Metal-free intermolecular oxidative C-N bond formation via tandem C-H and N-H bond functionalization

Article abstract of DOI:10.1021/ja2087085

The development of a novel intermolecular oxidative amination reaction, a synthetic transformation that involves the simultaneous functionalization of both a N-H and C-H bond, is described. The process, which is mediated by an I(III) oxidant and contains no metal catalysts, provides a rapid and green method for synthesizing protected anilines from simple arenes and phthalimide. Mechanistic investigations indicate that the reaction proceeds via nucleophilic attack of the phthalimide on an aromatic radical cation, as opposed to the electrophilic aromatic amination that has been reported for other I(III) amination reactions. The application of this new reaction to the synthesis of a variety of substituted aniline derivatives is demonstrated.

Full text of DOI:10.1021/ja2087085

ARTICLE
pubs.acs.org/JACS
Metal-Free Intermolecular Oxidative CÀN Bond Formation via
Tandem CÀH and NÀH Bond Functionalization
Abhishek A. Kantak, Shathaverdhan Potavathri, Rose A. Barham, Kaitlyn M. Romano, and Brenton DeBoef*
Department of Chemistry, University of Rhode Island, 51 Lower College Road, Kingston, Rhode Island 02881, United States
S Supporting Information
b
ABSTRACT: The development of a novel intermolecular oxidative
amination reaction, a synthetic transformation that involves the
simultaneous functionalization of both a NÀH and CÀH bond, is
described. The process, which is mediated by an I(III) oxidant and
contains no metal catalysts, provides a rapid and green method for
synthesizing protected anilines from simple arenes and phthalimide.
Mechanistic investigations indicate that the reaction proceeds via
nucleophilic attack of the phthalimide on an aromatic radical cation, as
opposed to the electrophilic aromatic amination that has been
reported for other I(III) amination reactions. The application of this new reaction to the synthesis of a variety of substituted
aniline derivatives is demonstrated.
’ INTRODUCTION
The formation of carbonÀcarbon (CÀC) bonds via the oxidative
cross-coupling of two carbonÀhydrogen (CÀH) bonds has
recently become a field of intense interest and has resulted
in the discovery of numerous novel synthetic methods.1
The analogous technology for the oxidative cross-coupling of
CÀH and nitrogenÀhydrogen (NÀH) bonds to form carbonÀ
nitrogen (CÀN) bonds would also be an important synthetic
advance, as amine and amide functional groups are ubiquitous in
biologically active molecules (Figure 1). However, a relatively
small amount of work has focused on the development of
oxidative methods for constructing N-arylamines and amides
via tandem CÀH/NÀH activation. The majority of literature in
this field describes the insertion of nitrenoid intermediates into
CÀH bonds, mediated by transition-metal catalysts.2 Cu and Pd-
Figure 1. Examples of high-value molecules containing anilines.
catalyzed reactions, as well as metal-free conditions, have also
been recently explored, but these methods are limited to the intramo-
lecular synthesis of carbazoles, oxindoles, and diazapenones.3À5
trace metals are not the cause of the transformation, as reactions
performed in new, acid-washed flasks were similar in both yield
The only reported examples of intermolecular oxidative amina-
and rate to those performed in old flasks. Furthermore, reagents
tion involve azole-type heterocycles and proceed by attack of an
amine nucleophile on the substrate’s imine moiety.6,7 Herein, we
disclose a novel intermolecular reaction that oxidatively con-
from different commercial sources perform similarly.
While optimizing the process, we quickly discovered that the
best conditions employed microwave heating and 2.5 equiv of the
I(III) oxidant, phenyliodine(III) diacetate (PIDA). Less than
structs the CÀN bond of phthalimide-protected anilines via the
tandem activation of NÀH and CÀH bonds.
2.5 equiv of PIDA did not allow the reactions to proceed to
completion (compare entries 2, 3, and 4 in Table 1).
Importantly, we found that the arene substrate does not need
’ DISCUSSION
to be in large excess (i.e., solvent) for the intermolecular oxidative
amination reaction to occur. This is in stark contrast to many of
the oxidative arylation reactions that have been previously
Reaction Discovery. We recently discovered that heating a
solution of phthalimide (1) and PhI(OAc)2 in benzene provides
the phthalimide-protected aniline (2) in an 88% yield (Table 1,
entry 4). We initially explored the potential of Cu(I)/(III)
catalysts to perform this oxidative amination but quickly realized
Received: September 15, 2011
Published: October 19, 2011
that a metal catalyst was not necessary.5 We are confident that
r
2011 American Chemical Society
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Table 1. Discovery of the Intermolecular Oxidative
Aminationa
Scheme 1. Oxidative Amination of Substituted Arenes
oxidant (equiv) solvent temp. (°C) time (h)
yield (%)c
1
2
PIDA (1.5)
PIDA (1.5)
PIDA (2.0)
PIDA (2.5)
PIDA (2.5)
PIDA (2.5)
PIDA (2.5)
PIDA (2.5)
PIDA (2.5)
NCS (2.5)
oxone (2.5)
IBX (2.5)
PhH
PhH
145b
145
145
145
120
145
145
145
145
145
145
145
145
145
100
25b
12
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
26
28
3
PhH
45
4
PhH
88
5
PhH
no reaction
6
TFE
13
4d
7
DMF
DMSO
MeCN
MeCN
MeCN
MeCN
PhH
8
no reaction
9
51
3d
10
11
12
13
14
15
16
17
18
no reaction
no reaction
PIFA (1.0)
PIFA (1.25)
PIFA (1.0)
PIFA (1.0)
PIFA (1.0)
PIFA (1.0)
5d
This confirmed our hypothesis that the source of the aryl group
that forms the new CÀN bond was the solvent, not the phenyl
group that resides on the oxidant.
PhH
decomposition
PhH
trace
0
3.5d
3.5d
PhH
Cleavage of the phthalimide protecting group allowed for the
determination of the regiomeric ratios by comparison to the
commercially available toluidine isomers. Interestingly, the major
product of the reaction was o-toluidine (4). Amination of the sp3-
hybridized CÀH bonds was not observed.
TFE
145
145
MeCN
a General reaction conditions: 1 (0.68 mmol), oxidant (1.5À2.5 equiv),
benzene (1.5 equiv or solvent), solvent (4 mL), microwave heating.
PIDA = phenyliodine(III) diacetate, PIFA = phenyliodine(III) bis-
(trifluoroacetate), NCS = N-chloro-succinimide, IBX = 2-iodoxybenzoic
acid, oxone = potassium peroxymonosulfate, TFE = 2,2,2-trifluoro-
ethanol. b Oil bath. c Yield of isolated product after column chromatog-
raphy. d GC yield calculated using dodecane as internal standard.
Substrate Scope. In addition to benzene, toluene, and
p-xylene, a variety of other simple arenes could be oxidatively
coupled to phthalimide (Table 2). Sterically encumbered arenes
(6) and those that contain electron-withdrawing groups (7À11)
were oxidatively aminated, albeit at reduced yields. Like toluene,
monosubstituted and asymmetrically disubstituted benzenes
produced mixtures of protected aniline products (10À19).
Electron-rich heterocycles, such as furan, decomposed under
the reaction conditions, and electron-poor heterocycles, such as
benzoxazole, failed to produce any aminated products.
studied.8 As shown in Table 1, entry 9, acetonitrile was used as
the solvent, and the concentration of the arene substrate was
lowered to a near-stoichiometric level (1.5 equiv). Under these
conditions, the yield for the amination of benzene dropped
from 88% to 51%, but we hypothesized that this was due to the
volatility of the arene. This was verified by the reaction of the
less volatile substrate, p-xylene, which provided an 80% yield
(Scheme 1A).
The regioselectivity of these amination reactions appears to be
slightly directed by electronic factors. For example, p-methylani-
sole was 50% more likely to be aminated at the position ortho to
the larger, but more electron-donating methoxy group (15).
Likewise, both the ortho and para positions of toluene were
67% more likely to be aminated than the meta position. The only
exception to this rule was the amination of p-tert-butylanisole (16),
where the size of the tert-butyl group prevented ortho-amination.
Other amine sources, in addition to phthalimide, were also
investigated. Succinimide also provided very good yields of
oxidative amination products (20), while pyrrolidin-2-one per-
formed the oxidative amination reaction but resulted in a poor
yield (16%, 21). N-tosylamide and pyrrolidine failed to oxida-
tively aminate benzene. These data led us to conclude that the
requirements for the amine coupling partner were two-fold: (1)
The NÀH bond must be relatively acidic (phthalimide pKa =
8.3), and (2) the amine coupling partner must be secondary,
preferably a cyclic imide. In keeping with these requirements,
other imides with acidic NÀH bonds performed the oxidative
amination reaction, albeit in lower yields (22À24). Surprisingly,
acyclic imides, such as diacetamide, N-acetylanilines, and hetercycles,
Other solvent and oxidant combinations proved to be less
effective. In particular, 2,2,2-trifluoroethanol (TFE), a solvent
that has been shown to be particularly compatible with I(III)-
mediated arene substitutions provided a minimal yield (Table 1,
entry 6). The fluorinated derivative of PIDA, phenlyiodine(III)
bis(trifluoroacetate) (PIFA), proved to be too harsh of an oxidant
for these reactions. Any loading of the oxidant in excess of 1 equiv
resulted in a complex mixture of products. Lowering the reaction
temperature and altering the cosolvent also failed to provide the
desired aniline 2 (Table 1, entries 13À18).
To determine whether the arene that participated in the oxidative
amination originated from the benzene solvent or the oxidant, a
crossover experiment was performed (Scheme 1B). When toluene
wasusedasthesolventandPhI(OAc)2 was the oxidant, the reaction
did not produce any N-phenylphthalimide (2). Rather, an insepar-
able mixture of regiomers arising from the oxidative amination
of the sp2-hybridized CÀH bonds of toluene was observed (3).
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Table 2. Substrate Scope of the Intermolecular Oxidative
Amination
Table 3. Competition Reactions
a Mole fractions determined by GC/MS.
Competition and Kinetic Studies. Competition studies were
performed to explore the mechanism of the novel process
(Table 3). In all cases, the amination of electron-rich arenes
was favored. In particular, the competition between p-xylene and
p-difluorobenzene shows a dramatic preference for the amination
of the electron-rich p-xylene substrate (Table 3, entry 2).
The kinetic isotope effect (KIE) of the reaction was assessed
using a competition experiment between equimolar amounts of
benzene and benzene-d6. The near-unity KIE of 1.03 implies that
CÀH bond breaking is not involved in the rate-determining step
of the reaction. This is also a stark contrast with the literature
describing oxidative arylation processes for forming CÀC bonds,
where CÀH bond breaking is often rate limiting, as indicated by
large KIEs.9 The KIE of the reaction involving equimolar
amounts of phthalimide and phthalimide-d was observed to be
0.98, which indicates that the cleavage of the NÀH bond is also
not rate limiting.
Kinetic analysis of the oxidative amination provided more
mechanistic clues. The reaction rate was unaffected by changing
the concentration of the arene but was dependent on the con-
centration of the both oxidant and phthalimide. Both reagents
demonstrated first-order dependencies (Figure 2).
The preference for imides and electron-rich arenes is consis-
tent with two possible mechanisms (Scheme 2). The first in-
volves the in situ formation of a PhI(OAc)(NR2) species (25
and 26), which is highly electrophilic, functioning essentially as
an R2N+ equivalent.10 Electrophilic aromatic substitution then
forms the desired CÀN bond (2) (Scheme 2A).11 Alternatively,
a single electron transfer may occur, forming an ion pair with the
arene substrate and the I(III) reagent. The radical cation 27
could then undergo a nucleophilic attack by phthalimide (or its
anion), giving rise to the desired product (3, Scheme 2B). Kita
has previously described such a mechanism for oxidative reac-
tions between arenes and soft nucleophiles, such as β-diketones
and TMS-N3.12
a 1 (0.68 mmol), PhI(OAc)2 (2.5 equiv), 4 mL of arene substrate,
145 °C (microwave), 3 h. b 1 (0.68 mmol), PhI(OAc)2 (2.5 equiv),
Arene substrate (1.5 equiv.), 4 mL of acetonitrile, 145 °C (microwave),
c
3 h. Amide substrate (0.68 mmol), PhI(OAc)2 (2.5 equiv), 4 mL of
N-centered radicals have also been proposed in I(III)
mediated CÀN forming reactions,13 but they are not likely to
be involved in the reactions shown in Table 1. The weaker CÀH
bonds of the methyl group of toluene were not aminated, as one
would expect for reactions involving N-centered radicals.
benzene, 145 °C (microwave), 3 h.
such as indole and benzimidazole, produced only trace amounts
of products.
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Scheme 3. Resonance Structures of the Aryl Radical Cation
Explain the Observed Regioselectivities
Scheme 4. Formation of Substitution Products Corroborates
the Intermediacy of Arene Radical Cations
Figure 2. Kinetic analysis of oxidative amination reaction with various
amounts of PhI(OAc)2 (oxidant) and phthalimide.
Scheme 2. Two Possible Mechanisms for the Oxidative
Amination
the ratio of products obtained from the oxidative amination of
toluene (3) are not indicative of the expected EAS regioselec-
tivity (Scheme 2A). While the ortho- and para-aminated pro-
ducts were somewhat favored in the reaction of arenes containing
electron-donating groups, reactions operating via SEAr mechan-
isms tend to form little, if any, meta-substituted products.
Alternatively, PhI(OAc)2 could oxidize the electron-rich arene
substrate to a radical cation (27), and nucleophilic attack on such a
radical cation should be relatively nonregioselective (Scheme 2B).
The consequent radical intermediate (28) could then be oxidized to
form a Wheland-type arenium ion. These two individual oxidation
steps may indicate why two equivalents of PhI(OAc)2 are required to
achieve complete conversion. The fates of the reduced iodine
intermediates are less clear, but the two other byproducts that are
observed in all of these reactions are iodobenzene and phenyl acetate.
Consequently, we hypothesize that a single electron-transfer
mechanism is operating in these oxidative amination reactions. This
hypothesis is supported by the observation that the reaction was
partially inhibited by BHT and completely inhibited by TEMPO,
common radical inhibitors. Our hypothesis is supported by the
prior work of Kita, who has extensively shown that arene radical
cation intermediates, such as 27, are formed by the action of I(III)
oxidants and can be directly observed by EPR spectroscopy.12
It should be noted that Cho and Chang have recently proposed
an electrophilic mechanism for the same reaction described
herein.7b This hypothesis was supported by the observation of
25 by mass spectrometry. In comparing our data with those of Kita
and both Cho and Chang, it seems likely that several I(III) species
Proposed Mechanism. Based these data, a mechanism invol-
ving electrophilic aromatic substitution (EAS) seems unlikely, as
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are simultaneously present in solution. However, we reason that the
observed regioselectivities for aminations of monosubstituted arenes
that were observed by both us and Cho and Chang are best
explained by the intermediacy of a radical cation intermediate (27).
Furthermore, the unique regioselectivities that were observed
in the oxidative amination of toluene (o:m:p = 10:6:5) corrobo-
rate the intermediacy of an aromatic radical cation (Scheme 3).
The yields of ortho- and para-aminated products, which arise
from the nucleophilic attack on resonance forms 27b and 27c, are
statistically equivalent. This seems plausible as both contain a
tertiary radical and a secondary carbocation. Additionally, reac-
tions with p-methylanisole and p-tert-butylanisole (28) not only
produced the aforementioned aminated products (14À16), but
substitution products, arising from SNAr-type attack on the
tertiary cation intermediate (29b) followed by ejection of the
methoxide leaving group (30), were also observed (Scheme 4).
132.05, 133.27, 134.29, 136.72, 167.47. LRMS EI (m/z): [M+] calcd for
C16H13NO2 251.09, observed 251.10 m/z.
2-(Perfluorophenyl)isoindoline-1,3-dione 7. Yield = 7 0.04 g (20%).
Rf = 0.18, hexane/ethyl acetate (9:1 v/v). 1H NMR (300 MHz, CDCl3):
δ = 7.87 (dd, J = 3 Hz, J = 3 Hz, 2H), 8.01 (dd, J = 3 Hz, J = 3 Hz, 2H).
13C NMR (75 MHz, CDCl3): δ = 123.89, 123.91, 124.35, 124.5, 125.82,
128.13, 131.69, 134.62, 134.88, 134.95, 135.05, 138.27. LRMS EI (m/z):
[M+] calcd for C14H4 F5NO2 313.02, observed 313.0 m/z
2-(2, 5-Difluorophenyl)isoindoline-1,3-dione 8. Yield = 0.0917 g
(53%). Rf = 0.19, hexane/ethyl acetate (9:1 v/v). 1H NMR (300 MHz,
CDCl3): δ = 7.12À7.26 (m, 3H), 7.82 (dd, J = 3 Hz, J = 3 Hz, 2H), 7.98
(dd, J = 3 Hz, J = 3 Hz, 2H). 13C NMR (75 MHz, CDCl3): δ = 116.00,
116.30, 116.64, 124.10, 128.44, 131.77, 134.67, 166.06, 167.22. LRMS
EI (m/z): [M+] calcd for C14H7F2NO2 259.04, observed 259.1 m/z.
2-(2, 5-bis(Trifluoromethyl)phenyl)isoindoline-1, 3-dione 9. Yield =
0.2441 g (24%). Rf = 0.2187, hexane/ethyl acetate (9:1 v/v) . 1H NMR
(300 MHz, CDCl3): δ = 7.22À7.26 (m, 1H), 7.67 (s, 1H), 7.82À8.02
(m, 5H). 13C NMR (75 MHz, CDCl3): δ = 123.89, 124.25, 127.18,
128.13, 129.00, 130.48, 131.72, 134.63, 134.82, 138.27, 166.66. LRMS
EI (m/z): [M+] calcd for C16H7 F6NO2 359.0, observed 359.0 m/z.
2-(3,4-Dichlorophenyl)isoindoline-1,3-dione 10. Yield = 0.1118 g
(56%). Rf = 0.19, hexane/ethyl acetate (9:1 v/v). 1H NMR (300 MHz,
CDCl3): δ = 7.37 (dd, J = 8.6, 2.4 Hz, 1H), 7.58 (d, J = 8.6 Hz, 1H), 7.64
(d, J = 2.4 Hz, 1H), 7.86 À 7.79 (m, 2H), 7.98 À 7.94 (m, 2H). 13C
NMR (75 MHz, CDCl3): δ = 124.01, 125.53, 128.16, 130.70, 131.05,
131.43, 132.12, 133.02, 134.77, 166.63. LRMS EI (m/z): [M+] calcd for
C14H7F2NO2 291.0, observed 291.0 m/z.
2-(2,3-Dichlorophenyl)isoindoline-1,3-dione 11. Yield = 0.034 g
(17%). Rf = 0.09, hexane/ethyl acetate (9:1 v/v). 1H NMR (300
MHz, CDCl3): δ = 7.27À7.4 (m, 2H), 7.59À7.62 (m, 1H), 7.83 (dd,
J = 3, 3 Hz, 2H), 7.99 (dd, J = 3 Hz, 3 Hz, 2H). 13C NMR (75 MHz,
CDCl3): δ = 124.11, 127.71, 128.97, 131.32, 131.49, 131.75, 132.32,
134.35, 134.66, 166.37. LRMS EI (m/z): [M+] calcd for C14H7F2NO2
291.0, observed 291.0 m/z.
14 and 15: Yield = 0.1287 g (70%, 14:15 = 2:3). Rf = 0.1714, hexane/
ethyl acetate (9:1 v/v) . 1H NMR (300 MHz, CDCl3): δ = 2.13 (s, 2H),
2.34 (s, 3H), 3.78 (dd, J = 9.6, 2.1 Hz, 6H), 6.75 (d, J = 2.5 Hz, 1H), 6.95
(d, J = 8.4 Hz, 2H), 7.07 (s, 1H), 7.20 À 7.30 (m, 3H), 7.76À7.82 (m,
4H), 7.91À7.99 (m, 4H). 13C NMR (75 MHz, CDCl3): δ = 17.15,
20.40, 55.45, 55.91, 112.02, 113.85, 115.65, 119.75, 123.66, 123.80,
128.29, 130.38, 131.16, 131.70, 131.96, 132.24, 134.10, 134.36, 153.22,
158.27, 167.30, 167.53. LRMS EI (m/z): [M+] calcd for C14H9NO2
267.09, observed 267.10 m/z.
12 and 13: Yield = 0.1333 g (80%, 12:13 = 3:4). Rf = 0.22, hexane/
ethyl acetate (9:1 v/v) . 1H NMR (300 MHz, CDCl3): δ = 2.08 (s, 3H),
2.31 (s, 5H), 2.35 (s, 3H), 7.23À7.28 (m, 7H), 7.76À7.81 (m, 4H),
7.93À7.98 (m, 4H). 13C NMR (75 MHz, CDCl3): δ = 14.67, 19.55,
19.91, 20.45, 123.67, 123.77, 124.16, 126.28, 127.76, 129.12, 130.29,
130.48, 131.00, 131.88, 132.06, 134.29, 135.13, 137.07, 137.66, 138.43,
167.57. LRMS EI (m/z): [M+] calcd for C14H9NO2 251.09, observed
251.10 m/z.
17, 18, and 19: Yield = 0.128 g (75%, 17:18:19 = 4:3:4). Rf = 0.1666,
hexane/ethyl acetate (9:1 v/v). 1H NMR (300 MHz, CDCl3): δ = 2.17
(s, 9H), 2.38 (s, 7H), 7.32À6.99 (m, 11H), 7.76À7.84 (m, 6H),
7.92À8.00 (m, 6H). 13C NMR (75 MHz, CDCl3): δ = 17.94, 18.09,
21.21, 21.31, 123.73, 123.79, 124.52, 127.65, 127.85, 128.45, 128.49,
129.48, 130.16, 131.91, 132.07, 134.26, 134.33, 136.16, 136.86, 138.93,
139.50, 167.55. LRMS EI (m/z): [M+] calcd for C14H9NO2 251.09,
observed 251.10 m/z.
’ CONCLUSION
In conclusion, the ability to oxidatively couple phthalimide
to unfunctionalized arenes is a useful method for synthesizing
anilines that is orthogonal to conventional amination techniques,
which rely on electrophilic nitration/reduction strategies or metal-
catalyzed coupling of prefunctionalized arenes. Phthalimide, in
particular, is an ideal starting point for the development of the
aforementioned oxidative amination technology. It is commer-
cially available, inexpensive, and easy to handle, and once coupled,
itcanbereadilyconvertedto a primaryamine, whichcan befurther
derivatized. Additionally, N-arylphthalimides like those shown in
Table 1 have recently been shown to have anticancer activity.14
Future work in our laboratory will be dedicated to the mechanistic
study and application of this unique method for constructing
CÀN bonds.
’ EXPERIMENTAL SECTION
Representative Procedure with Arene Solvent. A magneti-
cally stirred solution of the imide substrate (0.68 mmol) and iodoben-
zene diacetate (1.7 mmol) in 4 mL of the simple arene substrate was
microwave heated at 145 °C for 3 h. The excess solvent from the mixture
was removed at reduced pressure by rotary evaporation, and the crude
product was purified by column chromatography (see Supporting
Information for more details).
N-phenylphthalimide 2. Yield = 0.133 g (88%). The NMR spectra
matched the previously published data.15 Rf = 0.31, hexane/ethyl acetate
(8:2 v/v). 1H NMR (400 MHz, CDCl3): δ = 7.39À7.53 (m, 5H), 7.80
(dd, J = 5.4 Hz, 2.8 Hz, 2H), 7.96 (dd, J = 5.6 Hz, 3.2 Hz, 2H). 13C NMR
(100 MHz, CDCl3): δ = 123.7, 126.5, 128.1, 129.1, 131.7, 134.4, 167.30.
LRMS EI (m/z): [M+] calcd for C14H9NO2 223.06, observed 223.10 m/z.
3 (o:m:p = 10:6:5) 0.1071 g (70%). The isomers were identified by
comparing with known NMR spectra.14 Rf = 0.2, hexane/ethyl acetate
(9:1 v/v) . 1H NMR (300 MHz, CDCl3): δ = 2.21 (s, 3H), 2.41 (s, 1H),
2.42 (s, 2H), 7.18À7.43 (m, 10H), 7.80 (dd, J = 5.4, 3.1 Hz, 5H),
7.92À7.99 (m, 4H). 13C NMR (75 MHz, CDCl3): δ = 18.06, 21.23,
21.42, 123.70, 123.72, 123.78, 126.47, 126.89, 127.29, 128.73, 128.95,
129.07, 129.47, 129.80, 130.57, 131.17, 131.48, 131.80, 132.02, 134.33,
134.35, 136.55, 138.20, 139.15, 167.37. LRMS EI (m/z): [M+] calcd for
C14H9NO2 237.08, observed 237.10 m/z.
1-Phenylpyrrolidine-2,5-dione 20. Yield = 0.0982 g (83%). The
NMR spectra matched with that of previously published.15 Rf = 0.44
hexane/ethyl acetate (1:1 v/v) . 1H NMR (400 MHz, CDCl3): δ = 2.9(s,
4H), 7.28 (d, J = 7.2 Hz, 2H),7.39À7.4 (m,1H), 7.49À7.5(m, 2H).
13C NMR (100 MHz, CDCl3): δ = 28.4, 126.4, 128.6, 129.2, 131.8,
2-(2,5-Dimethylphenyl)isoindoline-1,3-dione 5. Yield = 0.1535 g
(90%). Rf =0.19, hexane/ethyl acetate (9:1 v/v).1H NMR (300 MHz,
CDCl3): δ = 2.16(s, 3H), 2.36 (s, 3H), 7.17À7.28 (m, 3H), 7.80 (dd, J =
6 Hz, J = 3 Hz, 2H), 7.97 (dd, J = 3 Hz, J = 3 Hz, 2H). 13C NMR (75
MHz, CDCl3): δ = 17.56, 20.83, 123.74, 129.15, 130.29, 130.37, 130.95,
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ARTICLE
176.2. LRMS EI (m/z): [M+] calcd for C10H9 NO2 175.06, observed
175.10 m/z.
40, 5068–5083. (b) Yeung, C. S.; Dong, V. M. Chem. Rev. 2011,
111, 1215. (c) McGlacken, G. P.; Bateman, L. M. Chem. Soc. Rev. 2009,
38, 2447.
(2) For recent reviews describing C-N formation via nitreneoid
intermediates, see: (a) Davies, H. M. L.; Manning, J. R. Nature 2008,
451, 417. (b) M€uller, P.; Fruit, C. Chem. Rev. 2003, 103, 2905.
(3) For a partial review, see: Cho, S. H.; Kim, J. Y.; Kwak, J.;
Chang, S. Chem. Soc. Rev. 2011, 40, 5079–5082.
5-Nitro-2-phenylisoindoline-1,3-dione 22. Yield = 0.0557 g (40%).
Rf = 0.33, hexane/ethyl acetate (8:2 v/v). 1H NMR (300 MHz, CDCl3):
δ = 7.26À7.55 (m, 5H), 8.17 (d, J = 9 Hz, 1H), 8.68 (d, J = 6 Hz, 1H),
8.78 (s, 1H). 13C NMR (75 MHz, CDCl3): δ= 119.21, 125.04, 126.36,
128.75, 129.35, 129.62, 133.13, 151.82, 164.93. LRMS EI (m/z): [M+]
calcd for C14H8 N2O4 268.05, observed 268.0 m/z.
(4) For recent examples of Cu and Pd-catalyzed aminations, see:
(a) Tsang, W. C. P.; Zheng, N.; Buchwald, S. L. J. Am. Chem. Soc. 2005,
127, 14560. (b) Thu, H.-Y.; Yu, W.-Y.; Che, C. M. J. Am. Chem. Soc.
2006, 128, 9048. (c) Tsang, W. C. P.; Munday, R. H.; Brasche, G.;
Zheng, N.; Buchwald, S. L. J. Org. Chem. 2008, 73, 7603. (d) Li, B.;
Tian, S.; Fang, Z.; Shi, Z. Angew. Chem., Int. Ed. 2008, 47, 1115.
(e) Jordan-Hore, J. A.; Johansson, C. C. C.; Beck, E. M.; Gaunt, M. J.
J. Am. Chem. Soc. 2008, 130, 16184. (f) Miura, T.; Murakami, M. Chem.
Lett. 2009, 38, 328. (g) John, A.; Nicholas, K. M. J. Org. Chem. 2011,
76, 4158. (h) Xiao, B.; Gong, T.-J.; Xu, J.; Liu, Z.-J.; Liu, L. J. Am. Chem.
Soc. 2011, 133, 1466. (i) Sun, K.; Li, Y.; Xiong, T.; Zhang, J.; Zhan, Q.
J. Am. Chem. Soc. 2011, 133, 1694. (j) Yoo, E. J.; Ma, S.; Mei, T.-S.; Chan,
K. S. L.; Yu, J.-Q. J. Am. Chem. Soc. 2011, 133, 7652.
(5) For recent examples of a metal-free aminations, see: (a) Cho,
S. H.; Yoon, J.; Chang, S. J. Am. Chem. Soc. 2011, 133, 5696. (b) Lamani,
M.; Prabhu, K. R. J. Org. Chem. 2011, 76 (19), 7938–7944.
(6) (a) Monguchi, D.; Fujiwara, T.; Furukawa, H.; Mori, A. Org. Lett.
2009, 11, 1607. (b) Wang, Q.; Schreiber, S. L. Org. Lett. 2009, 11, 5178.
(c) Cho, S. H.; Kim, J. Y.; Lee, S. Y.; Chang, S. Angew. Chem., Int. Ed.
2009, 48, 9127. (d) Kim, J. Y.; Cho, S. H.; Joseph, J.; Chang, S. Angew.
Chem., Int. Ed. 2010, 49, 9899. (e) Wang, J.; Hou, J.-T.; Wen, J.; Zhang, J;
Yu, X.-Q. Chem. Commun. 2011, 47, 3652.
N-Phenyl-1,8-naphthalimide 23. Yield = 0.0356 g (27%). Rf = 0.34,
hexane/ethyl acetate (7:3 v/v). H NMR (300 MHz, CDCl3): δ =
7.32À7.59 (m, 5H), 7.78À7.83(m, 2H), 8.28 (d, J = 9 Hz, 2H), 8.66 (d,
J = 6 Hz, 2H). 13C NMR (75 MHz, CDCl3): δ = 122.81, 127.05, 128.61,
128.73, 129.42, 131.64, 134.30, 135.41, 164.39. LRMS EI (m/z): [M+]
calcd for C18H11NO2, 273.08, observed 273.10 m/z.
1
N-Phenyl-1,1-dioxo-1,2-benzothiazol-3-one 24. Yield = 0.037 g
(26%). Rf = 0.26, hexane/ethyl acetate (7:3 v/v) 1H NMR (300 MHz,
CDCl3): δ = 7.55 (s, 5H), 7.87À8.01(m, 3H), 8.15 (d, J = 9 Hz, 1H).
13C NMR (75 MHz, CDCl3): δ = 120.75, 121.25, 125.65, 127.16,
128.69, 128.75, 129.94, 130.13, 134.49, 135.12, 137.56, 158.40. LRMS
EI (m/z): [M+] calcd for C13H9 NO3S, 259.03, observed 259.0 m/z.
Representative Procedure with Stoichiometric Arene. A
magnetically stirred solution of phthalimide (0.68 mmol), iodobenzene
diacetate (1.7 mmol), and the simple arene substrate (2.0 mmol) in 4 mL
of acetonitrile was microwave heated at 145 °C for 3 h. The excess solvent
from the mixture was removed at reduced pressure by rotary evaporation,
and the crude product was purified by column chromatography.
2-(2,3,4,5,6-Pentamethylphenyl)isoindoline-1,3-dione 6. Yield =
1
0.085 g (43%). Rf = 0.23, hexane/ethyl acetate (9:1 v/v). H NMR
(300 MHz, CDCl3): δ = 2.06À2.26 (m, 15H), 7.79 (dd, J = 3 Hz, 3 Hz,
2H), 7.97 (dd, J = 3 Hz, 3 Hz, 2H). 13C NMR (75 MHz, CDCl3): δ =
15.51, 16.81, 17.04, 123.76, 126.99, 131.77, 131.97, 133.57, 134.26,
136.9, 167.81. LRMS EI (m/z): [M+] calcd for C19H19NO2 293.14,
observed 293.15 m/z.
(7) While preparing this manuscript, two communications were
published that describe metal-free intermolecular C-H amination: (a)
Antonchick, A. P.; Samanta, R.; Kulikov, K.; Lategahn, J. Angew. Chem.,
Int. Ed. 2011, 50, 8605. (b) Kim, H. J.; Kim, J.; Cho, S. H.; Chang, S.
J. Am. Chem. Soc. 2011, 133, 16382.
2-(5-tert-Butyl-2-methoxyphenyl)isoindoline-1,3-dione 16. Yield =
0.117 g (56%), Rf = 0.11, hexane/ethyl acetate (9:1 v/v) 1H NMR (300 MHz,
CDCl3): δ = 1.29À1.32 (m, 9H), 3.77 (s, 3H), 6.98 (d, J = 9 Hz, 1H),
7.25 (m, 1H) 7.44 (dd, J = 3 Hz, 3 Hz, 1 H) 7.77 (dd, J = 3 Hz, 3 Hz, 2H),
7.94 (dd, J = 3 Hz, 3 Hz, 2H). 13C NMR (75 MHz, CDCl3): δ = 31.42,
34.17, 55.87, 111.64, 119.51, 123.61, 126.98, 132.29, 134.06, 143.74,
153.05, 167.55. LRMS EI (m/z): [M+] calcd for C19H19NO3 309.14,
observed 309.12 m/z.
(8) For examples, see:(a) Stuart, D. R.; Fagnou, K. Science 2007,
316, 1172. (b) Dwight, T. A.; Rue, N. R.; Charyk, D.; Josselyn, R.;
DeBoef, B. Org. Lett. 2007, 9, 3137. (c) Yeung, C. S.; Zhao, X.; Borduas,
N.; Dong, V. M. Chem. Sci. 2010, 1, 331. (d) Potavathri, S.; Pereira, K. C.;
Gorelsky, S. I.; Pike, A.; LeBris, A. P.; DeBoef, B. J. Am. Chem. Soc. 2010,
132, 14676.
(9) (a) Campeau, L.; Parisien, M.; Jean, A.; Fagnou, K. J. Am. Chem.
Soc. 2006, 128, 581. (b) Pascual, S.; de Mendoza, P.; Echavarren, A. M.
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’ ASSOCIATED CONTENT
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(b) Yu, W.; Du, Y.; Zhao, K. Org. Lett. 2009, 11, 2417.
S
Supporting Information. Complete experimental de-
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tails, compound characterization, analysis of product purity and
both 1H and 13C NMR data for novel compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
(15) Xie, Y.-T.; Hou, R.-S.; Want, H.-M.; Kang, I.-J.; Chen, L.-C.
J. Chin. Chem. Soc. 2009, 56, 839–842.
Corresponding Author
bdeboef@chm.uri.edu.
’ ACKNOWLEDGMENT
This work was supported by the National Science Foundation
(CAREER 0847222) and the National Institutes of Health
(NIGMS, 1R15GM097708-01).
’ REFERENCES
(1) For recent reviews describing oxidative C-C formation, see: (a)
Cho, S. H.; Kim, J. Y.; Kwak, J.; Chang, S. Chem. Soc. Rev. 2011,
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dx.doi.org/10.1021/ja2087085 |J. Am. Chem. Soc. 2011, 133, 19960–19965