 7.05 (dd, J = 1.4, 7.8 Hz, 1 H), 6.42 (d, J = 8.0 Hz, 1 H),
1.32 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 183.4, 159.2, 154.1, 149.6,
138.7, 131.7, 130.5, 130.2, 129.4, 128.4, 125.4, 124.2, 11.8, 112.7, 35.8, 31.9;
HRMS (EI) calcd for C18H17NO2 279.1259, found 279.1265.
5,6-Dimethoxy-1-phenylindoline-2,3-dione (21aa). The pro-
duct was isolated as a dark red solid (128.2 mg, 86%): mp =211ꢀ214 °C;
1H NMR (400 MHz, CDCl3) δ 7.34 (d, J = 8.4 Hz, 2 H), 7.26 (d, J = 8.0
Hz, 2 H), 7.15 (s, 2 H), 3.871 (s, 3 H), 3.867 (s, 3 H), 2.42 (s, 3 H); 13C
NMR (100 MHz, CDCl3) δ 180.7, 158.8, 158.4, 150.0, 146.3, 138.9, 130.8,
130.4, 126.1, 109.2, 107.4, 95.4, 56.9, 56.7, 21.5; HRMS (EI) calcd for
[M þ H]þ (M = C17H15NO4) 298.1074, found 298.1068.
1-[(1,10-Biphenyl)-2-yl]indoline-2,3-dione (14aa). The pro-
duct was isolated as a red solid (119.6 mg, 80%): mp = 157ꢀ162 °C; 1H
NMR (400 MHz, CDCl3) δ 7.56ꢀ7.53 (m, 4 H), 7.40ꢀ7.36 (m, 2 H),
7.26ꢀ7.23 (m, 5 H), 7.03 (t, J = 7.3 Hz, 1 H), 6.48 (d, J = 7.5 Hz, 1 H);
13C NMR (100 MHz, CDCl3) δ 182.8, 158.0, 152.2, 141.1, 138.3, 138.2,
131.7, 130.6, 130.1, 129.3, 128.74, 128.69, 128.2, 128.1, 125.4, 124.1,
117.2, 111.6; HRMS (EI) calcd for C20H13NO2 299.0946, found
299.0946.
Experimental Procedure for 1,10-(1,3-Phenylene)bis-
(indoline-2,3-dione) (22aa). To a dry 5 dram vial containing
a solution of the amide (0.5 mmol) and the aryne precursor
(1.75 mmol, 0.522 g) in anhydrous THF (5 mL) was added TBAT
(2.33 mmol, 1.257 g). The vial was sealed, placed in an oil bath at
50 °C, and allowed to stir for 20 h. The reaction mixture was then
filtered through a plug of silica gel using ethyl acetate, concentrated in
vacuo, and purified by flash chromatography using gradient solvent
combinations of ethyl acetate/hexanes. The product was isolated as
1-(2,4-Dimethoxyphenyl)indoline-2,3-dione (15aa). The
product was isolated as an orange solid (106.2 mg, 75%): mp =
1
1
114ꢀ117 °C; H NMR (400 MHz, CDCl3) δ 7.64 (dd, J = 0.7, 7.5
a light orange solid (78.2 mg, 40%): mp = 328ꢀ331 °C; H NMR
Hz, 1 H), 7.49 (t, J = 1.4, 7.9 Hz, 1 H), 7.11 (td, J = 0.73, 7.5 Hz, 1 H),
(300 MHz, DMSO-d6) δ 7.82 (t, J = 7.9 Hz, 1 H), 7.69ꢀ7.60 (m, 7 H),
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7.22 (t, J = 7.5 Hz, 2 H), 7.00 (d, J = 7.8 Hz, 2 H); 13C NMR (75 MHz,
DMSO-d6) δ 187.7, 182.4, 157.4, 150.7, 137.9, 134.3, 130.8, 126.0,
124.8, 123.8, 117.8, 110.8; HRMS (EI) calcd for [M þ H]þ (M =
C22H12N2O4) 369.0870, found 369.0869.
Chem. 1990, 33, 2358. (c) Sarges, R.; Howard, H. R.; Koe, B. K.;
Weissman, A. J. Med. Chem. 1989, 32, 437.
(10) Peet, N. J. Heterocycl. Chem. 1990, 17, 1513.
(11) For reviews, see: (a) Chen, Y.; Larock, R. C. In Modern
Arylation Methods; Ackerman, J., Ed.; Wiley/VCH: New York, 2009,
pp 401. (b) Sanz, R. Org Prep. Proced. Int. 2008, 40, 215.
(12) (a) Liu, Z.; Larock, R. C. J. Org. Chem. 2006, 71, 3198. (b) Liu,
Z.; Larock, R. C. Org. Lett. 2003, 5, 4673. (c) Liu, Z.; Larock, R. C. Org.
Lett. 2004, 6, 99.
(13) Liu, Z.; Larock, R. C. J. Am. Chem. Soc. 2005, 127, 13112.
(14) Pintori, D. G.; Greaney, M. F. Org. Lett. 2010, 12, 168.
(15) Yoshida, H.; Shirakawa, E.; Honda, Y.; Hiyama, T. Angew.
Chem., Int. Ed. 2002, 41, 3246.
Experimental Procedure for 3-Hydroxy-1,3-diphenylindo-
lin-2-one (23aa). To a dry 5 dram vial containing a solution of the
amide (0.5 mmol) and the aryne precursor (0.875 mmol, 0.261 g) in
THF (5 mL, anhydrous) was added TBAT (1.17 mmol, 0.629 g). The
vial was sealed, placed in an oil bath at 50 °C, and allowed to stir for 20 h.
The reaction mixture was then filtered through a plug of silica gel using
ethyl acetate, concentrated in vacuo, and purified by flash chromatogra-
phy using gradient solvent combinations of ethyl acetate/hexanes.
The product was isolated as a white solid (132.8 mg, 82%): mp =
(16) Zhao, J.; Larock, R. C. J. Org. Chem. 2007, 72, 583.
(17) Rogness, D. C.; Larock, R. C. Tetrahedron Lett. 2009, 50, 4003.
(18) Liu, Z.; Larock, R. C. J. Org. Chem. 2006, 71, 3198.
(19) Peddibhotla, S. Curr. Bioact. Compd. 2009, 5, 20.
1
166ꢀ170 °C; H NMR (400 MHz, CDCl3) δ 7.57ꢀ7.26 (m, 12 H),
7.12 (t, J = 7.5 Hz, 1 H), 6.90 (d, J = 7.9 Hz, 1 H), 3.82 (s, 1 H); 13C
NMR (100 MHz, CDCl3) δ 177.1, 143.5, 140.5, 134.1, 131.5, 129.9
(3 C), 128.9 (2 C), 128.53, 128.49, 126.6 (2 C), 125.5 (3 C), 124.2,
110.2, 78.3; HRMS (EI) calcd for [M þ Na]þ (M = C20H15NO2)
324.0995, found 324.1002.
’ ASSOCIATED CONTENT
S
Supporting Information. Copies of NMR spectra for all
b
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: larock@iastate.edu.
’ ACKNOWLEDGMENT
We gratefully acknowledge the National Science Foundation
for funding this work. We would also like to thank Dr. Feng Shi
for his help in preparing benzyne precursors and Dr. Jesse Waldo
and Anton Dubrovskiy for their advice.
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